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Could GLP-1 receptor agonists ease knee osteoarthritis pain, slow progression?
Could glucagon-like peptide-1 receptor agonists, such as liraglutide and semaglutide, also be potential disease-modifying treatments for knee osteoarthritis (KOA)?
Weight loss is recommended for patients with KOA, and GLP-1 receptor agonists are approved for weight loss. New early research suggests these drugs might have a disease-modifying effect for KOA.
Three recently published studies investigated this:
- The LOSEIT phase 4, randomized controlled trial of liraglutide vs. placebo in patients with obesity/overweight and KOA.
- A large observational study out of China in patients with KOA and type 2 diabetes.
- A preclinical trial of liraglutide in mouse models of KOA.
The preclinical trial and the observational study report promising results, and the lack of KOA pain relief in patients in the phase 4 trial may be explained by the trial design. Three other trials are in the works.
This news organization invited two researchers and two outside experts to discuss these studies and potential future treatment of KOA with GLP-1 receptor agonists.
The big picture, as seen by two experts
The GLP-1 receptor agonists liraglutide (Victoza) and semaglutide (Ozempic) are approved for type 2 diabetes, and, in higher doses, liraglutide (Saxenda) and semaglutide (Wegovy) are approved for weight loss in patients with obesity (or overweight with comorbidities), and given as weekly injections.
Victoza and Saxenda are expected to come off patent in December 2023, and in 2026, respectively.
Lauren King, MD, PhD, a rheumatologist and clinician scientist who was not involved with the recent investigational studies of GLP-1 receptor agonists for KOA, noted that obesity is the most important, guideline-recommended, modifiable risk factor for KOA.
“In people with overweight and obesity, losing weight can improve knee osteoarthritis symptoms, and some evidence supports that it may also slow joint structural changes,” Dr. King, of the department of medicine at the University of Toronto, said in an interview.
Large trials of GLP-1 receptor agonists in people with overweight and obesity, such as the STEP trials of semaglutide, she noted, “provide evidence that these medications are safe and effective, facilitating clinically relevant and sustained weight loss.”
Further research is needed, she said, to better understand disease-modifying effects of GLP-1 receptor agonists in patients with KOA.
Similarly, W. Timothy Garvey, MD, professor in the department of nutrition sciences at the University of Alabama at Birmingham and director of the UAB Diabetes Research Center, who was not involved with this research, noted that weight loss improves KOA symptoms.
Dr. Garvey was lead investigator in the STEP 5 trial of semaglutide and lead author of the American Association of Clinical Endocrinologists 2016 Obesity Management guidelines.
“The question is whether these GLP-1 receptor agonists have anything to offer over and above weight loss per se, and we don’t know for sure,” he said.
They “do have anti-inflammatory actions,” and “there are GLP-1 receptors in locations where you think GLP-1 receptor agonism may help inflammation in the knee, in joints, and in other tissues,” he noted.
He looks forward to results of the phase 3 trial of semaglutide in patients with KOA, expected this fall.
Three published studies
LOSEIT: RCT of liraglutide for pain and weight control in KOA
Henrik Rindel Gudbergsen, MD, PhD, and colleagues published results of the only randomized controlled trial of a GLP-1 receptor agonist (liraglutide, Saxenda) vs. placebo in patients with overweight/obesity and KOA, the LOSEIT trial.
All patients first entered an 8-week, pre-randomization phase where they had strict caloric restriction (and ate meal replacements) and lost at least 5% of their initial weight. They also had less knee pain at the end of this phase.
Then they were randomly assigned to receive 3 mg liraglutide or placebo daily injections for 1 year.
From randomization until week 52, the liraglutide group had greater mean weight loss than the placebo group (but this was < 5% of their weight). They did not have greater reduction in knee pain than patients in the placebo group.
“Our interpretation was that dieting results in weight loss and diminishes knee pain (which we knew), and that the impact of liraglutide following severe calorie restriction and weight loss and improvement of pain was limited,” Dr. Gudbergsen, a physician and associate professor at The Parker Institute, University of Copenhagen, told this news organization.
“That was the surprise for us as investigators,” he said, “and, I assume, why Novo Nordisk is now pursuing the investigation of semaglutide for KOA, as this is expected to create a larger effect on body weight and knee symptoms.”
The weight loss was about 12.5 kg (27.5 pounds) prior to randomization, and the subsequent weight loss with liraglutide was about 2.8 kg (6 pounds; about 4% of their weight). “Thus, it could seem that the participants’ potential for weight loss as well as symptom reduction was fully exploited in the pre–random assignment dietary intervention period,” according to the researchers.
“It seems highly relevant to use liraglutide or semaglutide for patients impacted by obesity and KOA, as it is in line with guidelines suggesting weight loss for this group,” Dr. Gudbergsen said. “However, whether liraglutide and/or semaglutide, acting via an anti-inflammatory effect, for example, has an added positive impact on cartilage quality remains to be clarified,” he said.
Others who were not involved in this study suggest that the lack of pain-reduction benefit with liraglutide vs. placebo can be explained by the short-term use of liraglutide (1 year), small weight loss (< 5%), and systemic rather than intraarticular injection.
The LOSEIT trial design “is problematic and could not provide a confirmative conclusion,” Hongyi Zhu, MD, PhD, Shanghai Sixth People’s Hospital, China, and colleagues wrote in their observational study. The small weight loss of < 5% in the liraglutide group may explain why the pain relief was not better than with placebo. A longer study duration with significant weight loss/maintenance may be needed, they noted.
Francis Berenbaum, MD, PhD, senior author of a preclinical study of liraglutide, said that in the LOSEIT trial, “daily systemic injections of liraglutide did not ameliorate OA-related pain, probably because of poor access and hence poor local concentrations of liraglutide in the knee joint.”
Dr. Berenbaum is professor of rheumatology at Sorbonne University and director of the department of rheumatology at AP-HP Saint-Antoine Hospital in Paris. He is cofounder and CEO of 4Moving Biotech (a subsidiary of 4P Pharma, an innovator accelerator biotech company), which is testing liraglutide for KOA.
In experiments in mice, systemic injections of liraglutide did not lead to high enough concentration in synovial fluid to show efficacy for pain relief, he told this news organization. “In order to get the direct effect of liraglutide, it should be injected intraarticularly,” he said.
Observational study of patients with diabetes and KOA
Dr. Zhu and colleagues recently published results of the first clinical investigation of long-term effects of GLP-1 receptor agonists on KOA in patients with comorbid type 2 diabetes.
They analyzed data from a subset of patients with KOA and type 2 diabetes from the Shanghai Osteoarthritis Cohort, including 233 patients who received a GLP-1 receptor agonist (semaglutide, liraglutide, or dulaglutide [Trulicity]) for at least 2 years and 1,574 patients who did not receive this therapy.
The patients had a mean weight of 66 kg (145 pounds), a mean body mass index of 27 kg/m2, and a mean A1c of 7.3%.
“According to conventional wisdom, a weight change greater than 5% is considered clinically relevant for KOA,” the researchers wrote. They found that patients had substantial weight loss after GLP-1 receptor agonist therapy.
The primary outcome, the incidence of knee surgery, was lower in the patients who received a GLP-1 receptor agonist than in the other patients (1.7% vs. 5.9%; adjusted P = .014).
Patients who received a GLP-1 receptor agonist also had greater improvements in secondary outcomes than did other patients, including pain subscale scores and cartilage-loss velocity of the medial femorotibial joint in patients with predominantly lateral OA.
“The effects of GLP-1 receptor agonists on arthritic knees were largely mediated by weight loss instead of glycemic control,” Dr. Zhu and colleagues reported.
They concluded that with long-enough treatment, “GLP-1 receptor agonist therapies might be disease-modifying for KOA patients with comorbid [type 2 diabetes mellitus].”
They called for further research to elucidate the effects of GLP-1 receptor agonists on the disease process, joint structure, and patient-reported outcomes of OA.
Dr. Garvey noted that “whether your BMI is 30 or 40, if there are complications, that tells you that degree of adiposity is sufficient to impair health.” So, if a patient in southeast China has a BMI of 27 kg/m2 and has osteoarthritis, he or she could still benefit from weight loss, he said.
Liraglutide and pain-related behavior in mouse models of OA
Dr. Berenbaum and colleagues reported that liraglutide alleviated pain-related behavior in sodium monoiodoacetate mouse models of KOA.
In addition, liraglutide had anti-inflammatory and anticatabolic effects in synovial fluid from the knees of six patients with OA of varying severity.
The researchers analyzed generic liraglutide (from Hybio Pharmaceuticals, Shenzhen, China) and nongeneric liraglutide (from Novo Nordisk, Bagsværd, Denmark).
They found that “when injected intra-articularly, liraglutide blunts the inflammatory process that is present in OA synovial tissue, explaining the acute analgesic effect,” Dr. Berenbaum said.
“Liraglutide could be a game-changer,” he said, “by demonstrating not only an effect on joint structures like synovial tissue and cartilage, but also on symptoms in a short-term period.”
Dr. Garvey said the symptom improvements after intrasynovial infusion of liraglutide in this trial were “impressive.” This study “adds credence to the hypothesis that these GLP-1 receptor agonists could have effects above and beyond weight loss,” he said.
Two trials near completion, one is upcoming
Phase 1 and 2 trials of 4P-004
“We are now in a phase 1 clinical trial [of 4P-004/liraglutide] in patients suffering from knee OA and should start a large phase 2 trial next year,” said Dr. Berenbaum.
The phase 1 LASARE trial, sponsored by 4Moving Biotech, planned to enroll 32 patients with KOA.
The primary outcome is safety and tolerability of single IA administration of 4P-004 at escalating doses in patients with KOA. Secondary outcomes include plasma concentration of liraglutide when administered this way.
Phase 3 trial of semaglutide for KOA
Novo Nordisk is performing a phase 3 study, “Effect of Subcutaneous Semaglutide 2.4 mg Once-weekly Compared to Placebo in Subjects With Obesity and Knee Osteoarthritis,” with an expected enrollment of 407 patients with KOA and estimated trial completion in September.
Eligible patients were aged 18 and older, with BMI > 30 kg/m2 and KOA with Kellgren-Lawrence grades 2 or 3. The co-primary outcomes are change in body weight and change in WOMAC pain score, from baseline to 68 weeks.
The LOSEIT trial was supported by Novo Nordisk and the Cambridge Weight Plan. The observational study in China was supported by the Shanghai Shenkang Hospital Development Centre, the Clinical Research Plan of SHDC, and the National Natural Science Foundation of China. The preclinical trial was supported by 4P Pharma/4Moving Biotech.
Dr. Berenbaum is CEO of 4Moving Biotech and chair of the scientific advisory board of 4P Pharma. He has received personal fees from 4P Pharma as well as numerous other pharmaceutical companies. Dr. Garvey has reported being a consultant to Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck, Fractyl Health, and Alnylam Pharmaceuticals, and reported being an investigator for studies sponsored by Novo Nordisk, Eli Lilly, Pfizer, and Epitomee. Dr. Gudbergsen, Dr. King, and Dr. Zhu report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Could glucagon-like peptide-1 receptor agonists, such as liraglutide and semaglutide, also be potential disease-modifying treatments for knee osteoarthritis (KOA)?
Weight loss is recommended for patients with KOA, and GLP-1 receptor agonists are approved for weight loss. New early research suggests these drugs might have a disease-modifying effect for KOA.
Three recently published studies investigated this:
- The LOSEIT phase 4, randomized controlled trial of liraglutide vs. placebo in patients with obesity/overweight and KOA.
- A large observational study out of China in patients with KOA and type 2 diabetes.
- A preclinical trial of liraglutide in mouse models of KOA.
The preclinical trial and the observational study report promising results, and the lack of KOA pain relief in patients in the phase 4 trial may be explained by the trial design. Three other trials are in the works.
This news organization invited two researchers and two outside experts to discuss these studies and potential future treatment of KOA with GLP-1 receptor agonists.
The big picture, as seen by two experts
The GLP-1 receptor agonists liraglutide (Victoza) and semaglutide (Ozempic) are approved for type 2 diabetes, and, in higher doses, liraglutide (Saxenda) and semaglutide (Wegovy) are approved for weight loss in patients with obesity (or overweight with comorbidities), and given as weekly injections.
Victoza and Saxenda are expected to come off patent in December 2023, and in 2026, respectively.
Lauren King, MD, PhD, a rheumatologist and clinician scientist who was not involved with the recent investigational studies of GLP-1 receptor agonists for KOA, noted that obesity is the most important, guideline-recommended, modifiable risk factor for KOA.
