Clinical Endocrinology News

The “twincretin” tirzepatide scored another pivotal-trial win in full, published results from the multicenter SURPASS-4 trial, which compared the investigational agent to insulin glargine for treatment of type 2 diabetes. The study comprised 1,995 randomized patients with inadequately controlled type 2 diabetes and high cardiovascular disease risk.

Positive results for tirzepatide from SURPASS-4, the fifth and final registration trial for the drug, as well as in the other four studies, tee up the agent for a planned approval submission to the Food and Drug Administration by the end of 2021.

SURPASS-4 differed from the four other pivotal trials not only in its comparator agent, but also by being the longest of the five and the only one that, by design, enrolled exclusively patients with either established cardiovascular disease or high risk for the disease.

The new results “provide initial support for glycemic control [by tirzepatide] being sustained for more than 1 year,” wrote Stefano Del Prato, MD, and associates in their published report in The Lancet.

Despite the trial’s primary endpoint of change in hemoglobin A1c after 52 weeks on treatment, the study continued for another year and had a median time on treatment of 85 weeks, with 7% of enrolled patients remaining on treatment for the maximum on-treatment follow-up of 104 weeks.

Potent glycemic control

The primary endpoint showed that treatment with tirzepatide produced an average incremental reduction in A1c of 0.99% among 328 patients treated with a 10 mg weekly subcutaneous dosage compared with the 1,000 patients who received insulin glargine (Basaglar, Lantus, Toujeo), and an average 1.14% incremental reduction in A1c among 338 patients on a 15-mg dosage once weekly, reported Dr. Del Prato, professor and chief of the section of diabetes at the University of Pisa (Italy).

This met the prespecified criteria for noninferiority of tirzepatide to insulin glargine for reduction of A1c, the study’s primary objective, and also met the study’s prespecified definition of superiority, both statistically significant results. The study also tested a weekly tirzepatide dosage of 5 mg that was significantly superior to insulin glargine for glycemic control.

“The magnitude of A1c reduction and the proportions of patients reaching glycemic targets appear to be larger than in similar studies in which GLP-1 [glucagon-like peptide–1] receptor agonists have been compared with glargine,” the investigators wrote in their report.

The A1c effect of tirzepatide seen across all five SURPASS trials “surpasses what we’ve seen with other [glycemia control] drugs, with the possible exception of insulin,” said Jan W. Eriksson, MD, PhD, professor of clinical diabetes and metabolism at Uppsala (Sweden) University.

MDedge News

Safety appears similar to GLP-1 receptor agonists

The safety profile of tirzepatide in SURPASS-4, as it was in all of the other four trials in the SURPASS series, was consistent with previously reported safety of agents in the GLP-1 receptor agonist class, said Dr. Del Prato. It was an expected finding as tirzepatide combines activity as a GLP-1 receptor agonist with activity as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist in a single molecule.

The most common adverse effects were gastrointestinal, including diarrhea, nausea, decreased appetite, and vomiting. Most of these effects were mild or moderate, and they occurred most often during dose escalation of tirzepatide in the first 24 weeks on treatment.

The GIP receptor agonist effect of tirzepatide may diminish the nausea experienced by patients as a result of the drug’s GLP-1 receptor agonist action, Dr. Eriksson, designated discussant for the SURPASS trials, said during a session Sept. 30 at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

Clinically significant or severe hypoglycemia occurred in 8% of all patients on tirzepatide, with no apparent dose relationship, about half the rate of the patients treated with insulin glargine. Notably, the hypoglycemia episodes among patients treated with tirzepatide clustered almost entirely in the subgroup of patients who also took a sulfonylurea agent during the study. (SURPASS-4 allowed enrolled patients to be on their background antidiabetes regimen throughout the study, and at baseline 95% were taking metformin, 54% were on a sulfonylurea, and about a quarter were on a sodium-glucose cotransporter-2 inhibitor.)

“I would advise not using tirzepatide with insulin or with a sulfonylurea,” Dr. Eriksson said. Aside from this risk for hypoglycemia when tirzepatide is used concurrently with certain other antidiabetes drugs, the SURPASS trials have shown “no other important safety signals,” Dr. Eriksson added.

Cardiovascular safety

All enrolled patients had either known coronary, cerebrovascular, or peripheral arterial disease or were at high risk for having one or more of these conditions because they were at least 50 years old with a history of either chronic kidney disease with depressed glomerular filtration or heart failure.

During complete follow-up, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina was numerically less in the patients who received tirzepatide, 5%, than in those on insulin glargine, 6%, a 26% relative risk reduction that did not achieve significance. The rate of total mortality was 3% in the tirzepatide group and 4% among those on glargine, a 30% relative risk reduction that was not significant.

The cardiovascular disease outcomes “suggest that tirzepatide is safe from a cardiovascular perspective,” Dr. Del Prato said when he presented the SURPASS-4 results during the virtual annual meeting of the EASD. However, a much larger cardiovascular outcomes trial of tirzepatide, SURPASS-CVOT, with more than 12,000 randomized patients and using a GLP-1 receptor agonist as the comparator, is now in progress, with a report on the findings expected in 2025.

Sara Freeman/MDedge News

Overall, results from all five SURPASS trials of tirzepatide have shown that the drug is “effective and safe in people with type 2 diabetes, providing stringent glycemic control and additional metabolic benefits including weight reduction and an improvement in other cardiometabolic markers,” said Melanie J. Davies, MD, professor of diabetes medicine at the University of Leicester, England.

Looking forward to when tirzepatide will be available for routine use, Dr. Eriksson positioned it near-term as part of a dual or triple regimen, especially for patients with type 2 diabetes who are obese or have uncontrolled hyperglycemia, renal impairment, high cardiovascular disease risk, or high risk for clinically significant or severe hypoglycemia. 
A role for tirzepatide as a first-line agent is currently “more speculative,” he added, with more data needed on cardiovascular outcomes, long-term safety, and cost effectiveness.

The existing evidence base for tirzepatide shows “very promising efficacy” for weight loss and glucose lowering with “reassuring safety and tolerability,” and is a “very important addition to current options,” although the long-term safety of chronic tirzepatide treatment remains unproven, he said.

Dr. Eriksson called the drug’s glycemic control “strong and durable” based on the entire SURPASS program, with a “major” weight loss effect. He also suggested that while the adverse effect profile of tirzepatide appears similar to the GLP-1 receptor agonists, the incidence of gastrointestinal adverse events may be lower with tirzepatide.

SURPASS-4 and the other SURPASS trials were funded by Lilly, the company developing tirzepatide. Dr. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Dr. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.

mzoler@mdedge.com

The “twincretin” tirzepatide scored another pivotal-trial win in full, published results from the multicenter SURPASS-4 trial, which compared the investigational agent to insulin glargine for treatment of type 2 diabetes. The study comprised 1,995 randomized patients with inadequately controlled type 2 diabetes and high cardiovascular disease risk.

Positive results for tirzepatide from SURPASS-4, the fifth and final registration trial for the drug, as well as in the other four studies, tee up the agent for a planned approval submission to the Food and Drug Administration by the end of 2021.

SURPASS-4 differed from the four other pivotal trials not only in its comparator agent, but also by being the longest of the five and the only one that, by design, enrolled exclusively patients with either established cardiovascular disease or high risk for the disease.

The new results “provide initial support for glycemic control [by tirzepatide] being sustained for more than 1 year,” wrote Stefano Del Prato, MD, and associates in their published report in The Lancet.

Despite the trial’s primary endpoint of change in hemoglobin A1c after 52 weeks on treatment, the study continued for another year and had a median time on treatment of 85 weeks, with 7% of enrolled patients remaining on treatment for the maximum on-treatment follow-up of 104 weeks.

Potent glycemic control

The primary endpoint showed that treatment with tirzepatide produced an average incremental reduction in A1c of 0.99% among 328 patients treated with a 10 mg weekly subcutaneous dosage compared with the 1,000 patients who received insulin glargine (Basaglar, Lantus, Toujeo), and an average 1.14% incremental reduction in A1c among 338 patients on a 15-mg dosage once weekly, reported Dr. Del Prato, professor and chief of the section of diabetes at the University of Pisa (Italy).

This met the prespecified criteria for noninferiority of tirzepatide to insulin glargine for reduction of A1c, the study’s primary objective, and also met the study’s prespecified definition of superiority, both statistically significant results. The study also tested a weekly tirzepatide dosage of 5 mg that was significantly superior to insulin glargine for glycemic control.

“The magnitude of A1c reduction and the proportions of patients reaching glycemic targets appear to be larger than in similar studies in which GLP-1 [glucagon-like peptide–1] receptor agonists have been compared with glargine,” the investigators wrote in their report.

The A1c effect of tirzepatide seen across all five SURPASS trials “surpasses what we’ve seen with other [glycemia control] drugs, with the possible exception of insulin,” said Jan W. Eriksson, MD, PhD, professor of clinical diabetes and metabolism at Uppsala (Sweden) University.

MDedge News

Safety appears similar to GLP-1 receptor agonists

The safety profile of tirzepatide in SURPASS-4, as it was in all of the other four trials in the SURPASS series, was consistent with previously reported safety of agents in the GLP-1 receptor agonist class, said Dr. Del Prato. It was an expected finding as tirzepatide combines activity as a GLP-1 receptor agonist with activity as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist in a single molecule.

The most common adverse effects were gastrointestinal, including diarrhea, nausea, decreased appetite, and vomiting. Most of these effects were mild or moderate, and they occurred most often during dose escalation of tirzepatide in the first 24 weeks on treatment.

The GIP receptor agonist effect of tirzepatide may diminish the nausea experienced by patients as a result of the drug’s GLP-1 receptor agonist action, Dr. Eriksson, designated discussant for the SURPASS trials, said during a session Sept. 30 at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

Clinically significant or severe hypoglycemia occurred in 8% of all patients on tirzepatide, with no apparent dose relationship, about half the rate of the patients treated with insulin glargine. Notably, the hypoglycemia episodes among patients treated with tirzepatide clustered almost entirely in the subgroup of patients who also took a sulfonylurea agent during the study. (SURPASS-4 allowed enrolled patients to be on their background antidiabetes regimen throughout the study, and at baseline 95% were taking metformin, 54% were on a sulfonylurea, and about a quarter were on a sodium-glucose cotransporter-2 inhibitor.)

“I would advise not using tirzepatide with insulin or with a sulfonylurea,” Dr. Eriksson said. Aside from this risk for hypoglycemia when tirzepatide is used concurrently with certain other antidiabetes drugs, the SURPASS trials have shown “no other important safety signals,” Dr. Eriksson added.

Cardiovascular safety

All enrolled patients had either known coronary, cerebrovascular, or peripheral arterial disease or were at high risk for having one or more of these conditions because they were at least 50 years old with a history of either chronic kidney disease with depressed glomerular filtration or heart failure.

During complete follow-up, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina was numerically less in the patients who received tirzepatide, 5%, than in those on insulin glargine, 6%, a 26% relative risk reduction that did not achieve significance. The rate of total mortality was 3% in the tirzepatide group and 4% among those on glargine, a 30% relative risk reduction that was not significant.

