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Screening finds high rates of CVD in diabetes, COPD patients
AMSTERDAM – , compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.
Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.
“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.
“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
A ‘very simple’ symptom questionnaire
The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.
The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.
The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.
About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.
The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.
The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
More than doubling the CVD diagnosis rate
The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.
The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.
An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.
RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.
A version of this article first appeared on Medscape.com.
AMSTERDAM – , compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.
Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.
“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.
“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
A ‘very simple’ symptom questionnaire
The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.
The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.
The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.
About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.
The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.
The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
More than doubling the CVD diagnosis rate
The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.
The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.
An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.
RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.
A version of this article first appeared on Medscape.com.
AMSTERDAM – , compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.
Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.
“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.
“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
A ‘very simple’ symptom questionnaire
The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.
The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.
The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.
About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.
The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.
The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
More than doubling the CVD diagnosis rate
The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.
The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.
An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.
RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.
A version of this article first appeared on Medscape.com.
AT ESC CONGRESS 2023
More weight loss linked with more benefit in STEP-HFpEF
AMSTERDAM – , including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.
At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.
His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.
The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.
Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.
In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m2), class 2 (35-39 kg/m2), and class 3 (≥ 40 kg/m2) obesity.
Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
Not every benefit was fully mediated by weight loss
These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”
He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.
“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.
“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.
Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.
“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.
Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.
“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.
STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
AMSTERDAM – , including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.
At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.
His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.
The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.
Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.
In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m2), class 2 (35-39 kg/m2), and class 3 (≥ 40 kg/m2) obesity.
Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
Not every benefit was fully mediated by weight loss
These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”
He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.
“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.
“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.
Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.
“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.
Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.
“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.
STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
AMSTERDAM – , including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.
At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.
His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.
The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.
Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.
In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m2), class 2 (35-39 kg/m2), and class 3 (≥ 40 kg/m2) obesity.
Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
Not every benefit was fully mediated by weight loss
These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”
He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.
“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.
“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.
Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.
“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.
Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.
“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.
STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
AT THE ESC CONGRESS 2023
ESC backs SGLT2 inhibitor plus GLP-1 in diabetes with high CVD risk
AMSTERDAM – The era of guidelines that recommended treatment with either a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagonlike peptide-1 (GLP-1) receptor agonist in people with type 2 diabetes mellitus and established cardiovascular disease (CVD) ended with new recommendations from the European Society of Cardiology that call for starting both classes simultaneously.
said Darren K. McGuire, MD, at the annual congress of the European Society of Cardiology.
The society’s new guidelines for managing CVD in patients with diabetes, released on Aug. 25 and presented in several sessions at the Congress, also break with the past by calling for starting treatment with both an SGLT-2 inhibitor and a GLP-1 receptor agonist without regard to a person’s existing level of glucose control, including their current and target hemoglobin A1c levels, and regardless of background therapy, added Dr. McGuire, a cardiologist and professor at the UT Southwestern Medical Center in Dallas and a member of the ESC panel that wrote the new guidelines.
Instead, the new guidance calls for starting both drug classes promptly in people diagnosed with type 2 diabetes and established atherosclerotic CVD.
Both the previous ESC guidelines from 2019 as well as the current Standards of Care for 2023 document from the American Diabetes Association call for using one class or the other, but they hedge on combined treatment as discretionary.
Different mechanisms mean additive benefits
“With increasing numbers of patients with type 2 diabetes in trials for SGLT-2 inhibitors or GLP-1 receptor agonists who were also on the other drug class, we’ve done large, stratified analyses that suggest no treatment-effect modification” when people received agents from both drug classes, Dr. McGuire explained in an interview. “While we don’t understand the mechanisms of action of these drugs for CVD, we’ve become very confident that they use different mechanisms” that appear to have at least partially additive effects.
“Their benefits for CVD risk reduction are completely independent of their glucose effects. They are cardiology drugs,” Dr. McGuire added.
The new ESC guidelines highlight two other clinical settings where people with type 2 diabetes should receive an SGLT-2 inhibitor regardless of their existing level of glucose control and any other medical treatment: people with heart failure and people with chronic kidney disease (CKD) based on a depressed estimated glomerular filtration rate and an elevated urine albumin-to-creatinine ratio.
Nephropathy was considered by the ESC’s guideline panel to confer risk that is similar to that of established atherosclerotic CVD, Dr. McGuire said.
The guidelines also, for the first time for ESC recommendations, made treatment with finerenone (Kerendia, Bayer) a class 1 level A recommendation for people with type 2 diabetes and CKD.
SCORE2-Diabetes risk estimator
Another major change in the new ESC guideline revision is introduction of a CVD risk calculator intended to estimate the risk among people with type 2 diabetes but without established CVD, heart failure, or CKD.
Called the SCORE2-Diabetes risk estimator, it calculates a person’s 10-year risk for CVD and includes adjustment based on the European region where a person lives; it also tallies different risk levels for women and for men.
The researchers who developed the SCORE2-Diabetes calculator used data from nearly 230,000 people to devise the tool and then validated it with data from an additional 217,000 Europeans with type 2 diabetes.
Key features of the calculator include its use of routinely collected clinical values, such as age, sex, systolic blood pressure, smoking status, serum cholesterol levels, age at diabetes diagnosis, hemoglobin A1c level, and estimated glomerular filtration rate.
“For the first time we have a clear score to categorize risk” in people with type 2 diabetes and identify who needs more aggressive treatment to prevent CVD development,” said Emanuele Di Angelantonio, MD, PhD, deputy director of the cardiovascular epidemiology unit at the University of Cambridge (England).
The guidelines say that people who have a low (< 5%) or moderate (5%-9%) 10-year risk for CVD are possible candidates for metformin treatment. Those with high (10%-19%) or very high (≥ 20%) risk are possible candidates for treatment with metformin and/or an SGLT-2 inhibitor and/or a GLP-1 receptor agonist, said Dr. Di Angelantonio during his talk at the congress on the new risk score.