“In people with overweight and obesity, losing weight can improve knee osteoarthritis symptoms, and some evidence supports that it may also slow joint structural changes,” Dr. King, of the department of medicine at the University of Toronto, said in an interview.
Large trials of GLP-1 receptor agonists in people with overweight and obesity, such as the STEP trials of semaglutide, she noted, “provide evidence that these medications are safe and effective, facilitating clinically relevant and sustained weight loss.”
Further research is needed, she said, to better understand disease-modifying effects of GLP-1 receptor agonists in patients with KOA.
Similarly, W. Timothy Garvey, MD, professor in the department of nutrition sciences at the University of Alabama at Birmingham and director of the UAB Diabetes Research Center, who was not involved with this research, noted that weight loss improves KOA symptoms.
Dr. Garvey was lead investigator in the STEP 5 trial of semaglutide and lead author of the American Association of Clinical Endocrinologists 2016 Obesity Management guidelines.
“The question is whether these GLP-1 receptor agonists have anything to offer over and above weight loss per se, and we don’t know for sure,” he said.
They “do have anti-inflammatory actions,” and “there are GLP-1 receptors in locations where you think GLP-1 receptor agonism may help inflammation in the knee, in joints, and in other tissues,” he noted.
He looks forward to results of the phase 3 trial of semaglutide in patients with KOA, expected this fall.
Three published studies
LOSEIT: RCT of liraglutide for pain and weight control in KOA
Henrik Rindel Gudbergsen, MD, PhD, and colleagues published results of the only randomized controlled trial of a GLP-1 receptor agonist (liraglutide, Saxenda) vs. placebo in patients with overweight/obesity and KOA, the LOSEIT trial.
All patients first entered an 8-week, pre-randomization phase where they had strict caloric restriction (and ate meal replacements) and lost at least 5% of their initial weight. They also had less knee pain at the end of this phase.
Then they were randomly assigned to receive 3 mg liraglutide or placebo daily injections for 1 year.
From randomization until week 52, the liraglutide group had greater mean weight loss than the placebo group (but this was < 5% of their weight). They did not have greater reduction in knee pain than patients in the placebo group.
“Our interpretation was that dieting results in weight loss and diminishes knee pain (which we knew), and that the impact of liraglutide following severe calorie restriction and weight loss and improvement of pain was limited,” Dr. Gudbergsen, a physician and associate professor at The Parker Institute, University of Copenhagen, told this news organization.
“That was the surprise for us as investigators,” he said, “and, I assume, why Novo Nordisk is now pursuing the investigation of semaglutide for KOA, as this is expected to create a larger effect on body weight and knee symptoms.”
The weight loss was about 12.5 kg (27.5 pounds) prior to randomization, and the subsequent weight loss with liraglutide was about 2.8 kg (6 pounds; about 4% of their weight). “Thus, it could seem that the participants’ potential for weight loss as well as symptom reduction was fully exploited in the pre–random assignment dietary intervention period,” according to the researchers.
“It seems highly relevant to use liraglutide or semaglutide for patients impacted by obesity and KOA, as it is in line with guidelines suggesting weight loss for this group,” Dr. Gudbergsen said. “However, whether liraglutide and/or semaglutide, acting via an anti-inflammatory effect, for example, has an added positive impact on cartilage quality remains to be clarified,” he said.
Others who were not involved in this study suggest that the lack of pain-reduction benefit with liraglutide vs. placebo can be explained by the short-term use of liraglutide (1 year), small weight loss (< 5%), and systemic rather than intraarticular injection.
The LOSEIT trial design “is problematic and could not provide a confirmative conclusion,” Hongyi Zhu, MD, PhD, Shanghai Sixth People’s Hospital, China, and colleagues wrote in their observational study. The small weight loss of < 5% in the liraglutide group may explain why the pain relief was not better than with placebo. A longer study duration with significant weight loss/maintenance may be needed, they noted.
Francis Berenbaum, MD, PhD, senior author of a preclinical study of liraglutide, said that in the LOSEIT trial, “daily systemic injections of liraglutide did not ameliorate OA-related pain, probably because of poor access and hence poor local concentrations of liraglutide in the knee joint.”
Dr. Berenbaum is professor of rheumatology at Sorbonne University and director of the department of rheumatology at AP-HP Saint-Antoine Hospital in Paris. He is cofounder and CEO of 4Moving Biotech (a subsidiary of 4P Pharma, an innovator accelerator biotech company), which is testing liraglutide for KOA.
In experiments in mice, systemic injections of liraglutide did not lead to high enough concentration in synovial fluid to show efficacy for pain relief, he told this news organization. “In order to get the direct effect of liraglutide, it should be injected intraarticularly,” he said.
Observational study of patients with diabetes and KOA
Dr. Zhu and colleagues recently published results of the first clinical investigation of long-term effects of GLP-1 receptor agonists on KOA in patients with comorbid type 2 diabetes.
They analyzed data from a subset of patients with KOA and type 2 diabetes from the Shanghai Osteoarthritis Cohort, including 233 patients who received a GLP-1 receptor agonist (semaglutide, liraglutide, or dulaglutide [Trulicity]) for at least 2 years and 1,574 patients who did not receive this therapy.
The patients had a mean weight of 66 kg (145 pounds), a mean body mass index of 27 kg/m2, and a mean A1c of 7.3%.
“According to conventional wisdom, a weight change greater than 5% is considered clinically relevant for KOA,” the researchers wrote. They found that patients had substantial weight loss after GLP-1 receptor agonist therapy.
The primary outcome, the incidence of knee surgery, was lower in the patients who received a GLP-1 receptor agonist than in the other patients (1.7% vs. 5.9%; adjusted P = .014).
Patients who received a GLP-1 receptor agonist also had greater improvements in secondary outcomes than did other patients, including pain subscale scores and cartilage-loss velocity of the medial femorotibial joint in patients with predominantly lateral OA.
“The effects of GLP-1 receptor agonists on arthritic knees were largely mediated by weight loss instead of glycemic control,” Dr. Zhu and colleagues reported.
They concluded that with long-enough treatment, “GLP-1 receptor agonist therapies might be disease-modifying for KOA patients with comorbid [type 2 diabetes mellitus].”
They called for further research to elucidate the effects of GLP-1 receptor agonists on the disease process, joint structure, and patient-reported outcomes of OA.
Dr. Garvey noted that “whether your BMI is 30 or 40, if there are complications, that tells you that degree of adiposity is sufficient to impair health.” So, if a patient in southeast China has a BMI of 27 kg/m2 and has osteoarthritis, he or she could still benefit from weight loss, he said.
Liraglutide and pain-related behavior in mouse models of OA
Dr. Berenbaum and colleagues reported that liraglutide alleviated pain-related behavior in sodium monoiodoacetate mouse models of KOA.
In addition, liraglutide had anti-inflammatory and anticatabolic effects in synovial fluid from the knees of six patients with OA of varying severity.
The researchers analyzed generic liraglutide (from Hybio Pharmaceuticals, Shenzhen, China) and nongeneric liraglutide (from Novo Nordisk, Bagsværd, Denmark).
They found that “when injected intra-articularly, liraglutide blunts the inflammatory process that is present in OA synovial tissue, explaining the acute analgesic effect,” Dr. Berenbaum said.
“Liraglutide could be a game-changer,” he said, “by demonstrating not only an effect on joint structures like synovial tissue and cartilage, but also on symptoms in a short-term period.”
Dr. Garvey said the symptom improvements after intrasynovial infusion of liraglutide in this trial were “impressive.” This study “adds credence to the hypothesis that these GLP-1 receptor agonists could have effects above and beyond weight loss,” he said.
Two trials near completion, one is upcoming
Phase 1 and 2 trials of 4P-004
“We are now in a phase 1 clinical trial [of 4P-004/liraglutide] in patients suffering from knee OA and should start a large phase 2 trial next year,” said Dr. Berenbaum.
The phase 1 LASARE trial, sponsored by 4Moving Biotech, planned to enroll 32 patients with KOA.
The primary outcome is safety and tolerability of single IA administration of 4P-004 at escalating doses in patients with KOA. Secondary outcomes include plasma concentration of liraglutide when administered this way.
Phase 3 trial of semaglutide for KOA
Novo Nordisk is performing a phase 3 study, “Effect of Subcutaneous Semaglutide 2.4 mg Once-weekly Compared to Placebo in Subjects With Obesity and Knee Osteoarthritis,” with an expected enrollment of 407 patients with KOA and estimated trial completion in September.
Eligible patients were aged 18 and older, with BMI > 30 kg/m2 and KOA with Kellgren-Lawrence grades 2 or 3. The co-primary outcomes are change in body weight and change in WOMAC pain score, from baseline to 68 weeks.
The LOSEIT trial was supported by Novo Nordisk and the Cambridge Weight Plan. The observational study in China was supported by the Shanghai Shenkang Hospital Development Centre, the Clinical Research Plan of SHDC, and the National Natural Science Foundation of China. The preclinical trial was supported by 4P Pharma/4Moving Biotech.
Dr. Berenbaum is CEO of 4Moving Biotech and chair of the scientific advisory board of 4P Pharma. He has received personal fees from 4P Pharma as well as numerous other pharmaceutical companies. Dr. Garvey has reported being a consultant to Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck, Fractyl Health, and Alnylam Pharmaceuticals, and reported being an investigator for studies sponsored by Novo Nordisk, Eli Lilly, Pfizer, and Epitomee. Dr. Gudbergsen, Dr. King, and Dr. Zhu report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Could glucagon-like peptide-1 receptor agonists, such as liraglutide and semaglutide, also be potential disease-modifying treatments for knee osteoarthritis (KOA)?
Weight loss is recommended for patients with KOA, and GLP-1 receptor agonists are approved for weight loss. New early research suggests these drugs might have a disease-modifying effect for KOA.
Three recently published studies investigated this:
- The LOSEIT phase 4, randomized controlled trial of liraglutide vs. placebo in patients with obesity/overweight and KOA.
- A large observational study out of China in patients with KOA and type 2 diabetes.
- A preclinical trial of liraglutide in mouse models of KOA.
The preclinical trial and the observational study report promising results, and the lack of KOA pain relief in patients in the phase 4 trial may be explained by the trial design. Three other trials are in the works.
This news organization invited two researchers and two outside experts to discuss these studies and potential future treatment of KOA with GLP-1 receptor agonists.
The big picture, as seen by two experts
The GLP-1 receptor agonists liraglutide (Victoza) and semaglutide (Ozempic) are approved for type 2 diabetes, and, in higher doses, liraglutide (Saxenda) and semaglutide (Wegovy) are approved for weight loss in patients with obesity (or overweight with comorbidities), and given as weekly injections.
Victoza and Saxenda are expected to come off patent in December 2023, and in 2026, respectively.
Lauren King, MD, PhD, a rheumatologist and clinician scientist who was not involved with the recent investigational studies of GLP-1 receptor agonists for KOA, noted that obesity is the most important, guideline-recommended, modifiable risk factor for KOA.
“In people with overweight and obesity, losing weight can improve knee osteoarthritis symptoms, and some evidence supports that it may also slow joint structural changes,” Dr. King, of the department of medicine at the University of Toronto, said in an interview.
Large trials of GLP-1 receptor agonists in people with overweight and obesity, such as the STEP trials of semaglutide, she noted, “provide evidence that these medications are safe and effective, facilitating clinically relevant and sustained weight loss.”
Further research is needed, she said, to better understand disease-modifying effects of GLP-1 receptor agonists in patients with KOA.
Similarly, W. Timothy Garvey, MD, professor in the department of nutrition sciences at the University of Alabama at Birmingham and director of the UAB Diabetes Research Center, who was not involved with this research, noted that weight loss improves KOA symptoms.
Dr. Garvey was lead investigator in the STEP 5 trial of semaglutide and lead author of the American Association of Clinical Endocrinologists 2016 Obesity Management guidelines.
“The question is whether these GLP-1 receptor agonists have anything to offer over and above weight loss per se, and we don’t know for sure,” he said.
They “do have anti-inflammatory actions,” and “there are GLP-1 receptors in locations where you think GLP-1 receptor agonism may help inflammation in the knee, in joints, and in other tissues,” he noted.
He looks forward to results of the phase 3 trial of semaglutide in patients with KOA, expected this fall.
Three published studies
LOSEIT: RCT of liraglutide for pain and weight control in KOA
Henrik Rindel Gudbergsen, MD, PhD, and colleagues published results of the only randomized controlled trial of a GLP-1 receptor agonist (liraglutide, Saxenda) vs. placebo in patients with overweight/obesity and KOA, the LOSEIT trial.