The cardiovascular disease outcomes “suggest that tirzepatide is safe from a cardiovascular perspective,” Dr. Del Prato said when he presented the SURPASS-4 results during the virtual annual meeting of the EASD. However, a much larger cardiovascular outcomes trial of tirzepatide, SURPASS-CVOT, with more than 12,000 randomized patients and using a GLP-1 receptor agonist as the comparator, is now in progress, with a report on the findings expected in 2025.

Sara Freeman/MDedge News

Overall, results from all five SURPASS trials of tirzepatide have shown that the drug is “effective and safe in people with type 2 diabetes, providing stringent glycemic control and additional metabolic benefits including weight reduction and an improvement in other cardiometabolic markers,” said Melanie J. Davies, MD, professor of diabetes medicine at the University of Leicester, England.

Looking forward to when tirzepatide will be available for routine use, Dr. Eriksson positioned it near-term as part of a dual or triple regimen, especially for patients with type 2 diabetes who are obese or have uncontrolled hyperglycemia, renal impairment, high cardiovascular disease risk, or high risk for clinically significant or severe hypoglycemia. 
A role for tirzepatide as a first-line agent is currently “more speculative,” he added, with more data needed on cardiovascular outcomes, long-term safety, and cost effectiveness.

The existing evidence base for tirzepatide shows “very promising efficacy” for weight loss and glucose lowering with “reassuring safety and tolerability,” and is a “very important addition to current options,” although the long-term safety of chronic tirzepatide treatment remains unproven, he said.

Dr. Eriksson called the drug’s glycemic control “strong and durable” based on the entire SURPASS program, with a “major” weight loss effect. He also suggested that while the adverse effect profile of tirzepatide appears similar to the GLP-1 receptor agonists, the incidence of gastrointestinal adverse events may be lower with tirzepatide.

SURPASS-4 and the other SURPASS trials were funded by Lilly, the company developing tirzepatide. Dr. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Dr. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.

mzoler@mdedge.com

The “twincretin” tirzepatide scored another pivotal-trial win in full, published results from the multicenter SURPASS-4 trial, which compared the investigational agent to insulin glargine for treatment of type 2 diabetes. The study comprised 1,995 randomized patients with inadequately controlled type 2 diabetes and high cardiovascular disease risk.

Positive results for tirzepatide from SURPASS-4, the fifth and final registration trial for the drug, as well as in the other four studies, tee up the agent for a planned approval submission to the Food and Drug Administration by the end of 2021.

SURPASS-4 differed from the four other pivotal trials not only in its comparator agent, but also by being the longest of the five and the only one that, by design, enrolled exclusively patients with either established cardiovascular disease or high risk for the disease.

The new results “provide initial support for glycemic control [by tirzepatide] being sustained for more than 1 year,” wrote Stefano Del Prato, MD, and associates in their published report in The Lancet.

Despite the trial’s primary endpoint of change in hemoglobin A1c after 52 weeks on treatment, the study continued for another year and had a median time on treatment of 85 weeks, with 7% of enrolled patients remaining on treatment for the maximum on-treatment follow-up of 104 weeks.

Potent glycemic control

The primary endpoint showed that treatment with tirzepatide produced an average incremental reduction in A1c of 0.99% among 328 patients treated with a 10 mg weekly subcutaneous dosage compared with the 1,000 patients who received insulin glargine (Basaglar, Lantus, Toujeo), and an average 1.14% incremental reduction in A1c among 338 patients on a 15-mg dosage once weekly, reported Dr. Del Prato, professor and chief of the section of diabetes at the University of Pisa (Italy).

This met the prespecified criteria for noninferiority of tirzepatide to insulin glargine for reduction of A1c, the study’s primary objective, and also met the study’s prespecified definition of superiority, both statistically significant results. The study also tested a weekly tirzepatide dosage of 5 mg that was significantly superior to insulin glargine for glycemic control.

“The magnitude of A1c reduction and the proportions of patients reaching glycemic targets appear to be larger than in similar studies in which GLP-1 [glucagon-like peptide–1] receptor agonists have been compared with glargine,” the investigators wrote in their report.

The A1c effect of tirzepatide seen across all five SURPASS trials “surpasses what we’ve seen with other [glycemia control] drugs, with the possible exception of insulin,” said Jan W. Eriksson, MD, PhD, professor of clinical diabetes and metabolism at Uppsala (Sweden) University.

MDedge News

Safety appears similar to GLP-1 receptor agonists

The safety profile of tirzepatide in SURPASS-4, as it was in all of the other four trials in the SURPASS series, was consistent with previously reported safety of agents in the GLP-1 receptor agonist class, said Dr. Del Prato. It was an expected finding as tirzepatide combines activity as a GLP-1 receptor agonist with activity as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist in a single molecule.

The most common adverse effects were gastrointestinal, including diarrhea, nausea, decreased appetite, and vomiting. Most of these effects were mild or moderate, and they occurred most often during dose escalation of tirzepatide in the first 24 weeks on treatment.

The GIP receptor agonist effect of tirzepatide may diminish the nausea experienced by patients as a result of the drug’s GLP-1 receptor agonist action, Dr. Eriksson, designated discussant for the SURPASS trials, said during a session Sept. 30 at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

Clinically significant or severe hypoglycemia occurred in 8% of all patients on tirzepatide, with no apparent dose relationship, about half the rate of the patients treated with insulin glargine. Notably, the hypoglycemia episodes among patients treated with tirzepatide clustered almost entirely in the subgroup of patients who also took a sulfonylurea agent during the study. (SURPASS-4 allowed enrolled patients to be on their background antidiabetes regimen throughout the study, and at baseline 95% were taking metformin, 54% were on a sulfonylurea, and about a quarter were on a sodium-glucose cotransporter-2 inhibitor.)

“I would advise not using tirzepatide with insulin or with a sulfonylurea,” Dr. Eriksson said. Aside from this risk for hypoglycemia when tirzepatide is used concurrently with certain other antidiabetes drugs, the SURPASS trials have shown “no other important safety signals,” Dr. Eriksson added.

Cardiovascular safety

All enrolled patients had either known coronary, cerebrovascular, or peripheral arterial disease or were at high risk for having one or more of these conditions because they were at least 50 years old with a history of either chronic kidney disease with depressed glomerular filtration or heart failure.

During complete follow-up, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina was numerically less in the patients who received tirzepatide, 5%, than in those on insulin glargine, 6%, a 26% relative risk reduction that did not achieve significance. The rate of total mortality was 3% in the tirzepatide group and 4% among those on glargine, a 30% relative risk reduction that was not significant.

The cardiovascular disease outcomes “suggest that tirzepatide is safe from a cardiovascular perspective,” Dr. Del Prato said when he presented the SURPASS-4 results during the virtual annual meeting of the EASD. However, a much larger cardiovascular outcomes trial of tirzepatide, SURPASS-CVOT, with more than 12,000 randomized patients and using a GLP-1 receptor agonist as the comparator, is now in progress, with a report on the findings expected in 2025.

Sara Freeman/MDedge News

Overall, results from all five SURPASS trials of tirzepatide have shown that the drug is “effective and safe in people with type 2 diabetes, providing stringent glycemic control and additional metabolic benefits including weight reduction and an improvement in other cardiometabolic markers,” said Melanie J. Davies, MD, professor of diabetes medicine at the University of Leicester, England.

Looking forward to when tirzepatide will be available for routine use, Dr. Eriksson positioned it near-term as part of a dual or triple regimen, especially for patients with type 2 diabetes who are obese or have uncontrolled hyperglycemia, renal impairment, high cardiovascular disease risk, or high risk for clinically significant or severe hypoglycemia. 
A role for tirzepatide as a first-line agent is currently “more speculative,” he added, with more data needed on cardiovascular outcomes, long-term safety, and cost effectiveness.

The existing evidence base for tirzepatide shows “very promising efficacy” for weight loss and glucose lowering with “reassuring safety and tolerability,” and is a “very important addition to current options,” although the long-term safety of chronic tirzepatide treatment remains unproven, he said.

Dr. Eriksson called the drug’s glycemic control “strong and durable” based on the entire SURPASS program, with a “major” weight loss effect. He also suggested that while the adverse effect profile of tirzepatide appears similar to the GLP-1 receptor agonists, the incidence of gastrointestinal adverse events may be lower with tirzepatide.

SURPASS-4 and the other SURPASS trials were funded by Lilly, the company developing tirzepatide. Dr. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Dr. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.

mzoler@mdedge.com

Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.

But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.

“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,

The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
 

‘Cost must be considered’

“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”

“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.

“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.

The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.

“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.

“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
 

Banking on biomarkers

Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.

More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.

The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.

“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”

It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.

A Texas two-step process

“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.

“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.

Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.

Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m², while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.

In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.

Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.

“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.

The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
 

Asymptomatic diabetic cardiomyopathy

Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.

A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”

“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.

Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”

“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”

The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”

“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
 

Clinicians don’t like risk scores

Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?

“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.

“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”

Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.

“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.

Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.

mzoler@mdedge.com

Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.

But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.

“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,

The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
 

‘Cost must be considered’

“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”

“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.

“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.

The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.

“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.

“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
 

Banking on biomarkers

Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.

More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.

The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.

“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”

It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.

A Texas two-step process

“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.

“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.

Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.

Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m², while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.

In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.

Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.

“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.

The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
 

Asymptomatic diabetic cardiomyopathy

Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.

A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”

“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.

Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”

“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”

The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”

“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
 

Clinicians don’t like risk scores

Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?

“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.

“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”

Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.

“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.

Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.

mzoler@mdedge.com

Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.

But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.

“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,

The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
 

‘Cost must be considered’

“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”

“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.

“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.

The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.

“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.

“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
 

Banking on biomarkers

Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.

More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.

The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.

“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”

It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.

A Texas two-step process

“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.

“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.

Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.

Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m², while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.

In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.

Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.

“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.

The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
 

Asymptomatic diabetic cardiomyopathy

Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.

A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”

“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.

Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”

“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”

The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”

“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
 

Clinicians don’t like risk scores

Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?

“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.

“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”

Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.

“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.

Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.

mzoler@mdedge.com

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

A version of this article first appeared on WebMD.com.

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

A version of this article first appeared on WebMD.com.

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

A version of this article first appeared on WebMD.com.

While type 2 diabetes is associated with a greater risk for cardiovascular events than type 1 diabetes, the latter is more associated with chronic kidney complications, according to data from a French observational study.

That’s not to say that type 1 diabetes isn’t also associated with poor heart health that is of concern, according to Denis Angoulvant, MD, of Tours (France) Regional University Hospital and Trousseau Hospital in Paris.

“The difference is that, in the middle or older ages, we suddenly see a surge of cardiovascular events in type 1 diabetic patients,” he said at the annual meeting of the European Association for the Study of Diabetes. “As a cardiologist, I must say that we are barely see these patients ahead of those complications, so we advocate that there’s a gap to be filled here to prevent these events in these patients.”

Few studies have looked at the comparative risks for cardiovascular and renal outcomes between patients with type 1 and type 2 diabetes, Dr. Angoulvant said, so the aim of the study he presented was to look at this in more detail.
 

Comparing cardiovascular and renal outcomes

Data from the French hospital discharge database (PMSI), which covers more than 98% of the country’s population, were used to find all adults with type 1 or type 2 diabetes who had at least 5 years of follow-up data starting from 2013.

