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New Canadian BC Guidelines Emphasize Personal Choice
The draft guidelines stem from a review of more than 165 recent randomized controlled trials, observational studies, mathematical models, and other data.
The guideline working group included four breast cancer experts (a medical oncologist, a radiation oncologist, a surgical oncologist, and a radiologist), three patient partners, six family physicians, a nurse practitioner, evidence review teams, and other experts.
To avoid potential conflicts of interest, the oncologists provided input but did not vote on the final recommendations, Guylène Thériault, MD, a family physician and chair of the task force and Breast Cancer Working Group, said in an interview.
The guideline recommends that, after the potential benefits and harms of screening have been considered, mammography should be accessible every 2-3 years to women (ie, people assigned female at birth) between ages 40 and 74 years who are at average or moderately increased risk.
Women with a personal or extensive family history of breast cancer or genetic mutations that would increase breast cancer risk; those who have symptoms, such as a lump; those who feel they may be at high risk; and those who are transgender women should consult a healthcare provider about appropriate options, according to the updated guidelines, which do not apply to these patients.
The draft guidelines were published online on May 30 and are open for public comment until August 30.
‘Three Big Questions’
To develop the guidelines, the work group asked “three big questions,” said Dr. Thériault. The first was the effectiveness of breast cancer screening for women aged 40 years and over. For this question, this systematic review, unlike the 2018 guideline update, included not only randomized trials but also observational data to ensure that the work group considered all available data.
“The second question was about comparative effectiveness,” which is something the United States considered for the latest US Preventive Services Task Force (USPSTF) update, said Dr. Thériault. The USPSTF asked questions such as “What happens if we start screening patients at age 40 years? Or at age 50 years? What happens if we stop at age 74 years? Or if we use different tests such as 3D versus digital mammography?”
The Canadian Task Force relied on the evidence that the USPSTF found after grading it with its own criteria, she said. The results were similar, and so are the recommendations in this area. “For example, we don’t recommend supplementary screening for women with dense breasts because there are no studies to inform patient-oriented benefits.”
The third question was about the values and preferences of women regarding breast cancer screening, which is something the United States didn’t examine. “We had looked at that issue in 2018, and this time around, even though we expanded the type of studies, we got the same message: That there are differences between women in their 40s and those who are age 50 years and over.”
“The majority of women in their 40s think that the harms outweigh the benefits and are not interested in screening,” said Dr. Thériault. “But when I say the majority, that’s not every woman. So, we had to recognize that there is variability. And the majority, but not all, of women ages 50-74 years thinks the benefits are higher than the harms. That’s why we say in our recommendation that from ages 40 to 74, it’s a personal choice.”
Responding to Objections
Not surprisingly, the task force has heard objections to its draft guidelines. The first is that women aged 40-49 years are being denied mammograms, said Michelle Nadler, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto, Canada. “This [objection] has attained a lot of media coverage, which is unfortunate, because people who have not read the guidelines may believe this is true. The guidelines clearly state that an eligible, informed woman of this age group who wants a screening mammogram should receive one.”
The second commonly heard objection is that the task force is overestimating the harms of screening, such as anxiety and overdiagnosis, she said. But an outcome of “anxiety” was not factored into the guideline. Overdiagnosis was calculated on the basis of the literature, and estimates were converted to a common denominator so that they could be compared, said Dr. Nadler. The same was true of benefits.
Another objection was that screening could mean less need for chemotherapy or full axillary dissection, Dr. Nadler said. However, the task force did not find any primary studies that evaluated these outcomes.
Critics also said that the recommendations do not account for racial or ethnic variations. Although more research is likely needed in this area, “the task force states that individuals should be informed of all of their breast cancer risk factors, including race/ethnicity, and that this should be factored into decisions about screening,” said Dr. Nadler.
“I was very surprised that the task force was accused by some parties of paternalism,” added René Wittmer, MD, adjunct clinical professor of family medicine at the University of Montreal and chair of Choosing Wisely Quebec, Montreal, Canada. “In my opinion, the importance they place on shared decision-making is contrary to medical paternalism and aims to empower women to make a decision that fits with their values and preferences.”
Nevertheless, the inclusion of modeling studies and observational trials “may cause the potential benefits to be amplified, compared with what is seen in randomized controlled trials,” he said in an interview.
Decision Aids Help
Once the guidelines are finalized, decision aids will be available to patients and providers to help guide screening discussions, said Dr. Nadler. “Primary care providers need to be aware of an individual’s personal risk factors for breast cancer to know if they are at average, above average, or high lifetime risk of breast cancer. These guidelines do not apply to those with > 20% lifetime risk of breast cancer.”
“The standards for risk communication are in absolute numbers over a common denominator,” she noted. “This is how primary care providers discuss other important primary care topics like smoking cessation, cardiovascular disease (and decisions about statin medications), and osteoporosis risk. These same standards should apply for breast cancer screening.”
Furthermore, she said, providers “should be aware that individuals from marginalized communities may benefit from more than one conversation until they are able to make a decision about screening that is right for them.”
“There is good evidence showing that most advances we’ve seen in breast cancer outcomes (ie, reduction in breast cancer mortality) are likely due to improvements in treatment, not screening,” said Dr. Wittmer. “In fact, mortality reductions are seen even in age groups or countries where there is no routine screening. This means that women benefit from advances in treatments, whether they choose to get screened or not.”
‘Mammography Saves Lives’
Commenting on the updated guidelines, Janie Lee, MD, professor of radiology at the University of Washington School of Medicine and director of breast imaging at the Fred Hutchinson Cancer Center, both in Seattle, said: “For the USPSTF, benefits of life years gained were also considered, in addition to breast cancer deaths averted. To save more lives from breast cancer, guidelines may focus on screening women at older ages, when annual rates of breast cancer are higher.” By contrast, when thinking in terms of years of life saved, focusing on screening younger women, who have more years of life left, increases benefits. “Both are important outcomes that we want to improve with effective screening.”
That said, “we should follow the guidelines of our specific national organizations,” she continued. “Overall populations and healthcare systems are different between the US and Canada.”
For example, “the USPSTF specifically highlighted the potential for reducing breast cancer mortality in Black women, who are more likely to develop biologically aggressive tumors that are diagnosed at more advanced stages, when making updated recommendations earlier this year,” she said. “The Canadian guidelines did not make specific recommendations by race or ethnicity group, instead highlighting the need for more research on the impact of screening in these groups.”
In addition, “screening every year versus every other year is more routine in the US compared with Canada,” she noted. And nonmedical factors that influence health and that may influence access to medical care and timely diagnosis of breast cancer “may be different between our two countries.”
“The most important take-home message is that the scientific evidence is strong that screening mammography saves lives,” said Dr. Lee. “These new recommendations will hopefully result in more early diagnoses of breast cancer and save more lives. Screening works best when it’s used regularly, regardless of how frequently you return. Once you start screening, please urge your patients to plan to return.”
Dr. Nadler disclosed speaker honoraria and consulting fees from Novartis and Exact Sciences outside the scope of this interview and innovation funding from the NSH/UHN AMO Innovation Fund Competition for Developing and Implementing a Consensus Recommendation for Breast Cancer Screening Best Practices. Dr. Thériault is chair of the task force and chair of the working group for the draft guidelines. Dr. Wittmer is chair of Choosing Wisely Quebec. Dr. Lee reported no relevant financial relationships related to her interview.
A version of this article appeared on Medscape.com.
The draft guidelines stem from a review of more than 165 recent randomized controlled trials, observational studies, mathematical models, and other data.
The guideline working group included four breast cancer experts (a medical oncologist, a radiation oncologist, a surgical oncologist, and a radiologist), three patient partners, six family physicians, a nurse practitioner, evidence review teams, and other experts.
To avoid potential conflicts of interest, the oncologists provided input but did not vote on the final recommendations, Guylène Thériault, MD, a family physician and chair of the task force and Breast Cancer Working Group, said in an interview.
The guideline recommends that, after the potential benefits and harms of screening have been considered, mammography should be accessible every 2-3 years to women (ie, people assigned female at birth) between ages 40 and 74 years who are at average or moderately increased risk.
Women with a personal or extensive family history of breast cancer or genetic mutations that would increase breast cancer risk; those who have symptoms, such as a lump; those who feel they may be at high risk; and those who are transgender women should consult a healthcare provider about appropriate options, according to the updated guidelines, which do not apply to these patients.
The draft guidelines were published online on May 30 and are open for public comment until August 30.
‘Three Big Questions’
To develop the guidelines, the work group asked “three big questions,” said Dr. Thériault. The first was the effectiveness of breast cancer screening for women aged 40 years and over. For this question, this systematic review, unlike the 2018 guideline update, included not only randomized trials but also observational data to ensure that the work group considered all available data.
“The second question was about comparative effectiveness,” which is something the United States considered for the latest US Preventive Services Task Force (USPSTF) update, said Dr. Thériault. The USPSTF asked questions such as “What happens if we start screening patients at age 40 years? Or at age 50 years? What happens if we stop at age 74 years? Or if we use different tests such as 3D versus digital mammography?”
The Canadian Task Force relied on the evidence that the USPSTF found after grading it with its own criteria, she said. The results were similar, and so are the recommendations in this area. “For example, we don’t recommend supplementary screening for women with dense breasts because there are no studies to inform patient-oriented benefits.”
The third question was about the values and preferences of women regarding breast cancer screening, which is something the United States didn’t examine. “We had looked at that issue in 2018, and this time around, even though we expanded the type of studies, we got the same message: That there are differences between women in their 40s and those who are age 50 years and over.”
“The majority of women in their 40s think that the harms outweigh the benefits and are not interested in screening,” said Dr. Thériault. “But when I say the majority, that’s not every woman. So, we had to recognize that there is variability. And the majority, but not all, of women ages 50-74 years thinks the benefits are higher than the harms. That’s why we say in our recommendation that from ages 40 to 74, it’s a personal choice.”
Responding to Objections
Not surprisingly, the task force has heard objections to its draft guidelines. The first is that women aged 40-49 years are being denied mammograms, said Michelle Nadler, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto, Canada. “This [objection] has attained a lot of media coverage, which is unfortunate, because people who have not read the guidelines may believe this is true. The guidelines clearly state that an eligible, informed woman of this age group who wants a screening mammogram should receive one.”
The second commonly heard objection is that the task force is overestimating the harms of screening, such as anxiety and overdiagnosis, she said. But an outcome of “anxiety” was not factored into the guideline. Overdiagnosis was calculated on the basis of the literature, and estimates were converted to a common denominator so that they could be compared, said Dr. Nadler. The same was true of benefits.
Another objection was that screening could mean less need for chemotherapy or full axillary dissection, Dr. Nadler said. However, the task force did not find any primary studies that evaluated these outcomes.
Critics also said that the recommendations do not account for racial or ethnic variations. Although more research is likely needed in this area, “the task force states that individuals should be informed of all of their breast cancer risk factors, including race/ethnicity, and that this should be factored into decisions about screening,” said Dr. Nadler.
“I was very surprised that the task force was accused by some parties of paternalism,” added René Wittmer, MD, adjunct clinical professor of family medicine at the University of Montreal and chair of Choosing Wisely Quebec, Montreal, Canada. “In my opinion, the importance they place on shared decision-making is contrary to medical paternalism and aims to empower women to make a decision that fits with their values and preferences.”
Nevertheless, the inclusion of modeling studies and observational trials “may cause the potential benefits to be amplified, compared with what is seen in randomized controlled trials,” he said in an interview.
Decision Aids Help
Once the guidelines are finalized, decision aids will be available to patients and providers to help guide screening discussions, said Dr. Nadler. “Primary care providers need to be aware of an individual’s personal risk factors for breast cancer to know if they are at average, above average, or high lifetime risk of breast cancer. These guidelines do not apply to those with > 20% lifetime risk of breast cancer.”
“The standards for risk communication are in absolute numbers over a common denominator,” she noted. “This is how primary care providers discuss other important primary care topics like smoking cessation, cardiovascular disease (and decisions about statin medications), and osteoporosis risk. These same standards should apply for breast cancer screening.”
Furthermore, she said, providers “should be aware that individuals from marginalized communities may benefit from more than one conversation until they are able to make a decision about screening that is right for them.”
“There is good evidence showing that most advances we’ve seen in breast cancer outcomes (ie, reduction in breast cancer mortality) are likely due to improvements in treatment, not screening,” said Dr. Wittmer. “In fact, mortality reductions are seen even in age groups or countries where there is no routine screening. This means that women benefit from advances in treatments, whether they choose to get screened or not.”
‘Mammography Saves Lives’
Commenting on the updated guidelines, Janie Lee, MD, professor of radiology at the University of Washington School of Medicine and director of breast imaging at the Fred Hutchinson Cancer Center, both in Seattle, said: “For the USPSTF, benefits of life years gained were also considered, in addition to breast cancer deaths averted. To save more lives from breast cancer, guidelines may focus on screening women at older ages, when annual rates of breast cancer are higher.” By contrast, when thinking in terms of years of life saved, focusing on screening younger women, who have more years of life left, increases benefits. “Both are important outcomes that we want to improve with effective screening.”
That said, “we should follow the guidelines of our specific national organizations,” she continued. “Overall populations and healthcare systems are different between the US and Canada.”
For example, “the USPSTF specifically highlighted the potential for reducing breast cancer mortality in Black women, who are more likely to develop biologically aggressive tumors that are diagnosed at more advanced stages, when making updated recommendations earlier this year,” she said. “The Canadian guidelines did not make specific recommendations by race or ethnicity group, instead highlighting the need for more research on the impact of screening in these groups.”
In addition, “screening every year versus every other year is more routine in the US compared with Canada,” she noted. And nonmedical factors that influence health and that may influence access to medical care and timely diagnosis of breast cancer “may be different between our two countries.”