“The risk score is a good addition” because it estimates future CVD risk better and more systematically than usual practice, which generally relies on no systematic tool, said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow (Scotland) and also a member of the guideline-writing panel.
The new risk score “is a reasonable way” to identify people without CVD but at elevated risk who might benefit from treatment with a relatively expensive drug, such as an SGLT-2 inhibitor, Dr. Sattar said in an interview. “It doesn’t rely on any fancy biomarkers or imaging, and it takes about 30 seconds to calculate. It’s not perfect, but it gets the job done,” and it will increase the number of people with type 2 diabetes who will receive an SGLT-2 inhibitor, he predicted.
Dr. McGuire has been a consultant to Altimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Intercept, Lexion, Lilly, Merck, New Amsterdam, and Pfizer. Dr. Di Angelantonio had no disclosures. Dr. Sattar has been a consultant to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics.
A version of this article appeared on Medscape.com.
AMSTERDAM – The era of guidelines that recommended treatment with either a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagonlike peptide-1 (GLP-1) receptor agonist in people with type 2 diabetes mellitus and established cardiovascular disease (CVD) ended with new recommendations from the European Society of Cardiology that call for starting both classes simultaneously.
said Darren K. McGuire, MD, at the annual congress of the European Society of Cardiology.
The society’s new guidelines for managing CVD in patients with diabetes, released on Aug. 25 and presented in several sessions at the Congress, also break with the past by calling for starting treatment with both an SGLT-2 inhibitor and a GLP-1 receptor agonist without regard to a person’s existing level of glucose control, including their current and target hemoglobin A1c levels, and regardless of background therapy, added Dr. McGuire, a cardiologist and professor at the UT Southwestern Medical Center in Dallas and a member of the ESC panel that wrote the new guidelines.
Instead, the new guidance calls for starting both drug classes promptly in people diagnosed with type 2 diabetes and established atherosclerotic CVD.
Both the previous ESC guidelines from 2019 as well as the current Standards of Care for 2023 document from the American Diabetes Association call for using one class or the other, but they hedge on combined treatment as discretionary.
Different mechanisms mean additive benefits
“With increasing numbers of patients with type 2 diabetes in trials for SGLT-2 inhibitors or GLP-1 receptor agonists who were also on the other drug class, we’ve done large, stratified analyses that suggest no treatment-effect modification” when people received agents from both drug classes, Dr. McGuire explained in an interview. “While we don’t understand the mechanisms of action of these drugs for CVD, we’ve become very confident that they use different mechanisms” that appear to have at least partially additive effects.
“Their benefits for CVD risk reduction are completely independent of their glucose effects. They are cardiology drugs,” Dr. McGuire added.
The new ESC guidelines highlight two other clinical settings where people with type 2 diabetes should receive an SGLT-2 inhibitor regardless of their existing level of glucose control and any other medical treatment: people with heart failure and people with chronic kidney disease (CKD) based on a depressed estimated glomerular filtration rate and an elevated urine albumin-to-creatinine ratio.
Nephropathy was considered by the ESC’s guideline panel to confer risk that is similar to that of established atherosclerotic CVD, Dr. McGuire said.
The guidelines also, for the first time for ESC recommendations, made treatment with finerenone (Kerendia, Bayer) a class 1 level A recommendation for people with type 2 diabetes and CKD.
SCORE2-Diabetes risk estimator
Another major change in the new ESC guideline revision is introduction of a CVD risk calculator intended to estimate the risk among people with type 2 diabetes but without established CVD, heart failure, or CKD.
Called the SCORE2-Diabetes risk estimator, it calculates a person’s 10-year risk for CVD and includes adjustment based on the European region where a person lives; it also tallies different risk levels for women and for men.
The researchers who developed the SCORE2-Diabetes calculator used data from nearly 230,000 people to devise the tool and then validated it with data from an additional 217,000 Europeans with type 2 diabetes.
Key features of the calculator include its use of routinely collected clinical values, such as age, sex, systolic blood pressure, smoking status, serum cholesterol levels, age at diabetes diagnosis, hemoglobin A1c level, and estimated glomerular filtration rate.
“For the first time we have a clear score to categorize risk” in people with type 2 diabetes and identify who needs more aggressive treatment to prevent CVD development,” said Emanuele Di Angelantonio, MD, PhD, deputy director of the cardiovascular epidemiology unit at the University of Cambridge (England).
The guidelines say that people who have a low (< 5%) or moderate (5%-9%) 10-year risk for CVD are possible candidates for metformin treatment. Those with high (10%-19%) or very high (≥ 20%) risk are possible candidates for treatment with metformin and/or an SGLT-2 inhibitor and/or a GLP-1 receptor agonist, said Dr. Di Angelantonio during his talk at the congress on the new risk score.
“The risk score is a good addition” because it estimates future CVD risk better and more systematically than usual practice, which generally relies on no systematic tool, said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow (Scotland) and also a member of the guideline-writing panel.
The new risk score “is a reasonable way” to identify people without CVD but at elevated risk who might benefit from treatment with a relatively expensive drug, such as an SGLT-2 inhibitor, Dr. Sattar said in an interview. “It doesn’t rely on any fancy biomarkers or imaging, and it takes about 30 seconds to calculate. It’s not perfect, but it gets the job done,” and it will increase the number of people with type 2 diabetes who will receive an SGLT-2 inhibitor, he predicted.
Dr. McGuire has been a consultant to Altimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Intercept, Lexion, Lilly, Merck, New Amsterdam, and Pfizer. Dr. Di Angelantonio had no disclosures. Dr. Sattar has been a consultant to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics.
A version of this article appeared on Medscape.com.