Not surprisingly, there were eight times as many individuals with type 2 diabetes (425,207) than those with type 1 diabetes (50,623), and patients with type 2 diabetes tended to be older than those with type 1 diabetes (mean age, 68.6 vs. 61.4 years).

There were many significant differences between the two groups of patients in terms of clinical variables, such as patients with type 2 diabetes having more cardiovascular risk factors or preexisting heart problems, and those with type 1 diabetes more likely to have diabetic eye disease.

Indeed, Dr. Angoulvant pointed out that those with type 2 diabetes were significantly more likely (all P < .0001) than those with type 1 diabetes to have: hypertension (70.8% vs. 50.5%), heart failure (35.7% vs. 16.4%), valvular heart disease (7.2% vs. 3.5%), dilated cardiomyopathy (5.5% vs. 2.7%), coronary artery disease (27.6 vs. 18.6%), previous MI (3.0% vs. 2.4%), peripheral vascular disease (22.0% vs. 15.5%), and ischemic stroke (3.3 vs. 2.2%).

“Regarding more specific microvascular diabetic complications, we had a higher incidence of chronic kidney disease in type 2 diabetes patients [10.2% vs. 9.1%], but a higher incidence of diabetic retinopathy in type 1 diabetes patients [6.6% vs. 12.2%],” Dr. Angoulvant said.

Considering more than 2 million person-years of follow-up, the annual rates of MI, new-onset heart failure, ischemic stroke, and chronic kidney disease for the whole study population were respective 1.4%, 5.4%, 1.2%, and 3.4%. The annual rates for death from any cause was 9.7%, and for a cardiovascular reason was 2.4%.
 

Cardiovascular disease prevalence and event rates

The mean follow-up period was 4.3 years, and over this time the age- and sex-adjusted prevalence of cardiovascular disease was found to be highest in individuals with type 2 diabetes, especially after the age of 40 years.

Looking at the rates of different cardiovascular events showed that both younger (18-29 years) and older (60+ years) people with type 1 diabetes had a 1.2-fold higher risk for MI than similarly aged individuals with type 2 diabetes.

Furthermore, younger and older type 1 diabetes individuals had a 1.1- to 1.4-fold greater risk of new-onset heart failure than those with type 2 diabetes.

“Interestingly, regarding the incidence of ischemic stroke in our population, we found no significant difference between patients with type 1 diabetes, and patients with type 2 diabetes,” Dr. Angoulvant said.
 

Chronic kidney disease and risk for death

Chronic kidney disease was most common in individuals with type 1 diabetes who were aged between 18 and 69 years, with a greater prevalence also seen in those with type 2 diabetes only after age 80.

The risk of new chronic kidney disease was significantly increased in patients with type 1 diabetes, compared with patients with type 2 diabetes, with a 1.1- to 2.4-fold increase seen, first in individuals aged 18-49 years, and then again after the age of 60 years.

Dr. Angoulvant reported that the risk of dying from any cause was 1.1-fold higher in people with type 1 diabetes, compared with those with type 2 diabetes, but after the age of 60 years.

The risk of death from cardiovascular events was also increased in people with type 1 diabetes, but between the ages of 60 and 69 years.

Asked what his take-home message might be, Dr. Angoulvant stressed the importance of heart failure, in all patients with diabetes but particularly in those with type 1 diabetes.

“I think there is room for improvement in terms of assessing who is going to have heart failure, how to assess heart failure, and more importantly, how to prevent heart failure,” perhaps by “introducing those drugs that have shown tremendous benefit regarding hospitalization, such as [sodium-glucose transporter 2] inhibitors” in patients with type 1 diabetes ahead of the events, he said.

Dr. Angoulvant had no conflicts of interest to disclose.

While type 2 diabetes is associated with a greater risk for cardiovascular events than type 1 diabetes, the latter is more associated with chronic kidney complications, according to data from a French observational study.

That’s not to say that type 1 diabetes isn’t also associated with poor heart health that is of concern, according to Denis Angoulvant, MD, of Tours (France) Regional University Hospital and Trousseau Hospital in Paris.

“The difference is that, in the middle or older ages, we suddenly see a surge of cardiovascular events in type 1 diabetic patients,” he said at the annual meeting of the European Association for the Study of Diabetes. “As a cardiologist, I must say that we are barely see these patients ahead of those complications, so we advocate that there’s a gap to be filled here to prevent these events in these patients.”

Few studies have looked at the comparative risks for cardiovascular and renal outcomes between patients with type 1 and type 2 diabetes, Dr. Angoulvant said, so the aim of the study he presented was to look at this in more detail.
 

Comparing cardiovascular and renal outcomes

Data from the French hospital discharge database (PMSI), which covers more than 98% of the country’s population, were used to find all adults with type 1 or type 2 diabetes who had at least 5 years of follow-up data starting from 2013.

Not surprisingly, there were eight times as many individuals with type 2 diabetes (425,207) than those with type 1 diabetes (50,623), and patients with type 2 diabetes tended to be older than those with type 1 diabetes (mean age, 68.6 vs. 61.4 years).

There were many significant differences between the two groups of patients in terms of clinical variables, such as patients with type 2 diabetes having more cardiovascular risk factors or preexisting heart problems, and those with type 1 diabetes more likely to have diabetic eye disease.

Indeed, Dr. Angoulvant pointed out that those with type 2 diabetes were significantly more likely (all P < .0001) than those with type 1 diabetes to have: hypertension (70.8% vs. 50.5%), heart failure (35.7% vs. 16.4%), valvular heart disease (7.2% vs. 3.5%), dilated cardiomyopathy (5.5% vs. 2.7%), coronary artery disease (27.6 vs. 18.6%), previous MI (3.0% vs. 2.4%), peripheral vascular disease (22.0% vs. 15.5%), and ischemic stroke (3.3 vs. 2.2%).

“Regarding more specific microvascular diabetic complications, we had a higher incidence of chronic kidney disease in type 2 diabetes patients [10.2% vs. 9.1%], but a higher incidence of diabetic retinopathy in type 1 diabetes patients [6.6% vs. 12.2%],” Dr. Angoulvant said.

Considering more than 2 million person-years of follow-up, the annual rates of MI, new-onset heart failure, ischemic stroke, and chronic kidney disease for the whole study population were respective 1.4%, 5.4%, 1.2%, and 3.4%. The annual rates for death from any cause was 9.7%, and for a cardiovascular reason was 2.4%.
 

Cardiovascular disease prevalence and event rates

The mean follow-up period was 4.3 years, and over this time the age- and sex-adjusted prevalence of cardiovascular disease was found to be highest in individuals with type 2 diabetes, especially after the age of 40 years.

Looking at the rates of different cardiovascular events showed that both younger (18-29 years) and older (60+ years) people with type 1 diabetes had a 1.2-fold higher risk for MI than similarly aged individuals with type 2 diabetes.

Furthermore, younger and older type 1 diabetes individuals had a 1.1- to 1.4-fold greater risk of new-onset heart failure than those with type 2 diabetes.

“Interestingly, regarding the incidence of ischemic stroke in our population, we found no significant difference between patients with type 1 diabetes, and patients with type 2 diabetes,” Dr. Angoulvant said.
 

Chronic kidney disease and risk for death

Chronic kidney disease was most common in individuals with type 1 diabetes who were aged between 18 and 69 years, with a greater prevalence also seen in those with type 2 diabetes only after age 80.

The risk of new chronic kidney disease was significantly increased in patients with type 1 diabetes, compared with patients with type 2 diabetes, with a 1.1- to 2.4-fold increase seen, first in individuals aged 18-49 years, and then again after the age of 60 years.

Dr. Angoulvant reported that the risk of dying from any cause was 1.1-fold higher in people with type 1 diabetes, compared with those with type 2 diabetes, but after the age of 60 years.

The risk of death from cardiovascular events was also increased in people with type 1 diabetes, but between the ages of 60 and 69 years.

Asked what his take-home message might be, Dr. Angoulvant stressed the importance of heart failure, in all patients with diabetes but particularly in those with type 1 diabetes.

“I think there is room for improvement in terms of assessing who is going to have heart failure, how to assess heart failure, and more importantly, how to prevent heart failure,” perhaps by “introducing those drugs that have shown tremendous benefit regarding hospitalization, such as [sodium-glucose transporter 2] inhibitors” in patients with type 1 diabetes ahead of the events, he said.

Dr. Angoulvant had no conflicts of interest to disclose.

While type 2 diabetes is associated with a greater risk for cardiovascular events than type 1 diabetes, the latter is more associated with chronic kidney complications, according to data from a French observational study.

That’s not to say that type 1 diabetes isn’t also associated with poor heart health that is of concern, according to Denis Angoulvant, MD, of Tours (France) Regional University Hospital and Trousseau Hospital in Paris.

“The difference is that, in the middle or older ages, we suddenly see a surge of cardiovascular events in type 1 diabetic patients,” he said at the annual meeting of the European Association for the Study of Diabetes. “As a cardiologist, I must say that we are barely see these patients ahead of those complications, so we advocate that there’s a gap to be filled here to prevent these events in these patients.”

Few studies have looked at the comparative risks for cardiovascular and renal outcomes between patients with type 1 and type 2 diabetes, Dr. Angoulvant said, so the aim of the study he presented was to look at this in more detail.
 

Comparing cardiovascular and renal outcomes

Data from the French hospital discharge database (PMSI), which covers more than 98% of the country’s population, were used to find all adults with type 1 or type 2 diabetes who had at least 5 years of follow-up data starting from 2013.

Not surprisingly, there were eight times as many individuals with type 2 diabetes (425,207) than those with type 1 diabetes (50,623), and patients with type 2 diabetes tended to be older than those with type 1 diabetes (mean age, 68.6 vs. 61.4 years).

There were many significant differences between the two groups of patients in terms of clinical variables, such as patients with type 2 diabetes having more cardiovascular risk factors or preexisting heart problems, and those with type 1 diabetes more likely to have diabetic eye disease.

Indeed, Dr. Angoulvant pointed out that those with type 2 diabetes were significantly more likely (all P < .0001) than those with type 1 diabetes to have: hypertension (70.8% vs. 50.5%), heart failure (35.7% vs. 16.4%), valvular heart disease (7.2% vs. 3.5%), dilated cardiomyopathy (5.5% vs. 2.7%), coronary artery disease (27.6 vs. 18.6%), previous MI (3.0% vs. 2.4%), peripheral vascular disease (22.0% vs. 15.5%), and ischemic stroke (3.3 vs. 2.2%).

“Regarding more specific microvascular diabetic complications, we had a higher incidence of chronic kidney disease in type 2 diabetes patients [10.2% vs. 9.1%], but a higher incidence of diabetic retinopathy in type 1 diabetes patients [6.6% vs. 12.2%],” Dr. Angoulvant said.

Considering more than 2 million person-years of follow-up, the annual rates of MI, new-onset heart failure, ischemic stroke, and chronic kidney disease for the whole study population were respective 1.4%, 5.4%, 1.2%, and 3.4%. The annual rates for death from any cause was 9.7%, and for a cardiovascular reason was 2.4%.
 

Cardiovascular disease prevalence and event rates

The mean follow-up period was 4.3 years, and over this time the age- and sex-adjusted prevalence of cardiovascular disease was found to be highest in individuals with type 2 diabetes, especially after the age of 40 years.