“The most important take-home message is that the scientific evidence is strong that screening mammography saves lives,” said Dr. Lee. “These new recommendations will hopefully result in more early diagnoses of breast cancer and save more lives. Screening works best when it’s used regularly, regardless of how frequently you return. Once you start screening, please urge your patients to plan to return.”
Dr. Nadler disclosed speaker honoraria and consulting fees from Novartis and Exact Sciences outside the scope of this interview and innovation funding from the NSH/UHN AMO Innovation Fund Competition for Developing and Implementing a Consensus Recommendation for Breast Cancer Screening Best Practices. Dr. Thériault is chair of the task force and chair of the working group for the draft guidelines. Dr. Wittmer is chair of Choosing Wisely Quebec. Dr. Lee reported no relevant financial relationships related to her interview.
A version of this article appeared on Medscape.com.
The draft guidelines stem from a review of more than 165 recent randomized controlled trials, observational studies, mathematical models, and other data.
The guideline working group included four breast cancer experts (a medical oncologist, a radiation oncologist, a surgical oncologist, and a radiologist), three patient partners, six family physicians, a nurse practitioner, evidence review teams, and other experts.
To avoid potential conflicts of interest, the oncologists provided input but did not vote on the final recommendations, Guylène Thériault, MD, a family physician and chair of the task force and Breast Cancer Working Group, said in an interview.
The guideline recommends that, after the potential benefits and harms of screening have been considered, mammography should be accessible every 2-3 years to women (ie, people assigned female at birth) between ages 40 and 74 years who are at average or moderately increased risk.
Women with a personal or extensive family history of breast cancer or genetic mutations that would increase breast cancer risk; those who have symptoms, such as a lump; those who feel they may be at high risk; and those who are transgender women should consult a healthcare provider about appropriate options, according to the updated guidelines, which do not apply to these patients.
The draft guidelines were published online on May 30 and are open for public comment until August 30.
‘Three Big Questions’
To develop the guidelines, the work group asked “three big questions,” said Dr. Thériault. The first was the effectiveness of breast cancer screening for women aged 40 years and over. For this question, this systematic review, unlike the 2018 guideline update, included not only randomized trials but also observational data to ensure that the work group considered all available data.
“The second question was about comparative effectiveness,” which is something the United States considered for the latest US Preventive Services Task Force (USPSTF) update, said Dr. Thériault. The USPSTF asked questions such as “What happens if we start screening patients at age 40 years? Or at age 50 years? What happens if we stop at age 74 years? Or if we use different tests such as 3D versus digital mammography?”
The Canadian Task Force relied on the evidence that the USPSTF found after grading it with its own criteria, she said. The results were similar, and so are the recommendations in this area. “For example, we don’t recommend supplementary screening for women with dense breasts because there are no studies to inform patient-oriented benefits.”
The third question was about the values and preferences of women regarding breast cancer screening, which is something the United States didn’t examine. “We had looked at that issue in 2018, and this time around, even though we expanded the type of studies, we got the same message: That there are differences between women in their 40s and those who are age 50 years and over.”
“The majority of women in their 40s think that the harms outweigh the benefits and are not interested in screening,” said Dr. Thériault. “But when I say the majority, that’s not every woman. So, we had to recognize that there is variability. And the majority, but not all, of women ages 50-74 years thinks the benefits are higher than the harms. That’s why we say in our recommendation that from ages 40 to 74, it’s a personal choice.”
Responding to Objections
Not surprisingly, the task force has heard objections to its draft guidelines. The first is that women aged 40-49 years are being denied mammograms, said Michelle Nadler, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto, Canada. “This [objection] has attained a lot of media coverage, which is unfortunate, because people who have not read the guidelines may believe this is true. The guidelines clearly state that an eligible, informed woman of this age group who wants a screening mammogram should receive one.”
The second commonly heard objection is that the task force is overestimating the harms of screening, such as anxiety and overdiagnosis, she said. But an outcome of “anxiety” was not factored into the guideline. Overdiagnosis was calculated on the basis of the literature, and estimates were converted to a common denominator so that they could be compared, said Dr. Nadler. The same was true of benefits.
Another objection was that screening could mean less need for chemotherapy or full axillary dissection, Dr. Nadler said. However, the task force did not find any primary studies that evaluated these outcomes.
Critics also said that the recommendations do not account for racial or ethnic variations. Although more research is likely needed in this area, “the task force states that individuals should be informed of all of their breast cancer risk factors, including race/ethnicity, and that this should be factored into decisions about screening,” said Dr. Nadler.
“I was very surprised that the task force was accused by some parties of paternalism,” added René Wittmer, MD, adjunct clinical professor of family medicine at the University of Montreal and chair of Choosing Wisely Quebec, Montreal, Canada. “In my opinion, the importance they place on shared decision-making is contrary to medical paternalism and aims to empower women to make a decision that fits with their values and preferences.”
Nevertheless, the inclusion of modeling studies and observational trials “may cause the potential benefits to be amplified, compared with what is seen in randomized controlled trials,” he said in an interview.
Decision Aids Help
Once the guidelines are finalized, decision aids will be available to patients and providers to help guide screening discussions, said Dr. Nadler. “Primary care providers need to be aware of an individual’s personal risk factors for breast cancer to know if they are at average, above average, or high lifetime risk of breast cancer. These guidelines do not apply to those with > 20% lifetime risk of breast cancer.”
“The standards for risk communication are in absolute numbers over a common denominator,” she noted. “This is how primary care providers discuss other important primary care topics like smoking cessation, cardiovascular disease (and decisions about statin medications), and osteoporosis risk. These same standards should apply for breast cancer screening.”
Furthermore, she said, providers “should be aware that individuals from marginalized communities may benefit from more than one conversation until they are able to make a decision about screening that is right for them.”
“There is good evidence showing that most advances we’ve seen in breast cancer outcomes (ie, reduction in breast cancer mortality) are likely due to improvements in treatment, not screening,” said Dr. Wittmer. “In fact, mortality reductions are seen even in age groups or countries where there is no routine screening. This means that women benefit from advances in treatments, whether they choose to get screened or not.”
‘Mammography Saves Lives’
Commenting on the updated guidelines, Janie Lee, MD, professor of radiology at the University of Washington School of Medicine and director of breast imaging at the Fred Hutchinson Cancer Center, both in Seattle, said: “For the USPSTF, benefits of life years gained were also considered, in addition to breast cancer deaths averted. To save more lives from breast cancer, guidelines may focus on screening women at older ages, when annual rates of breast cancer are higher.” By contrast, when thinking in terms of years of life saved, focusing on screening younger women, who have more years of life left, increases benefits. “Both are important outcomes that we want to improve with effective screening.”
That said, “we should follow the guidelines of our specific national organizations,” she continued. “Overall populations and healthcare systems are different between the US and Canada.”
For example, “the USPSTF specifically highlighted the potential for reducing breast cancer mortality in Black women, who are more likely to develop biologically aggressive tumors that are diagnosed at more advanced stages, when making updated recommendations earlier this year,” she said. “The Canadian guidelines did not make specific recommendations by race or ethnicity group, instead highlighting the need for more research on the impact of screening in these groups.”
In addition, “screening every year versus every other year is more routine in the US compared with Canada,” she noted. And nonmedical factors that influence health and that may influence access to medical care and timely diagnosis of breast cancer “may be different between our two countries.”
“The most important take-home message is that the scientific evidence is strong that screening mammography saves lives,” said Dr. Lee. “These new recommendations will hopefully result in more early diagnoses of breast cancer and save more lives. Screening works best when it’s used regularly, regardless of how frequently you return. Once you start screening, please urge your patients to plan to return.”
Dr. Nadler disclosed speaker honoraria and consulting fees from Novartis and Exact Sciences outside the scope of this interview and innovation funding from the NSH/UHN AMO Innovation Fund Competition for Developing and Implementing a Consensus Recommendation for Breast Cancer Screening Best Practices. Dr. Thériault is chair of the task force and chair of the working group for the draft guidelines. Dr. Wittmer is chair of Choosing Wisely Quebec. Dr. Lee reported no relevant financial relationships related to her interview.
A version of this article appeared on Medscape.com.
Should Cancer Trial Eligibility Become More Inclusive?
The study, published online in Clinical Cancer Research, highlighted the potential benefits of broadening eligibility criteria for clinical trials.
“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” senior author Hans Gelderblom, MD, chair of the Department of Medical Oncology at the Leiden University Medical Center, Leiden, the Netherlands, said in a press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”
Although experts have expressed interest in improving trial inclusivity, it’s unclear how doing so might impact treatment safety and efficacy.
In the Drug Rediscovery Protocol (DRUP), Dr. Gelderblom and colleagues examined the impact of broadening trial eligibility on patient outcomes. DRUP is an ongoing Dutch national, multicenter, pan-cancer, nonrandomized clinical trial in which patients are treated off-label with approved molecularly targeted or immunotherapies.
In the trial, 1019 patients with treatment-refractory disease were matched to one of the available study drugs based on their tumor molecular profile and enrolled in parallel cohorts. Cohorts were defined by tumor type, molecular profile, and study drug.
Among these patients, 82 patients — 8% of the cohort — were granted waivers to participate. Most waivers (45%) were granted as exceptions to general- or drug-related eligibility criteria, often because of out-of-range lab results. Other categories included treatment and testing exceptions, as well as out-of-window testing.
The researchers then compared safety and efficacy outcomes between the 82 participants granted waivers and the 937 who did not receive waivers.
Overall, Dr. Gelderblom’s team found that the rate of serious adverse events was similar between patients who received a waiver and those who did not: 39% vs 41%, respectively.
A relationship between waivers and serious adverse events was deemed “unlikely” for 86% of patients and “possible” for 14%. In two cases concerning a direct relationship, for instance, patients who received waivers for decreased hemoglobin levels developed anemia.
The rate of clinical benefit — defined as an objective response or stable disease for at least 16 weeks — was similar between the groups. Overall, 40% of patients who received a waiver (33 of 82) had a clinical benefit vs 33% of patients without a waiver (P = .43). Median overall survival for patients that received a waiver was also similar — 11 months in the waiver group and 8 months in the nonwaiver group (hazard ratio, 0.87; P = .33).
“Safety and clinical benefit were preserved in patients for whom a waiver was granted,” the authors concluded.
The study had several limitations. The diversity of cancer types, treatments, and reasons for protocol exemptions precluded subgroup analyses. In addition, because the decision to grant waivers depended in large part on the likelihood of clinical benefit, “it is possible that patients who received waivers were positively selected for clinical benefit compared with the general study population,” the authors wrote.
So, “although the clinical benefit rate of the patient group for whom a waiver was granted appears to be slightly higher, this difference might be explained by the selection process of the central study team, in which each waiver request was carefully considered, weighing the risks and potential benefits for the patient in question,” the authors explained.
Overall, “these findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Dr. Gelderblom said.
Commenting on the study, Bishal Gyawali, MD, PhD, said that “relaxing eligibility criteria is important, and I support this. Trials should include patients that are more representative of the real-world, so that results are generalizable.”
However, “the paper overemphasized efficacy,” said Dr. Gyawali, from Queen’s University, Kingston, Ontario, Canada. The sample size of waiver-granted patients was small, plus “the clinical benefit rate is not a marker of efficacy.
“The response rate is somewhat better, but for a heterogeneous study with multiple targets and drugs, it is difficult to say much about treatment effects here,” Dr. Gyawali added. Overall, “we shouldn’t read too much into treatment benefits based on these numbers.”
Funding for the study was provided by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai Co., Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Gelderblom declared no conflicts of interest, and Dr. Gyawali declared no conflicts of interest related to his comment.
A version of this article appeared on Medscape.com.
The study, published online in Clinical Cancer Research, highlighted the potential benefits of broadening eligibility criteria for clinical trials.
“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” senior author Hans Gelderblom, MD, chair of the Department of Medical Oncology at the Leiden University Medical Center, Leiden, the Netherlands, said in a press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”
Although experts have expressed interest in improving trial inclusivity, it’s unclear how doing so might impact treatment safety and efficacy.
In the Drug Rediscovery Protocol (DRUP), Dr. Gelderblom and colleagues examined the impact of broadening trial eligibility on patient outcomes. DRUP is an ongoing Dutch national, multicenter, pan-cancer, nonrandomized clinical trial in which patients are treated off-label with approved molecularly targeted or immunotherapies.
In the trial, 1019 patients with treatment-refractory disease were matched to one of the available study drugs based on their tumor molecular profile and enrolled in parallel cohorts. Cohorts were defined by tumor type, molecular profile, and study drug.
Among these patients, 82 patients — 8% of the cohort — were granted waivers to participate. Most waivers (45%) were granted as exceptions to general- or drug-related eligibility criteria, often because of out-of-range lab results. Other categories included treatment and testing exceptions, as well as out-of-window testing.
The researchers then compared safety and efficacy outcomes between the 82 participants granted waivers and the 937 who did not receive waivers.
Overall, Dr. Gelderblom’s team found that the rate of serious adverse events was similar between patients who received a waiver and those who did not: 39% vs 41%, respectively.
A relationship between waivers and serious adverse events was deemed “unlikely” for 86% of patients and “possible” for 14%. In two cases concerning a direct relationship, for instance, patients who received waivers for decreased hemoglobin levels developed anemia.
The rate of clinical benefit — defined as an objective response or stable disease for at least 16 weeks — was similar between the groups. Overall, 40% of patients who received a waiver (33 of 82) had a clinical benefit vs 33% of patients without a waiver (P = .43). Median overall survival for patients that received a waiver was also similar — 11 months in the waiver group and 8 months in the nonwaiver group (hazard ratio, 0.87; P = .33).
“Safety and clinical benefit were preserved in patients for whom a waiver was granted,” the authors concluded.
The study had several limitations. The diversity of cancer types, treatments, and reasons for protocol exemptions precluded subgroup analyses. In addition, because the decision to grant waivers depended in large part on the likelihood of clinical benefit, “it is possible that patients who received waivers were positively selected for clinical benefit compared with the general study population,” the authors wrote.