All patients first entered an 8-week, pre-randomization phase where they had strict caloric restriction (and ate meal replacements) and lost at least 5% of their initial weight. They also had less knee pain at the end of this phase.
Then they were randomly assigned to receive 3 mg liraglutide or placebo daily injections for 1 year.
From randomization until week 52, the liraglutide group had greater mean weight loss than the placebo group (but this was < 5% of their weight). They did not have greater reduction in knee pain than patients in the placebo group.
“Our interpretation was that dieting results in weight loss and diminishes knee pain (which we knew), and that the impact of liraglutide following severe calorie restriction and weight loss and improvement of pain was limited,” Dr. Gudbergsen, a physician and associate professor at The Parker Institute, University of Copenhagen, told this news organization.
“That was the surprise for us as investigators,” he said, “and, I assume, why Novo Nordisk is now pursuing the investigation of semaglutide for KOA, as this is expected to create a larger effect on body weight and knee symptoms.”
The weight loss was about 12.5 kg (27.5 pounds) prior to randomization, and the subsequent weight loss with liraglutide was about 2.8 kg (6 pounds; about 4% of their weight). “Thus, it could seem that the participants’ potential for weight loss as well as symptom reduction was fully exploited in the pre–random assignment dietary intervention period,” according to the researchers.
“It seems highly relevant to use liraglutide or semaglutide for patients impacted by obesity and KOA, as it is in line with guidelines suggesting weight loss for this group,” Dr. Gudbergsen said. “However, whether liraglutide and/or semaglutide, acting via an anti-inflammatory effect, for example, has an added positive impact on cartilage quality remains to be clarified,” he said.
Others who were not involved in this study suggest that the lack of pain-reduction benefit with liraglutide vs. placebo can be explained by the short-term use of liraglutide (1 year), small weight loss (< 5%), and systemic rather than intraarticular injection.
The LOSEIT trial design “is problematic and could not provide a confirmative conclusion,” Hongyi Zhu, MD, PhD, Shanghai Sixth People’s Hospital, China, and colleagues wrote in their observational study. The small weight loss of < 5% in the liraglutide group may explain why the pain relief was not better than with placebo. A longer study duration with significant weight loss/maintenance may be needed, they noted.
Francis Berenbaum, MD, PhD, senior author of a preclinical study of liraglutide, said that in the LOSEIT trial, “daily systemic injections of liraglutide did not ameliorate OA-related pain, probably because of poor access and hence poor local concentrations of liraglutide in the knee joint.”
Dr. Berenbaum is professor of rheumatology at Sorbonne University and director of the department of rheumatology at AP-HP Saint-Antoine Hospital in Paris. He is cofounder and CEO of 4Moving Biotech (a subsidiary of 4P Pharma, an innovator accelerator biotech company), which is testing liraglutide for KOA.
In experiments in mice, systemic injections of liraglutide did not lead to high enough concentration in synovial fluid to show efficacy for pain relief, he told this news organization. “In order to get the direct effect of liraglutide, it should be injected intraarticularly,” he said.
Observational study of patients with diabetes and KOA
Dr. Zhu and colleagues recently published results of the first clinical investigation of long-term effects of GLP-1 receptor agonists on KOA in patients with comorbid type 2 diabetes.
They analyzed data from a subset of patients with KOA and type 2 diabetes from the Shanghai Osteoarthritis Cohort, including 233 patients who received a GLP-1 receptor agonist (semaglutide, liraglutide, or dulaglutide [Trulicity]) for at least 2 years and 1,574 patients who did not receive this therapy.
The patients had a mean weight of 66 kg (145 pounds), a mean body mass index of 27 kg/m2, and a mean A1c of 7.3%.
“According to conventional wisdom, a weight change greater than 5% is considered clinically relevant for KOA,” the researchers wrote. They found that patients had substantial weight loss after GLP-1 receptor agonist therapy.
The primary outcome, the incidence of knee surgery, was lower in the patients who received a GLP-1 receptor agonist than in the other patients (1.7% vs. 5.9%; adjusted P = .014).
Patients who received a GLP-1 receptor agonist also had greater improvements in secondary outcomes than did other patients, including pain subscale scores and cartilage-loss velocity of the medial femorotibial joint in patients with predominantly lateral OA.
“The effects of GLP-1 receptor agonists on arthritic knees were largely mediated by weight loss instead of glycemic control,” Dr. Zhu and colleagues reported.
They concluded that with long-enough treatment, “GLP-1 receptor agonist therapies might be disease-modifying for KOA patients with comorbid [type 2 diabetes mellitus].”
They called for further research to elucidate the effects of GLP-1 receptor agonists on the disease process, joint structure, and patient-reported outcomes of OA.
Dr. Garvey noted that “whether your BMI is 30 or 40, if there are complications, that tells you that degree of adiposity is sufficient to impair health.” So, if a patient in southeast China has a BMI of 27 kg/m2 and has osteoarthritis, he or she could still benefit from weight loss, he said.
Liraglutide and pain-related behavior in mouse models of OA
Dr. Berenbaum and colleagues reported that liraglutide alleviated pain-related behavior in sodium monoiodoacetate mouse models of KOA.
In addition, liraglutide had anti-inflammatory and anticatabolic effects in synovial fluid from the knees of six patients with OA of varying severity.
The researchers analyzed generic liraglutide (from Hybio Pharmaceuticals, Shenzhen, China) and nongeneric liraglutide (from Novo Nordisk, Bagsværd, Denmark).
They found that “when injected intra-articularly, liraglutide blunts the inflammatory process that is present in OA synovial tissue, explaining the acute analgesic effect,” Dr. Berenbaum said.
“Liraglutide could be a game-changer,” he said, “by demonstrating not only an effect on joint structures like synovial tissue and cartilage, but also on symptoms in a short-term period.”
Dr. Garvey said the symptom improvements after intrasynovial infusion of liraglutide in this trial were “impressive.” This study “adds credence to the hypothesis that these GLP-1 receptor agonists could have effects above and beyond weight loss,” he said.
Two trials near completion, one is upcoming
Phase 1 and 2 trials of 4P-004
“We are now in a phase 1 clinical trial [of 4P-004/liraglutide] in patients suffering from knee OA and should start a large phase 2 trial next year,” said Dr. Berenbaum.
The phase 1 LASARE trial, sponsored by 4Moving Biotech, planned to enroll 32 patients with KOA.
The primary outcome is safety and tolerability of single IA administration of 4P-004 at escalating doses in patients with KOA. Secondary outcomes include plasma concentration of liraglutide when administered this way.
Phase 3 trial of semaglutide for KOA
Novo Nordisk is performing a phase 3 study, “Effect of Subcutaneous Semaglutide 2.4 mg Once-weekly Compared to Placebo in Subjects With Obesity and Knee Osteoarthritis,” with an expected enrollment of 407 patients with KOA and estimated trial completion in September.
Eligible patients were aged 18 and older, with BMI > 30 kg/m2 and KOA with Kellgren-Lawrence grades 2 or 3. The co-primary outcomes are change in body weight and change in WOMAC pain score, from baseline to 68 weeks.
The LOSEIT trial was supported by Novo Nordisk and the Cambridge Weight Plan. The observational study in China was supported by the Shanghai Shenkang Hospital Development Centre, the Clinical Research Plan of SHDC, and the National Natural Science Foundation of China. The preclinical trial was supported by 4P Pharma/4Moving Biotech.
Dr. Berenbaum is CEO of 4Moving Biotech and chair of the scientific advisory board of 4P Pharma. He has received personal fees from 4P Pharma as well as numerous other pharmaceutical companies. Dr. Garvey has reported being a consultant to Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck, Fractyl Health, and Alnylam Pharmaceuticals, and reported being an investigator for studies sponsored by Novo Nordisk, Eli Lilly, Pfizer, and Epitomee. Dr. Gudbergsen, Dr. King, and Dr. Zhu report no relevant financial relationships.
A version of this article appeared on Medscape.com.
In new era of gene therapy, PCPs are ‘boots on the ground’
In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.
Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.
“They are boots on the ground for this kind of [work],” Ms. Gibbons, who is the newborn screen coordinator for SMA in both states, told this news organization. “I’m not even sure they realize it.” As of today, the U.S. Food and Drug Administration has approved 16 gene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.
The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.
Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins – proteins that heal wounds, restore muscle function, and fight cancer.
Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told this news organization. And primary care stands to be a linchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.
“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the center for Duchenne muscular dystrophy at the University of California, Los Angeles. These cases – some before gene therapy and some after – will show up in primary care offices before the textbook is written.
Unknown side effects, new diseases
Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”
At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own – comanaging them instead with subspecialists – they will be involved in the ordering and monitoring of safety labs and other tests.
General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Dr. Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.
Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Dr. Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.
In rural Wyoming, pediatricians and family doctors are especially important, Ms. Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.
But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.
In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.
But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Dr. Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.
“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Dr. Nelson said.
Finding patients
Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.
Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Dr. Nelson said.
But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Dr. Duncan said.
Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the center for precision medicine at Vanderbilt University Medical Center, in Nashville, Tenn., told this news organization.
A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.
Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Dr. Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.
Dr. Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.
Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally – and particularly in rural areas, Dr. Nelson said. Physicians likely will have to rely on their own counseling training to some degree.
“I feel very strongly that genetic counselors are in short supply,” Ms. Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.
The number of board-certified genetic counselors in the United States has doubled to more than 6,000 in the past 10 years – a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”
Equally important to the counseling experience, according to Dr. Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.
But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Dr. Duncan said.
The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Dr. Peterson said. “I think that is a key issue.”
Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Dr. Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
The whole patient
Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.
But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.
All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Dr. Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.
“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.
A version of this article first appeared on Medscape.com.
In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.
Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.
“They are boots on the ground for this kind of [work],” Ms. Gibbons, who is the newborn screen coordinator for SMA in both states, told this news organization. “I’m not even sure they realize it.” As of today, the U.S. Food and Drug Administration has approved 16 gene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.
The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.
Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins – proteins that heal wounds, restore muscle function, and fight cancer.
Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told this news organization. And primary care stands to be a linchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.
“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the center for Duchenne muscular dystrophy at the University of California, Los Angeles. These cases – some before gene therapy and some after – will show up in primary care offices before the textbook is written.
Unknown side effects, new diseases
Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”
At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own – comanaging them instead with subspecialists – they will be involved in the ordering and monitoring of safety labs and other tests.
General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Dr. Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.
Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Dr. Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.
In rural Wyoming, pediatricians and family doctors are especially important, Ms. Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.
But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.
In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.
But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Dr. Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.
“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Dr. Nelson said.
Finding patients
Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.
Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Dr. Nelson said.
But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Dr. Duncan said.
Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the center for precision medicine at Vanderbilt University Medical Center, in Nashville, Tenn., told this news organization.
A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.
Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Dr. Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.
Dr. Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.
Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally – and particularly in rural areas, Dr. Nelson said. Physicians likely will have to rely on their own counseling training to some degree.
“I feel very strongly that genetic counselors are in short supply,” Ms. Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.
The number of board-certified genetic counselors in the United States has doubled to more than 6,000 in the past 10 years – a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”
Equally important to the counseling experience, according to Dr. Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.
But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Dr. Duncan said.
The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Dr. Peterson said. “I think that is a key issue.”
Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Dr. Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
The whole patient
Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.
But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.
All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Dr. Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.
“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.
A version of this article first appeared on Medscape.com.
In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.
Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.
“They are boots on the ground for this kind of [work],” Ms. Gibbons, who is the newborn screen coordinator for SMA in both states, told this news organization. “I’m not even sure they realize it.” As of today, the U.S. Food and Drug Administration has approved 16 gene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.
The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.
Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins – proteins that heal wounds, restore muscle function, and fight cancer.
Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told this news organization. And primary care stands to be a linchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.
“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the center for Duchenne muscular dystrophy at the University of California, Los Angeles. These cases – some before gene therapy and some after – will show up in primary care offices before the textbook is written.
Unknown side effects, new diseases
Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”
At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own – comanaging them instead with subspecialists – they will be involved in the ordering and monitoring of safety labs and other tests.
General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Dr. Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.
Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Dr. Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.
In rural Wyoming, pediatricians and family doctors are especially important, Ms. Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.
But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.
In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.
But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Dr. Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.
“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Dr. Nelson said.
Finding patients
Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.
Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Dr. Nelson said.
But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Dr. Duncan said.
Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the center for precision medicine at Vanderbilt University Medical Center, in Nashville, Tenn., told this news organization.
A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.
Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Dr. Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.