Looking at the rates of different cardiovascular events showed that both younger (18-29 years) and older (60+ years) people with type 1 diabetes had a 1.2-fold higher risk for MI than similarly aged individuals with type 2 diabetes.

Furthermore, younger and older type 1 diabetes individuals had a 1.1- to 1.4-fold greater risk of new-onset heart failure than those with type 2 diabetes.

“Interestingly, regarding the incidence of ischemic stroke in our population, we found no significant difference between patients with type 1 diabetes, and patients with type 2 diabetes,” Dr. Angoulvant said.
 

Chronic kidney disease and risk for death

Chronic kidney disease was most common in individuals with type 1 diabetes who were aged between 18 and 69 years, with a greater prevalence also seen in those with type 2 diabetes only after age 80.

The risk of new chronic kidney disease was significantly increased in patients with type 1 diabetes, compared with patients with type 2 diabetes, with a 1.1- to 2.4-fold increase seen, first in individuals aged 18-49 years, and then again after the age of 60 years.

Dr. Angoulvant reported that the risk of dying from any cause was 1.1-fold higher in people with type 1 diabetes, compared with those with type 2 diabetes, but after the age of 60 years.

The risk of death from cardiovascular events was also increased in people with type 1 diabetes, but between the ages of 60 and 69 years.

Asked what his take-home message might be, Dr. Angoulvant stressed the importance of heart failure, in all patients with diabetes but particularly in those with type 1 diabetes.

“I think there is room for improvement in terms of assessing who is going to have heart failure, how to assess heart failure, and more importantly, how to prevent heart failure,” perhaps by “introducing those drugs that have shown tremendous benefit regarding hospitalization, such as [sodium-glucose transporter 2] inhibitors” in patients with type 1 diabetes ahead of the events, he said.

Dr. Angoulvant had no conflicts of interest to disclose.

Gender-affirmation surgery refers to a collection of procedures by which a transgender individual physically alters characteristics to align with their gender identity. While not all patients who identify as transgender will choose to undergo surgery, the surgeries are considered medically necessary and lead to significant improvements in emotional and psychological well-being.¹ With increasing insurance coverage and improved access to care, more and more patients are seeking gender-affirming surgery, and it is incumbent for providers to familiarize themselves with preoperative recommendations and requirements.

Ob.gyns. play a key role in patients seeking surgical treatment as patients may inquire about available procedures and what steps are necessary prior to scheduling a visit with the appropriate surgeon. The World Professional Association of Transgender Health has established standards of care that provide multidisciplinary, evidence-based guidance for patients seeking a variety of gender-affirming services ranging from mental health, hormone therapy, and surgery.

Basic preoperative surgical prerequisites set forth by WPATH include being a patient with well-documented gender dysphoria, being the age of majority, and having the ability to provide informed consent.¹

As with any surgical candidate, it is also equally important for a patient to have well-controlled medical and psychiatric comorbidities, which should also include smoking cessation. A variety of surgical procedures are available to patients and include breast/chest surgery, genital (bottom) surgery, and nongenital surgery (facial feminization, pectoral implant placement, thyroid chondroplasty, lipofilling/liposuction, body contouring, and voice modification). Patients may choose to undergo chest/breast surgery and/or bottom surgery or forgo surgical procedures altogether.

For transmasculine patients, breast/chest surgery, otherwise known as top surgery, is the most common and desired procedure. According to a recent survey, approximately 97% of transmasculine patients had or wanted masculinizing chest surgery.² In addition to patients meeting the basic requirements set forth by WPATH, one referral from a mental health provider specializing in gender-affirming care is also needed prior to this procedure. It is also important to note that testosterone use is no longer a needed prior to masculinizing chest surgery.

Transmasculine bottom surgery, which includes hysterectomy, bilateral salpingo-oophorectomy, metoidioplasty, vaginectomy, scrotoplasty, testicular implant placement, and/or phalloplasty have additional nuances. Compared with transmasculine individuals seeking top surgery, the number of patients who have had or desire metoidioplasty and phalloplasty is much lower, which is mainly because of the high complication rates of these procedures. In the same survey, only 4% of patients had undergone a metoidioplasty procedure and 2% of patients had undergone a phalloplasty.²

In evaluating rates of hysterectomy with or without salpingo-oophorectomy, approximately 21% of transgender men underwent hysterectomy, with 58% desiring it in the future.² Unlike patients pursuing top surgery, patients who desire any form of bottom surgery need to be on 12 months of continuous hormone therapy.¹ They also must provide two letters from two different mental health providers, one of whom must have either an MD/DO or PhD. In cases in which a patient requests a hysterectomy for reasons other than gender dysphoria, such as pelvic pain or abnormal uterine bleeding, these criteria do not apply.

For transfeminine individuals, augmentation mammoplasty is performed following 12 months of continuous hormone therapy. This is to allow maximum breast growth, which occurs approximately 2-3 months after hormone initiation and peaks at 1-2 years.³ Rates of transfeminine individuals seeking augmentation mammoplasty is similar to that of their transmasculine counterparts at 74%.² One referral letter from a mental health provider is also needed prior to augmentation mammoplasty.

Transfeminine patients who desire bottom surgery, which can involve an orchiectomy or vaginoplasty (single-stage penile inversion, peritoneal, or colonic interposition), have the same additional requirements as transmasculine individuals seeking bottom surgery. Furthermore, it is interesting to note that 25% of transfeminine individuals had already undergone orchiectomy and 87% had either undergone or desired a vaginoplasty in the future.² This is in stark contrast to transmasculine patients and rates of bottom surgery.

Unless there is a specific medical contraindication to hormone therapy, emphasis is placed on 12 months of continuous hormone usage. Additional emphasis is placed on patients seeking bottom surgery to live for a minimum of 12 months in their congruent gender role. This also allows patients to further explore their gender identity and make appropriate preparations for surgery.

As with any surgical procedure, obtaining informed consent and reviewing patient expectations are key. In my clinical practice, I discuss with patients that the general surgical goals are to achieve both function and good aesthetic outcome but that their results are also tailored to their individual bodies. Assessing a patient’s support system and social factors is also equally important in the preoperative planning period. As this field continues to grow, it is essential for providers to understand the evolving distinctions in surgical care to improve access to patients.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no conflicts. Email her at obnews@mdedge.com.

References

1. The World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. https://www.wpath.org/publications/soc.

2. James SE et al. The report of the 2015 U.S. Transgender survey. Washington, D.C.: National Center for Transgender Equality. 2016.

3. Thomas TN. Overview of surgery for transgender patients, in “Comprehensive care for the transgender patient.” Philadelphia: Elsevier, 2020. pp. 48-53.

Gender-affirmation surgery refers to a collection of procedures by which a transgender individual physically alters characteristics to align with their gender identity. While not all patients who identify as transgender will choose to undergo surgery, the surgeries are considered medically necessary and lead to significant improvements in emotional and psychological well-being.¹ With increasing insurance coverage and improved access to care, more and more patients are seeking gender-affirming surgery, and it is incumbent for providers to familiarize themselves with preoperative recommendations and requirements.

Ob.gyns. play a key role in patients seeking surgical treatment as patients may inquire about available procedures and what steps are necessary prior to scheduling a visit with the appropriate surgeon. The World Professional Association of Transgender Health has established standards of care that provide multidisciplinary, evidence-based guidance for patients seeking a variety of gender-affirming services ranging from mental health, hormone therapy, and surgery.

Basic preoperative surgical prerequisites set forth by WPATH include being a patient with well-documented gender dysphoria, being the age of majority, and having the ability to provide informed consent.¹

As with any surgical candidate, it is also equally important for a patient to have well-controlled medical and psychiatric comorbidities, which should also include smoking cessation. A variety of surgical procedures are available to patients and include breast/chest surgery, genital (bottom) surgery, and nongenital surgery (facial feminization, pectoral implant placement, thyroid chondroplasty, lipofilling/liposuction, body contouring, and voice modification). Patients may choose to undergo chest/breast surgery and/or bottom surgery or forgo surgical procedures altogether.

For transmasculine patients, breast/chest surgery, otherwise known as top surgery, is the most common and desired procedure. According to a recent survey, approximately 97% of transmasculine patients had or wanted masculinizing chest surgery.² In addition to patients meeting the basic requirements set forth by WPATH, one referral from a mental health provider specializing in gender-affirming care is also needed prior to this procedure. It is also important to note that testosterone use is no longer a needed prior to masculinizing chest surgery.

Transmasculine bottom surgery, which includes hysterectomy, bilateral salpingo-oophorectomy, metoidioplasty, vaginectomy, scrotoplasty, testicular implant placement, and/or phalloplasty have additional nuances. Compared with transmasculine individuals seeking top surgery, the number of patients who have had or desire metoidioplasty and phalloplasty is much lower, which is mainly because of the high complication rates of these procedures. In the same survey, only 4% of patients had undergone a metoidioplasty procedure and 2% of patients had undergone a phalloplasty.²

In evaluating rates of hysterectomy with or without salpingo-oophorectomy, approximately 21% of transgender men underwent hysterectomy, with 58% desiring it in the future.² Unlike patients pursuing top surgery, patients who desire any form of bottom surgery need to be on 12 months of continuous hormone therapy.¹ They also must provide two letters from two different mental health providers, one of whom must have either an MD/DO or PhD. In cases in which a patient requests a hysterectomy for reasons other than gender dysphoria, such as pelvic pain or abnormal uterine bleeding, these criteria do not apply.

For transfeminine individuals, augmentation mammoplasty is performed following 12 months of continuous hormone therapy. This is to allow maximum breast growth, which occurs approximately 2-3 months after hormone initiation and peaks at 1-2 years.³ Rates of transfeminine individuals seeking augmentation mammoplasty is similar to that of their transmasculine counterparts at 74%.² One referral letter from a mental health provider is also needed prior to augmentation mammoplasty.

Transfeminine patients who desire bottom surgery, which can involve an orchiectomy or vaginoplasty (single-stage penile inversion, peritoneal, or colonic interposition), have the same additional requirements as transmasculine individuals seeking bottom surgery. Furthermore, it is interesting to note that 25% of transfeminine individuals had already undergone orchiectomy and 87% had either undergone or desired a vaginoplasty in the future.² This is in stark contrast to transmasculine patients and rates of bottom surgery.

Unless there is a specific medical contraindication to hormone therapy, emphasis is placed on 12 months of continuous hormone usage. Additional emphasis is placed on patients seeking bottom surgery to live for a minimum of 12 months in their congruent gender role. This also allows patients to further explore their gender identity and make appropriate preparations for surgery.

As with any surgical procedure, obtaining informed consent and reviewing patient expectations are key. In my clinical practice, I discuss with patients that the general surgical goals are to achieve both function and good aesthetic outcome but that their results are also tailored to their individual bodies. Assessing a patient’s support system and social factors is also equally important in the preoperative planning period. As this field continues to grow, it is essential for providers to understand the evolving distinctions in surgical care to improve access to patients.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no conflicts. Email her at obnews@mdedge.com.

References

1. The World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. https://www.wpath.org/publications/soc.

2. James SE et al. The report of the 2015 U.S. Transgender survey. Washington, D.C.: National Center for Transgender Equality. 2016.