AMSTERDAM – The era of guidelines that recommended treatment with either a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagonlike peptide-1 (GLP-1) receptor agonist in people with type 2 diabetes mellitus and established cardiovascular disease (CVD) ended with new recommendations from the European Society of Cardiology that call for starting both classes simultaneously.
said Darren K. McGuire, MD, at the annual congress of the European Society of Cardiology.
The society’s new guidelines for managing CVD in patients with diabetes, released on Aug. 25 and presented in several sessions at the Congress, also break with the past by calling for starting treatment with both an SGLT-2 inhibitor and a GLP-1 receptor agonist without regard to a person’s existing level of glucose control, including their current and target hemoglobin A1c levels, and regardless of background therapy, added Dr. McGuire, a cardiologist and professor at the UT Southwestern Medical Center in Dallas and a member of the ESC panel that wrote the new guidelines.
Instead, the new guidance calls for starting both drug classes promptly in people diagnosed with type 2 diabetes and established atherosclerotic CVD.
Both the previous ESC guidelines from 2019 as well as the current Standards of Care for 2023 document from the American Diabetes Association call for using one class or the other, but they hedge on combined treatment as discretionary.
Different mechanisms mean additive benefits
“With increasing numbers of patients with type 2 diabetes in trials for SGLT-2 inhibitors or GLP-1 receptor agonists who were also on the other drug class, we’ve done large, stratified analyses that suggest no treatment-effect modification” when people received agents from both drug classes, Dr. McGuire explained in an interview. “While we don’t understand the mechanisms of action of these drugs for CVD, we’ve become very confident that they use different mechanisms” that appear to have at least partially additive effects.
“Their benefits for CVD risk reduction are completely independent of their glucose effects. They are cardiology drugs,” Dr. McGuire added.
The new ESC guidelines highlight two other clinical settings where people with type 2 diabetes should receive an SGLT-2 inhibitor regardless of their existing level of glucose control and any other medical treatment: people with heart failure and people with chronic kidney disease (CKD) based on a depressed estimated glomerular filtration rate and an elevated urine albumin-to-creatinine ratio.
Nephropathy was considered by the ESC’s guideline panel to confer risk that is similar to that of established atherosclerotic CVD, Dr. McGuire said.
The guidelines also, for the first time for ESC recommendations, made treatment with finerenone (Kerendia, Bayer) a class 1 level A recommendation for people with type 2 diabetes and CKD.
SCORE2-Diabetes risk estimator
Another major change in the new ESC guideline revision is introduction of a CVD risk calculator intended to estimate the risk among people with type 2 diabetes but without established CVD, heart failure, or CKD.
Called the SCORE2-Diabetes risk estimator, it calculates a person’s 10-year risk for CVD and includes adjustment based on the European region where a person lives; it also tallies different risk levels for women and for men.
The researchers who developed the SCORE2-Diabetes calculator used data from nearly 230,000 people to devise the tool and then validated it with data from an additional 217,000 Europeans with type 2 diabetes.
Key features of the calculator include its use of routinely collected clinical values, such as age, sex, systolic blood pressure, smoking status, serum cholesterol levels, age at diabetes diagnosis, hemoglobin A1c level, and estimated glomerular filtration rate.
“For the first time we have a clear score to categorize risk” in people with type 2 diabetes and identify who needs more aggressive treatment to prevent CVD development,” said Emanuele Di Angelantonio, MD, PhD, deputy director of the cardiovascular epidemiology unit at the University of Cambridge (England).
The guidelines say that people who have a low (< 5%) or moderate (5%-9%) 10-year risk for CVD are possible candidates for metformin treatment. Those with high (10%-19%) or very high (≥ 20%) risk are possible candidates for treatment with metformin and/or an SGLT-2 inhibitor and/or a GLP-1 receptor agonist, said Dr. Di Angelantonio during his talk at the congress on the new risk score.
“The risk score is a good addition” because it estimates future CVD risk better and more systematically than usual practice, which generally relies on no systematic tool, said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow (Scotland) and also a member of the guideline-writing panel.
The new risk score “is a reasonable way” to identify people without CVD but at elevated risk who might benefit from treatment with a relatively expensive drug, such as an SGLT-2 inhibitor, Dr. Sattar said in an interview. “It doesn’t rely on any fancy biomarkers or imaging, and it takes about 30 seconds to calculate. It’s not perfect, but it gets the job done,” and it will increase the number of people with type 2 diabetes who will receive an SGLT-2 inhibitor, he predicted.
Dr. McGuire has been a consultant to Altimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Intercept, Lexion, Lilly, Merck, New Amsterdam, and Pfizer. Dr. Di Angelantonio had no disclosures. Dr. Sattar has been a consultant to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics.
A version of this article appeared on Medscape.com.
AT ESC CONGRESS 2023
Liraglutide fixes learning limit tied to insulin resistance
A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Dr. Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
‘Liraglutide can normalize learning of associations’
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Dr. Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune’ ” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Dr. Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide.
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the section of medical psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Dr. Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide treatment leveled learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity, compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Dr. Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Dr. Tittgemyer and most of his coauthors had no disclosures. One coauthor had several disclosures, which are detailed in the report. Dr. Kroemer had no disclosures.
A version of this article first appeared on Medscape.com.
A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Dr. Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
‘Liraglutide can normalize learning of associations’
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Dr. Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune’ ” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Dr. Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide.
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the section of medical psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Dr. Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide treatment leveled learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity, compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Dr. Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Dr. Tittgemyer and most of his coauthors had no disclosures. One coauthor had several disclosures, which are detailed in the report. Dr. Kroemer had no disclosures.
A version of this article first appeared on Medscape.com.
A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Dr. Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
‘Liraglutide can normalize learning of associations’
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Dr. Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune’ ” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Dr. Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide.
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the section of medical psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Dr. Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide treatment leveled learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity, compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Dr. Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Dr. Tittgemyer and most of his coauthors had no disclosures. One coauthor had several disclosures, which are detailed in the report. Dr. Kroemer had no disclosures.