So, “although the clinical benefit rate of the patient group for whom a waiver was granted appears to be slightly higher, this difference might be explained by the selection process of the central study team, in which each waiver request was carefully considered, weighing the risks and potential benefits for the patient in question,” the authors explained.
Overall, “these findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Dr. Gelderblom said.
Commenting on the study, Bishal Gyawali, MD, PhD, said that “relaxing eligibility criteria is important, and I support this. Trials should include patients that are more representative of the real-world, so that results are generalizable.”
However, “the paper overemphasized efficacy,” said Dr. Gyawali, from Queen’s University, Kingston, Ontario, Canada. The sample size of waiver-granted patients was small, plus “the clinical benefit rate is not a marker of efficacy.
“The response rate is somewhat better, but for a heterogeneous study with multiple targets and drugs, it is difficult to say much about treatment effects here,” Dr. Gyawali added. Overall, “we shouldn’t read too much into treatment benefits based on these numbers.”
Funding for the study was provided by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai Co., Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Gelderblom declared no conflicts of interest, and Dr. Gyawali declared no conflicts of interest related to his comment.
A version of this article appeared on Medscape.com.
The study, published online in Clinical Cancer Research, highlighted the potential benefits of broadening eligibility criteria for clinical trials.
“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” senior author Hans Gelderblom, MD, chair of the Department of Medical Oncology at the Leiden University Medical Center, Leiden, the Netherlands, said in a press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”
Although experts have expressed interest in improving trial inclusivity, it’s unclear how doing so might impact treatment safety and efficacy.
In the Drug Rediscovery Protocol (DRUP), Dr. Gelderblom and colleagues examined the impact of broadening trial eligibility on patient outcomes. DRUP is an ongoing Dutch national, multicenter, pan-cancer, nonrandomized clinical trial in which patients are treated off-label with approved molecularly targeted or immunotherapies.
In the trial, 1019 patients with treatment-refractory disease were matched to one of the available study drugs based on their tumor molecular profile and enrolled in parallel cohorts. Cohorts were defined by tumor type, molecular profile, and study drug.
Among these patients, 82 patients — 8% of the cohort — were granted waivers to participate. Most waivers (45%) were granted as exceptions to general- or drug-related eligibility criteria, often because of out-of-range lab results. Other categories included treatment and testing exceptions, as well as out-of-window testing.
The researchers then compared safety and efficacy outcomes between the 82 participants granted waivers and the 937 who did not receive waivers.
Overall, Dr. Gelderblom’s team found that the rate of serious adverse events was similar between patients who received a waiver and those who did not: 39% vs 41%, respectively.
A relationship between waivers and serious adverse events was deemed “unlikely” for 86% of patients and “possible” for 14%. In two cases concerning a direct relationship, for instance, patients who received waivers for decreased hemoglobin levels developed anemia.
The rate of clinical benefit — defined as an objective response or stable disease for at least 16 weeks — was similar between the groups. Overall, 40% of patients who received a waiver (33 of 82) had a clinical benefit vs 33% of patients without a waiver (P = .43). Median overall survival for patients that received a waiver was also similar — 11 months in the waiver group and 8 months in the nonwaiver group (hazard ratio, 0.87; P = .33).
“Safety and clinical benefit were preserved in patients for whom a waiver was granted,” the authors concluded.
The study had several limitations. The diversity of cancer types, treatments, and reasons for protocol exemptions precluded subgroup analyses. In addition, because the decision to grant waivers depended in large part on the likelihood of clinical benefit, “it is possible that patients who received waivers were positively selected for clinical benefit compared with the general study population,” the authors wrote.
So, “although the clinical benefit rate of the patient group for whom a waiver was granted appears to be slightly higher, this difference might be explained by the selection process of the central study team, in which each waiver request was carefully considered, weighing the risks and potential benefits for the patient in question,” the authors explained.
Overall, “these findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Dr. Gelderblom said.
Commenting on the study, Bishal Gyawali, MD, PhD, said that “relaxing eligibility criteria is important, and I support this. Trials should include patients that are more representative of the real-world, so that results are generalizable.”
However, “the paper overemphasized efficacy,” said Dr. Gyawali, from Queen’s University, Kingston, Ontario, Canada. The sample size of waiver-granted patients was small, plus “the clinical benefit rate is not a marker of efficacy.
“The response rate is somewhat better, but for a heterogeneous study with multiple targets and drugs, it is difficult to say much about treatment effects here,” Dr. Gyawali added. Overall, “we shouldn’t read too much into treatment benefits based on these numbers.”
Funding for the study was provided by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai Co., Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Gelderblom declared no conflicts of interest, and Dr. Gyawali declared no conflicts of interest related to his comment.
A version of this article appeared on Medscape.com.
Severe Salt Restriction May Not Benefit Heart Failure
Strict sodium intake — with or without restrictions on fluid intake — is unlikely to confer clinical benefits on patients with heart failure, reported investigators.
Their review of
In fact, moderate daily intake of sodium (3.0-4.5 g) may improve the quality of life and functional status of these patients, even if it will not improve life expectancy or the hospitalization rate, Paolo Raggi, MD, from the University of Alberta, Edmonton, Alberta, Canada, explained in his narrative review published online in the European Journal of Clinical Investigation.
“It is always a little hard to give up long-held beliefs, and you try to find fault in the new evidence before your eyes,” he said.
Dr. Raggi, who is also coeditor of Atherosclerosis, explained this work was prompted in part by the large, multicenter SODIUM-HF study, which showed that sodium restriction did not reduce the composite outcome of all-cause mortality, cardiovascular hospitalization, and cardiovascular-related emergency department visits, although it did improve quality of life and New York Heart Association class.
And “excessive fluid restriction — typically we were taught to restrict fluid intake to 1 L/d or, at the most, 1.5 L — does not reduce mortality or hospitalization rates and inflicts unnecessary strain and pain on patients,” he said. “Clinicians need to get on board with this novel information.”
Examining the Evidence
For the narrative review, the researchers conducted a literature search for the terms heart failure, salt, sodium, and fluid intake to identify relevant reports.
Most randomized trials were small and examined widely heterogeneous interventions. The identified trials published from 2000 to 2021 had populations that ranged from 12 to 203 participants, had inpatients and outpatients, and included people with reduced and preserved ejection fraction. Sodium interventions varied from extreme reductions (< 800 mg/d) to more moderate approaches (2-3 g/d). No study, regardless of the level of restriction, showed a reduction in mortality or hospitalization rates.
Notably, SODIUM-HF — the randomized clinical trial of sodium restriction to a target of 1.5 g/d — was stopped early after an interim analysis demonstrated the futility of the intervention, and the COVID pandemic made it difficult to continue the trial.
Although a moderate sodium intake of 3-4.5 g/d “seems prudent” for patients with recurrent hospital admissions and fluid overload, an intake of 2-3 g/d may be a more acceptable level. “A more aggressive sodium restriction may be necessary in the presence of chronic kidney disease, where the handling of sodium by the kidneys is hampered,” Dr. Raggi reported.
“The debate on tight sodium restriction in heart failure continues to appear in major medical journals, yet it would seem that after many years of controversy, the time has come to close it,” he said.
‘One Approach Does Not Fit All’
Sodium restriction is difficult to quantify in a large cohort of patients because many studies are based on recall questionnaires and qualitative measurements, said Johanna Contreras, MD, an advanced heart failure and transplant cardiologist at the Mount Sinai Fuster Heart Hospital in New York City.
“Many patients are not aware that processed and precooked foods are very high in sodium and don’t count them as sodium-rich foods,” she said.
Nevertheless, heart failure has many etiologies and stages, so “one approach does not fit all,” she said. For example, patients with stage C heart failure “will clearly get more decompensated when they consume sodium-rich diets, which will increase water absorption.” And patients with heart failure secondary to hypertension are “particularly susceptible” and are likely to become more symptomatic and acutely congestive on diets high in sodium and water, which can increase both morbidity and mortality.
“It is important to understand the kinds of patients we are referring to, how advanced they are, and what comorbidities the patients have,” she said. “We also know that there are race, ethnicity, and gender differences in sensitivity to sodium.”
We should aim for a moderate sodium intake, she said, but patients with high sensitivity, multiple comorbidities, kidney disease, and certain demographic characteristics “need to be more careful.”
Overall, “patients should aim to consume fresh fruits and vegetables and [be aware of] processed foods and adding salt at the table when they are eating,” Dr. Contreras said.
A version of this article first appeared on Medscape.com.
Strict sodium intake — with or without restrictions on fluid intake — is unlikely to confer clinical benefits on patients with heart failure, reported investigators.
Their review of
In fact, moderate daily intake of sodium (3.0-4.5 g) may improve the quality of life and functional status of these patients, even if it will not improve life expectancy or the hospitalization rate, Paolo Raggi, MD, from the University of Alberta, Edmonton, Alberta, Canada, explained in his narrative review published online in the European Journal of Clinical Investigation.
“It is always a little hard to give up long-held beliefs, and you try to find fault in the new evidence before your eyes,” he said.
Dr. Raggi, who is also coeditor of Atherosclerosis, explained this work was prompted in part by the large, multicenter SODIUM-HF study, which showed that sodium restriction did not reduce the composite outcome of all-cause mortality, cardiovascular hospitalization, and cardiovascular-related emergency department visits, although it did improve quality of life and New York Heart Association class.
And “excessive fluid restriction — typically we were taught to restrict fluid intake to 1 L/d or, at the most, 1.5 L — does not reduce mortality or hospitalization rates and inflicts unnecessary strain and pain on patients,” he said. “Clinicians need to get on board with this novel information.”
Examining the Evidence
For the narrative review, the researchers conducted a literature search for the terms heart failure, salt, sodium, and fluid intake to identify relevant reports.
Most randomized trials were small and examined widely heterogeneous interventions. The identified trials published from 2000 to 2021 had populations that ranged from 12 to 203 participants, had inpatients and outpatients, and included people with reduced and preserved ejection fraction. Sodium interventions varied from extreme reductions (< 800 mg/d) to more moderate approaches (2-3 g/d). No study, regardless of the level of restriction, showed a reduction in mortality or hospitalization rates.
Notably, SODIUM-HF — the randomized clinical trial of sodium restriction to a target of 1.5 g/d — was stopped early after an interim analysis demonstrated the futility of the intervention, and the COVID pandemic made it difficult to continue the trial.
Although a moderate sodium intake of 3-4.5 g/d “seems prudent” for patients with recurrent hospital admissions and fluid overload, an intake of 2-3 g/d may be a more acceptable level. “A more aggressive sodium restriction may be necessary in the presence of chronic kidney disease, where the handling of sodium by the kidneys is hampered,” Dr. Raggi reported.
“The debate on tight sodium restriction in heart failure continues to appear in major medical journals, yet it would seem that after many years of controversy, the time has come to close it,” he said.
‘One Approach Does Not Fit All’
Sodium restriction is difficult to quantify in a large cohort of patients because many studies are based on recall questionnaires and qualitative measurements, said Johanna Contreras, MD, an advanced heart failure and transplant cardiologist at the Mount Sinai Fuster Heart Hospital in New York City.
“Many patients are not aware that processed and precooked foods are very high in sodium and don’t count them as sodium-rich foods,” she said.
Nevertheless, heart failure has many etiologies and stages, so “one approach does not fit all,” she said. For example, patients with stage C heart failure “will clearly get more decompensated when they consume sodium-rich diets, which will increase water absorption.” And patients with heart failure secondary to hypertension are “particularly susceptible” and are likely to become more symptomatic and acutely congestive on diets high in sodium and water, which can increase both morbidity and mortality.
“It is important to understand the kinds of patients we are referring to, how advanced they are, and what comorbidities the patients have,” she said. “We also know that there are race, ethnicity, and gender differences in sensitivity to sodium.”
We should aim for a moderate sodium intake, she said, but patients with high sensitivity, multiple comorbidities, kidney disease, and certain demographic characteristics “need to be more careful.”
Overall, “patients should aim to consume fresh fruits and vegetables and [be aware of] processed foods and adding salt at the table when they are eating,” Dr. Contreras said.
A version of this article first appeared on Medscape.com.
Strict sodium intake — with or without restrictions on fluid intake — is unlikely to confer clinical benefits on patients with heart failure, reported investigators.
Their review of
In fact, moderate daily intake of sodium (3.0-4.5 g) may improve the quality of life and functional status of these patients, even if it will not improve life expectancy or the hospitalization rate, Paolo Raggi, MD, from the University of Alberta, Edmonton, Alberta, Canada, explained in his narrative review published online in the European Journal of Clinical Investigation.
“It is always a little hard to give up long-held beliefs, and you try to find fault in the new evidence before your eyes,” he said.
Dr. Raggi, who is also coeditor of Atherosclerosis, explained this work was prompted in part by the large, multicenter SODIUM-HF study, which showed that sodium restriction did not reduce the composite outcome of all-cause mortality, cardiovascular hospitalization, and cardiovascular-related emergency department visits, although it did improve quality of life and New York Heart Association class.
And “excessive fluid restriction — typically we were taught to restrict fluid intake to 1 L/d or, at the most, 1.5 L — does not reduce mortality or hospitalization rates and inflicts unnecessary strain and pain on patients,” he said. “Clinicians need to get on board with this novel information.”
Examining the Evidence
For the narrative review, the researchers conducted a literature search for the terms heart failure, salt, sodium, and fluid intake to identify relevant reports.
Most randomized trials were small and examined widely heterogeneous interventions. The identified trials published from 2000 to 2021 had populations that ranged from 12 to 203 participants, had inpatients and outpatients, and included people with reduced and preserved ejection fraction. Sodium interventions varied from extreme reductions (< 800 mg/d) to more moderate approaches (2-3 g/d). No study, regardless of the level of restriction, showed a reduction in mortality or hospitalization rates.