Dr. Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.
Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally – and particularly in rural areas, Dr. Nelson said. Physicians likely will have to rely on their own counseling training to some degree.
“I feel very strongly that genetic counselors are in short supply,” Ms. Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.
The number of board-certified genetic counselors in the United States has doubled to more than 6,000 in the past 10 years – a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”
Equally important to the counseling experience, according to Dr. Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.
But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Dr. Duncan said.
The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Dr. Peterson said. “I think that is a key issue.”
Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Dr. Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
The whole patient
Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.
But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.
All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Dr. Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.
“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.
A version of this article first appeared on Medscape.com.
USPSTF maintains ‘insufficient evidence’ for lipid disorder screenings in kids and teens
The group’s final recommendation and corresponding evidence report were published in the Journal of the American Medical Association, following a draft recommendation in January.
The organization reached a similar conclusion following its evaluation in 2016.
“There’s just not enough evidence to determine whether or not screening all children for high cholesterol improves their heart health into adulthood,” said Katrina Donahue, MD, MPH, a USPSTF member and a professor in the department of family medicine at the University of North Carolina at Chapel Hill. “We’re calling for additional research on the effectiveness of screening for and treatment of high cholesterol in children and adolescents to prevent heart attacks, strokes, and death in adulthood.”
The task force recommended other evidence-based strategies to promote heart health, such as screening for obesity and interventions to prevent tobacco use.
The recommendation was the result of a review of 43 studies from MEDLINE and the Cochrane Central Register of Controlled Trials through May 16, 2022. No randomized controlled trial directly addressed the effectiveness or harms of lipid screening for children and adolescents. The task force continued to use article alerts and targeted journal searches through March 24, 2023.
Conditions such as familial hypercholesterolemia and multifactorial dyslipidemia can cause abnormally high lipid levels in children, potentially leading to premature cardiovascular events such as myocardial infarction, stroke, and death in adulthood. According to the USPSTF, the prevalence of FH in U.S. children and adolescents ranges from 0.2% to 0.4% (one in every 250-500 youth). Multifactorial dyslipidemia is more common – the prevalence in children and adolescents ranges from 7.1% to 9.4%.
In an editorial response to the task force’s statement, the authors, including Sarah D. de Ferranti, MD, department of pediatrics at Harvard Medical School, Boston, question the impact of not screening children to identify FH and other conditions and caution against the subsequent delay in treatment.
“Treating FH during childhood slows the progression of vascular finding in atherosclerosis,” the authors write.
They note that the recommendation “leaves a void for clinicians seeking to provide care for patients today” while additional research is conducted.
Sarah Nosal, MD, a member of the board of directors of the American Academy of Family Physicians, said that despite the lack of a recommendation, primary care clinicians can still encourage proper nutrition and physical activity for patients.
Dr. Nosal said that even without clear recommendations from the USPSTF, in the rare case of a patient with a family history of FH, she would order a lipid test and discuss treatment plans with the patient and family, if needed.
“We really don’t want to do tests that we don’t know what to do with the information,” she said.
One USPSTF member reported receiving grants from Healthwise, a nonprofit organization, outside the submitted work.
A version of this article first appeared on Medscape.com.
The group’s final recommendation and corresponding evidence report were published in the Journal of the American Medical Association, following a draft recommendation in January.
The organization reached a similar conclusion following its evaluation in 2016.
“There’s just not enough evidence to determine whether or not screening all children for high cholesterol improves their heart health into adulthood,” said Katrina Donahue, MD, MPH, a USPSTF member and a professor in the department of family medicine at the University of North Carolina at Chapel Hill. “We’re calling for additional research on the effectiveness of screening for and treatment of high cholesterol in children and adolescents to prevent heart attacks, strokes, and death in adulthood.”
The task force recommended other evidence-based strategies to promote heart health, such as screening for obesity and interventions to prevent tobacco use.
The recommendation was the result of a review of 43 studies from MEDLINE and the Cochrane Central Register of Controlled Trials through May 16, 2022. No randomized controlled trial directly addressed the effectiveness or harms of lipid screening for children and adolescents. The task force continued to use article alerts and targeted journal searches through March 24, 2023.
Conditions such as familial hypercholesterolemia and multifactorial dyslipidemia can cause abnormally high lipid levels in children, potentially leading to premature cardiovascular events such as myocardial infarction, stroke, and death in adulthood. According to the USPSTF, the prevalence of FH in U.S. children and adolescents ranges from 0.2% to 0.4% (one in every 250-500 youth). Multifactorial dyslipidemia is more common – the prevalence in children and adolescents ranges from 7.1% to 9.4%.
In an editorial response to the task force’s statement, the authors, including Sarah D. de Ferranti, MD, department of pediatrics at Harvard Medical School, Boston, question the impact of not screening children to identify FH and other conditions and caution against the subsequent delay in treatment.
“Treating FH during childhood slows the progression of vascular finding in atherosclerosis,” the authors write.
They note that the recommendation “leaves a void for clinicians seeking to provide care for patients today” while additional research is conducted.
Sarah Nosal, MD, a member of the board of directors of the American Academy of Family Physicians, said that despite the lack of a recommendation, primary care clinicians can still encourage proper nutrition and physical activity for patients.
Dr. Nosal said that even without clear recommendations from the USPSTF, in the rare case of a patient with a family history of FH, she would order a lipid test and discuss treatment plans with the patient and family, if needed.
“We really don’t want to do tests that we don’t know what to do with the information,” she said.
One USPSTF member reported receiving grants from Healthwise, a nonprofit organization, outside the submitted work.
A version of this article first appeared on Medscape.com.
The group’s final recommendation and corresponding evidence report were published in the Journal of the American Medical Association, following a draft recommendation in January.
The organization reached a similar conclusion following its evaluation in 2016.
“There’s just not enough evidence to determine whether or not screening all children for high cholesterol improves their heart health into adulthood,” said Katrina Donahue, MD, MPH, a USPSTF member and a professor in the department of family medicine at the University of North Carolina at Chapel Hill. “We’re calling for additional research on the effectiveness of screening for and treatment of high cholesterol in children and adolescents to prevent heart attacks, strokes, and death in adulthood.”
The task force recommended other evidence-based strategies to promote heart health, such as screening for obesity and interventions to prevent tobacco use.
The recommendation was the result of a review of 43 studies from MEDLINE and the Cochrane Central Register of Controlled Trials through May 16, 2022. No randomized controlled trial directly addressed the effectiveness or harms of lipid screening for children and adolescents. The task force continued to use article alerts and targeted journal searches through March 24, 2023.
Conditions such as familial hypercholesterolemia and multifactorial dyslipidemia can cause abnormally high lipid levels in children, potentially leading to premature cardiovascular events such as myocardial infarction, stroke, and death in adulthood. According to the USPSTF, the prevalence of FH in U.S. children and adolescents ranges from 0.2% to 0.4% (one in every 250-500 youth). Multifactorial dyslipidemia is more common – the prevalence in children and adolescents ranges from 7.1% to 9.4%.
In an editorial response to the task force’s statement, the authors, including Sarah D. de Ferranti, MD, department of pediatrics at Harvard Medical School, Boston, question the impact of not screening children to identify FH and other conditions and caution against the subsequent delay in treatment.
“Treating FH during childhood slows the progression of vascular finding in atherosclerosis,” the authors write.
They note that the recommendation “leaves a void for clinicians seeking to provide care for patients today” while additional research is conducted.
Sarah Nosal, MD, a member of the board of directors of the American Academy of Family Physicians, said that despite the lack of a recommendation, primary care clinicians can still encourage proper nutrition and physical activity for patients.
Dr. Nosal said that even without clear recommendations from the USPSTF, in the rare case of a patient with a family history of FH, she would order a lipid test and discuss treatment plans with the patient and family, if needed.
“We really don’t want to do tests that we don’t know what to do with the information,” she said.
One USPSTF member reported receiving grants from Healthwise, a nonprofit organization, outside the submitted work.
A version of this article first appeared on Medscape.com.
10 ways docs sabotage their patients’ weight loss journeys
Are there medical conditions other than obesity where physicians, if even inadvertently, regularly sabotage their patients’ efforts at managing them? Because
No doubt this list will be nonexhaustive, but here are what I see as the top 10 ways doctors sabotage their patients’ weight loss journeys.
- 1. Having an office that is anxiety provoking, exclusionary, and/or fat phobic for people with obesity, which in turn may remove trust and preclude conversation. Examples of this would be offices without chairs in the waiting room that are suitable for people with obesity; with reading materials such as glossy magazines like Men’s Health and Shape, glorifying unhealthy dieting and body ideals; or where the scale is in a nonprivate area or has a very narrow platform, or maxes out at a weight lower than many patients’.
- 2. Not taking an actual history. Meaning, physicians regularly launch into a “you should really lose weight” speech without exploring a patient’s history of weight loss and social determinants of health. In some cases, that patient may have a history of disordered eating or body dysmorphia, and then this discussion needs to be approached carefully with those facts underwriting its tenor and direction. In other cases, patients’ social determinants of health would make intentional behavior change efforts in the name of weight management an impossible luxury. And sometimes that same patient may in fact be maintaining a clinically meaningful weight loss from their peak weight already. In all cases, not speaking with your patients and instead speaking at your patients will not increase their likelihood to trust or follow or seek your advice.
- 3. Pushing useless diet advice. The most common and most useless are some variation on needing to just eat less and move more. That’s about as useful as telling someone that making money requires them to buy low and sell high. Or telling someone with depression that they should just cheer up and look at the bright side of things.
- 4. Pushing specific diet advice (intermittent fasting, keto, low carb, vegan, low fat, whatever) as if it’s the only way or the best way to lose weight. The research is clear: There is no one best dietary approach, and one person’s best diet is another person’s worst. Yet, some clinicians are themselves diet zealots and preach one diet over all others. Of course, many of their patients may well have already tried that approach, while others won’t enjoy it, and so promoting it above all others will fail a great many people.
- 5. Refusing to prescribe medications to patients who meet the clinical criteria for use, especially now that there are truly effective and useful medications. Do these same clinicians refuse to prescribe antihypertensives or oral hypoglycemics to patients whose blood pressures or blood sugars are risking their health? Related would be those clinicians who don’t bother to learn enough about pharmaceutical options for obesity to feel comfortable prescribing them. This, despite the fact that statistically, well over 30% of their patients have obesity, and polls suggest that at least half of those embark on weight loss efforts annually. If a patient meets clinical criteria for a medication’s approved indication and a doctor won’t prescribe it because of their personal beliefs, in my opinion that’s grounds for a regulatory complaint.
- 6. Fearmongering around medications regarding adverse or unknown effects. The media’s coverage of new antiobesity medications is alarmist, to say the least, and for reasons I can’t fathom, given how well tolerated these medications are when dose titration is slow, monitored, and adjusted appropriately. Many physicians are not only buying into media narratives but are also spreading them.
- 7. Stopping medications for obesity when weight is lost. Do you also stop blood pressure medications when they normalize a patient’s blood pressure? Chronic conditions require ongoing long-term treatment. And yet I hear about this in my practice regularly.
- 8. Prescribing medications that cause weight gain rather than alternatives that don’t, or without discussion of same, or without the concomitant prescription of medication to counter it. From atypical antipsychotics to antidepressants to certain antiseizure medications to some blood pressure medications, there are those that have been shown to lead to, at times, dramatic weight gain. Yet, physicians will still regularly prescribe them to patients with obesity without first trying patients on available alternatives that don’t lead to weight gain, or without at least monitoring and then considering the prescription of an antiobesity medication to try to mitigate iatrogenic gain.
- 9. Setting ridiculous and unrealistic weight loss goals with patients. Without medication, the average person may lose 10% of their weight with purely behavioral efforts, 15%-20% with the addition of medications to those behavioral efforts, and 30% with the addition of bariatric surgery to their behavioral efforts. So why do so many physicians suggest goals that greatly exceed those averages? Imagine being committed to learning to run and having your running coach tell you at your training outset that your goal is to run a marathon within a Boston Marathon qualifying time. The goal should be whatever weight a person reaches living the healthiest life that they can honestly enjoy, not the Boston Marathon of weight loss.
- 10. Not discussing all options with all patients. Yes, food and fitness levers can affect weight, but that doesn’t mean that patients who meet the medical criteria for antiobesity medication or bariatric surgery shouldn’t be informed of their options. Our job as physicians is to fully inform our patients about the risks and benefits of all treatment options and then to support our patients’ decisions as to what option they want to pursue (including none, by the way). Our job is not to exclude discussion of proven and available options because our weight biases see us personally not believing in them – or worse, thinking that patients haven’t tried food and fitness umpteen times before, and that we require them to fail those efforts yet again before we stop gatekeeping their access to effective adjunctive therapeutic interventions.