A version of this article first appeared on Medscape.com.
FROM NATURE METABOLISM
Wegovy scores HFpEF benefits in people with obesity
AMSTERDAM – Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks, compared with placebo, in the randomized STEP-HFpEF trial.
The results, which also showed the treatment’s safety in these patients, “indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity,” Mikhail Kosiborod, MD, said at the annual congress of the European Society of Cardiology.
The findings establish semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients’ scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline, compared with placebo, of 10.7%. Both were significant effects, compared with placebo, and clinically meaningful benefits for the study’s two primary endpoints.
Simultaneously with Kosiborod’s report the results also appeared in a report posted online in the New England Journal of Medicine.
A ‘paradigm shift’ for medical weight loss in cardiology
The findings from this study with 529 randomized patients immediately propelled the weight loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a press release from Novo Nordisk on Aug. 8.
The STEP-HFpEF and SELECT results will trigger “a paradigm shift” for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. This shift will require education to bring the clinical cardiology community on board, he added in an interview.
Given that semaglutide administered at this dose already has a Food and Drug Administration–approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Dr. Kosiborod and other cardiologists.
Weekly semaglutide injections “could be considered a treatment option right now” for people with obesity and HFpEF, Dr. Kosiborod said during a press briefing.
Other experts agreed, especially because the STEP-HFpEF results confirmed that weight loss treatment with semaglutide was safe in this population.
‘A terrific win for patients’
The new findings are “a terrific win and game changer for patients with HFpEF,” commented Gregg C. Fonarow, MD, professor and cochief of cardiology at the University of California, Los Angeles, who was not involved with the study.
“The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m2, patients who already fall within existing indications,” Dr. Fonarow said in an interview.
“Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions,” he added. “The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes.”
Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the “obesity paradox,” but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the department of medicine at Washington University in St. Louis, who also was not involved in the study.
No signal of an obesity paradox
“There’s been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it’s safe to use this weight loss treatment. The results show that patients feel better and lose weight with no signal of harm,” Dr. Sweitzer said in an interview.
The “encouraging findings” for semaglutide in patients with HFpEF “potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index,” commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report.
“How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism,” wrote Dr. Pinto, a professor and heart failure specialist at Amsterdam University Medical Center.
But Dr. Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. “Heart failure is defined clinically based on symptoms,” he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value “hard endpoints” such as survival.
The new findings, which indicate that two different and expensive classes of medications are now standard of care for many people with HFpEF and obesity – the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide – also raise concerns over patient access and affordability, as many U.S. insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.
But Dr. Sweitzer and Dr. Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it’s still not ideal.
Prior authorization hoops have decreased
“We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate,” said Dr. Sweitzer.
And “the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists,” she added.
“It’s not okay for insurers to say we are not going to cover weight loss medications because it’s a cosmetic indication,” said Dr. Kosiborod. “Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment.”
The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), “were the largest benefits in these outcomes we’ve seen,” compared with any other medical intervention in people with HFpEF, he noted.
“About 80% of U.S. patients with HFpEF have obesity or overweight,” Dr. Kosiborod noted. Using semaglutide on these patients “is an issue of access and insurance coverage. My hope is that these and other data will favorably change this.”
A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Dr. Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.
The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Dr. Sweitzer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AMSTERDAM – Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks, compared with placebo, in the randomized STEP-HFpEF trial.
The results, which also showed the treatment’s safety in these patients, “indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity,” Mikhail Kosiborod, MD, said at the annual congress of the European Society of Cardiology.
The findings establish semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients’ scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline, compared with placebo, of 10.7%. Both were significant effects, compared with placebo, and clinically meaningful benefits for the study’s two primary endpoints.
Simultaneously with Kosiborod’s report the results also appeared in a report posted online in the New England Journal of Medicine.
A ‘paradigm shift’ for medical weight loss in cardiology
The findings from this study with 529 randomized patients immediately propelled the weight loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a press release from Novo Nordisk on Aug. 8.
The STEP-HFpEF and SELECT results will trigger “a paradigm shift” for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. This shift will require education to bring the clinical cardiology community on board, he added in an interview.
Given that semaglutide administered at this dose already has a Food and Drug Administration–approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Dr. Kosiborod and other cardiologists.
Weekly semaglutide injections “could be considered a treatment option right now” for people with obesity and HFpEF, Dr. Kosiborod said during a press briefing.
Other experts agreed, especially because the STEP-HFpEF results confirmed that weight loss treatment with semaglutide was safe in this population.
‘A terrific win for patients’
The new findings are “a terrific win and game changer for patients with HFpEF,” commented Gregg C. Fonarow, MD, professor and cochief of cardiology at the University of California, Los Angeles, who was not involved with the study.
“The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m2, patients who already fall within existing indications,” Dr. Fonarow said in an interview.
“Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions,” he added. “The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes.”
Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the “obesity paradox,” but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the department of medicine at Washington University in St. Louis, who also was not involved in the study.
No signal of an obesity paradox
“There’s been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it’s safe to use this weight loss treatment. The results show that patients feel better and lose weight with no signal of harm,” Dr. Sweitzer said in an interview.
The “encouraging findings” for semaglutide in patients with HFpEF “potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index,” commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report.
“How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism,” wrote Dr. Pinto, a professor and heart failure specialist at Amsterdam University Medical Center.
But Dr. Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. “Heart failure is defined clinically based on symptoms,” he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value “hard endpoints” such as survival.
The new findings, which indicate that two different and expensive classes of medications are now standard of care for many people with HFpEF and obesity – the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide – also raise concerns over patient access and affordability, as many U.S. insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.
But Dr. Sweitzer and Dr. Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it’s still not ideal.
Prior authorization hoops have decreased
“We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate,” said Dr. Sweitzer.