Notably, SODIUM-HF — the randomized clinical trial of sodium restriction to a target of 1.5 g/d — was stopped early after an interim analysis demonstrated the futility of the intervention, and the COVID pandemic made it difficult to continue the trial.
Although a moderate sodium intake of 3-4.5 g/d “seems prudent” for patients with recurrent hospital admissions and fluid overload, an intake of 2-3 g/d may be a more acceptable level. “A more aggressive sodium restriction may be necessary in the presence of chronic kidney disease, where the handling of sodium by the kidneys is hampered,” Dr. Raggi reported.
“The debate on tight sodium restriction in heart failure continues to appear in major medical journals, yet it would seem that after many years of controversy, the time has come to close it,” he said.
‘One Approach Does Not Fit All’
Sodium restriction is difficult to quantify in a large cohort of patients because many studies are based on recall questionnaires and qualitative measurements, said Johanna Contreras, MD, an advanced heart failure and transplant cardiologist at the Mount Sinai Fuster Heart Hospital in New York City.
“Many patients are not aware that processed and precooked foods are very high in sodium and don’t count them as sodium-rich foods,” she said.
Nevertheless, heart failure has many etiologies and stages, so “one approach does not fit all,” she said. For example, patients with stage C heart failure “will clearly get more decompensated when they consume sodium-rich diets, which will increase water absorption.” And patients with heart failure secondary to hypertension are “particularly susceptible” and are likely to become more symptomatic and acutely congestive on diets high in sodium and water, which can increase both morbidity and mortality.
“It is important to understand the kinds of patients we are referring to, how advanced they are, and what comorbidities the patients have,” she said. “We also know that there are race, ethnicity, and gender differences in sensitivity to sodium.”
We should aim for a moderate sodium intake, she said, but patients with high sensitivity, multiple comorbidities, kidney disease, and certain demographic characteristics “need to be more careful.”
Overall, “patients should aim to consume fresh fruits and vegetables and [be aware of] processed foods and adding salt at the table when they are eating,” Dr. Contreras said.
A version of this article first appeared on Medscape.com.
FROM THE EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
Can Cannabis Help to Reduce Diabetes Risk?
ORLANDO, FLORIDA — , ongoing research suggests.
In the findings from the SONIC trial, Angela Bryan, PhD, professor and codirector of CUChange at the University of Colorado, Boulder, and colleagues hypothesized that “those inflammatory profiles would improve over the course of 4 weeks, particularly for those using a CBD [cannabidiol] as opposed to a THC [tetrahydrocannabinol] product.”
She presented the findings at the American Diabetes Association (ADA) 84th Scientific Sessions.
Other recent work by Dr. Bryan and her colleagues focused on the public health implications of cannabis legalization. One study examined the acute effects of legal-market cannabis on regular users’ subjective responses while running and found that cannabis use prior to exercise may lead to more enjoyment and runner’s high symptoms, although it also led to feelings of greater exertion. The positive effects could make exercise more appealing to individuals — including those with or at risk for diabetes — who might not otherwise engage in it, Bryan suggested.
Another study found that CBD-dominant forms of cannabis were associated with acute tension reduction, which might lead to longer-term reductions in anxiety. Bryan said the findings could be relevant in the context of diabetes distress.
‘Complicated’ Connection to Diabetes
In the SONIC study, participants who were regular cannabis users had an average age of 30 years and had body mass index (BMI) in the healthy range; 86% were White individuals, and 59% were men. They were matched with a similar group of individuals who had not used cannabis for at least a year. At baseline, participants’ NSDR Healthy Eating Index score overall was 51.24, showing a “need for improvement/poor diet.”
“Folks were maybe not killing it in the dietary domain,” Dr. Bryan acknowledged. “However, they were absolutely killing it in the physical activity domain.”
The researchers did oral glucose tolerance tests to calculate participants’ Matsuda index of insulin sensitivity and measured inflammatory markers, including tumor necrosis factor alpha, interleukin 6 (IL6), IL1 beta, IL12, interferon gamma, IL4, and monocyte chemoattractant protein 1 (MCP-1). In a “randomized encouragement” design, users were assigned to purchase and use a flower product for 4 weeks, however much they wanted. They completed daily assessments of their cannabis use, alcohol use, diet, and physical activity.
Between-group eating patterns were similar over the 4 weeks, with cannabis users reporting “marginally” more servings of salty snacks and food relative to nonusers. None of the daily associations were moderated by which cannabis product was used.
At 4 weeks, the team repeated the tests and, surprisingly, found no change in participants’ inflammatory markers. But what “popped out,” she said, was the “stark difference” between users and nonusers, with users having significantly lower levels of inflammatory biomarkers, circulating cytokines than the nonusers.
An exception were levels of MCP-1, which increased over time in the users but didn’t change in nonusers. Bryan said the finding is “perplexing” and asked the audience for thoughts, especially given that MCP-1 levels are positively associated with diabetes.
After controlling for BMI and inflammation, “we saw absolutely no effects of group or group by time interaction on the Matsuda index of insulin sensitivity,” she said. “Seemingly, there are no chronic effects of cannabis use on insulin sensitivity.”
Regarding limitations, Dr. Bryan acknowledged that the study is being conducted with “a very healthy sample of individuals who exercise a lot, and that might be factoring into our results, especially on insulin sensitivity.” The team could not use “gold standard” randomization because of the schedule-1 status of CannaVan cannabis, and the MCP-1 findings are difficult to interpret.
Furthermore, she noted, “our day-to-day level data show only slight differences in behavior between those who use cannabis and those who don’t and also very slight differences between users’ behavior on days that they use vs days that they don’t.
“I think all of this put together shows us that the relationship between cannabis use and potential implications for diabetes is a lot more complicated than just couch to couchlock [very deep relaxation/sedation] or runner’s high,” she said.
Bring On the CannaVan
The team’s next step, currently underway, is to get an acute response to cannabis with an oral glucose tolerance test that’s done immediately after the participant uses a product. Since cannabis is a schedule-1 drug, it can’t be taken into the laboratory. Therefore, the researchers are using a CannaVan — a mobile lab. “We drive it to their homes, they come out, we draw blood, and we send them back into their homes to use as much of their product as they want,” Bryan explained. “They come back out to the van. They do all the follow-up assessments. We take blood again to verify their exposure. And that’s how we collect those data.”
“Invite me back next year, and I will tell you what we found,” she quipped.
Dr. Bryan had no disclosures to report.
A version of this article first appeared on Medscape.com.
ORLANDO, FLORIDA — , ongoing research suggests.
In the findings from the SONIC trial, Angela Bryan, PhD, professor and codirector of CUChange at the University of Colorado, Boulder, and colleagues hypothesized that “those inflammatory profiles would improve over the course of 4 weeks, particularly for those using a CBD [cannabidiol] as opposed to a THC [tetrahydrocannabinol] product.”
She presented the findings at the American Diabetes Association (ADA) 84th Scientific Sessions.
Other recent work by Dr. Bryan and her colleagues focused on the public health implications of cannabis legalization. One study examined the acute effects of legal-market cannabis on regular users’ subjective responses while running and found that cannabis use prior to exercise may lead to more enjoyment and runner’s high symptoms, although it also led to feelings of greater exertion. The positive effects could make exercise more appealing to individuals — including those with or at risk for diabetes — who might not otherwise engage in it, Bryan suggested.
Another study found that CBD-dominant forms of cannabis were associated with acute tension reduction, which might lead to longer-term reductions in anxiety. Bryan said the findings could be relevant in the context of diabetes distress.
‘Complicated’ Connection to Diabetes
In the SONIC study, participants who were regular cannabis users had an average age of 30 years and had body mass index (BMI) in the healthy range; 86% were White individuals, and 59% were men. They were matched with a similar group of individuals who had not used cannabis for at least a year. At baseline, participants’ NSDR Healthy Eating Index score overall was 51.24, showing a “need for improvement/poor diet.”
“Folks were maybe not killing it in the dietary domain,” Dr. Bryan acknowledged. “However, they were absolutely killing it in the physical activity domain.”
The researchers did oral glucose tolerance tests to calculate participants’ Matsuda index of insulin sensitivity and measured inflammatory markers, including tumor necrosis factor alpha, interleukin 6 (IL6), IL1 beta, IL12, interferon gamma, IL4, and monocyte chemoattractant protein 1 (MCP-1). In a “randomized encouragement” design, users were assigned to purchase and use a flower product for 4 weeks, however much they wanted. They completed daily assessments of their cannabis use, alcohol use, diet, and physical activity.
Between-group eating patterns were similar over the 4 weeks, with cannabis users reporting “marginally” more servings of salty snacks and food relative to nonusers. None of the daily associations were moderated by which cannabis product was used.
At 4 weeks, the team repeated the tests and, surprisingly, found no change in participants’ inflammatory markers. But what “popped out,” she said, was the “stark difference” between users and nonusers, with users having significantly lower levels of inflammatory biomarkers, circulating cytokines than the nonusers.
An exception were levels of MCP-1, which increased over time in the users but didn’t change in nonusers. Bryan said the finding is “perplexing” and asked the audience for thoughts, especially given that MCP-1 levels are positively associated with diabetes.
After controlling for BMI and inflammation, “we saw absolutely no effects of group or group by time interaction on the Matsuda index of insulin sensitivity,” she said. “Seemingly, there are no chronic effects of cannabis use on insulin sensitivity.”
Regarding limitations, Dr. Bryan acknowledged that the study is being conducted with “a very healthy sample of individuals who exercise a lot, and that might be factoring into our results, especially on insulin sensitivity.” The team could not use “gold standard” randomization because of the schedule-1 status of CannaVan cannabis, and the MCP-1 findings are difficult to interpret.
Furthermore, she noted, “our day-to-day level data show only slight differences in behavior between those who use cannabis and those who don’t and also very slight differences between users’ behavior on days that they use vs days that they don’t.
“I think all of this put together shows us that the relationship between cannabis use and potential implications for diabetes is a lot more complicated than just couch to couchlock [very deep relaxation/sedation] or runner’s high,” she said.
Bring On the CannaVan
The team’s next step, currently underway, is to get an acute response to cannabis with an oral glucose tolerance test that’s done immediately after the participant uses a product. Since cannabis is a schedule-1 drug, it can’t be taken into the laboratory. Therefore, the researchers are using a CannaVan — a mobile lab. “We drive it to their homes, they come out, we draw blood, and we send them back into their homes to use as much of their product as they want,” Bryan explained. “They come back out to the van. They do all the follow-up assessments. We take blood again to verify their exposure. And that’s how we collect those data.”
“Invite me back next year, and I will tell you what we found,” she quipped.
Dr. Bryan had no disclosures to report.
A version of this article first appeared on Medscape.com.
ORLANDO, FLORIDA — , ongoing research suggests.
In the findings from the SONIC trial, Angela Bryan, PhD, professor and codirector of CUChange at the University of Colorado, Boulder, and colleagues hypothesized that “those inflammatory profiles would improve over the course of 4 weeks, particularly for those using a CBD [cannabidiol] as opposed to a THC [tetrahydrocannabinol] product.”
She presented the findings at the American Diabetes Association (ADA) 84th Scientific Sessions.
Other recent work by Dr. Bryan and her colleagues focused on the public health implications of cannabis legalization. One study examined the acute effects of legal-market cannabis on regular users’ subjective responses while running and found that cannabis use prior to exercise may lead to more enjoyment and runner’s high symptoms, although it also led to feelings of greater exertion. The positive effects could make exercise more appealing to individuals — including those with or at risk for diabetes — who might not otherwise engage in it, Bryan suggested.
Another study found that CBD-dominant forms of cannabis were associated with acute tension reduction, which might lead to longer-term reductions in anxiety. Bryan said the findings could be relevant in the context of diabetes distress.
‘Complicated’ Connection to Diabetes
In the SONIC study, participants who were regular cannabis users had an average age of 30 years and had body mass index (BMI) in the healthy range; 86% were White individuals, and 59% were men. They were matched with a similar group of individuals who had not used cannabis for at least a year. At baseline, participants’ NSDR Healthy Eating Index score overall was 51.24, showing a “need for improvement/poor diet.”
“Folks were maybe not killing it in the dietary domain,” Dr. Bryan acknowledged. “However, they were absolutely killing it in the physical activity domain.”
The researchers did oral glucose tolerance tests to calculate participants’ Matsuda index of insulin sensitivity and measured inflammatory markers, including tumor necrosis factor alpha, interleukin 6 (IL6), IL1 beta, IL12, interferon gamma, IL4, and monocyte chemoattractant protein 1 (MCP-1). In a “randomized encouragement” design, users were assigned to purchase and use a flower product for 4 weeks, however much they wanted. They completed daily assessments of their cannabis use, alcohol use, diet, and physical activity.
Between-group eating patterns were similar over the 4 weeks, with cannabis users reporting “marginally” more servings of salty snacks and food relative to nonusers. None of the daily associations were moderated by which cannabis product was used.
At 4 weeks, the team repeated the tests and, surprisingly, found no change in participants’ inflammatory markers. But what “popped out,” she said, was the “stark difference” between users and nonusers, with users having significantly lower levels of inflammatory biomarkers, circulating cytokines than the nonusers.
An exception were levels of MCP-1, which increased over time in the users but didn’t change in nonusers. Bryan said the finding is “perplexing” and asked the audience for thoughts, especially given that MCP-1 levels are positively associated with diabetes.
After controlling for BMI and inflammation, “we saw absolutely no effects of group or group by time interaction on the Matsuda index of insulin sensitivity,” she said. “Seemingly, there are no chronic effects of cannabis use on insulin sensitivity.”
Regarding limitations, Dr. Bryan acknowledged that the study is being conducted with “a very healthy sample of individuals who exercise a lot, and that might be factoring into our results, especially on insulin sensitivity.” The team could not use “gold standard” randomization because of the schedule-1 status of CannaVan cannabis, and the MCP-1 findings are difficult to interpret.