3. Thomas TN. Overview of surgery for transgender patients, in “Comprehensive care for the transgender patient.” Philadelphia: Elsevier, 2020. pp. 48-53.

Gender-affirmation surgery refers to a collection of procedures by which a transgender individual physically alters characteristics to align with their gender identity. While not all patients who identify as transgender will choose to undergo surgery, the surgeries are considered medically necessary and lead to significant improvements in emotional and psychological well-being.¹ With increasing insurance coverage and improved access to care, more and more patients are seeking gender-affirming surgery, and it is incumbent for providers to familiarize themselves with preoperative recommendations and requirements.

Ob.gyns. play a key role in patients seeking surgical treatment as patients may inquire about available procedures and what steps are necessary prior to scheduling a visit with the appropriate surgeon. The World Professional Association of Transgender Health has established standards of care that provide multidisciplinary, evidence-based guidance for patients seeking a variety of gender-affirming services ranging from mental health, hormone therapy, and surgery.

Basic preoperative surgical prerequisites set forth by WPATH include being a patient with well-documented gender dysphoria, being the age of majority, and having the ability to provide informed consent.¹

As with any surgical candidate, it is also equally important for a patient to have well-controlled medical and psychiatric comorbidities, which should also include smoking cessation. A variety of surgical procedures are available to patients and include breast/chest surgery, genital (bottom) surgery, and nongenital surgery (facial feminization, pectoral implant placement, thyroid chondroplasty, lipofilling/liposuction, body contouring, and voice modification). Patients may choose to undergo chest/breast surgery and/or bottom surgery or forgo surgical procedures altogether.

For transmasculine patients, breast/chest surgery, otherwise known as top surgery, is the most common and desired procedure. According to a recent survey, approximately 97% of transmasculine patients had or wanted masculinizing chest surgery.² In addition to patients meeting the basic requirements set forth by WPATH, one referral from a mental health provider specializing in gender-affirming care is also needed prior to this procedure. It is also important to note that testosterone use is no longer a needed prior to masculinizing chest surgery.

Transmasculine bottom surgery, which includes hysterectomy, bilateral salpingo-oophorectomy, metoidioplasty, vaginectomy, scrotoplasty, testicular implant placement, and/or phalloplasty have additional nuances. Compared with transmasculine individuals seeking top surgery, the number of patients who have had or desire metoidioplasty and phalloplasty is much lower, which is mainly because of the high complication rates of these procedures. In the same survey, only 4% of patients had undergone a metoidioplasty procedure and 2% of patients had undergone a phalloplasty.²

In evaluating rates of hysterectomy with or without salpingo-oophorectomy, approximately 21% of transgender men underwent hysterectomy, with 58% desiring it in the future.² Unlike patients pursuing top surgery, patients who desire any form of bottom surgery need to be on 12 months of continuous hormone therapy.¹ They also must provide two letters from two different mental health providers, one of whom must have either an MD/DO or PhD. In cases in which a patient requests a hysterectomy for reasons other than gender dysphoria, such as pelvic pain or abnormal uterine bleeding, these criteria do not apply.

For transfeminine individuals, augmentation mammoplasty is performed following 12 months of continuous hormone therapy. This is to allow maximum breast growth, which occurs approximately 2-3 months after hormone initiation and peaks at 1-2 years.³ Rates of transfeminine individuals seeking augmentation mammoplasty is similar to that of their transmasculine counterparts at 74%.² One referral letter from a mental health provider is also needed prior to augmentation mammoplasty.

Transfeminine patients who desire bottom surgery, which can involve an orchiectomy or vaginoplasty (single-stage penile inversion, peritoneal, or colonic interposition), have the same additional requirements as transmasculine individuals seeking bottom surgery. Furthermore, it is interesting to note that 25% of transfeminine individuals had already undergone orchiectomy and 87% had either undergone or desired a vaginoplasty in the future.² This is in stark contrast to transmasculine patients and rates of bottom surgery.

Unless there is a specific medical contraindication to hormone therapy, emphasis is placed on 12 months of continuous hormone usage. Additional emphasis is placed on patients seeking bottom surgery to live for a minimum of 12 months in their congruent gender role. This also allows patients to further explore their gender identity and make appropriate preparations for surgery.

As with any surgical procedure, obtaining informed consent and reviewing patient expectations are key. In my clinical practice, I discuss with patients that the general surgical goals are to achieve both function and good aesthetic outcome but that their results are also tailored to their individual bodies. Assessing a patient’s support system and social factors is also equally important in the preoperative planning period. As this field continues to grow, it is essential for providers to understand the evolving distinctions in surgical care to improve access to patients.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no conflicts. Email her at obnews@mdedge.com.

References

1. The World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. https://www.wpath.org/publications/soc.

2. James SE et al. The report of the 2015 U.S. Transgender survey. Washington, D.C.: National Center for Transgender Equality. 2016.

3. Thomas TN. Overview of surgery for transgender patients, in “Comprehensive care for the transgender patient.” Philadelphia: Elsevier, 2020. pp. 48-53.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

Low androgen levels appear to be linked to the development of posttransplantation diabetes mellitus (PTDM) in male kidney transplant recipients, new research suggests.

London_England/Thinkstock

Among 243 men who did not have diabetes prior to undergoing kidney transplantation, levels of both dihydrotestosterone (DHT) and testosterone were inversely related to the risk for developing diabetes the next 5 years.

“These results suggest that androgen insufficiency could play a role in the frequent deterioration of the glucose metabolism after kidney transplantation,” Suzanne P. Stam and colleagues wrote in Diabetes Care.

However, “our study has unfortunately no direct clinical findings as it was of an observational nature,” Ms. Stam told this news organization. “As a result, we can say that we have observed an association and have not established a causal relationship. So based on our study alone there is not a reason to start screening for low androgen values.”

Previous data have suggested that failure of pancreatic beta cell secretion of insulin plays a role in PTDM. In addition, DHT appears to act on the androgen receptor in pancreatic beta cells to enhance insulin secretion, while testosterone deficiency has been shown to play a role in the development of type 2 diabetes in aging males and in men receiving androgen-deprivation therapy. And, randomized clinical trials have found favorable metabolic effects of testosterone replacement therapy in hypogonadal men with type 2 diabetes.

The current post hoc analysis of a prospective single-center cohort study is the first longitudinal epidemiological investigation of the role of androgens in PTDM in kidney transplant recipients. The subjects, all men, had functioning grafts for at least a year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry.

At a median follow-up duration of 5.3 years, 28 (11.5%) of the men had developed PTDM. By DHT tertile, the proportions developing diabetes were 19% (15) for the lowest, 12% (10) for the middle, and 4% (3) for men with the highest DHT tertile (P = .008). A similar relationship was seen with tertiles of testosterone, with 17% (14), 14% (11), and 4% (3) developing diabetes in the lowest, middle, and highest tertiles, respectively (P = .01).

In unadjusted analysis, every doubling of DHT was linked to a 27% increased risk for PTDM (P < .001). The association remained significant after adjustments for age, estimated glomerular filtration rate, time between transplantation and baseline, body mass index, high sensitivity C-reactive protein, medication use, and baseline hemoglobin A1c (all P < .001). Similar results were found with total testosterone.

Ms. Stam, of the division of nephrology at the University Medical Center Groningen, the Netherlands, noted in an interview that, in the Netherlands, about 15% of those with kidney failure have preexisting diabetes, compared with about 50% in other western countries, including the United States.

She said that her team is currently working on a study to investigate the association between androgens and the development of PTDM in female kidney transplant recipients.

The study was funded by the TransplantLines Food and Nutrition Biobank and Cohort Study, Top Institute Food and Nutrition, and partly by the European Union’s Horizon 2020 research and innovation program. Ms. Stam and the other authors have no further disclosures.

Low androgen levels appear to be linked to the development of posttransplantation diabetes mellitus (PTDM) in male kidney transplant recipients, new research suggests.

London_England/Thinkstock

Among 243 men who did not have diabetes prior to undergoing kidney transplantation, levels of both dihydrotestosterone (DHT) and testosterone were inversely related to the risk for developing diabetes the next 5 years.

“These results suggest that androgen insufficiency could play a role in the frequent deterioration of the glucose metabolism after kidney transplantation,” Suzanne P. Stam and colleagues wrote in Diabetes Care.

However, “our study has unfortunately no direct clinical findings as it was of an observational nature,” Ms. Stam told this news organization. “As a result, we can say that we have observed an association and have not established a causal relationship. So based on our study alone there is not a reason to start screening for low androgen values.”

Previous data have suggested that failure of pancreatic beta cell secretion of insulin plays a role in PTDM. In addition, DHT appears to act on the androgen receptor in pancreatic beta cells to enhance insulin secretion, while testosterone deficiency has been shown to play a role in the development of type 2 diabetes in aging males and in men receiving androgen-deprivation therapy. And, randomized clinical trials have found favorable metabolic effects of testosterone replacement therapy in hypogonadal men with type 2 diabetes.

The current post hoc analysis of a prospective single-center cohort study is the first longitudinal epidemiological investigation of the role of androgens in PTDM in kidney transplant recipients. The subjects, all men, had functioning grafts for at least a year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry.

At a median follow-up duration of 5.3 years, 28 (11.5%) of the men had developed PTDM. By DHT tertile, the proportions developing diabetes were 19% (15) for the lowest, 12% (10) for the middle, and 4% (3) for men with the highest DHT tertile (P = .008). A similar relationship was seen with tertiles of testosterone, with 17% (14), 14% (11), and 4% (3) developing diabetes in the lowest, middle, and highest tertiles, respectively (P = .01).

In unadjusted analysis, every doubling of DHT was linked to a 27% increased risk for PTDM (P < .001). The association remained significant after adjustments for age, estimated glomerular filtration rate, time between transplantation and baseline, body mass index, high sensitivity C-reactive protein, medication use, and baseline hemoglobin A1c (all P < .001). Similar results were found with total testosterone.

Ms. Stam, of the division of nephrology at the University Medical Center Groningen, the Netherlands, noted in an interview that, in the Netherlands, about 15% of those with kidney failure have preexisting diabetes, compared with about 50% in other western countries, including the United States.

She said that her team is currently working on a study to investigate the association between androgens and the development of PTDM in female kidney transplant recipients.

The study was funded by the TransplantLines Food and Nutrition Biobank and Cohort Study, Top Institute Food and Nutrition, and partly by the European Union’s Horizon 2020 research and innovation program. Ms. Stam and the other authors have no further disclosures.

Low androgen levels appear to be linked to the development of posttransplantation diabetes mellitus (PTDM) in male kidney transplant recipients, new research suggests.

London_England/Thinkstock

Among 243 men who did not have diabetes prior to undergoing kidney transplantation, levels of both dihydrotestosterone (DHT) and testosterone were inversely related to the risk for developing diabetes the next 5 years.

“These results suggest that androgen insufficiency could play a role in the frequent deterioration of the glucose metabolism after kidney transplantation,” Suzanne P. Stam and colleagues wrote in Diabetes Care.

However, “our study has unfortunately no direct clinical findings as it was of an observational nature,” Ms. Stam told this news organization. “As a result, we can say that we have observed an association and have not established a causal relationship. So based on our study alone there is not a reason to start screening for low androgen values.”