And “the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists,” she added.
“It’s not okay for insurers to say we are not going to cover weight loss medications because it’s a cosmetic indication,” said Dr. Kosiborod. “Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment.”
The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), “were the largest benefits in these outcomes we’ve seen,” compared with any other medical intervention in people with HFpEF, he noted.
“About 80% of U.S. patients with HFpEF have obesity or overweight,” Dr. Kosiborod noted. Using semaglutide on these patients “is an issue of access and insurance coverage. My hope is that these and other data will favorably change this.”
A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Dr. Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.
The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Dr. Sweitzer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AMSTERDAM – Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks, compared with placebo, in the randomized STEP-HFpEF trial.
The results, which also showed the treatment’s safety in these patients, “indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity,” Mikhail Kosiborod, MD, said at the annual congress of the European Society of Cardiology.
The findings establish semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients’ scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline, compared with placebo, of 10.7%. Both were significant effects, compared with placebo, and clinically meaningful benefits for the study’s two primary endpoints.
Simultaneously with Kosiborod’s report the results also appeared in a report posted online in the New England Journal of Medicine.
A ‘paradigm shift’ for medical weight loss in cardiology
The findings from this study with 529 randomized patients immediately propelled the weight loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a press release from Novo Nordisk on Aug. 8.
The STEP-HFpEF and SELECT results will trigger “a paradigm shift” for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. This shift will require education to bring the clinical cardiology community on board, he added in an interview.
Given that semaglutide administered at this dose already has a Food and Drug Administration–approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Dr. Kosiborod and other cardiologists.
Weekly semaglutide injections “could be considered a treatment option right now” for people with obesity and HFpEF, Dr. Kosiborod said during a press briefing.
Other experts agreed, especially because the STEP-HFpEF results confirmed that weight loss treatment with semaglutide was safe in this population.
‘A terrific win for patients’
The new findings are “a terrific win and game changer for patients with HFpEF,” commented Gregg C. Fonarow, MD, professor and cochief of cardiology at the University of California, Los Angeles, who was not involved with the study.
“The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m2, patients who already fall within existing indications,” Dr. Fonarow said in an interview.
“Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions,” he added. “The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes.”
Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the “obesity paradox,” but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the department of medicine at Washington University in St. Louis, who also was not involved in the study.
No signal of an obesity paradox
“There’s been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it’s safe to use this weight loss treatment. The results show that patients feel better and lose weight with no signal of harm,” Dr. Sweitzer said in an interview.
The “encouraging findings” for semaglutide in patients with HFpEF “potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index,” commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report.
“How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism,” wrote Dr. Pinto, a professor and heart failure specialist at Amsterdam University Medical Center.
But Dr. Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. “Heart failure is defined clinically based on symptoms,” he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value “hard endpoints” such as survival.
The new findings, which indicate that two different and expensive classes of medications are now standard of care for many people with HFpEF and obesity – the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide – also raise concerns over patient access and affordability, as many U.S. insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.
But Dr. Sweitzer and Dr. Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it’s still not ideal.
Prior authorization hoops have decreased
“We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate,” said Dr. Sweitzer.
And “the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists,” she added.
“It’s not okay for insurers to say we are not going to cover weight loss medications because it’s a cosmetic indication,” said Dr. Kosiborod. “Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment.”
The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), “were the largest benefits in these outcomes we’ve seen,” compared with any other medical intervention in people with HFpEF, he noted.
“About 80% of U.S. patients with HFpEF have obesity or overweight,” Dr. Kosiborod noted. Using semaglutide on these patients “is an issue of access and insurance coverage. My hope is that these and other data will favorably change this.”
A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Dr. Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.
The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Dr. Sweitzer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT THE ESC CONGRESS 2023
New weight loss drugs appeal to half of U.S. adults
A recent survey of more than 1,000 U.S. adults showed that 18% were “somewhat interested” in taking a “safe, effective” weight loss drug, 27% were “very interested,” and 4% said they were already using such an agent, together constituting 49% of the surveyed adults.
The newer, more potent and generally safe agents that work by stimulating receptors to nutrient-stimulated hormones, such as incretins like glucagonlike peptide–1, seem to drive this interest.
When asked: “How much have you heard, if anything, about a new class of drugs being used for weight loss, such as Ozempic [semaglutide formulated and approved for people with type 2 diabetes], Wegovy [semaglutide for weight loss], and Mounjaro [tirzepatide, currently approved for treating only people with type 2 diabetes]?” 43% said they had heard some, or a lot, about these agents.
This was particularly true among people at least 65 years old, who had a 55% prevalence of knowing some, or a lot, about these new weight-loss agents, while an additional 26% had heard at least “a little” about them, reported staff members of KFF (formerly the Kaiser Family Foundation) in a report posted online in early August.
Weight loss drugs garner ‘increasing’ attention
“A new class of prescription drugs, initially developed to treat type 2 diabetes, have been garnering an increasing amount of attention due to their ability to act as highly effective weight loss drugs for overweight or obese adults,” wrote the report’s authors.
However, surveyed interest fell markedly when respondents answered further questions that hinged on certain limitations of the newer weight loss formulations.
For example, the percent interested held nearly steady, at 44%, when told the weight loss agent in question was an oral pill, but when asked about formulations requiring weekly injections the prevalence of people who had some interest, or were very interested, dropped to 23%. And when presented with the premise that they would need to take the drug chronically to keep their weight off and that stopping the agent would mean weight regain, those with “higher levels of interest” in the agent fell to 14% of the study sample.
Other deal breakers for most survey respondents were lack of a weight-loss indication approved by the Food and Drug Administration, a hypothetical that left 16% still somewhat or very interested, and lack of insurance coverage, which also dropped the higher interest levels to 16% of respondents. On the flip side of that sentiment, 80% of survey respondents believe that health insurance should cover the cost for a prescription weight loss drug for people with overweight or obesity.