Furthermore, she noted, “our day-to-day level data show only slight differences in behavior between those who use cannabis and those who don’t and also very slight differences between users’ behavior on days that they use vs days that they don’t.
“I think all of this put together shows us that the relationship between cannabis use and potential implications for diabetes is a lot more complicated than just couch to couchlock [very deep relaxation/sedation] or runner’s high,” she said.
Bring On the CannaVan
The team’s next step, currently underway, is to get an acute response to cannabis with an oral glucose tolerance test that’s done immediately after the participant uses a product. Since cannabis is a schedule-1 drug, it can’t be taken into the laboratory. Therefore, the researchers are using a CannaVan — a mobile lab. “We drive it to their homes, they come out, we draw blood, and we send them back into their homes to use as much of their product as they want,” Bryan explained. “They come back out to the van. They do all the follow-up assessments. We take blood again to verify their exposure. And that’s how we collect those data.”
“Invite me back next year, and I will tell you what we found,” she quipped.
Dr. Bryan had no disclosures to report.
A version of this article first appeared on Medscape.com.
FROM ADA 2024
Lung Cancer Screening Can Boost Early Diagnosis, Survival
TOPLINE:
Lung cancer screening was associated with earlier-stage diagnoses and improved survival in a retrospective analysis of a large cohort with low screening uptake.
METHODOLOGY:
- Randomized trials have shown a mortality benefit with low-dose CT screening to detect lung cancer, but the benefits in clinical practice remain unclear, and lung cancer screening uptake has been slow.
- In this study, researchers assessed the impact of lung cancer screening among Veteran Health Administration patients diagnosed with lung cancer between 2011 and 2018.
- The team evaluated lung cancer stage at diagnosis, lung cancer–specific survival, and overall survival in patients with lung cancer who did vs did not receive screening before their diagnosis.
- Statistical analyses included Cox regression modeling and inverse propensity weighting with lead-time bias adjustment.
TAKEAWAY:
- Among 57,919 individuals diagnosed with lung cancer during the study period, 2167 (3.9%) underwent screening with at least one low-dose CT before receiving their diagnosis. There were no significant differences in age, gender, or race among patients who had prior screening and those who did not.
- Screened patients had double the rate of stage I diagnoses compared with unscreened patients (52% vs 27%) and about one third the rate of stage IV diagnoses (11% vs 32%).
- Patients who received screening before their cancer diagnosis had better overall survival rates compared with unscreened patients. The overall survival rates were 81.2% vs 56.6% at 1 year, 69.9% vs 41.1% at 2 years, and 44.9% vs 22.3% at 5 years, respectively. Lung cancer–specific survival was also better: The survival rates were 82.5% vs 58.7% at 1 year, 74.3% vs 44.4% at 2 years, and 59.0% vs 29.7% at 5 years, respectively.
- A subset analysis of screening-eligible patients (defined as those between the ages of 50-88 who were smokers with a pack-year history of ≥ 20 years or former smokers who quit within 15 years) showed that among those who underwent National Comprehensive Cancer Network guideline-concordant treatment within 12 months of diagnosis, screening resulted in “substantial” reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79) and lung cancer–specific mortality (aHR, 0.61).
IN PRACTICE:
“These findings provide corroboration of the results of randomized [lung cancer screening] trials in clinical practice,” the authors wrote. “We hope that the striking association between [lung cancer screening], earlier stage diagnosis of lung cancer, and improved mortality spurs a more robust uptake of this life-saving intervention into clinical practice.”
SOURCE:
The study, led by Donna M. Edwards MD, PhD, of the University of Michigan School of Medicine, Ann Arbor, Michigan, was published online in Cancer.
LIMITATIONS:
The study was limited by its retrospective and correlative design, and the authors also were unable to assess whether lung cancer screening contributed to more subsequence procedures in screened vs unscreened patients.
DISCLOSURES:
The study was funded by the LUNGevity Foundation, US Department of Veterans Affairs, National Cancer Institute, and Lung Precision Oncology Program. One author declared being a consultant for industry. The other authors declared no conflicts of interest.
A version of this article first appeared on Medscape.com.
TOPLINE:
Lung cancer screening was associated with earlier-stage diagnoses and improved survival in a retrospective analysis of a large cohort with low screening uptake.
METHODOLOGY:
- Randomized trials have shown a mortality benefit with low-dose CT screening to detect lung cancer, but the benefits in clinical practice remain unclear, and lung cancer screening uptake has been slow.
- In this study, researchers assessed the impact of lung cancer screening among Veteran Health Administration patients diagnosed with lung cancer between 2011 and 2018.
- The team evaluated lung cancer stage at diagnosis, lung cancer–specific survival, and overall survival in patients with lung cancer who did vs did not receive screening before their diagnosis.
- Statistical analyses included Cox regression modeling and inverse propensity weighting with lead-time bias adjustment.
TAKEAWAY:
- Among 57,919 individuals diagnosed with lung cancer during the study period, 2167 (3.9%) underwent screening with at least one low-dose CT before receiving their diagnosis. There were no significant differences in age, gender, or race among patients who had prior screening and those who did not.
- Screened patients had double the rate of stage I diagnoses compared with unscreened patients (52% vs 27%) and about one third the rate of stage IV diagnoses (11% vs 32%).
- Patients who received screening before their cancer diagnosis had better overall survival rates compared with unscreened patients. The overall survival rates were 81.2% vs 56.6% at 1 year, 69.9% vs 41.1% at 2 years, and 44.9% vs 22.3% at 5 years, respectively. Lung cancer–specific survival was also better: The survival rates were 82.5% vs 58.7% at 1 year, 74.3% vs 44.4% at 2 years, and 59.0% vs 29.7% at 5 years, respectively.
- A subset analysis of screening-eligible patients (defined as those between the ages of 50-88 who were smokers with a pack-year history of ≥ 20 years or former smokers who quit within 15 years) showed that among those who underwent National Comprehensive Cancer Network guideline-concordant treatment within 12 months of diagnosis, screening resulted in “substantial” reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79) and lung cancer–specific mortality (aHR, 0.61).
IN PRACTICE:
“These findings provide corroboration of the results of randomized [lung cancer screening] trials in clinical practice,” the authors wrote. “We hope that the striking association between [lung cancer screening], earlier stage diagnosis of lung cancer, and improved mortality spurs a more robust uptake of this life-saving intervention into clinical practice.”
SOURCE:
The study, led by Donna M. Edwards MD, PhD, of the University of Michigan School of Medicine, Ann Arbor, Michigan, was published online in Cancer.
LIMITATIONS:
The study was limited by its retrospective and correlative design, and the authors also were unable to assess whether lung cancer screening contributed to more subsequence procedures in screened vs unscreened patients.
DISCLOSURES:
The study was funded by the LUNGevity Foundation, US Department of Veterans Affairs, National Cancer Institute, and Lung Precision Oncology Program. One author declared being a consultant for industry. The other authors declared no conflicts of interest.
A version of this article first appeared on Medscape.com.
TOPLINE:
Lung cancer screening was associated with earlier-stage diagnoses and improved survival in a retrospective analysis of a large cohort with low screening uptake.
METHODOLOGY:
- Randomized trials have shown a mortality benefit with low-dose CT screening to detect lung cancer, but the benefits in clinical practice remain unclear, and lung cancer screening uptake has been slow.
- In this study, researchers assessed the impact of lung cancer screening among Veteran Health Administration patients diagnosed with lung cancer between 2011 and 2018.
- The team evaluated lung cancer stage at diagnosis, lung cancer–specific survival, and overall survival in patients with lung cancer who did vs did not receive screening before their diagnosis.
- Statistical analyses included Cox regression modeling and inverse propensity weighting with lead-time bias adjustment.
TAKEAWAY:
- Among 57,919 individuals diagnosed with lung cancer during the study period, 2167 (3.9%) underwent screening with at least one low-dose CT before receiving their diagnosis. There were no significant differences in age, gender, or race among patients who had prior screening and those who did not.
- Screened patients had double the rate of stage I diagnoses compared with unscreened patients (52% vs 27%) and about one third the rate of stage IV diagnoses (11% vs 32%).
- Patients who received screening before their cancer diagnosis had better overall survival rates compared with unscreened patients. The overall survival rates were 81.2% vs 56.6% at 1 year, 69.9% vs 41.1% at 2 years, and 44.9% vs 22.3% at 5 years, respectively. Lung cancer–specific survival was also better: The survival rates were 82.5% vs 58.7% at 1 year, 74.3% vs 44.4% at 2 years, and 59.0% vs 29.7% at 5 years, respectively.
- A subset analysis of screening-eligible patients (defined as those between the ages of 50-88 who were smokers with a pack-year history of ≥ 20 years or former smokers who quit within 15 years) showed that among those who underwent National Comprehensive Cancer Network guideline-concordant treatment within 12 months of diagnosis, screening resulted in “substantial” reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79) and lung cancer–specific mortality (aHR, 0.61).
IN PRACTICE:
“These findings provide corroboration of the results of randomized [lung cancer screening] trials in clinical practice,” the authors wrote. “We hope that the striking association between [lung cancer screening], earlier stage diagnosis of lung cancer, and improved mortality spurs a more robust uptake of this life-saving intervention into clinical practice.”
SOURCE:
The study, led by Donna M. Edwards MD, PhD, of the University of Michigan School of Medicine, Ann Arbor, Michigan, was published online in Cancer.
LIMITATIONS:
The study was limited by its retrospective and correlative design, and the authors also were unable to assess whether lung cancer screening contributed to more subsequence procedures in screened vs unscreened patients.
DISCLOSURES:
The study was funded by the LUNGevity Foundation, US Department of Veterans Affairs, National Cancer Institute, and Lung Precision Oncology Program. One author declared being a consultant for industry. The other authors declared no conflicts of interest.
A version of this article first appeared on Medscape.com.
Intermittent Fasting Tops Calorie Restriction for Gut Health
TOPLINE:
Individuals on an intermittent-fasting and protein-pacing (IF-P) diet had fewer gastrointestinal symptoms and increased diversity in gut microbiota than those on a calorie-restricted (CR) Mediterranean-style diet in a small, randomized trial.
METHODOLOGY:
- Researchers compared the effects on gastrointestinal symptoms, the gut microbiome, and circulating cytokines and metabolites of two low-calorie, 8-week dietary interventions: A Mediterranean-style continuous CR diet based on US dietary recommendations and an IF-P diet. The interventions were matched for energy intake.
- Participants included men and women with overweight/obesity who were randomly assigned to one of the two groups: CR diet (n = 20) and IF-P diet (n = 21).
- Researchers used samples and data from an ongoing randomized controlled trial (https://clinicaltrials.gov/study/NCT04327141) comparing the effects of the CR diet vs the IF-P diet on anthropometric and cardiometabolic outcomes.
- In a subanalysis for the current study, researchers compared outcomes in “high” and “low” responders to the IF-P regimen, based on relative weight loss.
TAKEAWAY:
- and in the abundance of microbial families and genera associated with favorable metabolic profiles, such as Christensenellaceae, Rikenellaceae, and Marvinbryantia, than the CR diet.
- The IF-P diet significantly increased cytokines linked to lipolysis, weight loss, inflammation, and the immune response.
- With the CR diet, metabolites associated with a longevity-related metabolic pathway increased.
- The subgroup analysis of high and low responders to the IF-P diet showed an increased abundance of certain bacteria associated with metabolic benefits and anti-inflammatory effects among high responders, whereas low responders showed an increased abundance of butyrate-producing and nutritionally adaptive species such as Eubacterium ventriosum and Roseburia inulinivorans.
- A fecal metabolome analysis revealed that high responders showed enrichment of fecal metabolites involved in lipid metabolism, whereas more prominent pathways in low responders were related to the metabolism of amino acids and peptides, as well as tyrosine metabolism and arginine biosynthesis.
IN PRACTICE:
“These findings shed light on the differential effects of IF regimens, including IF-P, as a promising dietary intervention for obesity management and microbiotic and metabolic health.”
SOURCE:
The study, with corresponding author Paul J. Arciero, PhD, of the Human Nutrition and Metabolism Laboratory at Skidmore College, Saratoga Springs, New York, was published online in Nature Communications.
LIMITATIONS:
The reliance on fecal samples to represent the gut microbiome may have overlooked potential microbial populations in the upper gastrointestinal tract. Other limitations include the short, 8-week duration of the trial and small number of patients.
DISCLOSURES:
The study was primarily funded by an unrestricted grant from Isagenix International LLC to Arciero, with secondary funding provided to a coauthor. Dr. Arciero is a consultant for Isagenix International LLC, is an advisory board member of the International Protein Board, and received financial compensation for books and keynote presentations on protein pacing. One coauthor is employed by the funder.
A version of this article appeared on Medscape.com.
TOPLINE:
Individuals on an intermittent-fasting and protein-pacing (IF-P) diet had fewer gastrointestinal symptoms and increased diversity in gut microbiota than those on a calorie-restricted (CR) Mediterranean-style diet in a small, randomized trial.
METHODOLOGY:
- Researchers compared the effects on gastrointestinal symptoms, the gut microbiome, and circulating cytokines and metabolites of two low-calorie, 8-week dietary interventions: A Mediterranean-style continuous CR diet based on US dietary recommendations and an IF-P diet. The interventions were matched for energy intake.
- Participants included men and women with overweight/obesity who were randomly assigned to one of the two groups: CR diet (n = 20) and IF-P diet (n = 21).
- Researchers used samples and data from an ongoing randomized controlled trial (https://clinicaltrials.gov/study/NCT04327141) comparing the effects of the CR diet vs the IF-P diet on anthropometric and cardiometabolic outcomes.
- In a subanalysis for the current study, researchers compared outcomes in “high” and “low” responders to the IF-P regimen, based on relative weight loss.
TAKEAWAY:
- and in the abundance of microbial families and genera associated with favorable metabolic profiles, such as Christensenellaceae, Rikenellaceae, and Marvinbryantia, than the CR diet.