Previous data have suggested that failure of pancreatic beta cell secretion of insulin plays a role in PTDM. In addition, DHT appears to act on the androgen receptor in pancreatic beta cells to enhance insulin secretion, while testosterone deficiency has been shown to play a role in the development of type 2 diabetes in aging males and in men receiving androgen-deprivation therapy. And, randomized clinical trials have found favorable metabolic effects of testosterone replacement therapy in hypogonadal men with type 2 diabetes.

The current post hoc analysis of a prospective single-center cohort study is the first longitudinal epidemiological investigation of the role of androgens in PTDM in kidney transplant recipients. The subjects, all men, had functioning grafts for at least a year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry.

At a median follow-up duration of 5.3 years, 28 (11.5%) of the men had developed PTDM. By DHT tertile, the proportions developing diabetes were 19% (15) for the lowest, 12% (10) for the middle, and 4% (3) for men with the highest DHT tertile (P = .008). A similar relationship was seen with tertiles of testosterone, with 17% (14), 14% (11), and 4% (3) developing diabetes in the lowest, middle, and highest tertiles, respectively (P = .01).

In unadjusted analysis, every doubling of DHT was linked to a 27% increased risk for PTDM (P < .001). The association remained significant after adjustments for age, estimated glomerular filtration rate, time between transplantation and baseline, body mass index, high sensitivity C-reactive protein, medication use, and baseline hemoglobin A1c (all P < .001). Similar results were found with total testosterone.

Ms. Stam, of the division of nephrology at the University Medical Center Groningen, the Netherlands, noted in an interview that, in the Netherlands, about 15% of those with kidney failure have preexisting diabetes, compared with about 50% in other western countries, including the United States.

She said that her team is currently working on a study to investigate the association between androgens and the development of PTDM in female kidney transplant recipients.

The study was funded by the TransplantLines Food and Nutrition Biobank and Cohort Study, Top Institute Food and Nutrition, and partly by the European Union’s Horizon 2020 research and innovation program. Ms. Stam and the other authors have no further disclosures.

Obesity interventions would be more effective at preventing premature mortality if they focused less on weight loss and more on increased physical activity and improved cardiorespiratory fitness, a pair of researchers concluded in a recent review.

The authors promote a “weight-neutral approach to treating obesity-related health conditions,” which they say is “as or more effective than a weight-loss centric approach.”

One expert agrees. “The obsession with the bathroom scale as the primary determinant of treatment efficacy when managing obesity is just not right,” Robert Ross, PhD, said in an interview.

“It masks the tremendous health benefits of improved fitness regardless of obesity. If you increase fitness, you improve outcomes even when people don’t lose weight,” noted Dr. Ross, a researcher in the School of Kinesiology and Health Studies at Queen’s University in Kingston, Ontario, Canada.

However, this proposition reprises a long-standing gulf between two schools of thought on obesity intervention.

One indication of the divided sentiment came in another expert review, published just days later, that strongly calls for weight loss of at least 15% of starting body weight as the primary intervention goal for most patients with obesity and type 2 diabetes. (According to 2020 statistics from the U.S. Centers for Disease Control and Prevention, more than 60% of U.S. adults with diabetes are obese.)

However, some question whether it must be all one, or the other, when obesity management could instead combine these approaches and simultaneously promote weight loss, increased activity, and improved fitness.

“It only muddies the water to dichotomize this as either weight management or activity and physical fitness,” observed Scott Kahan, MD, an obesity specialist and director of the National Center for Weight and Wellness in Washington, D.C.
 

Weight-neutral ‘is the way to go’

“The most significant new information [in the review] is the direct comparison of the magnitude of mortality risk reduction associated with weight loss compared with increasing fitness, physical activity, or both,” said Glenn A. Gaesser, PhD, the first author of the new review and professor of exercise physiology at Arizona State University, Phoenix.

“The results are quite clear: Increasing fitness, physical activity, or both are associated with greater mortality reductions than intentional weight loss. We argue that a weight-neutral approach to treating obesity is the way to go.”

The data call “into question the widely perceived notion of ‘lose weight, live longer,’” resulting in a “paradigm shift,” Dr. Gaesser said in an interview.

“There are no downsides to exercise, but there are significant downsides to weight loss, especially when it is inevitably followed by weight regain, which gives rise to the undesirable ‘weight-loss futile cycle’,” he added.
 

No simple, single solutions

Dr. Kahan said, however, that comparison of the effects of weight loss with the effects of increased activity and fitness on mortality is inherently problematic.

“It’s hard to make definitive conclusions from observational studies,” he cautioned, noting that the data cited in the review of activity and fitness compared with weight loss are generally “estimations” that carry a “lot of cloudiness.”

Dr. Kahan also takes issue with the premise detailed in the review that targeting reduced weight and implementing healthful and evidence-based approaches to try to achieve it are bound to fail and have frequent adverse consequences.

“Managing weight in a reasonable, patient-centered, thoughtful way is a standard and central part of long-term health,” he said in an interview.

He did concede, however, that the U.S. weight-loss landscape is awash with hucksterism that takes advantage of many patients, and he cautioned against approaches that focus on weight loss at all costs and as a pathway to selling products.

“But staying focused on activity and not paying attention to healthy eating is extreme,” he said, reemphasizing that obesity management is not a simple intervention with a single solution.
 

Not the first time

This is not the first time that Dr. Gaesser, and others, have published articles promoting a pivot away from weight loss as the primary goal of obesity interventions. In 2015, Dr. Gaesser and colleagues published an evidence review that gave this recommendation for managing people with obesity: “We propose that the proxy for health improvements should not be weight loss but instead improvements in cardiometabolic parameters, functional status, and fitness.”

Dr. Gaesser’s latest review also acknowledges similar recommendations from others, including Dr. Ross, who said it’s nothing new to conclude that increased fitness and activity in the absence of weight loss is not failure.

“It’s something we’ve promoted for decades,” but “it’s not understood and acted on in clinical settings, and that’s unfortunate,” he said.

More than a decade ago, Dr. Ross and his coauthor wrote in a published review that “a monolithic focus on weight loss as the only determinant of success for strategies that aim to reduce obesity is not justified and, more importantly, eliminates opportunities to focus on lifestyle behaviors that are associated with benefit across a wide range of health outcomes.”

And an effective intervention that focuses on activity and fitness means that, at the least, patients should not gain weight, and they may lose weight as a side benefit, he stressed.

“We always advocate a balanced diet, so that people do not gain more weight.”

Dr. Ross also highlighted the usefulness of measuring fitness as an alternative to recording weight to track the response by patients with obesity to various interventions. Dr. Ross recommends nonexercise prediction equations for routine practice to easily estimate cardiorespiratory fitness, an approach detailed in a 2016 statement from the American Heart Association by a writing panel chaired by Dr. Ross.

The AHA statement notes that “not including cardiorespiratory fitness measurement in routine clinical practice fails to provide an optimal approach for stratifying patients according to risk.”

The AHA also advises that “routine estimation of cardiorespiratory fitness in clinical practice is no more difficult than measuring blood pressure,” and details ways of incorporating this into routine clinical assessment.

Dr. Gaesser and Dr. Kahan have reported no relevant financial relationships. Dr. Ross has been an advisor to the Canadian Sugar Institute.

A version of this article first appeared on Medscape.com.

Obesity interventions would be more effective at preventing premature mortality if they focused less on weight loss and more on increased physical activity and improved cardiorespiratory fitness, a pair of researchers concluded in a recent review.

The authors promote a “weight-neutral approach to treating obesity-related health conditions,” which they say is “as or more effective than a weight-loss centric approach.”

One expert agrees. “The obsession with the bathroom scale as the primary determinant of treatment efficacy when managing obesity is just not right,” Robert Ross, PhD, said in an interview.

“It masks the tremendous health benefits of improved fitness regardless of obesity. If you increase fitness, you improve outcomes even when people don’t lose weight,” noted Dr. Ross, a researcher in the School of Kinesiology and Health Studies at Queen’s University in Kingston, Ontario, Canada.

However, this proposition reprises a long-standing gulf between two schools of thought on obesity intervention.

One indication of the divided sentiment came in another expert review, published just days later, that strongly calls for weight loss of at least 15% of starting body weight as the primary intervention goal for most patients with obesity and type 2 diabetes. (According to 2020 statistics from the U.S. Centers for Disease Control and Prevention, more than 60% of U.S. adults with diabetes are obese.)

However, some question whether it must be all one, or the other, when obesity management could instead combine these approaches and simultaneously promote weight loss, increased activity, and improved fitness.

“It only muddies the water to dichotomize this as either weight management or activity and physical fitness,” observed Scott Kahan, MD, an obesity specialist and director of the National Center for Weight and Wellness in Washington, D.C.
 

Weight-neutral ‘is the way to go’

“The most significant new information [in the review] is the direct comparison of the magnitude of mortality risk reduction associated with weight loss compared with increasing fitness, physical activity, or both,” said Glenn A. Gaesser, PhD, the first author of the new review and professor of exercise physiology at Arizona State University, Phoenix.

“The results are quite clear: Increasing fitness, physical activity, or both are associated with greater mortality reductions than intentional weight loss. We argue that a weight-neutral approach to treating obesity is the way to go.”

The data call “into question the widely perceived notion of ‘lose weight, live longer,’” resulting in a “paradigm shift,” Dr. Gaesser said in an interview.

“There are no downsides to exercise, but there are significant downsides to weight loss, especially when it is inevitably followed by weight regain, which gives rise to the undesirable ‘weight-loss futile cycle’,” he added.
 

No simple, single solutions

Dr. Kahan said, however, that comparison of the effects of weight loss with the effects of increased activity and fitness on mortality is inherently problematic.

“It’s hard to make definitive conclusions from observational studies,” he cautioned, noting that the data cited in the review of activity and fitness compared with weight loss are generally “estimations” that carry a “lot of cloudiness.”

Dr. Kahan also takes issue with the premise detailed in the review that targeting reduced weight and implementing healthful and evidence-based approaches to try to achieve it are bound to fail and have frequent adverse consequences.

“Managing weight in a reasonable, patient-centered, thoughtful way is a standard and central part of long-term health,” he said in an interview.

He did concede, however, that the U.S. weight-loss landscape is awash with hucksterism that takes advantage of many patients, and he cautioned against approaches that focus on weight loss at all costs and as a pathway to selling products.

“But staying focused on activity and not paying attention to healthy eating is extreme,” he said, reemphasizing that obesity management is not a simple intervention with a single solution.
 

Not the first time

This is not the first time that Dr. Gaesser, and others, have published articles promoting a pivot away from weight loss as the primary goal of obesity interventions. In 2015, Dr. Gaesser and colleagues published an evidence review that gave this recommendation for managing people with obesity: “We propose that the proxy for health improvements should not be weight loss but instead improvements in cardiometabolic parameters, functional status, and fitness.”

Dr. Gaesser’s latest review also acknowledges similar recommendations from others, including Dr. Ross, who said it’s nothing new to conclude that increased fitness and activity in the absence of weight loss is not failure.

“It’s something we’ve promoted for decades,” but “it’s not understood and acted on in clinical settings, and that’s unfortunate,” he said.

More than a decade ago, Dr. Ross and his coauthor wrote in a published review that “a monolithic focus on weight loss as the only determinant of success for strategies that aim to reduce obesity is not justified and, more importantly, eliminates opportunities to focus on lifestyle behaviors that are associated with benefit across a wide range of health outcomes.”