The survey was designed and analyzed by public-opinion researchers at KFF and run both online and by telephone in both English and Spanish during July 11-19, 2023. The margin of sampling error was plus or minus 3 percentage points for the full sample but may have been even higher for results based on subgroup analyses.
The survey report includes no funding or disclosure information. However, KFF describes itself as “independent” and “nonpartisan” and that it “does everything based on facts and data, and we do so objectively without taking policy positions and without affiliation to any political party or external interest.”
A version of this article first appeared on Medscape.com.
A recent survey of more than 1,000 U.S. adults showed that 18% were “somewhat interested” in taking a “safe, effective” weight loss drug, 27% were “very interested,” and 4% said they were already using such an agent, together constituting 49% of the surveyed adults.
The newer, more potent and generally safe agents that work by stimulating receptors to nutrient-stimulated hormones, such as incretins like glucagonlike peptide–1, seem to drive this interest.
When asked: “How much have you heard, if anything, about a new class of drugs being used for weight loss, such as Ozempic [semaglutide formulated and approved for people with type 2 diabetes], Wegovy [semaglutide for weight loss], and Mounjaro [tirzepatide, currently approved for treating only people with type 2 diabetes]?” 43% said they had heard some, or a lot, about these agents.
This was particularly true among people at least 65 years old, who had a 55% prevalence of knowing some, or a lot, about these new weight-loss agents, while an additional 26% had heard at least “a little” about them, reported staff members of KFF (formerly the Kaiser Family Foundation) in a report posted online in early August.
Weight loss drugs garner ‘increasing’ attention
“A new class of prescription drugs, initially developed to treat type 2 diabetes, have been garnering an increasing amount of attention due to their ability to act as highly effective weight loss drugs for overweight or obese adults,” wrote the report’s authors.
However, surveyed interest fell markedly when respondents answered further questions that hinged on certain limitations of the newer weight loss formulations.
For example, the percent interested held nearly steady, at 44%, when told the weight loss agent in question was an oral pill, but when asked about formulations requiring weekly injections the prevalence of people who had some interest, or were very interested, dropped to 23%. And when presented with the premise that they would need to take the drug chronically to keep their weight off and that stopping the agent would mean weight regain, those with “higher levels of interest” in the agent fell to 14% of the study sample.
Other deal breakers for most survey respondents were lack of a weight-loss indication approved by the Food and Drug Administration, a hypothetical that left 16% still somewhat or very interested, and lack of insurance coverage, which also dropped the higher interest levels to 16% of respondents. On the flip side of that sentiment, 80% of survey respondents believe that health insurance should cover the cost for a prescription weight loss drug for people with overweight or obesity.
The survey was designed and analyzed by public-opinion researchers at KFF and run both online and by telephone in both English and Spanish during July 11-19, 2023. The margin of sampling error was plus or minus 3 percentage points for the full sample but may have been even higher for results based on subgroup analyses.
The survey report includes no funding or disclosure information. However, KFF describes itself as “independent” and “nonpartisan” and that it “does everything based on facts and data, and we do so objectively without taking policy positions and without affiliation to any political party or external interest.”
A version of this article first appeared on Medscape.com.
A recent survey of more than 1,000 U.S. adults showed that 18% were “somewhat interested” in taking a “safe, effective” weight loss drug, 27% were “very interested,” and 4% said they were already using such an agent, together constituting 49% of the surveyed adults.
The newer, more potent and generally safe agents that work by stimulating receptors to nutrient-stimulated hormones, such as incretins like glucagonlike peptide–1, seem to drive this interest.
When asked: “How much have you heard, if anything, about a new class of drugs being used for weight loss, such as Ozempic [semaglutide formulated and approved for people with type 2 diabetes], Wegovy [semaglutide for weight loss], and Mounjaro [tirzepatide, currently approved for treating only people with type 2 diabetes]?” 43% said they had heard some, or a lot, about these agents.
This was particularly true among people at least 65 years old, who had a 55% prevalence of knowing some, or a lot, about these new weight-loss agents, while an additional 26% had heard at least “a little” about them, reported staff members of KFF (formerly the Kaiser Family Foundation) in a report posted online in early August.
Weight loss drugs garner ‘increasing’ attention
“A new class of prescription drugs, initially developed to treat type 2 diabetes, have been garnering an increasing amount of attention due to their ability to act as highly effective weight loss drugs for overweight or obese adults,” wrote the report’s authors.
However, surveyed interest fell markedly when respondents answered further questions that hinged on certain limitations of the newer weight loss formulations.
For example, the percent interested held nearly steady, at 44%, when told the weight loss agent in question was an oral pill, but when asked about formulations requiring weekly injections the prevalence of people who had some interest, or were very interested, dropped to 23%. And when presented with the premise that they would need to take the drug chronically to keep their weight off and that stopping the agent would mean weight regain, those with “higher levels of interest” in the agent fell to 14% of the study sample.
Other deal breakers for most survey respondents were lack of a weight-loss indication approved by the Food and Drug Administration, a hypothetical that left 16% still somewhat or very interested, and lack of insurance coverage, which also dropped the higher interest levels to 16% of respondents. On the flip side of that sentiment, 80% of survey respondents believe that health insurance should cover the cost for a prescription weight loss drug for people with overweight or obesity.
The survey was designed and analyzed by public-opinion researchers at KFF and run both online and by telephone in both English and Spanish during July 11-19, 2023. The margin of sampling error was plus or minus 3 percentage points for the full sample but may have been even higher for results based on subgroup analyses.
The survey report includes no funding or disclosure information. However, KFF describes itself as “independent” and “nonpartisan” and that it “does everything based on facts and data, and we do so objectively without taking policy positions and without affiliation to any political party or external interest.”
A version of this article first appeared on Medscape.com.