Until recently, underwriting weight bias in medicine has been the dearth of effective treatments which in turn probably contributed to the overall lack of education for physicians in obesity management despite its extremely high prevalence. The times, though, are definitely a-changin’. Consequent to these new generations of medications rapidly coming online, by necessity we will see improvements in medical education around obesity management. Meanwhile, their efficacy will help dispel the bias that underlies much of this list. A decade or 2 from now, we will see obesity treated as we do every other chronic noncommunicable disease with lifestyle levers – with patient-centered care free from judgment and blame, and with a myriad of therapeutic options that physicians objectively, not subjectively, inform and prescribe to their patients.
Dr. Freedhoff is associate professor, department of family medicine, University of Ottawa, and medical director, Bariatric Medical Institute, also in Ottawa. He reported conflicts of interest with Constant Health and Novo Nordisk.
A version of this article first appeared on Medscape.com.
Are there medical conditions other than obesity where physicians, if even inadvertently, regularly sabotage their patients’ efforts at managing them? Because
No doubt this list will be nonexhaustive, but here are what I see as the top 10 ways doctors sabotage their patients’ weight loss journeys.
- 1. Having an office that is anxiety provoking, exclusionary, and/or fat phobic for people with obesity, which in turn may remove trust and preclude conversation. Examples of this would be offices without chairs in the waiting room that are suitable for people with obesity; with reading materials such as glossy magazines like Men’s Health and Shape, glorifying unhealthy dieting and body ideals; or where the scale is in a nonprivate area or has a very narrow platform, or maxes out at a weight lower than many patients’.
- 2. Not taking an actual history. Meaning, physicians regularly launch into a “you should really lose weight” speech without exploring a patient’s history of weight loss and social determinants of health. In some cases, that patient may have a history of disordered eating or body dysmorphia, and then this discussion needs to be approached carefully with those facts underwriting its tenor and direction. In other cases, patients’ social determinants of health would make intentional behavior change efforts in the name of weight management an impossible luxury. And sometimes that same patient may in fact be maintaining a clinically meaningful weight loss from their peak weight already. In all cases, not speaking with your patients and instead speaking at your patients will not increase their likelihood to trust or follow or seek your advice.
- 3. Pushing useless diet advice. The most common and most useless are some variation on needing to just eat less and move more. That’s about as useful as telling someone that making money requires them to buy low and sell high. Or telling someone with depression that they should just cheer up and look at the bright side of things.
- 4. Pushing specific diet advice (intermittent fasting, keto, low carb, vegan, low fat, whatever) as if it’s the only way or the best way to lose weight. The research is clear: There is no one best dietary approach, and one person’s best diet is another person’s worst. Yet, some clinicians are themselves diet zealots and preach one diet over all others. Of course, many of their patients may well have already tried that approach, while others won’t enjoy it, and so promoting it above all others will fail a great many people.
- 5. Refusing to prescribe medications to patients who meet the clinical criteria for use, especially now that there are truly effective and useful medications. Do these same clinicians refuse to prescribe antihypertensives or oral hypoglycemics to patients whose blood pressures or blood sugars are risking their health? Related would be those clinicians who don’t bother to learn enough about pharmaceutical options for obesity to feel comfortable prescribing them. This, despite the fact that statistically, well over 30% of their patients have obesity, and polls suggest that at least half of those embark on weight loss efforts annually. If a patient meets clinical criteria for a medication’s approved indication and a doctor won’t prescribe it because of their personal beliefs, in my opinion that’s grounds for a regulatory complaint.
- 6. Fearmongering around medications regarding adverse or unknown effects. The media’s coverage of new antiobesity medications is alarmist, to say the least, and for reasons I can’t fathom, given how well tolerated these medications are when dose titration is slow, monitored, and adjusted appropriately. Many physicians are not only buying into media narratives but are also spreading them.
- 7. Stopping medications for obesity when weight is lost. Do you also stop blood pressure medications when they normalize a patient’s blood pressure? Chronic conditions require ongoing long-term treatment. And yet I hear about this in my practice regularly.
- 8. Prescribing medications that cause weight gain rather than alternatives that don’t, or without discussion of same, or without the concomitant prescription of medication to counter it. From atypical antipsychotics to antidepressants to certain antiseizure medications to some blood pressure medications, there are those that have been shown to lead to, at times, dramatic weight gain. Yet, physicians will still regularly prescribe them to patients with obesity without first trying patients on available alternatives that don’t lead to weight gain, or without at least monitoring and then considering the prescription of an antiobesity medication to try to mitigate iatrogenic gain.
- 9. Setting ridiculous and unrealistic weight loss goals with patients. Without medication, the average person may lose 10% of their weight with purely behavioral efforts, 15%-20% with the addition of medications to those behavioral efforts, and 30% with the addition of bariatric surgery to their behavioral efforts. So why do so many physicians suggest goals that greatly exceed those averages? Imagine being committed to learning to run and having your running coach tell you at your training outset that your goal is to run a marathon within a Boston Marathon qualifying time. The goal should be whatever weight a person reaches living the healthiest life that they can honestly enjoy, not the Boston Marathon of weight loss.
- 10. Not discussing all options with all patients. Yes, food and fitness levers can affect weight, but that doesn’t mean that patients who meet the medical criteria for antiobesity medication or bariatric surgery shouldn’t be informed of their options. Our job as physicians is to fully inform our patients about the risks and benefits of all treatment options and then to support our patients’ decisions as to what option they want to pursue (including none, by the way). Our job is not to exclude discussion of proven and available options because our weight biases see us personally not believing in them – or worse, thinking that patients haven’t tried food and fitness umpteen times before, and that we require them to fail those efforts yet again before we stop gatekeeping their access to effective adjunctive therapeutic interventions.
Until recently, underwriting weight bias in medicine has been the dearth of effective treatments which in turn probably contributed to the overall lack of education for physicians in obesity management despite its extremely high prevalence. The times, though, are definitely a-changin’. Consequent to these new generations of medications rapidly coming online, by necessity we will see improvements in medical education around obesity management. Meanwhile, their efficacy will help dispel the bias that underlies much of this list. A decade or 2 from now, we will see obesity treated as we do every other chronic noncommunicable disease with lifestyle levers – with patient-centered care free from judgment and blame, and with a myriad of therapeutic options that physicians objectively, not subjectively, inform and prescribe to their patients.
Dr. Freedhoff is associate professor, department of family medicine, University of Ottawa, and medical director, Bariatric Medical Institute, also in Ottawa. He reported conflicts of interest with Constant Health and Novo Nordisk.
A version of this article first appeared on Medscape.com.
Are there medical conditions other than obesity where physicians, if even inadvertently, regularly sabotage their patients’ efforts at managing them? Because
No doubt this list will be nonexhaustive, but here are what I see as the top 10 ways doctors sabotage their patients’ weight loss journeys.
- 1. Having an office that is anxiety provoking, exclusionary, and/or fat phobic for people with obesity, which in turn may remove trust and preclude conversation. Examples of this would be offices without chairs in the waiting room that are suitable for people with obesity; with reading materials such as glossy magazines like Men’s Health and Shape, glorifying unhealthy dieting and body ideals; or where the scale is in a nonprivate area or has a very narrow platform, or maxes out at a weight lower than many patients’.
- 2. Not taking an actual history. Meaning, physicians regularly launch into a “you should really lose weight” speech without exploring a patient’s history of weight loss and social determinants of health. In some cases, that patient may have a history of disordered eating or body dysmorphia, and then this discussion needs to be approached carefully with those facts underwriting its tenor and direction. In other cases, patients’ social determinants of health would make intentional behavior change efforts in the name of weight management an impossible luxury. And sometimes that same patient may in fact be maintaining a clinically meaningful weight loss from their peak weight already. In all cases, not speaking with your patients and instead speaking at your patients will not increase their likelihood to trust or follow or seek your advice.
- 3. Pushing useless diet advice. The most common and most useless are some variation on needing to just eat less and move more. That’s about as useful as telling someone that making money requires them to buy low and sell high. Or telling someone with depression that they should just cheer up and look at the bright side of things.
- 4. Pushing specific diet advice (intermittent fasting, keto, low carb, vegan, low fat, whatever) as if it’s the only way or the best way to lose weight. The research is clear: There is no one best dietary approach, and one person’s best diet is another person’s worst. Yet, some clinicians are themselves diet zealots and preach one diet over all others. Of course, many of their patients may well have already tried that approach, while others won’t enjoy it, and so promoting it above all others will fail a great many people.
- 5. Refusing to prescribe medications to patients who meet the clinical criteria for use, especially now that there are truly effective and useful medications. Do these same clinicians refuse to prescribe antihypertensives or oral hypoglycemics to patients whose blood pressures or blood sugars are risking their health? Related would be those clinicians who don’t bother to learn enough about pharmaceutical options for obesity to feel comfortable prescribing them. This, despite the fact that statistically, well over 30% of their patients have obesity, and polls suggest that at least half of those embark on weight loss efforts annually. If a patient meets clinical criteria for a medication’s approved indication and a doctor won’t prescribe it because of their personal beliefs, in my opinion that’s grounds for a regulatory complaint.
- 6. Fearmongering around medications regarding adverse or unknown effects. The media’s coverage of new antiobesity medications is alarmist, to say the least, and for reasons I can’t fathom, given how well tolerated these medications are when dose titration is slow, monitored, and adjusted appropriately. Many physicians are not only buying into media narratives but are also spreading them.
- 7. Stopping medications for obesity when weight is lost. Do you also stop blood pressure medications when they normalize a patient’s blood pressure? Chronic conditions require ongoing long-term treatment. And yet I hear about this in my practice regularly.
- 8. Prescribing medications that cause weight gain rather than alternatives that don’t, or without discussion of same, or without the concomitant prescription of medication to counter it. From atypical antipsychotics to antidepressants to certain antiseizure medications to some blood pressure medications, there are those that have been shown to lead to, at times, dramatic weight gain. Yet, physicians will still regularly prescribe them to patients with obesity without first trying patients on available alternatives that don’t lead to weight gain, or without at least monitoring and then considering the prescription of an antiobesity medication to try to mitigate iatrogenic gain.
- 9. Setting ridiculous and unrealistic weight loss goals with patients. Without medication, the average person may lose 10% of their weight with purely behavioral efforts, 15%-20% with the addition of medications to those behavioral efforts, and 30% with the addition of bariatric surgery to their behavioral efforts. So why do so many physicians suggest goals that greatly exceed those averages? Imagine being committed to learning to run and having your running coach tell you at your training outset that your goal is to run a marathon within a Boston Marathon qualifying time. The goal should be whatever weight a person reaches living the healthiest life that they can honestly enjoy, not the Boston Marathon of weight loss.
- 10. Not discussing all options with all patients. Yes, food and fitness levers can affect weight, but that doesn’t mean that patients who meet the medical criteria for antiobesity medication or bariatric surgery shouldn’t be informed of their options. Our job as physicians is to fully inform our patients about the risks and benefits of all treatment options and then to support our patients’ decisions as to what option they want to pursue (including none, by the way). Our job is not to exclude discussion of proven and available options because our weight biases see us personally not believing in them – or worse, thinking that patients haven’t tried food and fitness umpteen times before, and that we require them to fail those efforts yet again before we stop gatekeeping their access to effective adjunctive therapeutic interventions.
Until recently, underwriting weight bias in medicine has been the dearth of effective treatments which in turn probably contributed to the overall lack of education for physicians in obesity management despite its extremely high prevalence. The times, though, are definitely a-changin’. Consequent to these new generations of medications rapidly coming online, by necessity we will see improvements in medical education around obesity management. Meanwhile, their efficacy will help dispel the bias that underlies much of this list. A decade or 2 from now, we will see obesity treated as we do every other chronic noncommunicable disease with lifestyle levers – with patient-centered care free from judgment and blame, and with a myriad of therapeutic options that physicians objectively, not subjectively, inform and prescribe to their patients.
Dr. Freedhoff is associate professor, department of family medicine, University of Ottawa, and medical director, Bariatric Medical Institute, also in Ottawa. He reported conflicts of interest with Constant Health and Novo Nordisk.
A version of this article first appeared on Medscape.com.
Meta-analysis finds increase in type 1 diabetes incidence, ketoacidosis during COVID pandemic
according to a recent meta-analysis.