- The IF-P diet significantly increased cytokines linked to lipolysis, weight loss, inflammation, and the immune response.
- With the CR diet, metabolites associated with a longevity-related metabolic pathway increased.
- The subgroup analysis of high and low responders to the IF-P diet showed an increased abundance of certain bacteria associated with metabolic benefits and anti-inflammatory effects among high responders, whereas low responders showed an increased abundance of butyrate-producing and nutritionally adaptive species such as Eubacterium ventriosum and Roseburia inulinivorans.
- A fecal metabolome analysis revealed that high responders showed enrichment of fecal metabolites involved in lipid metabolism, whereas more prominent pathways in low responders were related to the metabolism of amino acids and peptides, as well as tyrosine metabolism and arginine biosynthesis.
IN PRACTICE:
“These findings shed light on the differential effects of IF regimens, including IF-P, as a promising dietary intervention for obesity management and microbiotic and metabolic health.”
SOURCE:
The study, with corresponding author Paul J. Arciero, PhD, of the Human Nutrition and Metabolism Laboratory at Skidmore College, Saratoga Springs, New York, was published online in Nature Communications.
LIMITATIONS:
The reliance on fecal samples to represent the gut microbiome may have overlooked potential microbial populations in the upper gastrointestinal tract. Other limitations include the short, 8-week duration of the trial and small number of patients.
DISCLOSURES:
The study was primarily funded by an unrestricted grant from Isagenix International LLC to Arciero, with secondary funding provided to a coauthor. Dr. Arciero is a consultant for Isagenix International LLC, is an advisory board member of the International Protein Board, and received financial compensation for books and keynote presentations on protein pacing. One coauthor is employed by the funder.
A version of this article appeared on Medscape.com.
TOPLINE:
Individuals on an intermittent-fasting and protein-pacing (IF-P) diet had fewer gastrointestinal symptoms and increased diversity in gut microbiota than those on a calorie-restricted (CR) Mediterranean-style diet in a small, randomized trial.
METHODOLOGY:
- Researchers compared the effects on gastrointestinal symptoms, the gut microbiome, and circulating cytokines and metabolites of two low-calorie, 8-week dietary interventions: A Mediterranean-style continuous CR diet based on US dietary recommendations and an IF-P diet. The interventions were matched for energy intake.
- Participants included men and women with overweight/obesity who were randomly assigned to one of the two groups: CR diet (n = 20) and IF-P diet (n = 21).
- Researchers used samples and data from an ongoing randomized controlled trial (https://clinicaltrials.gov/study/NCT04327141) comparing the effects of the CR diet vs the IF-P diet on anthropometric and cardiometabolic outcomes.
- In a subanalysis for the current study, researchers compared outcomes in “high” and “low” responders to the IF-P regimen, based on relative weight loss.
TAKEAWAY:
- and in the abundance of microbial families and genera associated with favorable metabolic profiles, such as Christensenellaceae, Rikenellaceae, and Marvinbryantia, than the CR diet.
- The IF-P diet significantly increased cytokines linked to lipolysis, weight loss, inflammation, and the immune response.
- With the CR diet, metabolites associated with a longevity-related metabolic pathway increased.
- The subgroup analysis of high and low responders to the IF-P diet showed an increased abundance of certain bacteria associated with metabolic benefits and anti-inflammatory effects among high responders, whereas low responders showed an increased abundance of butyrate-producing and nutritionally adaptive species such as Eubacterium ventriosum and Roseburia inulinivorans.
- A fecal metabolome analysis revealed that high responders showed enrichment of fecal metabolites involved in lipid metabolism, whereas more prominent pathways in low responders were related to the metabolism of amino acids and peptides, as well as tyrosine metabolism and arginine biosynthesis.
IN PRACTICE:
“These findings shed light on the differential effects of IF regimens, including IF-P, as a promising dietary intervention for obesity management and microbiotic and metabolic health.”
SOURCE:
The study, with corresponding author Paul J. Arciero, PhD, of the Human Nutrition and Metabolism Laboratory at Skidmore College, Saratoga Springs, New York, was published online in Nature Communications.
LIMITATIONS:
The reliance on fecal samples to represent the gut microbiome may have overlooked potential microbial populations in the upper gastrointestinal tract. Other limitations include the short, 8-week duration of the trial and small number of patients.
DISCLOSURES:
The study was primarily funded by an unrestricted grant from Isagenix International LLC to Arciero, with secondary funding provided to a coauthor. Dr. Arciero is a consultant for Isagenix International LLC, is an advisory board member of the International Protein Board, and received financial compensation for books and keynote presentations on protein pacing. One coauthor is employed by the funder.
A version of this article appeared on Medscape.com.
Do Artificial Sweeteners Really Help People With Diabetes?
It seems intuitive that, because people with type 2 diabetes (T2D) generally need to avoid sugar, clinicians should recommend eating foods and using recipes containing artificial sweeteners such as sucralose instead.
Splenda, which produces sucralose and other non-sugar sweeteners (NSS), is a sponsor of the American Diabetes Association (ADA) Diabetes Food Hub. Earlier in 2024, the ADA settled a lawsuit regarding its former director of nutrition’s refusal to approve recipes containing sucralose (Splenda), which she believed “flew in the face of the ADA’s mission.”
“There’s not a lot of evidence that sweeteners like sucralose provide significant benefits, especially over the long term,” said Susan Swithers, PhD, professor, department of psychological sciences and associate dean for faculty affairs at Purdue University, West Lafayette, Indiana.
Dr. Swithers authored an article several years ago cautioning that consuming nonnutritive sweeteners in beverages not only fails to prevent disease but also is associated with an increase in risks for the same health outcomes associated with sugar-sweetened beverages, including T2D, cardiovascular disease, hypertension, and stroke.
“At this point, we have pretty good evidence that these chemicals that were once touted as being completely inert are, in fact, not inert,” she said. “We know that they’re unlikely to be toxic in the short term, but they are not benign, and they have consequences. Right now, we have little understanding of the outcomes of consumption of these products chronically.”
What the Science Says
In 2023, the World Health Organization (WHO) released a guideline on NSS that recommended against their use for weight control or to reduce the risk for noncommunicable diseases.
The systematic review and meta-analysis upon which the guideline is based found that high intakes of NSS were associated with increases in body mass index and, as Dr. Swithers found, risks of developing T2D, cardiovascular events, and any type of stroke, as well as hypertension, bladder cancer, and all-cause mortality.
In a press release announcing the guideline, Francesco Branca, WHO director for Nutrition and Food Safety, said, “NSS are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health.”
The “common” NSS named by WHO included sucralose, as well as acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, stevia, and stevia derivatives.
If NSS consumption can increase T2D risk, what about people who already have T2D?
Some research suggests that NSS may affect people with and without T2D differently, said Dr. Swithers. For example, one small study showed that sucralose enhanced glucagon-like peptide 1 release and lowered blood glucose in healthy patients but not in patients with newly diagnosed T2D.
Similarly, Jotham Suez, PhD, an assistant professor in the department of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said in an interview that his group “showed for the first time in 2014 that disruption of the microbiome by artificial sweeteners is causally linked to disrupted glycemic control.”
Recently, the team studied the impact of sucralose, aspartame, saccharin, and stevia in healthy adults and “were surprised to discover that all four sweeteners altered gut bacteria and the molecules they secrete,” he said. However, subsequent glucose tolerance tests in healthy humans showed varying results, “suggesting that human microbiome responses to the nonnutritive sweeteners we assessed are highly personalized and may lead to glycemic alterations in some, but not all, consumers depending on their microbes and the sweeteners they consume.”
Nevertheless, a recent review led by researchers in Mexico concluded that sucralose consumption “is associated with various adverse health effects. Despite being considered safe following previous studies, recent research suggests possible links to systemic inflammation, metabolic diseases, disruptions in gut microbiota, liver damage, and toxic effects at the cellular level.”
In addition, they wrote, “it is crucial to highlight the persistence of sucralose in the body, its ability to cross the placenta, and its presence in breast milk, raising concerns about prenatal and neonatal exposure.”
Sabyasachi Sen, MD, a professor of biochemistry and molecular medicine at George Washington School of Medicine & Health Sciences, Washington, DC, has led and coauthored preclinical and clinical studies demonstrating the potential ill effects of sucralose and other artificial sweeteners. One showed that sucralose and acesulfame potassium–containing diet soda altered microbial taxa in two pilot studies in healthy young adults; another showed a connection between artificial sweeteners and inflammation.
But Dr. Sen’s current work is directed at his team’s finding that sucralose promotes the accumulation of reactive oxygen species and adipogenesis in human stem cells, he said in an interview. “It is essentially an additive that is clearly harmful to cells. Our concern is that stem cells are going to remain in the system for a long period of time. If it is causing inflammation in these cells, then that may lead to adverse outcomes.”
Ruchi Mathur, MD, director of the Diabetes Outpatient Treatment & Education Center at Cedars-Sinai in Los Angeles, California, is the principal investigator of a recent study suggesting that non-aspartame NSS and aspartame alone may alter the structure and function of the stool and duodenal microbiomes. Levels of circulating inflammatory markers were also altered in participants who consumed artificial sweeteners, compared with control participants who did not.
In addition to these potential adverse effects, “we have to think about the fact that patients with diabetes often have other comorbidities like obesity and are at higher risk for cardiovascular disease and other conditions,” she said in an interview. “If you’re taking a patient who’s already at risk for those things and you don’t have a detailed discussion with them about pros and cons, you’re doing them a disservice.”
Industry Interests
Addressing the largely negative but varying findings, Dr. Swithers said, “one of the difficulties with getting clear answers about the science is that the food and beverage industry has an interest in confusing the picture. If people are selling or using a product, the best thing is for them not have a clear reason to change their behavior. All that needs to happen is for them to be able say, ‘well, it’s not clear, and we don’t really know what’s going on, so I’m just going to keep doing what I’m doing.’ Then the producers and sellers of that product have won.”
“As Upton Sinclair said,” she added, “‘It is difficult to get a man to understand something when his salary depends on his not understanding it.’ When organizations like ADA appear to be promoting a product like sucralose, and they’re not always being clear about disclosing the funding, I think that’s problematic.”
In fact, some recipes in the ADA’s hub that contain Splenda are marked sponsored, such as the four-ingredient peanut butter cookies; others, such as gluten-free brownies, are not — even though the latter contains “1/4 cup plus 1 tbsp” of Splenda Sugar Blend (Splenda produces several nonnutritive sweeteners, not all of which contain sucralose). Splenda is a sponsor of the ADA’s hub.
Consume in Moderation?
Regarding the use of Splenda products, Robert Gabbay, MD, PhD, the ADA’s chief scientific and medical officer, said in an interview that “some people with diabetes are accustomed to regularly consuming sugar-sweetened products, which can make management of their diabetes more challenging. As highlighted in the ADA’s Standards of Care, nonnutritive sweeteners (containing few or no calories) may be an acceptable substitute for sweeteners that contain sugar and calories when consumed in moderation. By providing a diabetes-friendly way to prepare foods people are used to eating, we can meet people where they are in offering support to effectively manage their diabetes.”
Of course, “moderation” means different things to different people. “With sucralose in particular, you can bake with it, you can cook with it, and beverages and packaged foods contain it, so it’s easy to end up overconsuming foods that may be fine if they’re occasional treats but aren’t healthy choices to have every single day,” Dr. Swithers said. “If you’re having a cookie containing sucralose once a week, it’s not a big deal, but if you’re having a cookie or a brownie every day, that’s something different.”
“I think ‘everything in moderation’ is a very reasonable approach here,” Dr. Mathur said. “Anything too much is probably not good, and that includes sweeteners like sucralose and others.”
Dr. Suez, whose team is currently exploring the mechanisms through which gut bacteria interact with nonnutritive sweeteners in the pathogenesis of cardiometabolic diseases, was more circumspect.
“We believe that additional, long-term, and non–industry-sponsored studies in humans are needed before we can make a recommendation in favor or against the use of nonnutritive sweeteners,” he said.
“However, our results demonstrating that nonnutritive sweeteners are not inert, when taken together with a growing body of evidence on potential harms of these sweeteners, merit caution until additional studies are completed,” he added. “Our findings do not imply in any way that sugar consumption, shown to be harmful to human health in many studies, is superior to nonnutritive sweeteners. Sugar consumption should be minimized, especially in individuals with obesity or diabetes. Of all the options, unsweetened beverages, specifically water, seem to be the safest and best options.”
Dr. Sen, who also “tries to convince patients to have sparkling or cold bottled water,” instead of artificially sweetened soda, agreed. “If a diabetes patient is trying to choose between sugar and sucralose, I’m not sure which one is worse.”
Dr. Swithers, Dr. Mathur, Dr. Sen, and Dr. Suez declared no competing interests.
A version of this article first appeared on Medscape.com.
It seems intuitive that, because people with type 2 diabetes (T2D) generally need to avoid sugar, clinicians should recommend eating foods and using recipes containing artificial sweeteners such as sucralose instead.
Splenda, which produces sucralose and other non-sugar sweeteners (NSS), is a sponsor of the American Diabetes Association (ADA) Diabetes Food Hub. Earlier in 2024, the ADA settled a lawsuit regarding its former director of nutrition’s refusal to approve recipes containing sucralose (Splenda), which she believed “flew in the face of the ADA’s mission.”
“There’s not a lot of evidence that sweeteners like sucralose provide significant benefits, especially over the long term,” said Susan Swithers, PhD, professor, department of psychological sciences and associate dean for faculty affairs at Purdue University, West Lafayette, Indiana.
Dr. Swithers authored an article several years ago cautioning that consuming nonnutritive sweeteners in beverages not only fails to prevent disease but also is associated with an increase in risks for the same health outcomes associated with sugar-sweetened beverages, including T2D, cardiovascular disease, hypertension, and stroke.