And an effective intervention that focuses on activity and fitness means that, at the least, patients should not gain weight, and they may lose weight as a side benefit, he stressed.

“We always advocate a balanced diet, so that people do not gain more weight.”

Dr. Ross also highlighted the usefulness of measuring fitness as an alternative to recording weight to track the response by patients with obesity to various interventions. Dr. Ross recommends nonexercise prediction equations for routine practice to easily estimate cardiorespiratory fitness, an approach detailed in a 2016 statement from the American Heart Association by a writing panel chaired by Dr. Ross.

The AHA statement notes that “not including cardiorespiratory fitness measurement in routine clinical practice fails to provide an optimal approach for stratifying patients according to risk.”

The AHA also advises that “routine estimation of cardiorespiratory fitness in clinical practice is no more difficult than measuring blood pressure,” and details ways of incorporating this into routine clinical assessment.

Dr. Gaesser and Dr. Kahan have reported no relevant financial relationships. Dr. Ross has been an advisor to the Canadian Sugar Institute.

A version of this article first appeared on Medscape.com.

Obesity interventions would be more effective at preventing premature mortality if they focused less on weight loss and more on increased physical activity and improved cardiorespiratory fitness, a pair of researchers concluded in a recent review.

The authors promote a “weight-neutral approach to treating obesity-related health conditions,” which they say is “as or more effective than a weight-loss centric approach.”

One expert agrees. “The obsession with the bathroom scale as the primary determinant of treatment efficacy when managing obesity is just not right,” Robert Ross, PhD, said in an interview.

“It masks the tremendous health benefits of improved fitness regardless of obesity. If you increase fitness, you improve outcomes even when people don’t lose weight,” noted Dr. Ross, a researcher in the School of Kinesiology and Health Studies at Queen’s University in Kingston, Ontario, Canada.

However, this proposition reprises a long-standing gulf between two schools of thought on obesity intervention.

One indication of the divided sentiment came in another expert review, published just days later, that strongly calls for weight loss of at least 15% of starting body weight as the primary intervention goal for most patients with obesity and type 2 diabetes. (According to 2020 statistics from the U.S. Centers for Disease Control and Prevention, more than 60% of U.S. adults with diabetes are obese.)

However, some question whether it must be all one, or the other, when obesity management could instead combine these approaches and simultaneously promote weight loss, increased activity, and improved fitness.

“It only muddies the water to dichotomize this as either weight management or activity and physical fitness,” observed Scott Kahan, MD, an obesity specialist and director of the National Center for Weight and Wellness in Washington, D.C.
 

Weight-neutral ‘is the way to go’

“The most significant new information [in the review] is the direct comparison of the magnitude of mortality risk reduction associated with weight loss compared with increasing fitness, physical activity, or both,” said Glenn A. Gaesser, PhD, the first author of the new review and professor of exercise physiology at Arizona State University, Phoenix.

“The results are quite clear: Increasing fitness, physical activity, or both are associated with greater mortality reductions than intentional weight loss. We argue that a weight-neutral approach to treating obesity is the way to go.”

The data call “into question the widely perceived notion of ‘lose weight, live longer,’” resulting in a “paradigm shift,” Dr. Gaesser said in an interview.

“There are no downsides to exercise, but there are significant downsides to weight loss, especially when it is inevitably followed by weight regain, which gives rise to the undesirable ‘weight-loss futile cycle’,” he added.
 

No simple, single solutions

Dr. Kahan said, however, that comparison of the effects of weight loss with the effects of increased activity and fitness on mortality is inherently problematic.

“It’s hard to make definitive conclusions from observational studies,” he cautioned, noting that the data cited in the review of activity and fitness compared with weight loss are generally “estimations” that carry a “lot of cloudiness.”

Dr. Kahan also takes issue with the premise detailed in the review that targeting reduced weight and implementing healthful and evidence-based approaches to try to achieve it are bound to fail and have frequent adverse consequences.

“Managing weight in a reasonable, patient-centered, thoughtful way is a standard and central part of long-term health,” he said in an interview.

He did concede, however, that the U.S. weight-loss landscape is awash with hucksterism that takes advantage of many patients, and he cautioned against approaches that focus on weight loss at all costs and as a pathway to selling products.

“But staying focused on activity and not paying attention to healthy eating is extreme,” he said, reemphasizing that obesity management is not a simple intervention with a single solution.
 

Not the first time

This is not the first time that Dr. Gaesser, and others, have published articles promoting a pivot away from weight loss as the primary goal of obesity interventions. In 2015, Dr. Gaesser and colleagues published an evidence review that gave this recommendation for managing people with obesity: “We propose that the proxy for health improvements should not be weight loss but instead improvements in cardiometabolic parameters, functional status, and fitness.”

Dr. Gaesser’s latest review also acknowledges similar recommendations from others, including Dr. Ross, who said it’s nothing new to conclude that increased fitness and activity in the absence of weight loss is not failure.

“It’s something we’ve promoted for decades,” but “it’s not understood and acted on in clinical settings, and that’s unfortunate,” he said.

More than a decade ago, Dr. Ross and his coauthor wrote in a published review that “a monolithic focus on weight loss as the only determinant of success for strategies that aim to reduce obesity is not justified and, more importantly, eliminates opportunities to focus on lifestyle behaviors that are associated with benefit across a wide range of health outcomes.”

And an effective intervention that focuses on activity and fitness means that, at the least, patients should not gain weight, and they may lose weight as a side benefit, he stressed.

“We always advocate a balanced diet, so that people do not gain more weight.”

Dr. Ross also highlighted the usefulness of measuring fitness as an alternative to recording weight to track the response by patients with obesity to various interventions. Dr. Ross recommends nonexercise prediction equations for routine practice to easily estimate cardiorespiratory fitness, an approach detailed in a 2016 statement from the American Heart Association by a writing panel chaired by Dr. Ross.

The AHA statement notes that “not including cardiorespiratory fitness measurement in routine clinical practice fails to provide an optimal approach for stratifying patients according to risk.”

The AHA also advises that “routine estimation of cardiorespiratory fitness in clinical practice is no more difficult than measuring blood pressure,” and details ways of incorporating this into routine clinical assessment.

Dr. Gaesser and Dr. Kahan have reported no relevant financial relationships. Dr. Ross has been an advisor to the Canadian Sugar Institute.

A version of this article first appeared on Medscape.com.

Editor’s note: This story was updated with the CDC director’s endorsement.

Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky, MD, has signed off on an advisory panel’s earlier unanimous vote to recommend boosters for the Moderna and Johnson and Johnson COVID vaccines.

The decision now means that millions of Americans are eligible to get a booster shot for either the Pfizer, Moderna, or J&J COVID vaccines.

“The evidence shows that all three COVID-19 vaccines authorized in the United States are safe – as demonstrated by the over 400 million vaccine doses already given. And, they are all highly effective in reducing the risk of severe disease, hospitalization, and death, even in the midst of the widely circulating Delta variant,” Dr. Walensky said in a CDC news release.

She also signed off on the panel’s suggestion that individuals can mix or match the booster from any one of the three available COVID-19 vaccines.

The Advisory Committee on Immunization Practices (ACIP) recommended in a late afternoon 15-0 vote that everyone over age 18 who are at least 2 months past their Johnson & Johnson vaccine should get a booster, an endorsement that affects an estimated 13 million Americans.

Those eligible for a booster at least 6 months after their last Moderna shot are the same groups who can get a Pfizer booster.

They are:

• Anyone over age 65.
• Those over age 18 with an underlying health condition that puts them at risk of severe COVID-19.
• Those over age 18 who may be at higher risk of a COVID-19 infection because they live or work in a risky setting.

These recommendations are in line with the Food and Drug Administration’s Oct. 20 authorization of the boosters, along with the ability to mix-and-match vaccines.

There are an estimated 47 million Pfizer recipients and 39 million people vaccinated with Moderna who are now eligible for a booster dose, according to data presented by the CDC.
 

Questions, concerns

Before voting, some committee members expressed discomfort in broadly recommending boosters, stressing that there is very little evidence supporting the need for boosters in people younger than age 50.

“I can’t say that I am comfortable that anybody under 50 – an otherwise healthy individual – needs a booster vaccine at this time with either Moderna or Pfizer,” said ACIP member Sarah Long, MD, professor of pediatrics at Drexel University in Philadelphia.

She said she would try to mitigate any potential harm by having some kind of age restriction on the otherwise worried well.

“We don’t usually have the vaccines [for] the worried well. We give it because we have a need that’s worth the risk, and there’s a burden of severity of disease,” Dr. Long said.

The evidence to date shows that all the vaccines authorized for use in the U.S. continue to protect people well against severe COVID-19 outcomes, including hospitalization and death.

But breakthrough infections are on the rise, especially for people who initially received the Johnson and Johnson one-dose vaccine.

On Oct. 21, Pfizer released data from a study of more than 10,000 fully vaccinated people. Half were randomly assigned to get a booster of their Comirnaty vaccine, the other half were given a placebo.

Over the ensuing 2.5 months, there were 5 COVID-19 cases in the boosted group, and 109 in the group that got a placebo.

The data were posted in a press release and have not yet been peer reviewed, but are the first to show clinical effectiveness of boosters at preventing COVID-19 infections.

Data recently considered by the FDA and CDC for booster doses come from studies that were mostly shorter and smaller. These studies looked at biomarkers of immunity like the concentration of antibodies in a person’s blood and the percentage of study participants who saw a boost to those antibodies.

The studies demonstrated that boosters indeed restore high levels of antibodies, but unlike the newest Pfizer data they were not able to show that these antibodies prevented COVID-19.

These studies also weren’t powered to pick up on any less common safety problems that might arise after another dose of the shots.
 

“Real world” recommendations

In the end, however, the panel felt it was more important to be permissive in allowing boosters so that individuals and their doctors could be free to make their own decisions.

“The decision made by the FDA and the ACIP recommendations, I think, reflects the real world. The public is going to do what they feel driven to do. This at least adds a scientific review of the currently available data,” said Jay Varkey, MD, an infectious disease physician and associate professor at Emory University in Atlanta, who was not involved in the ACIP’s deliberations.

Dr. Varkey said he would recommend that anyone who is younger than 65, and who has no underlying medical conditions such as diabetes or obesity, speak with their doctor about their individual benefits and risks before getting a booster.

The CDC is planning to release a detailed suite of clinical considerations to help people weigh the risks and benefits of getting a booster.

Safety updates presented at the meeting show that serious adverse events after vaccination are extremely rare, but in some cases, they may rise above the risk for those problems generally seen in the population.

Those rare events include the disabling autoimmune condition Guillain-Barré syndrome and the platelet disorder thrombosis with thrombocytopenia (TTS), which causes blood clots along with the risk of excess bleeding because of a low platelet count.

Both can occur after the J&J vaccine. Out of 15.3 million doses of the vaccine given to date, there have been 47 cases of TTS and five deaths. These events are more common in younger women.

The mRNA vaccines, such as those from Pfizer and Moderna, can cause heart inflammation called myocarditis or pericarditis. This side effect is more common in men 18-24 years old. The reported rate of myocarditis after vaccination is 39 cases for every 1 million doses.