‘Triple G’ agonist hits new weight loss heights
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Growth hormone links with worse T2D control in adolescents
SAN DIEGO – Plasma levels of three proteins involved in growth hormone activity showed significant links to the controllability of type 2 diabetes in children, a finding that suggests these proteins may serve as risk markers for incident type 2 diabetes and help identify adolescents who could benefit from aggressive preventive care.
“Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes,” Chang Lu, MD, said at the at the annual scientific sessions of the American Diabetes Association. “Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset,” she added in an interview.
Another potential application is to “leverage these data to find predictive markers” that could identify adolescents with type 2 diabetes “at risk for particularly aggressive disease and target them for more intervention,” added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston.
Does growth hormone cause incident T2D at puberty?
Changes in levels of growth hormone–associated peptides during puberty “could potentially explain why children with type 2 diabetes have a more aggressive course” of the disorder, added Dr. Lu, a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital.
Puberty-associated changes in growth hormone and related peptides “could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10,” Dr. Isganaitis said in an interview.
A current hypothesis is that “high levels of growth hormone is a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin and so they do not develop diabetes,” said Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver.
“But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition” to developing type 2 diabetes, Dr. Nadeau said in an interview.
The analyses run by Dr. Lu, Dr. Isganaitis, and their coauthors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which randomized 699 children aged 10-17 years with type 2 diabetes to one of three antidiabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.
The primary outcome showed a 39%-52% incidence of failure during 5 years of follow-up depending on the specific treatments the study participants received.
Growth hormone correlates of glycemic failure
The new analyses focused on 310 study participants from TODAY who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline and after 3 years, and assessed these changes relative to the endpoint of glycemic failure.
The results showed that an increase in insulin-like growth factor-1 significantly linked with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.
In contrast, Also, an increase in insulin-like growth factor binding protein-1 significantly linked with glycemic failure and hyperglycemia at 36 months, and with higher insulin sensitivity at baseline. All these analyses adjusted for baseline differences in several demographic and clinical variables.
But these post hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure, cautioned Dr. Lu.
Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Dr. Lu said.
Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in children identified as high risk.
Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Dr. Lu said.
The study received no commercial funding. Dr. Lu, Dr. Isganaitis, and Dr. Nadeau reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO – Plasma levels of three proteins involved in growth hormone activity showed significant links to the controllability of type 2 diabetes in children, a finding that suggests these proteins may serve as risk markers for incident type 2 diabetes and help identify adolescents who could benefit from aggressive preventive care.
“Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes,” Chang Lu, MD, said at the at the annual scientific sessions of the American Diabetes Association. “Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset,” she added in an interview.
Another potential application is to “leverage these data to find predictive markers” that could identify adolescents with type 2 diabetes “at risk for particularly aggressive disease and target them for more intervention,” added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston.
Does growth hormone cause incident T2D at puberty?
Changes in levels of growth hormone–associated peptides during puberty “could potentially explain why children with type 2 diabetes have a more aggressive course” of the disorder, added Dr. Lu, a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital.
Puberty-associated changes in growth hormone and related peptides “could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10,” Dr. Isganaitis said in an interview.
A current hypothesis is that “high levels of growth hormone is a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin and so they do not develop diabetes,” said Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver.
“But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition” to developing type 2 diabetes, Dr. Nadeau said in an interview.
The analyses run by Dr. Lu, Dr. Isganaitis, and their coauthors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which randomized 699 children aged 10-17 years with type 2 diabetes to one of three antidiabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.
The primary outcome showed a 39%-52% incidence of failure during 5 years of follow-up depending on the specific treatments the study participants received.
Growth hormone correlates of glycemic failure
The new analyses focused on 310 study participants from TODAY who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline and after 3 years, and assessed these changes relative to the endpoint of glycemic failure.
The results showed that an increase in insulin-like growth factor-1 significantly linked with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.
In contrast, Also, an increase in insulin-like growth factor binding protein-1 significantly linked with glycemic failure and hyperglycemia at 36 months, and with higher insulin sensitivity at baseline. All these analyses adjusted for baseline differences in several demographic and clinical variables.
But these post hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure, cautioned Dr. Lu.
Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Dr. Lu said.
Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in children identified as high risk.
Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Dr. Lu said.
The study received no commercial funding. Dr. Lu, Dr. Isganaitis, and Dr. Nadeau reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO – Plasma levels of three proteins involved in growth hormone activity showed significant links to the controllability of type 2 diabetes in children, a finding that suggests these proteins may serve as risk markers for incident type 2 diabetes and help identify adolescents who could benefit from aggressive preventive care.
“Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes,” Chang Lu, MD, said at the at the annual scientific sessions of the American Diabetes Association. “Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset,” she added in an interview.
Another potential application is to “leverage these data to find predictive markers” that could identify adolescents with type 2 diabetes “at risk for particularly aggressive disease and target them for more intervention,” added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston.
Does growth hormone cause incident T2D at puberty?
Changes in levels of growth hormone–associated peptides during puberty “could potentially explain why children with type 2 diabetes have a more aggressive course” of the disorder, added Dr. Lu, a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital.
Puberty-associated changes in growth hormone and related peptides “could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10,” Dr. Isganaitis said in an interview.
A current hypothesis is that “high levels of growth hormone is a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin and so they do not develop diabetes,” said Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver.
“But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition” to developing type 2 diabetes, Dr. Nadeau said in an interview.
The analyses run by Dr. Lu, Dr. Isganaitis, and their coauthors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which randomized 699 children aged 10-17 years with type 2 diabetes to one of three antidiabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.
The primary outcome showed a 39%-52% incidence of failure during 5 years of follow-up depending on the specific treatments the study participants received.
Growth hormone correlates of glycemic failure
The new analyses focused on 310 study participants from TODAY who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline and after 3 years, and assessed these changes relative to the endpoint of glycemic failure.