“At this point, we have pretty good evidence that these chemicals that were once touted as being completely inert are, in fact, not inert,” she said. “We know that they’re unlikely to be toxic in the short term, but they are not benign, and they have consequences. Right now, we have little understanding of the outcomes of consumption of these products chronically.”
What the Science Says
In 2023, the World Health Organization (WHO) released a guideline on NSS that recommended against their use for weight control or to reduce the risk for noncommunicable diseases.
The systematic review and meta-analysis upon which the guideline is based found that high intakes of NSS were associated with increases in body mass index and, as Dr. Swithers found, risks of developing T2D, cardiovascular events, and any type of stroke, as well as hypertension, bladder cancer, and all-cause mortality.
In a press release announcing the guideline, Francesco Branca, WHO director for Nutrition and Food Safety, said, “NSS are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health.”
The “common” NSS named by WHO included sucralose, as well as acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, stevia, and stevia derivatives.
If NSS consumption can increase T2D risk, what about people who already have T2D?
Some research suggests that NSS may affect people with and without T2D differently, said Dr. Swithers. For example, one small study showed that sucralose enhanced glucagon-like peptide 1 release and lowered blood glucose in healthy patients but not in patients with newly diagnosed T2D.
Similarly, Jotham Suez, PhD, an assistant professor in the department of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said in an interview that his group “showed for the first time in 2014 that disruption of the microbiome by artificial sweeteners is causally linked to disrupted glycemic control.”
Recently, the team studied the impact of sucralose, aspartame, saccharin, and stevia in healthy adults and “were surprised to discover that all four sweeteners altered gut bacteria and the molecules they secrete,” he said. However, subsequent glucose tolerance tests in healthy humans showed varying results, “suggesting that human microbiome responses to the nonnutritive sweeteners we assessed are highly personalized and may lead to glycemic alterations in some, but not all, consumers depending on their microbes and the sweeteners they consume.”
Nevertheless, a recent review led by researchers in Mexico concluded that sucralose consumption “is associated with various adverse health effects. Despite being considered safe following previous studies, recent research suggests possible links to systemic inflammation, metabolic diseases, disruptions in gut microbiota, liver damage, and toxic effects at the cellular level.”
In addition, they wrote, “it is crucial to highlight the persistence of sucralose in the body, its ability to cross the placenta, and its presence in breast milk, raising concerns about prenatal and neonatal exposure.”
Sabyasachi Sen, MD, a professor of biochemistry and molecular medicine at George Washington School of Medicine & Health Sciences, Washington, DC, has led and coauthored preclinical and clinical studies demonstrating the potential ill effects of sucralose and other artificial sweeteners. One showed that sucralose and acesulfame potassium–containing diet soda altered microbial taxa in two pilot studies in healthy young adults; another showed a connection between artificial sweeteners and inflammation.
But Dr. Sen’s current work is directed at his team’s finding that sucralose promotes the accumulation of reactive oxygen species and adipogenesis in human stem cells, he said in an interview. “It is essentially an additive that is clearly harmful to cells. Our concern is that stem cells are going to remain in the system for a long period of time. If it is causing inflammation in these cells, then that may lead to adverse outcomes.”
Ruchi Mathur, MD, director of the Diabetes Outpatient Treatment & Education Center at Cedars-Sinai in Los Angeles, California, is the principal investigator of a recent study suggesting that non-aspartame NSS and aspartame alone may alter the structure and function of the stool and duodenal microbiomes. Levels of circulating inflammatory markers were also altered in participants who consumed artificial sweeteners, compared with control participants who did not.
In addition to these potential adverse effects, “we have to think about the fact that patients with diabetes often have other comorbidities like obesity and are at higher risk for cardiovascular disease and other conditions,” she said in an interview. “If you’re taking a patient who’s already at risk for those things and you don’t have a detailed discussion with them about pros and cons, you’re doing them a disservice.”
Industry Interests
Addressing the largely negative but varying findings, Dr. Swithers said, “one of the difficulties with getting clear answers about the science is that the food and beverage industry has an interest in confusing the picture. If people are selling or using a product, the best thing is for them not have a clear reason to change their behavior. All that needs to happen is for them to be able say, ‘well, it’s not clear, and we don’t really know what’s going on, so I’m just going to keep doing what I’m doing.’ Then the producers and sellers of that product have won.”
“As Upton Sinclair said,” she added, “‘It is difficult to get a man to understand something when his salary depends on his not understanding it.’ When organizations like ADA appear to be promoting a product like sucralose, and they’re not always being clear about disclosing the funding, I think that’s problematic.”
In fact, some recipes in the ADA’s hub that contain Splenda are marked sponsored, such as the four-ingredient peanut butter cookies; others, such as gluten-free brownies, are not — even though the latter contains “1/4 cup plus 1 tbsp” of Splenda Sugar Blend (Splenda produces several nonnutritive sweeteners, not all of which contain sucralose). Splenda is a sponsor of the ADA’s hub.
Consume in Moderation?
Regarding the use of Splenda products, Robert Gabbay, MD, PhD, the ADA’s chief scientific and medical officer, said in an interview that “some people with diabetes are accustomed to regularly consuming sugar-sweetened products, which can make management of their diabetes more challenging. As highlighted in the ADA’s Standards of Care, nonnutritive sweeteners (containing few or no calories) may be an acceptable substitute for sweeteners that contain sugar and calories when consumed in moderation. By providing a diabetes-friendly way to prepare foods people are used to eating, we can meet people where they are in offering support to effectively manage their diabetes.”
Of course, “moderation” means different things to different people. “With sucralose in particular, you can bake with it, you can cook with it, and beverages and packaged foods contain it, so it’s easy to end up overconsuming foods that may be fine if they’re occasional treats but aren’t healthy choices to have every single day,” Dr. Swithers said. “If you’re having a cookie containing sucralose once a week, it’s not a big deal, but if you’re having a cookie or a brownie every day, that’s something different.”
“I think ‘everything in moderation’ is a very reasonable approach here,” Dr. Mathur said. “Anything too much is probably not good, and that includes sweeteners like sucralose and others.”
Dr. Suez, whose team is currently exploring the mechanisms through which gut bacteria interact with nonnutritive sweeteners in the pathogenesis of cardiometabolic diseases, was more circumspect.
“We believe that additional, long-term, and non–industry-sponsored studies in humans are needed before we can make a recommendation in favor or against the use of nonnutritive sweeteners,” he said.
“However, our results demonstrating that nonnutritive sweeteners are not inert, when taken together with a growing body of evidence on potential harms of these sweeteners, merit caution until additional studies are completed,” he added. “Our findings do not imply in any way that sugar consumption, shown to be harmful to human health in many studies, is superior to nonnutritive sweeteners. Sugar consumption should be minimized, especially in individuals with obesity or diabetes. Of all the options, unsweetened beverages, specifically water, seem to be the safest and best options.”
Dr. Sen, who also “tries to convince patients to have sparkling or cold bottled water,” instead of artificially sweetened soda, agreed. “If a diabetes patient is trying to choose between sugar and sucralose, I’m not sure which one is worse.”
Dr. Swithers, Dr. Mathur, Dr. Sen, and Dr. Suez declared no competing interests.
A version of this article first appeared on Medscape.com.
It seems intuitive that, because people with type 2 diabetes (T2D) generally need to avoid sugar, clinicians should recommend eating foods and using recipes containing artificial sweeteners such as sucralose instead.
Splenda, which produces sucralose and other non-sugar sweeteners (NSS), is a sponsor of the American Diabetes Association (ADA) Diabetes Food Hub. Earlier in 2024, the ADA settled a lawsuit regarding its former director of nutrition’s refusal to approve recipes containing sucralose (Splenda), which she believed “flew in the face of the ADA’s mission.”
“There’s not a lot of evidence that sweeteners like sucralose provide significant benefits, especially over the long term,” said Susan Swithers, PhD, professor, department of psychological sciences and associate dean for faculty affairs at Purdue University, West Lafayette, Indiana.
Dr. Swithers authored an article several years ago cautioning that consuming nonnutritive sweeteners in beverages not only fails to prevent disease but also is associated with an increase in risks for the same health outcomes associated with sugar-sweetened beverages, including T2D, cardiovascular disease, hypertension, and stroke.
“At this point, we have pretty good evidence that these chemicals that were once touted as being completely inert are, in fact, not inert,” she said. “We know that they’re unlikely to be toxic in the short term, but they are not benign, and they have consequences. Right now, we have little understanding of the outcomes of consumption of these products chronically.”
What the Science Says
In 2023, the World Health Organization (WHO) released a guideline on NSS that recommended against their use for weight control or to reduce the risk for noncommunicable diseases.
The systematic review and meta-analysis upon which the guideline is based found that high intakes of NSS were associated with increases in body mass index and, as Dr. Swithers found, risks of developing T2D, cardiovascular events, and any type of stroke, as well as hypertension, bladder cancer, and all-cause mortality.
In a press release announcing the guideline, Francesco Branca, WHO director for Nutrition and Food Safety, said, “NSS are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health.”
The “common” NSS named by WHO included sucralose, as well as acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, stevia, and stevia derivatives.
If NSS consumption can increase T2D risk, what about people who already have T2D?
Some research suggests that NSS may affect people with and without T2D differently, said Dr. Swithers. For example, one small study showed that sucralose enhanced glucagon-like peptide 1 release and lowered blood glucose in healthy patients but not in patients with newly diagnosed T2D.
Similarly, Jotham Suez, PhD, an assistant professor in the department of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said in an interview that his group “showed for the first time in 2014 that disruption of the microbiome by artificial sweeteners is causally linked to disrupted glycemic control.”
Recently, the team studied the impact of sucralose, aspartame, saccharin, and stevia in healthy adults and “were surprised to discover that all four sweeteners altered gut bacteria and the molecules they secrete,” he said. However, subsequent glucose tolerance tests in healthy humans showed varying results, “suggesting that human microbiome responses to the nonnutritive sweeteners we assessed are highly personalized and may lead to glycemic alterations in some, but not all, consumers depending on their microbes and the sweeteners they consume.”
Nevertheless, a recent review led by researchers in Mexico concluded that sucralose consumption “is associated with various adverse health effects. Despite being considered safe following previous studies, recent research suggests possible links to systemic inflammation, metabolic diseases, disruptions in gut microbiota, liver damage, and toxic effects at the cellular level.”
In addition, they wrote, “it is crucial to highlight the persistence of sucralose in the body, its ability to cross the placenta, and its presence in breast milk, raising concerns about prenatal and neonatal exposure.”
Sabyasachi Sen, MD, a professor of biochemistry and molecular medicine at George Washington School of Medicine & Health Sciences, Washington, DC, has led and coauthored preclinical and clinical studies demonstrating the potential ill effects of sucralose and other artificial sweeteners. One showed that sucralose and acesulfame potassium–containing diet soda altered microbial taxa in two pilot studies in healthy young adults; another showed a connection between artificial sweeteners and inflammation.
But Dr. Sen’s current work is directed at his team’s finding that sucralose promotes the accumulation of reactive oxygen species and adipogenesis in human stem cells, he said in an interview. “It is essentially an additive that is clearly harmful to cells. Our concern is that stem cells are going to remain in the system for a long period of time. If it is causing inflammation in these cells, then that may lead to adverse outcomes.”
Ruchi Mathur, MD, director of the Diabetes Outpatient Treatment & Education Center at Cedars-Sinai in Los Angeles, California, is the principal investigator of a recent study suggesting that non-aspartame NSS and aspartame alone may alter the structure and function of the stool and duodenal microbiomes. Levels of circulating inflammatory markers were also altered in participants who consumed artificial sweeteners, compared with control participants who did not.
In addition to these potential adverse effects, “we have to think about the fact that patients with diabetes often have other comorbidities like obesity and are at higher risk for cardiovascular disease and other conditions,” she said in an interview. “If you’re taking a patient who’s already at risk for those things and you don’t have a detailed discussion with them about pros and cons, you’re doing them a disservice.”
Industry Interests
Addressing the largely negative but varying findings, Dr. Swithers said, “one of the difficulties with getting clear answers about the science is that the food and beverage industry has an interest in confusing the picture. If people are selling or using a product, the best thing is for them not have a clear reason to change their behavior. All that needs to happen is for them to be able say, ‘well, it’s not clear, and we don’t really know what’s going on, so I’m just going to keep doing what I’m doing.’ Then the producers and sellers of that product have won.”
“As Upton Sinclair said,” she added, “‘It is difficult to get a man to understand something when his salary depends on his not understanding it.’ When organizations like ADA appear to be promoting a product like sucralose, and they’re not always being clear about disclosing the funding, I think that’s problematic.”
In fact, some recipes in the ADA’s hub that contain Splenda are marked sponsored, such as the four-ingredient peanut butter cookies; others, such as gluten-free brownies, are not — even though the latter contains “1/4 cup plus 1 tbsp” of Splenda Sugar Blend (Splenda produces several nonnutritive sweeteners, not all of which contain sucralose). Splenda is a sponsor of the ADA’s hub.
Consume in Moderation?
Regarding the use of Splenda products, Robert Gabbay, MD, PhD, the ADA’s chief scientific and medical officer, said in an interview that “some people with diabetes are accustomed to regularly consuming sugar-sweetened products, which can make management of their diabetes more challenging. As highlighted in the ADA’s Standards of Care, nonnutritive sweeteners (containing few or no calories) may be an acceptable substitute for sweeteners that contain sugar and calories when consumed in moderation. By providing a diabetes-friendly way to prepare foods people are used to eating, we can meet people where they are in offering support to effectively manage their diabetes.”
Of course, “moderation” means different things to different people. “With sucralose in particular, you can bake with it, you can cook with it, and beverages and packaged foods contain it, so it’s easy to end up overconsuming foods that may be fine if they’re occasional treats but aren’t healthy choices to have every single day,” Dr. Swithers said. “If you’re having a cookie containing sucralose once a week, it’s not a big deal, but if you’re having a cookie or a brownie every day, that’s something different.”