In voting to permit boosters, committee member Wilbur Chen, MD, professor at the University of Maryland’s Center for Vaccine Development, said he hoped boosters wouldn’t give Americans false confidence.

Dr. Chen stressed that ending the pandemic would depend on “a multilayered approach” that includes masking, social distancing, avoiding large crowds indoors, and convincing more Americans to take their first doses of the vaccines.

“We’re not just going to vaccinate ourselves out of this situation,” Dr. Chen said.
 

A version of this article first appeared on WebMD.com.

Editor’s note: This story was updated with the CDC director’s endorsement.

Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky, MD, has signed off on an advisory panel’s earlier unanimous vote to recommend boosters for the Moderna and Johnson and Johnson COVID vaccines.

The decision now means that millions of Americans are eligible to get a booster shot for either the Pfizer, Moderna, or J&J COVID vaccines.

“The evidence shows that all three COVID-19 vaccines authorized in the United States are safe – as demonstrated by the over 400 million vaccine doses already given. And, they are all highly effective in reducing the risk of severe disease, hospitalization, and death, even in the midst of the widely circulating Delta variant,” Dr. Walensky said in a CDC news release.

She also signed off on the panel’s suggestion that individuals can mix or match the booster from any one of the three available COVID-19 vaccines.

The Advisory Committee on Immunization Practices (ACIP) recommended in a late afternoon 15-0 vote that everyone over age 18 who are at least 2 months past their Johnson & Johnson vaccine should get a booster, an endorsement that affects an estimated 13 million Americans.

Those eligible for a booster at least 6 months after their last Moderna shot are the same groups who can get a Pfizer booster.

They are:

• Anyone over age 65.
• Those over age 18 with an underlying health condition that puts them at risk of severe COVID-19.
• Those over age 18 who may be at higher risk of a COVID-19 infection because they live or work in a risky setting.

These recommendations are in line with the Food and Drug Administration’s Oct. 20 authorization of the boosters, along with the ability to mix-and-match vaccines.

There are an estimated 47 million Pfizer recipients and 39 million people vaccinated with Moderna who are now eligible for a booster dose, according to data presented by the CDC.
 

Questions, concerns

Before voting, some committee members expressed discomfort in broadly recommending boosters, stressing that there is very little evidence supporting the need for boosters in people younger than age 50.

“I can’t say that I am comfortable that anybody under 50 – an otherwise healthy individual – needs a booster vaccine at this time with either Moderna or Pfizer,” said ACIP member Sarah Long, MD, professor of pediatrics at Drexel University in Philadelphia.

She said she would try to mitigate any potential harm by having some kind of age restriction on the otherwise worried well.

“We don’t usually have the vaccines [for] the worried well. We give it because we have a need that’s worth the risk, and there’s a burden of severity of disease,” Dr. Long said.

The evidence to date shows that all the vaccines authorized for use in the U.S. continue to protect people well against severe COVID-19 outcomes, including hospitalization and death.

But breakthrough infections are on the rise, especially for people who initially received the Johnson and Johnson one-dose vaccine.

On Oct. 21, Pfizer released data from a study of more than 10,000 fully vaccinated people. Half were randomly assigned to get a booster of their Comirnaty vaccine, the other half were given a placebo.

Over the ensuing 2.5 months, there were 5 COVID-19 cases in the boosted group, and 109 in the group that got a placebo.

The data were posted in a press release and have not yet been peer reviewed, but are the first to show clinical effectiveness of boosters at preventing COVID-19 infections.

Data recently considered by the FDA and CDC for booster doses come from studies that were mostly shorter and smaller. These studies looked at biomarkers of immunity like the concentration of antibodies in a person’s blood and the percentage of study participants who saw a boost to those antibodies.

The studies demonstrated that boosters indeed restore high levels of antibodies, but unlike the newest Pfizer data they were not able to show that these antibodies prevented COVID-19.

These studies also weren’t powered to pick up on any less common safety problems that might arise after another dose of the shots.
 

“Real world” recommendations

In the end, however, the panel felt it was more important to be permissive in allowing boosters so that individuals and their doctors could be free to make their own decisions.

“The decision made by the FDA and the ACIP recommendations, I think, reflects the real world. The public is going to do what they feel driven to do. This at least adds a scientific review of the currently available data,” said Jay Varkey, MD, an infectious disease physician and associate professor at Emory University in Atlanta, who was not involved in the ACIP’s deliberations.

Dr. Varkey said he would recommend that anyone who is younger than 65, and who has no underlying medical conditions such as diabetes or obesity, speak with their doctor about their individual benefits and risks before getting a booster.

The CDC is planning to release a detailed suite of clinical considerations to help people weigh the risks and benefits of getting a booster.

Safety updates presented at the meeting show that serious adverse events after vaccination are extremely rare, but in some cases, they may rise above the risk for those problems generally seen in the population.

Those rare events include the disabling autoimmune condition Guillain-Barré syndrome and the platelet disorder thrombosis with thrombocytopenia (TTS), which causes blood clots along with the risk of excess bleeding because of a low platelet count.

Both can occur after the J&J vaccine. Out of 15.3 million doses of the vaccine given to date, there have been 47 cases of TTS and five deaths. These events are more common in younger women.

The mRNA vaccines, such as those from Pfizer and Moderna, can cause heart inflammation called myocarditis or pericarditis. This side effect is more common in men 18-24 years old. The reported rate of myocarditis after vaccination is 39 cases for every 1 million doses.

In voting to permit boosters, committee member Wilbur Chen, MD, professor at the University of Maryland’s Center for Vaccine Development, said he hoped boosters wouldn’t give Americans false confidence.

Dr. Chen stressed that ending the pandemic would depend on “a multilayered approach” that includes masking, social distancing, avoiding large crowds indoors, and convincing more Americans to take their first doses of the vaccines.

“We’re not just going to vaccinate ourselves out of this situation,” Dr. Chen said.
 

A version of this article first appeared on WebMD.com.

Editor’s note: This story was updated with the CDC director’s endorsement.

Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky, MD, has signed off on an advisory panel’s earlier unanimous vote to recommend boosters for the Moderna and Johnson and Johnson COVID vaccines.

The decision now means that millions of Americans are eligible to get a booster shot for either the Pfizer, Moderna, or J&J COVID vaccines.

“The evidence shows that all three COVID-19 vaccines authorized in the United States are safe – as demonstrated by the over 400 million vaccine doses already given. And, they are all highly effective in reducing the risk of severe disease, hospitalization, and death, even in the midst of the widely circulating Delta variant,” Dr. Walensky said in a CDC news release.

She also signed off on the panel’s suggestion that individuals can mix or match the booster from any one of the three available COVID-19 vaccines.

The Advisory Committee on Immunization Practices (ACIP) recommended in a late afternoon 15-0 vote that everyone over age 18 who are at least 2 months past their Johnson & Johnson vaccine should get a booster, an endorsement that affects an estimated 13 million Americans.

Those eligible for a booster at least 6 months after their last Moderna shot are the same groups who can get a Pfizer booster.

They are:

• Anyone over age 65.
• Those over age 18 with an underlying health condition that puts them at risk of severe COVID-19.
• Those over age 18 who may be at higher risk of a COVID-19 infection because they live or work in a risky setting.

These recommendations are in line with the Food and Drug Administration’s Oct. 20 authorization of the boosters, along with the ability to mix-and-match vaccines.

There are an estimated 47 million Pfizer recipients and 39 million people vaccinated with Moderna who are now eligible for a booster dose, according to data presented by the CDC.
 

Questions, concerns

Before voting, some committee members expressed discomfort in broadly recommending boosters, stressing that there is very little evidence supporting the need for boosters in people younger than age 50.

“I can’t say that I am comfortable that anybody under 50 – an otherwise healthy individual – needs a booster vaccine at this time with either Moderna or Pfizer,” said ACIP member Sarah Long, MD, professor of pediatrics at Drexel University in Philadelphia.

She said she would try to mitigate any potential harm by having some kind of age restriction on the otherwise worried well.

“We don’t usually have the vaccines [for] the worried well. We give it because we have a need that’s worth the risk, and there’s a burden of severity of disease,” Dr. Long said.

The evidence to date shows that all the vaccines authorized for use in the U.S. continue to protect people well against severe COVID-19 outcomes, including hospitalization and death.

But breakthrough infections are on the rise, especially for people who initially received the Johnson and Johnson one-dose vaccine.

On Oct. 21, Pfizer released data from a study of more than 10,000 fully vaccinated people. Half were randomly assigned to get a booster of their Comirnaty vaccine, the other half were given a placebo.

Over the ensuing 2.5 months, there were 5 COVID-19 cases in the boosted group, and 109 in the group that got a placebo.

The data were posted in a press release and have not yet been peer reviewed, but are the first to show clinical effectiveness of boosters at preventing COVID-19 infections.

Data recently considered by the FDA and CDC for booster doses come from studies that were mostly shorter and smaller. These studies looked at biomarkers of immunity like the concentration of antibodies in a person’s blood and the percentage of study participants who saw a boost to those antibodies.

The studies demonstrated that boosters indeed restore high levels of antibodies, but unlike the newest Pfizer data they were not able to show that these antibodies prevented COVID-19.

These studies also weren’t powered to pick up on any less common safety problems that might arise after another dose of the shots.
 

“Real world” recommendations

In the end, however, the panel felt it was more important to be permissive in allowing boosters so that individuals and their doctors could be free to make their own decisions.

“The decision made by the FDA and the ACIP recommendations, I think, reflects the real world. The public is going to do what they feel driven to do. This at least adds a scientific review of the currently available data,” said Jay Varkey, MD, an infectious disease physician and associate professor at Emory University in Atlanta, who was not involved in the ACIP’s deliberations.

Dr. Varkey said he would recommend that anyone who is younger than 65, and who has no underlying medical conditions such as diabetes or obesity, speak with their doctor about their individual benefits and risks before getting a booster.

The CDC is planning to release a detailed suite of clinical considerations to help people weigh the risks and benefits of getting a booster.

Safety updates presented at the meeting show that serious adverse events after vaccination are extremely rare, but in some cases, they may rise above the risk for those problems generally seen in the population.

Those rare events include the disabling autoimmune condition Guillain-Barré syndrome and the platelet disorder thrombosis with thrombocytopenia (TTS), which causes blood clots along with the risk of excess bleeding because of a low platelet count.

Both can occur after the J&J vaccine. Out of 15.3 million doses of the vaccine given to date, there have been 47 cases of TTS and five deaths. These events are more common in younger women.

The mRNA vaccines, such as those from Pfizer and Moderna, can cause heart inflammation called myocarditis or pericarditis. This side effect is more common in men 18-24 years old. The reported rate of myocarditis after vaccination is 39 cases for every 1 million doses.

In voting to permit boosters, committee member Wilbur Chen, MD, professor at the University of Maryland’s Center for Vaccine Development, said he hoped boosters wouldn’t give Americans false confidence.

Dr. Chen stressed that ending the pandemic would depend on “a multilayered approach” that includes masking, social distancing, avoiding large crowds indoors, and convincing more Americans to take their first doses of the vaccines.

“We’re not just going to vaccinate ourselves out of this situation,” Dr. Chen said.
 

A version of this article first appeared on WebMD.com.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.