The review compared 2 years of data from during the pandemic to data from a prepandemic period, and showed a higher incidence of type 1 diabetes in the first year (incidence rate ratio, 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also found an increase in the incidence of diabetic ketoacidosis (DKA) (IRR, 1.26).
The meta-analysis included 17 studies of 38,149 children and adolescents with newly diagnosed type 1 diabetes. “Putting them all together really gave us more confidence to say this is something that we think is real,” study author Rayzel Shulman, MD, PhD, an endocrinologist at The Hospital for Sick Children in Toronto and associate professor of pediatrics at the University of Toronto, said in an interview.
The study was published in JAMA Network Open.
Increased incidence
The investigators reviewed 42 studies, including 17 that examined rates of type 1 diabetes incidence, 10 on type 2 diabetes, and 15 on DKA. The included studies all had a minimum observation period of 12 months during the pandemic and at least 12 months before it. Relative to the prepandemic period, the meta-analysis found higher rates of type 1 diabetes and DKA during the pandemic.
The review was conducted in response to questions about the methodology of study results suggesting an association between the COVID-19 pandemic and the incidence of diabetes, according to Dr. Shulman.
Although this is not the first review of studies on the connection between diabetes and COVID-19, it adds to the literature by extending the study period to 2 years of the pandemic. The longer time frame helps address potential seasonal differences in incidence and increases confidence in the results.
The investigators also sought to look at the incidence of type 2 diabetes in children but found few studies that met the study criteria. Although some studies reported rates of type 2 diabetes, most lacked information about the population, specifically, the “denominator” needed for findings regarding any association with the COVID-19 pandemic.
With greater confidence in the increased incidence of type 1 diabetes, Dr. Shulman emphasized a need to ensure sufficient resources to care for newly diagnosed patients, including education and support for families.
The study’s secondary outcome was the change in incidence rate of DKA among children with newly diagnosed diabetes. Data reported in 15 studies showed a 26% increase in DKA incidence during the first year of the pandemic.
“DKA is a serious and life-threatening condition that is preventable,” said Dr. Shulman. Symptoms of type 1 diabetes include increased thirst and urination, weight loss, and fatigue. If parents or caregivers notice these signs, Dr. Shulman advises them to seek care immediately to reduce the risk of DKA.
Possible mechanisms
In a comment, Elizabeth Sellers, MD, an endocrinologist at the Children’s Hospital Research Institute of Manitoba and associate professor of pediatrics at the University of Manitoba, both in Winnipeg, said the study’s findings on DKA are an important reminder to be attentive to symptoms of diabetes. Dr. Sellers did not participate in the meta-analysis.
One possible explanation for the increase is a hesitancy to seek care among parents and caregivers during the pandemic. “I think we use that information and turn it into a positive,” said Dr. Sellers, by increasing recognition of the symptoms. Dr. Sellers, whose research is included in the review, is part of an initiative by the Canadian Pediatric Endocrine Group to increase diabetes awareness.
The study provides important findings, particularly the second-year results, but is not designed to answer why there has been an increase in diabetes incidence, said Dr. Sellers. “You have to identify the problem first and then you can go back and look at mechanisms.”
The meta-analysis did not seek to draw conclusions about the underlying mechanisms that would explain changes in diabetes incidence but rather indicates a need for further studies to seek a better understanding of the connection. Several theories may be considered, wrote Clemens Kamrath, MD, of the Centre of Child and Adolescent Medicine at Justus Liebig University in Giessen, Germany, and colleagues in an accompanying editorial.
Studies have suggested a direct effect of infections such as COVID-19, whereby the virus damages insulin-producing beta cells. However, the commentary notes these studies do not account for asymptomatic infections among children.
Dr. Kamrath and colleagues also considered the indirect effects of the COVID-19 pandemic, which they indicate may be more likely than direct effects. These indirect effects include autoimmunity and environmental changes that occurred during the pandemic.
Researchers will need to continue monitoring the data to see if the trend persists and continue working to determine the mechanisms, said Dr. Schulman. “I don’t think this is the end of the story.”
The study was supported in part by grant funding from the department of pediatrics at The Hospital for Sick Children. Dr. Shulman, Dr. Sellers, and Dr. Kamrath reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to a recent meta-analysis.
The review compared 2 years of data from during the pandemic to data from a prepandemic period, and showed a higher incidence of type 1 diabetes in the first year (incidence rate ratio, 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also found an increase in the incidence of diabetic ketoacidosis (DKA) (IRR, 1.26).
The meta-analysis included 17 studies of 38,149 children and adolescents with newly diagnosed type 1 diabetes. “Putting them all together really gave us more confidence to say this is something that we think is real,” study author Rayzel Shulman, MD, PhD, an endocrinologist at The Hospital for Sick Children in Toronto and associate professor of pediatrics at the University of Toronto, said in an interview.
The study was published in JAMA Network Open.
Increased incidence
The investigators reviewed 42 studies, including 17 that examined rates of type 1 diabetes incidence, 10 on type 2 diabetes, and 15 on DKA. The included studies all had a minimum observation period of 12 months during the pandemic and at least 12 months before it. Relative to the prepandemic period, the meta-analysis found higher rates of type 1 diabetes and DKA during the pandemic.
The review was conducted in response to questions about the methodology of study results suggesting an association between the COVID-19 pandemic and the incidence of diabetes, according to Dr. Shulman.
Although this is not the first review of studies on the connection between diabetes and COVID-19, it adds to the literature by extending the study period to 2 years of the pandemic. The longer time frame helps address potential seasonal differences in incidence and increases confidence in the results.
The investigators also sought to look at the incidence of type 2 diabetes in children but found few studies that met the study criteria. Although some studies reported rates of type 2 diabetes, most lacked information about the population, specifically, the “denominator” needed for findings regarding any association with the COVID-19 pandemic.
With greater confidence in the increased incidence of type 1 diabetes, Dr. Shulman emphasized a need to ensure sufficient resources to care for newly diagnosed patients, including education and support for families.
The study’s secondary outcome was the change in incidence rate of DKA among children with newly diagnosed diabetes. Data reported in 15 studies showed a 26% increase in DKA incidence during the first year of the pandemic.
“DKA is a serious and life-threatening condition that is preventable,” said Dr. Shulman. Symptoms of type 1 diabetes include increased thirst and urination, weight loss, and fatigue. If parents or caregivers notice these signs, Dr. Shulman advises them to seek care immediately to reduce the risk of DKA.
Possible mechanisms
In a comment, Elizabeth Sellers, MD, an endocrinologist at the Children’s Hospital Research Institute of Manitoba and associate professor of pediatrics at the University of Manitoba, both in Winnipeg, said the study’s findings on DKA are an important reminder to be attentive to symptoms of diabetes. Dr. Sellers did not participate in the meta-analysis.
One possible explanation for the increase is a hesitancy to seek care among parents and caregivers during the pandemic. “I think we use that information and turn it into a positive,” said Dr. Sellers, by increasing recognition of the symptoms. Dr. Sellers, whose research is included in the review, is part of an initiative by the Canadian Pediatric Endocrine Group to increase diabetes awareness.
The study provides important findings, particularly the second-year results, but is not designed to answer why there has been an increase in diabetes incidence, said Dr. Sellers. “You have to identify the problem first and then you can go back and look at mechanisms.”
The meta-analysis did not seek to draw conclusions about the underlying mechanisms that would explain changes in diabetes incidence but rather indicates a need for further studies to seek a better understanding of the connection. Several theories may be considered, wrote Clemens Kamrath, MD, of the Centre of Child and Adolescent Medicine at Justus Liebig University in Giessen, Germany, and colleagues in an accompanying editorial.
Studies have suggested a direct effect of infections such as COVID-19, whereby the virus damages insulin-producing beta cells. However, the commentary notes these studies do not account for asymptomatic infections among children.
Dr. Kamrath and colleagues also considered the indirect effects of the COVID-19 pandemic, which they indicate may be more likely than direct effects. These indirect effects include autoimmunity and environmental changes that occurred during the pandemic.
Researchers will need to continue monitoring the data to see if the trend persists and continue working to determine the mechanisms, said Dr. Schulman. “I don’t think this is the end of the story.”
The study was supported in part by grant funding from the department of pediatrics at The Hospital for Sick Children. Dr. Shulman, Dr. Sellers, and Dr. Kamrath reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to a recent meta-analysis.
The review compared 2 years of data from during the pandemic to data from a prepandemic period, and showed a higher incidence of type 1 diabetes in the first year (incidence rate ratio, 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also found an increase in the incidence of diabetic ketoacidosis (DKA) (IRR, 1.26).
The meta-analysis included 17 studies of 38,149 children and adolescents with newly diagnosed type 1 diabetes. “Putting them all together really gave us more confidence to say this is something that we think is real,” study author Rayzel Shulman, MD, PhD, an endocrinologist at The Hospital for Sick Children in Toronto and associate professor of pediatrics at the University of Toronto, said in an interview.
The study was published in JAMA Network Open.
Increased incidence
The investigators reviewed 42 studies, including 17 that examined rates of type 1 diabetes incidence, 10 on type 2 diabetes, and 15 on DKA. The included studies all had a minimum observation period of 12 months during the pandemic and at least 12 months before it. Relative to the prepandemic period, the meta-analysis found higher rates of type 1 diabetes and DKA during the pandemic.
The review was conducted in response to questions about the methodology of study results suggesting an association between the COVID-19 pandemic and the incidence of diabetes, according to Dr. Shulman.
Although this is not the first review of studies on the connection between diabetes and COVID-19, it adds to the literature by extending the study period to 2 years of the pandemic. The longer time frame helps address potential seasonal differences in incidence and increases confidence in the results.
The investigators also sought to look at the incidence of type 2 diabetes in children but found few studies that met the study criteria. Although some studies reported rates of type 2 diabetes, most lacked information about the population, specifically, the “denominator” needed for findings regarding any association with the COVID-19 pandemic.
With greater confidence in the increased incidence of type 1 diabetes, Dr. Shulman emphasized a need to ensure sufficient resources to care for newly diagnosed patients, including education and support for families.
The study’s secondary outcome was the change in incidence rate of DKA among children with newly diagnosed diabetes. Data reported in 15 studies showed a 26% increase in DKA incidence during the first year of the pandemic.
“DKA is a serious and life-threatening condition that is preventable,” said Dr. Shulman. Symptoms of type 1 diabetes include increased thirst and urination, weight loss, and fatigue. If parents or caregivers notice these signs, Dr. Shulman advises them to seek care immediately to reduce the risk of DKA.
Possible mechanisms
In a comment, Elizabeth Sellers, MD, an endocrinologist at the Children’s Hospital Research Institute of Manitoba and associate professor of pediatrics at the University of Manitoba, both in Winnipeg, said the study’s findings on DKA are an important reminder to be attentive to symptoms of diabetes. Dr. Sellers did not participate in the meta-analysis.
One possible explanation for the increase is a hesitancy to seek care among parents and caregivers during the pandemic. “I think we use that information and turn it into a positive,” said Dr. Sellers, by increasing recognition of the symptoms. Dr. Sellers, whose research is included in the review, is part of an initiative by the Canadian Pediatric Endocrine Group to increase diabetes awareness.
The study provides important findings, particularly the second-year results, but is not designed to answer why there has been an increase in diabetes incidence, said Dr. Sellers. “You have to identify the problem first and then you can go back and look at mechanisms.”
The meta-analysis did not seek to draw conclusions about the underlying mechanisms that would explain changes in diabetes incidence but rather indicates a need for further studies to seek a better understanding of the connection. Several theories may be considered, wrote Clemens Kamrath, MD, of the Centre of Child and Adolescent Medicine at Justus Liebig University in Giessen, Germany, and colleagues in an accompanying editorial.
Studies have suggested a direct effect of infections such as COVID-19, whereby the virus damages insulin-producing beta cells. However, the commentary notes these studies do not account for asymptomatic infections among children.
Dr. Kamrath and colleagues also considered the indirect effects of the COVID-19 pandemic, which they indicate may be more likely than direct effects. These indirect effects include autoimmunity and environmental changes that occurred during the pandemic.
Researchers will need to continue monitoring the data to see if the trend persists and continue working to determine the mechanisms, said Dr. Schulman. “I don’t think this is the end of the story.”
The study was supported in part by grant funding from the department of pediatrics at The Hospital for Sick Children. Dr. Shulman, Dr. Sellers, and Dr. Kamrath reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
FDA approves first over-the-counter birth control pill
The Food and Drug Administration’s approval today of the first birth control pill for women to be available without a prescription is being hailed by many as a long-needed development, but there remain questions to be resolved, including how much the drug will cost and how it will be used.