“I think ‘everything in moderation’ is a very reasonable approach here,” Dr. Mathur said. “Anything too much is probably not good, and that includes sweeteners like sucralose and others.”
Dr. Suez, whose team is currently exploring the mechanisms through which gut bacteria interact with nonnutritive sweeteners in the pathogenesis of cardiometabolic diseases, was more circumspect.
“We believe that additional, long-term, and non–industry-sponsored studies in humans are needed before we can make a recommendation in favor or against the use of nonnutritive sweeteners,” he said.
“However, our results demonstrating that nonnutritive sweeteners are not inert, when taken together with a growing body of evidence on potential harms of these sweeteners, merit caution until additional studies are completed,” he added. “Our findings do not imply in any way that sugar consumption, shown to be harmful to human health in many studies, is superior to nonnutritive sweeteners. Sugar consumption should be minimized, especially in individuals with obesity or diabetes. Of all the options, unsweetened beverages, specifically water, seem to be the safest and best options.”
Dr. Sen, who also “tries to convince patients to have sparkling or cold bottled water,” instead of artificially sweetened soda, agreed. “If a diabetes patient is trying to choose between sugar and sucralose, I’m not sure which one is worse.”
Dr. Swithers, Dr. Mathur, Dr. Sen, and Dr. Suez declared no competing interests.
A version of this article first appeared on Medscape.com.
New Oral Weight Loss Drugs: Where Are We and What’s Next?
, in line with patient preference.
One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.
Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD.
“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”
He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”
Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.
Here’s a look at other promising oral drugs on the horizon.
Oral Semaglutide
The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.
A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.
“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.
Oral Amycretin
Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.
“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”
APH-012
As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity.
The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.
The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”
Topline data from the first part of the study are expected to be released by the third quarter.
AZD5004
In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.
“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”
Ecnoglutide
In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.
The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.
Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.
The company is also developing an injectable formulation of ecnoglutide.
GSBR-1290
On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June.
In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.
A global phase 2b obesity study is planned for the fourth quarter of 2024.
Orforglipron
Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027.
Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks.
Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.
A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”
VK2735
VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.
In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.
Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
A version of this article appeared on Medscape.com.
, in line with patient preference.
One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.
Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD.
“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”
He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”
Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.
Here’s a look at other promising oral drugs on the horizon.
Oral Semaglutide
The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.
A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.
“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.
Oral Amycretin
Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.
“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”
APH-012
As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity.
The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.
The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”
Topline data from the first part of the study are expected to be released by the third quarter.
AZD5004
In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.
“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”
Ecnoglutide
In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.
The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.
Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.
The company is also developing an injectable formulation of ecnoglutide.
GSBR-1290
On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June.
In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.
A global phase 2b obesity study is planned for the fourth quarter of 2024.
Orforglipron
Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027.
Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks.
Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.
A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”
VK2735
VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.
In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.
Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
A version of this article appeared on Medscape.com.
, in line with patient preference.
One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.
Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD.
“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”
He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”
Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.
Here’s a look at other promising oral drugs on the horizon.
Oral Semaglutide
The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.
A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.
“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.
Oral Amycretin
Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.
“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”
APH-012
As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity.
The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.
The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”
Topline data from the first part of the study are expected to be released by the third quarter.
AZD5004
In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.
“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”
Ecnoglutide
In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.
The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.
Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.
The company is also developing an injectable formulation of ecnoglutide.
GSBR-1290
On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June.
In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.
A global phase 2b obesity study is planned for the fourth quarter of 2024.
Orforglipron
Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027.
Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks.
Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.
A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”
VK2735
VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.
In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.
Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
A version of this article appeared on Medscape.com.
Video Games Marketing Food Impacts Teens’ Eating
, according to research presented on May 12, 2024, at the 31st European Congress on Obesity in Venice, Italy.
The presentation by Rebecca Evans, University of Liverpool, United Kingdom, included findings from three recently published studies and a submitted randomized controlled trial. At the time of the research, the top VGLSPs globally were Twitch (with 77% of the market share by hours watched), YouTube Gaming (15%), and Facebook Gaming Live (7%).
“Endorsement deals for prominent streamers on Twitch can be worth many millions of dollars, and younger people, who are attractive to advertisers, are moving away from television to these more interactive forms of entertainment,” Evans said. “These deals involve collaborating with brands and promoting their products, including foods that are high in fats, salt, and/or sugar.”
To delve more deeply into the extent and consequences of VGLSP advertising for HFSS, the researchers first analyzed 52 hour-long Twitch videos uploaded to gaming platforms by three popular influencers. They found that food cues appeared at an average rate of 2.6 per hour, and the average duration of each cue was 20 minutes.
Most cues (70.7%) were for branded HFSS (80.5%), led by energy drinks (62.4%). Most (97.7%) were not accompanied by an advertising disclosure. Most food cues were either product placement (44.0%) and looping banners (40.6%) or features such as tie-ins, logos, or offers. Notably, these forms of advertising are always visible on the video game screen, so viewers cannot skip over them or close them.
Next, the team did a systematic review and meta-analysis to assess the relationship between exposure to digital game-based or influencer food marketing with food-related outcomes. They found that young people were twice as likely to prefer foods displayed via digital game-based marketing, and that influencer and digital game-based marketing was associated with increased HFSS food consumption of about 37 additional calories in one sitting.
Researchers then surveyed 490 youngsters (mean age, 16.8 years; 70%, female) to explore associations between recall of food marketing of the top VGLSPs and food-related outcomes. Recall was associated with more positive attitudes towards HFSS foods and, in turn, the purchase and consumption of the marketed HFSS foods.
In addition, the researchers conducted a lab-based randomized controlled trial to explore associations between HFSS food marketing via a mock Twitch stream and subsequent snack intake. A total of 91 youngsters (average age, 18 years; 69% women) viewed the mock stream, which contained either an advertisement (an image overlaid on the video featuring a brand logo and product) for an HFSS food, or a non-branded food. They were then offered a snack. Acute exposure to HFSS food marketing was not associated with immediate consumption, but more habitual use of VGLSPs was associated with increased intake of the marketed snack.
The observational studies could not prove cause and effect, and may not be generalizable to all teens, the authors acknowledged. They also noted that some of the findings are based on self-report surveys, which can lead to recall bias and may have affected the results.
Nevertheless, Ms. Evans said, “The high level of exposure to digital marketing of unhealthy food could drive excess calorie consumption and weight gain, particularly in adolescents who are more susceptible to advertising. It is important that digital food marketing restrictions encompass innovative and emerging digital media such as VGLSPs.”
The research formed Ms. Evans’ PhD work, which is funded by the University of Liverpool. Evans and colleagues declared no conflicts of interest.
A version of this article appeared on Medscape.com .
, according to research presented on May 12, 2024, at the 31st European Congress on Obesity in Venice, Italy.
The presentation by Rebecca Evans, University of Liverpool, United Kingdom, included findings from three recently published studies and a submitted randomized controlled trial. At the time of the research, the top VGLSPs globally were Twitch (with 77% of the market share by hours watched), YouTube Gaming (15%), and Facebook Gaming Live (7%).
“Endorsement deals for prominent streamers on Twitch can be worth many millions of dollars, and younger people, who are attractive to advertisers, are moving away from television to these more interactive forms of entertainment,” Evans said. “These deals involve collaborating with brands and promoting their products, including foods that are high in fats, salt, and/or sugar.”
To delve more deeply into the extent and consequences of VGLSP advertising for HFSS, the researchers first analyzed 52 hour-long Twitch videos uploaded to gaming platforms by three popular influencers. They found that food cues appeared at an average rate of 2.6 per hour, and the average duration of each cue was 20 minutes.
Most cues (70.7%) were for branded HFSS (80.5%), led by energy drinks (62.4%). Most (97.7%) were not accompanied by an advertising disclosure. Most food cues were either product placement (44.0%) and looping banners (40.6%) or features such as tie-ins, logos, or offers. Notably, these forms of advertising are always visible on the video game screen, so viewers cannot skip over them or close them.
Next, the team did a systematic review and meta-analysis to assess the relationship between exposure to digital game-based or influencer food marketing with food-related outcomes. They found that young people were twice as likely to prefer foods displayed via digital game-based marketing, and that influencer and digital game-based marketing was associated with increased HFSS food consumption of about 37 additional calories in one sitting.
Researchers then surveyed 490 youngsters (mean age, 16.8 years; 70%, female) to explore associations between recall of food marketing of the top VGLSPs and food-related outcomes. Recall was associated with more positive attitudes towards HFSS foods and, in turn, the purchase and consumption of the marketed HFSS foods.
In addition, the researchers conducted a lab-based randomized controlled trial to explore associations between HFSS food marketing via a mock Twitch stream and subsequent snack intake. A total of 91 youngsters (average age, 18 years; 69% women) viewed the mock stream, which contained either an advertisement (an image overlaid on the video featuring a brand logo and product) for an HFSS food, or a non-branded food. They were then offered a snack. Acute exposure to HFSS food marketing was not associated with immediate consumption, but more habitual use of VGLSPs was associated with increased intake of the marketed snack.
The observational studies could not prove cause and effect, and may not be generalizable to all teens, the authors acknowledged. They also noted that some of the findings are based on self-report surveys, which can lead to recall bias and may have affected the results.
Nevertheless, Ms. Evans said, “The high level of exposure to digital marketing of unhealthy food could drive excess calorie consumption and weight gain, particularly in adolescents who are more susceptible to advertising. It is important that digital food marketing restrictions encompass innovative and emerging digital media such as VGLSPs.”
The research formed Ms. Evans’ PhD work, which is funded by the University of Liverpool. Evans and colleagues declared no conflicts of interest.
A version of this article appeared on Medscape.com .
, according to research presented on May 12, 2024, at the 31st European Congress on Obesity in Venice, Italy.
The presentation by Rebecca Evans, University of Liverpool, United Kingdom, included findings from three recently published studies and a submitted randomized controlled trial. At the time of the research, the top VGLSPs globally were Twitch (with 77% of the market share by hours watched), YouTube Gaming (15%), and Facebook Gaming Live (7%).
“Endorsement deals for prominent streamers on Twitch can be worth many millions of dollars, and younger people, who are attractive to advertisers, are moving away from television to these more interactive forms of entertainment,” Evans said. “These deals involve collaborating with brands and promoting their products, including foods that are high in fats, salt, and/or sugar.”
To delve more deeply into the extent and consequences of VGLSP advertising for HFSS, the researchers first analyzed 52 hour-long Twitch videos uploaded to gaming platforms by three popular influencers. They found that food cues appeared at an average rate of 2.6 per hour, and the average duration of each cue was 20 minutes.
Most cues (70.7%) were for branded HFSS (80.5%), led by energy drinks (62.4%). Most (97.7%) were not accompanied by an advertising disclosure. Most food cues were either product placement (44.0%) and looping banners (40.6%) or features such as tie-ins, logos, or offers. Notably, these forms of advertising are always visible on the video game screen, so viewers cannot skip over them or close them.
Next, the team did a systematic review and meta-analysis to assess the relationship between exposure to digital game-based or influencer food marketing with food-related outcomes. They found that young people were twice as likely to prefer foods displayed via digital game-based marketing, and that influencer and digital game-based marketing was associated with increased HFSS food consumption of about 37 additional calories in one sitting.
Researchers then surveyed 490 youngsters (mean age, 16.8 years; 70%, female) to explore associations between recall of food marketing of the top VGLSPs and food-related outcomes. Recall was associated with more positive attitudes towards HFSS foods and, in turn, the purchase and consumption of the marketed HFSS foods.
In addition, the researchers conducted a lab-based randomized controlled trial to explore associations between HFSS food marketing via a mock Twitch stream and subsequent snack intake. A total of 91 youngsters (average age, 18 years; 69% women) viewed the mock stream, which contained either an advertisement (an image overlaid on the video featuring a brand logo and product) for an HFSS food, or a non-branded food. They were then offered a snack. Acute exposure to HFSS food marketing was not associated with immediate consumption, but more habitual use of VGLSPs was associated with increased intake of the marketed snack.
The observational studies could not prove cause and effect, and may not be generalizable to all teens, the authors acknowledged. They also noted that some of the findings are based on self-report surveys, which can lead to recall bias and may have affected the results.
Nevertheless, Ms. Evans said, “The high level of exposure to digital marketing of unhealthy food could drive excess calorie consumption and weight gain, particularly in adolescents who are more susceptible to advertising. It is important that digital food marketing restrictions encompass innovative and emerging digital media such as VGLSPs.”
The research formed Ms. Evans’ PhD work, which is funded by the University of Liverpool. Evans and colleagues declared no conflicts of interest.
A version of this article appeared on Medscape.com .
Can a Risk Score Predict Kidney Injury After Cisplatin?
Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.
Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.
A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.
Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.
However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.
Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.
“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
‘Herculean Effort’
“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.
“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.
The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.
The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.
Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.
Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.
Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.
The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.
Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
‘Definitive Work’
Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”
“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”
In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”
An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.
By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.
All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”
“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
‘Certainly Useful’
Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.
As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.
“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”
Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.
Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.
Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.
Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”
If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.
Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.
A version of this article appeared on Medscape.com.
Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.
Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.
A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.
Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.
However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.
Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.
“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
‘Herculean Effort’
“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.
“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.
The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.
The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.
Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.
Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.
Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.
The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.
Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
‘Definitive Work’
Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”
“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”
In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”
An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.
By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.
All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”
“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
‘Certainly Useful’
Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.
As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.
“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”
Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.
Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.
Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.
Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”
If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.
Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.
A version of this article appeared on Medscape.com.
Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.
Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.
A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.
Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.
However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.
Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.
“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
‘Herculean Effort’
“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.
“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.
The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.
The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.
Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.
Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.
Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.
The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.
Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
‘Definitive Work’
Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”
“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”
In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”
An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.
By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.
All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”
“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
‘Certainly Useful’
Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.
As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.
“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”
Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.
Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.
Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.
Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”
If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.
Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.
A version of this article appeared on Medscape.com.
FROM THE BMJ