The drug, Opill, is expected to be available early next year, and its maker has yet to reveal a retail price. It is the same birth control pill that has been available by prescription for 50 years. But for the first time, women will be able to buy the contraception at a local pharmacy, other retail locations, or online without having to see a doctor first.
Likely to drive debate
Contraception in the United States is not without controversy. The FDA’s approval spurred reactions both for and against making hormonal birth control for women available without a prescription.
“It’s an exciting time, especially right now when reproductive rights are being curtailed in a lot of states. Giving people an additional option for contraception will change people’s lives,” said Beverly Gray, MD, division director of Women’s Community and Population Health at Duke University Medical Center in Durham, N.C.
“It’s a huge win for patients who need better access to contraception,” said Dr. Gray, who is also a spokesperson for the American College of Obstetricians and Gynecologists.
Women who want hormonal birth control but live in areas without convenient access to a doctor, women who cannot easily take time off of work to see a doctor and get a prescription filled, and women without insurance are examples of people who will benefit, she said.
The Catholic Medical Association, in contrast, expressed “deep concern and disappointment” after an FDA advisory committee’s unanimous vote on May 11 recommending the drug be available over the counter. In a statement after the vote, the group cited “extensive medical studies demonstrating the risks and adverse effects of hormonal contraceptives,” adding that “the social impact of [full approval] would be dramatic.”
But doctors largely disagreed.
“It is definitely a huge win for reproductive autonomy. I’m glad that the FDA is prioritizing patient safety and well-being over politics,” said Catherine Cansino, MD, MPH, an ob.gyn. and clinical professor in the University of California Davis department of obstetrics and gynecology. She said the FDA approved the over-the-counter version because the medication is safe.
While opponents like the Catholic Medical Association cite safety concerns and believe doctors should screen all women before prescribing hormonal contraception, Dr. Gray disagreed. “There’s a lot of evidence that patients can figure out if a progestin-only pill is right for them and safe for them. Medical professionals don’t have to be the gatekeepers for contraception,” she said.
Pricing unknown
Whether insurance companies will pay for Opill now that it will be available without a prescription remains unknown. For some medications, paying a copay through insurance can be less expensive than buying at a retail price.
“Although pricing issues will be relevant, the FDA’s decision will enhance women’s access to hormonal birth control,” said Andrew M. Kaunitz, MD, a professor and associate chairman in the department of obstetrics and gynecology at the University of Florida College of Medicine in Jacksonville.
The drugmaker, Perrigo, based in Ireland, has not yet announced how much the pill will cost. The price tag could affect how widely available this form of birth control is. The drug has been shown to be as much as 93% effective for pregnancy prevention. Perrigo says it plans to make the pill available at low or no cost to some women.
Caveats to consider
There are some women for whom hormonal contraceptives have always carried greater risks. For example, women who have breast cancer or a history of breast cancer should not use hormonal contraceptives, the FDA said in a news release announcing the approval. Women with other types of cancer should check with their doctors first, the agency noted.
Women who smoke, who take some medications to lower blood pressure, or who have migraines should also take caution, Dr. Cansino said. “People with migraines may not be suitable for over-the-counter oral contraceptives. But a simple screening through a provider can identify whether you are truly eligible or not.”
Irregular bleeding, headaches, dizziness, nausea, increased appetite, belly pain, cramps, or bloating are the most common side effects of Opill, the FDA said.
The Opill is a progestin-only birth control pill. Similar pills have been available in the United Kingdiom for about 2 years, often referred to as “mini pills” because they contain a single hormone. In contrast, prescription birth control pills in the United States and elsewhere contain more than one hormone, estrogen and progestin, to prevent pregnancy.
Prescription pill packs for combination contraception often feature a week of placebo pills without an active ingredient. While skipping a placebo pill might not make a difference in pregnancy prevention, Opill is different. Every pill in the packet will contain medication, Gray said. “So it’s important to take the pill the same time every day for it to be most effective.”
Even though this may mean one less visit to your doctor, Dr. Kaunitz hopes women will stay up to date on their other medical checkups. “One of our challenges as providers of care to women will be to encourage them to continue to receive important services, including cancer screening and vaccinations, even while they can initiate and continue hormonal contraception without contact with a provider.”
Just the beginning?
The American Medical Association hopes this approval signals more to come.
“While we applaud this move, the AMA continues to urge the FDA and HHS to consider a variety of oral contraceptive options for over-the-counter use,” the association, which has more than 250,000 doctor members, said in a statement. “It is important patients have options when choosing which type of birth control works best for them,”
The American College of Obstetricians and Gynecologists said the FDA’s decision will help many women. “We are glad that more patients will now be empowered to choose when and where they obtain a safe method of contraception without having to wait for a medical appointment or for a prescription to be filled,” Verda J. Hicks, MD, the group’s president, and Christopher M. Zahn, MD, interim chief executive officer, said in a statement.
“Allowing individuals to access birth control at their local pharmacy or drug store will eliminate some barriers,” they said.
A version of this article first appeared on WebMD.com.
This article was updated 7/13/23.
The Food and Drug Administration’s approval today of the first birth control pill for women to be available without a prescription is being hailed by many as a long-needed development, but there remain questions to be resolved, including how much the drug will cost and how it will be used.
The drug, Opill, is expected to be available early next year, and its maker has yet to reveal a retail price. It is the same birth control pill that has been available by prescription for 50 years. But for the first time, women will be able to buy the contraception at a local pharmacy, other retail locations, or online without having to see a doctor first.
Likely to drive debate
Contraception in the United States is not without controversy. The FDA’s approval spurred reactions both for and against making hormonal birth control for women available without a prescription.
“It’s an exciting time, especially right now when reproductive rights are being curtailed in a lot of states. Giving people an additional option for contraception will change people’s lives,” said Beverly Gray, MD, division director of Women’s Community and Population Health at Duke University Medical Center in Durham, N.C.
“It’s a huge win for patients who need better access to contraception,” said Dr. Gray, who is also a spokesperson for the American College of Obstetricians and Gynecologists.
Women who want hormonal birth control but live in areas without convenient access to a doctor, women who cannot easily take time off of work to see a doctor and get a prescription filled, and women without insurance are examples of people who will benefit, she said.
The Catholic Medical Association, in contrast, expressed “deep concern and disappointment” after an FDA advisory committee’s unanimous vote on May 11 recommending the drug be available over the counter. In a statement after the vote, the group cited “extensive medical studies demonstrating the risks and adverse effects of hormonal contraceptives,” adding that “the social impact of [full approval] would be dramatic.”
But doctors largely disagreed.
“It is definitely a huge win for reproductive autonomy. I’m glad that the FDA is prioritizing patient safety and well-being over politics,” said Catherine Cansino, MD, MPH, an ob.gyn. and clinical professor in the University of California Davis department of obstetrics and gynecology. She said the FDA approved the over-the-counter version because the medication is safe.
While opponents like the Catholic Medical Association cite safety concerns and believe doctors should screen all women before prescribing hormonal contraception, Dr. Gray disagreed. “There’s a lot of evidence that patients can figure out if a progestin-only pill is right for them and safe for them. Medical professionals don’t have to be the gatekeepers for contraception,” she said.
Pricing unknown
Whether insurance companies will pay for Opill now that it will be available without a prescription remains unknown. For some medications, paying a copay through insurance can be less expensive than buying at a retail price.
“Although pricing issues will be relevant, the FDA’s decision will enhance women’s access to hormonal birth control,” said Andrew M. Kaunitz, MD, a professor and associate chairman in the department of obstetrics and gynecology at the University of Florida College of Medicine in Jacksonville.
The drugmaker, Perrigo, based in Ireland, has not yet announced how much the pill will cost. The price tag could affect how widely available this form of birth control is. The drug has been shown to be as much as 93% effective for pregnancy prevention. Perrigo says it plans to make the pill available at low or no cost to some women.
Caveats to consider
There are some women for whom hormonal contraceptives have always carried greater risks. For example, women who have breast cancer or a history of breast cancer should not use hormonal contraceptives, the FDA said in a news release announcing the approval. Women with other types of cancer should check with their doctors first, the agency noted.
Women who smoke, who take some medications to lower blood pressure, or who have migraines should also take caution, Dr. Cansino said. “People with migraines may not be suitable for over-the-counter oral contraceptives. But a simple screening through a provider can identify whether you are truly eligible or not.”
Irregular bleeding, headaches, dizziness, nausea, increased appetite, belly pain, cramps, or bloating are the most common side effects of Opill, the FDA said.
The Opill is a progestin-only birth control pill. Similar pills have been available in the United Kingdiom for about 2 years, often referred to as “mini pills” because they contain a single hormone. In contrast, prescription birth control pills in the United States and elsewhere contain more than one hormone, estrogen and progestin, to prevent pregnancy.
Prescription pill packs for combination contraception often feature a week of placebo pills without an active ingredient. While skipping a placebo pill might not make a difference in pregnancy prevention, Opill is different. Every pill in the packet will contain medication, Gray said. “So it’s important to take the pill the same time every day for it to be most effective.”
Even though this may mean one less visit to your doctor, Dr. Kaunitz hopes women will stay up to date on their other medical checkups. “One of our challenges as providers of care to women will be to encourage them to continue to receive important services, including cancer screening and vaccinations, even while they can initiate and continue hormonal contraception without contact with a provider.”
Just the beginning?
The American Medical Association hopes this approval signals more to come.
“While we applaud this move, the AMA continues to urge the FDA and HHS to consider a variety of oral contraceptive options for over-the-counter use,” the association, which has more than 250,000 doctor members, said in a statement. “It is important patients have options when choosing which type of birth control works best for them,”
The American College of Obstetricians and Gynecologists said the FDA’s decision will help many women. “We are glad that more patients will now be empowered to choose when and where they obtain a safe method of contraception without having to wait for a medical appointment or for a prescription to be filled,” Verda J. Hicks, MD, the group’s president, and Christopher M. Zahn, MD, interim chief executive officer, said in a statement.
“Allowing individuals to access birth control at their local pharmacy or drug store will eliminate some barriers,” they said.
A version of this article first appeared on WebMD.com.
This article was updated 7/13/23.
The Food and Drug Administration’s approval today of the first birth control pill for women to be available without a prescription is being hailed by many as a long-needed development, but there remain questions to be resolved, including how much the drug will cost and how it will be used.
The drug, Opill, is expected to be available early next year, and its maker has yet to reveal a retail price. It is the same birth control pill that has been available by prescription for 50 years. But for the first time, women will be able to buy the contraception at a local pharmacy, other retail locations, or online without having to see a doctor first.
Likely to drive debate
Contraception in the United States is not without controversy. The FDA’s approval spurred reactions both for and against making hormonal birth control for women available without a prescription.
“It’s an exciting time, especially right now when reproductive rights are being curtailed in a lot of states. Giving people an additional option for contraception will change people’s lives,” said Beverly Gray, MD, division director of Women’s Community and Population Health at Duke University Medical Center in Durham, N.C.
“It’s a huge win for patients who need better access to contraception,” said Dr. Gray, who is also a spokesperson for the American College of Obstetricians and Gynecologists.
Women who want hormonal birth control but live in areas without convenient access to a doctor, women who cannot easily take time off of work to see a doctor and get a prescription filled, and women without insurance are examples of people who will benefit, she said.
The Catholic Medical Association, in contrast, expressed “deep concern and disappointment” after an FDA advisory committee’s unanimous vote on May 11 recommending the drug be available over the counter. In a statement after the vote, the group cited “extensive medical studies demonstrating the risks and adverse effects of hormonal contraceptives,” adding that “the social impact of [full approval] would be dramatic.”
But doctors largely disagreed.
“It is definitely a huge win for reproductive autonomy. I’m glad that the FDA is prioritizing patient safety and well-being over politics,” said Catherine Cansino, MD, MPH, an ob.gyn. and clinical professor in the University of California Davis department of obstetrics and gynecology. She said the FDA approved the over-the-counter version because the medication is safe.
While opponents like the Catholic Medical Association cite safety concerns and believe doctors should screen all women before prescribing hormonal contraception, Dr. Gray disagreed. “There’s a lot of evidence that patients can figure out if a progestin-only pill is right for them and safe for them. Medical professionals don’t have to be the gatekeepers for contraception,” she said.
Pricing unknown
Whether insurance companies will pay for Opill now that it will be available without a prescription remains unknown. For some medications, paying a copay through insurance can be less expensive than buying at a retail price.
“Although pricing issues will be relevant, the FDA’s decision will enhance women’s access to hormonal birth control,” said Andrew M. Kaunitz, MD, a professor and associate chairman in the department of obstetrics and gynecology at the University of Florida College of Medicine in Jacksonville.
The drugmaker, Perrigo, based in Ireland, has not yet announced how much the pill will cost. The price tag could affect how widely available this form of birth control is. The drug has been shown to be as much as 93% effective for pregnancy prevention. Perrigo says it plans to make the pill available at low or no cost to some women.
Caveats to consider
There are some women for whom hormonal contraceptives have always carried greater risks. For example, women who have breast cancer or a history of breast cancer should not use hormonal contraceptives, the FDA said in a news release announcing the approval. Women with other types of cancer should check with their doctors first, the agency noted.
Women who smoke, who take some medications to lower blood pressure, or who have migraines should also take caution, Dr. Cansino said. “People with migraines may not be suitable for over-the-counter oral contraceptives. But a simple screening through a provider can identify whether you are truly eligible or not.”
Irregular bleeding, headaches, dizziness, nausea, increased appetite, belly pain, cramps, or bloating are the most common side effects of Opill, the FDA said.
The Opill is a progestin-only birth control pill. Similar pills have been available in the United Kingdiom for about 2 years, often referred to as “mini pills” because they contain a single hormone. In contrast, prescription birth control pills in the United States and elsewhere contain more than one hormone, estrogen and progestin, to prevent pregnancy.
Prescription pill packs for combination contraception often feature a week of placebo pills without an active ingredient. While skipping a placebo pill might not make a difference in pregnancy prevention, Opill is different. Every pill in the packet will contain medication, Gray said. “So it’s important to take the pill the same time every day for it to be most effective.”
Even though this may mean one less visit to your doctor, Dr. Kaunitz hopes women will stay up to date on their other medical checkups. “One of our challenges as providers of care to women will be to encourage them to continue to receive important services, including cancer screening and vaccinations, even while they can initiate and continue hormonal contraception without contact with a provider.”
Just the beginning?
The American Medical Association hopes this approval signals more to come.
“While we applaud this move, the AMA continues to urge the FDA and HHS to consider a variety of oral contraceptive options for over-the-counter use,” the association, which has more than 250,000 doctor members, said in a statement. “It is important patients have options when choosing which type of birth control works best for them,”
The American College of Obstetricians and Gynecologists said the FDA’s decision will help many women. “We are glad that more patients will now be empowered to choose when and where they obtain a safe method of contraception without having to wait for a medical appointment or for a prescription to be filled,” Verda J. Hicks, MD, the group’s president, and Christopher M. Zahn, MD, interim chief executive officer, said in a statement.
“Allowing individuals to access birth control at their local pharmacy or drug store will eliminate some barriers,” they said.
A version of this article first appeared on WebMD.com.
This article was updated 7/13/23.
Treating obesity: Will new drugs end the crisis?
This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? – and can be found here. Part three shows how doctors and patients can make treatment better and can be found here.
In the mid-1980s, Louis J. Aronne, MD, strolled into a lab at Rockefeller University in New York where a colleague was breeding mice. “I will never forget what he showed me,” said Dr. Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
When Dr. Aronne returned 3 days later, that obese mouse had turned thin.
It was proof of something Dr. Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.
Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research.
Since then, Dr. Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment.
All the while, the U.S. obesity rate soared.
Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results.
“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Dr. Aronne said. “It took longer than I expected, but it’s gratifying now to see.”
The big question
The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs is on the way.
Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:
How do these weight loss drugs work?
“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. “It was by accident that this was discovered.”
Oops, we created a weight loss drug
Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work.
In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, ‘By the way, you need to be ready because there’s a bunch of glucose coming,’ ” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health.
One of these hormones – or “incretins” – is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down.
“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Dr. Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s.
Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight.
Both Ozempic and Wegovy – brand names for semaglutide – are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose.
“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Dr. Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s.
By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, made by Novo Nordisk) can lead to about 10% weight loss.
“And one of the ironies is, we don’t really know why,” Dr. Seeley said. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.”
Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Dr. Seeley said. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”
For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Dr. Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)
The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight.
More of these hybrid drugs are on the way, Dr. Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
Shifting from prevention to damage control
Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss.
“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania, Philadelphia, and chief scientific officer at WW (formerly Weight Watchers).
There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system.
Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.
And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.”
Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Dr. Lustig said.
Concerns about pancreatitis did not really bear out in postmarketing reports. (The drugs are still not recommended in people with pancreatitis or multiple endocrine neoplasia.) But predicting longer-term outcomes can be difficult, noted Dr. Lustig.
Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”
‘We can’t treat our way out of this’
The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these.
“We can’t treat our way out of this,” said Jamy Ard, MD, codirector of Wake Forest Baptist Health Weight Management Center in Winston-Salem, N.C. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.”
Dr. Seeley agreed but added that we can’t diet-and-exercise our way out either.
“There’s no switch to be flipped,” Dr. Seeley said. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?”
And prevention efforts won’t help the millions already living with health problems from obesity, Dr. Aronne said.
“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Dr. Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.”
Dr. Seeley pointed out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated.
“People say, ‘When you stop taking it, you’re going to gain the weight back,’ ” Dr. Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”
Like obesity, blood pressure was once thought to be a behavioral problem, Dr. Aronne said. But blood pressure meds prevent heart attacks and strokes. And it’s likely obesity meds will do the same.
One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Dr. Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Dr. Aronne said.
In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Dr. Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now.
In the end, the drugs are another step toward what Dr. Aronne and many others have always pushed for: Treating obesity as a disease.
A version of this article originally appeared on WebMD.com.
This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? – and can be found here. Part three shows how doctors and patients can make treatment better and can be found here.
In the mid-1980s, Louis J. Aronne, MD, strolled into a lab at Rockefeller University in New York where a colleague was breeding mice. “I will never forget what he showed me,” said Dr. Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
When Dr. Aronne returned 3 days later, that obese mouse had turned thin.
It was proof of something Dr. Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.
Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research.
Since then, Dr. Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment.
All the while, the U.S. obesity rate soared.
Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results.
“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Dr. Aronne said. “It took longer than I expected, but it’s gratifying now to see.”
The big question
The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs is on the way.
Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:
How do these weight loss drugs work?
“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. “It was by accident that this was discovered.”
Oops, we created a weight loss drug
Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work.
In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, ‘By the way, you need to be ready because there’s a bunch of glucose coming,’ ” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health.
One of these hormones – or “incretins” – is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down.
“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Dr. Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s.
Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight.
Both Ozempic and Wegovy – brand names for semaglutide – are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose.
“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Dr. Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s.
By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, made by Novo Nordisk) can lead to about 10% weight loss.
“And one of the ironies is, we don’t really know why,” Dr. Seeley said. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.”
Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Dr. Seeley said. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”
For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Dr. Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)
The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight.
More of these hybrid drugs are on the way, Dr. Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
Shifting from prevention to damage control
Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss.
“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania, Philadelphia, and chief scientific officer at WW (formerly Weight Watchers).
There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system.
Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.
And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.”
Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Dr. Lustig said.
Concerns about pancreatitis did not really bear out in postmarketing reports. (The drugs are still not recommended in people with pancreatitis or multiple endocrine neoplasia.) But predicting longer-term outcomes can be difficult, noted Dr. Lustig.
Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”
‘We can’t treat our way out of this’
The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these.
“We can’t treat our way out of this,” said Jamy Ard, MD, codirector of Wake Forest Baptist Health Weight Management Center in Winston-Salem, N.C. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.”
Dr. Seeley agreed but added that we can’t diet-and-exercise our way out either.
“There’s no switch to be flipped,” Dr. Seeley said. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?”
And prevention efforts won’t help the millions already living with health problems from obesity, Dr. Aronne said.
“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Dr. Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.”
Dr. Seeley pointed out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated.
“People say, ‘When you stop taking it, you’re going to gain the weight back,’ ” Dr. Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”
Like obesity, blood pressure was once thought to be a behavioral problem, Dr. Aronne said. But blood pressure meds prevent heart attacks and strokes. And it’s likely obesity meds will do the same.
One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Dr. Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Dr. Aronne said.
In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Dr. Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now.
In the end, the drugs are another step toward what Dr. Aronne and many others have always pushed for: Treating obesity as a disease.
A version of this article originally appeared on WebMD.com.
This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? – and can be found here. Part three shows how doctors and patients can make treatment better and can be found here.
In the mid-1980s, Louis J. Aronne, MD, strolled into a lab at Rockefeller University in New York where a colleague was breeding mice. “I will never forget what he showed me,” said Dr. Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
When Dr. Aronne returned 3 days later, that obese mouse had turned thin.
It was proof of something Dr. Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.
Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research.
Since then, Dr. Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment.
All the while, the U.S. obesity rate soared.
Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results.
“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Dr. Aronne said. “It took longer than I expected, but it’s gratifying now to see.”
The big question
The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs is on the way.
Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:
How do these weight loss drugs work?
“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. “It was by accident that this was discovered.”
Oops, we created a weight loss drug
Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work.
In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, ‘By the way, you need to be ready because there’s a bunch of glucose coming,’ ” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health.
One of these hormones – or “incretins” – is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down.
“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Dr. Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s.
Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight.
Both Ozempic and Wegovy – brand names for semaglutide – are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose.
“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Dr. Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s.
By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, made by Novo Nordisk) can lead to about 10% weight loss.
“And one of the ironies is, we don’t really know why,” Dr. Seeley said. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.”
Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Dr. Seeley said. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”
For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Dr. Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)
The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight.
More of these hybrid drugs are on the way, Dr. Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
Shifting from prevention to damage control
Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss.
“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania, Philadelphia, and chief scientific officer at WW (formerly Weight Watchers).
There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system.
Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.
And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.”
Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Dr. Lustig said.
Concerns about pancreatitis did not really bear out in postmarketing reports. (The drugs are still not recommended in people with pancreatitis or multiple endocrine neoplasia.) But predicting longer-term outcomes can be difficult, noted Dr. Lustig.
Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”
‘We can’t treat our way out of this’
The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these.
“We can’t treat our way out of this,” said Jamy Ard, MD, codirector of Wake Forest Baptist Health Weight Management Center in Winston-Salem, N.C. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.”
Dr. Seeley agreed but added that we can’t diet-and-exercise our way out either.
“There’s no switch to be flipped,” Dr. Seeley said. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?”
And prevention efforts won’t help the millions already living with health problems from obesity, Dr. Aronne said.
“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Dr. Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.”
Dr. Seeley pointed out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated.
“People say, ‘When you stop taking it, you’re going to gain the weight back,’ ” Dr. Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”
Like obesity, blood pressure was once thought to be a behavioral problem, Dr. Aronne said. But blood pressure meds prevent heart attacks and strokes. And it’s likely obesity meds will do the same.
One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Dr. Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Dr. Aronne said.
In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Dr. Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now.
In the end, the drugs are another step toward what Dr. Aronne and many others have always pushed for: Treating obesity as a disease.
A version of this article originally appeared on WebMD.com.
Thirty-three percent of type 1 diabetes patients insulin free with stem cells
SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.
Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.
“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.
Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.
Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”
Two meet primary endpoint, three more on the right path
The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.
The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.
Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.
Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.
Safety: No major concerns thus far
Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.
Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”
However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”
Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”
In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.”
Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands.
The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.
A version of this article originally appeared on Medscape.com.
SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.
Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.
“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.
Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.
Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”
Two meet primary endpoint, three more on the right path
The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.
The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.
Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.
Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.
Safety: No major concerns thus far
Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.
Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”
However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”
Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”
In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.”
Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands.
The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.
A version of this article originally appeared on Medscape.com.
SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.
Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.
“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.
Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.
Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”
Two meet primary endpoint, three more on the right path
The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.
The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.
Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.
Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.
Safety: No major concerns thus far
Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.
Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”
However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”
Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”
In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.”
Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands.
The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.
A version of this article originally appeared on Medscape.com.
AT ADA 2023
‘Striking’ benefit of lipid lowering in primary prevention
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
AT ADA 2023
Does ‘skeletal age’ describe fracture impact on mortality?
Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.
The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.
Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.
In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.
They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.
The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.
For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.
The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.
The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.
However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”
Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.
Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).
While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.
Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.
A version of this article first appeared on Medscape.com.
Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.
The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.
Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.
In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.
They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.
The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.
For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.
The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.
The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.
However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”
Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.
Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).
While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.
Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.
A version of this article first appeared on Medscape.com.
Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.
The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.
Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.
In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.
They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.
The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.
For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.
The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.
The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.
However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”
Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.
Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).
While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.
Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.
A version of this article first appeared on Medscape.com.