The results showed that an increase in insulin-like growth factor-1 significantly linked with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.
In contrast, Also, an increase in insulin-like growth factor binding protein-1 significantly linked with glycemic failure and hyperglycemia at 36 months, and with higher insulin sensitivity at baseline. All these analyses adjusted for baseline differences in several demographic and clinical variables.
But these post hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure, cautioned Dr. Lu.
Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Dr. Lu said.
Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in children identified as high risk.
Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Dr. Lu said.
The study received no commercial funding. Dr. Lu, Dr. Isganaitis, and Dr. Nadeau reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
AT ADA 2023
Semaglutide cuts cardiovascular events in landmark trial
, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.
The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among U.S. payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.
According to top-line results from SELECT released by Novo Nordisk on Aug. 8, the people randomly assigned to receive weekly 2.4-mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.
The results also showed a level of safety and patient tolerance for weekly 2.4-mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the U.S. Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).
SELECT began in 2018 and randomly assigned 17,604 adults aged 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1,270 study participants with a first MACE event but did not break this total down based on treatment received.
‘A good result for patients’
“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show – as I suspect they will – a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.
Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.
Changing how obesity is regarded
“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.
“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”
Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of antiobesity agents and the wisdom of using medically aided weight loss to produce health benefits.
This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 U.S. law prohibited part D plans from providing this coverage.
Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.
According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”
SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.
A version of this article first appeared on Medscape.com.
, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.
The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among U.S. payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.
According to top-line results from SELECT released by Novo Nordisk on Aug. 8, the people randomly assigned to receive weekly 2.4-mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.
The results also showed a level of safety and patient tolerance for weekly 2.4-mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the U.S. Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).
SELECT began in 2018 and randomly assigned 17,604 adults aged 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1,270 study participants with a first MACE event but did not break this total down based on treatment received.
‘A good result for patients’
“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show – as I suspect they will – a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.
Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.
Changing how obesity is regarded
“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.
“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”
Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of antiobesity agents and the wisdom of using medically aided weight loss to produce health benefits.
This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 U.S. law prohibited part D plans from providing this coverage.
Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.
According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”
SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.
A version of this article first appeared on Medscape.com.
, in the pivotal SELECT trial, with more than 17,000 enrolled people with overweight or obesity and established cardiovascular disease (CVD), but no diabetes.
The finding should fuel improved patient access to this glucagon-like peptide-1 (GLP-1) agonist weight-loss agent that has historically been hindered by skepticism among U.S. payers, many of whom have criticized the health benefits and cost effectiveness of this drug in people whose only indication for treatment is overweight or obesity.
According to top-line results from SELECT released by Novo Nordisk on Aug. 8, the people randomly assigned to receive weekly 2.4-mg subcutaneous injections of semaglutide showed a significant 20% reduction in their incidence of the combined endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The announcement added that semaglutide treatment also significantly linked with a drop in the incidence of each of these individual three endpoints; the magnitude of these reductions, however, wasn’t specified, nor was the duration of treatment and follow-up.
The results also showed a level of safety and patient tolerance for weekly 2.4-mg injections of semaglutide that were consistent with prior reports on the agent. Semaglutide as Wegovy received marketing approval from the U.S. Food and Drug Administration in 2021 for weight loss, and in 2017 for glucose control in people with type 2 diabetes, at a weekly maximum dose of 2.0 mg (for which it’s marketed as Ozempic).
SELECT began in 2018 and randomly assigned 17,604 adults aged 45 years and older at more than 800 sites in 41 countries. The company’s announcement noted that the trial had accrued a total of 1,270 study participants with a first MACE event but did not break this total down based on treatment received.
‘A good result for patients’
“The topline results from SELECT are exciting, as preventing heart attacks and stroke with a drug that also lowers weight is very important for many patients, especially if the data also show – as I suspect they will – a meaningful improvement of quality of life for patients due to associated weight loss,” commented Naveed Sattar, PhD, a professor of metabolic medicine at the University of Glasgow who was not involved with the study.
Despite this lack of current clarity over the role that weight loss by itself played in driving the observed result, the SELECT findings seem poised to reset a long-standing prejudice against the medical necessity and safety of weight-loss agents when used for the sole indication of helping people lose weight.
Changing how obesity is regarded
“To date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke, or cardiovascular death,” said Martin Holst Lange, executive vice president for development at Novo Nordisk, in the company’s press release.
“SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.”
Several of the early medical options for aiding weight loss had substantial adverse effects, including increased MACE rates, a history that led to pervasive wariness among physicians over the safety of antiobesity agents and the wisdom of using medically aided weight loss to produce health benefits.
This attitude also helped dampen health insurance coverage of weight-loss treatments. For example, Medicare has a long-standing policy against reimbursing the cost for medications that are used for the indication of weight loss, and a 2003 U.S. law prohibited part D plans from providing this coverage.
Semaglutide belongs to the class of agents that mimic the action of the incretin GLP-1. The introduction of this class of GLP-1 agonists for weight loss began in 2014 with the FDA’s approval of liraglutide (Saxenda), a daily subcutaneous injection that marked the first step toward establishing the class as safe and effective for weight loss and launching a new era in weight-loss treatment.
According to the Novo Nordisk announcement, a full report on results from SELECT will occur “at a scientific meeting later in 2023.”
SELECT is sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Sattar is a consultant to several companies that market GLP-1 receptor agonists, including Novo Nordisk and Lilly, but has had no involvement in SELECT.
A version of this article first appeared on Medscape.com.
Time-restricted eating gains for weight and glycemic control
Time-restricted eating (TRE) can be a practical, easy-to-follow way for some people to control their daily food intake and lose weight. It precludes a person’s need to pay close attention to how much they eat as long as they confine consumption to a limited time window. Plus, results from several recent studies show TRE can further benefit people with type 2 diabetes as well as obesity via mechanisms beyond weight loss.
The most tested and recommended eating window is 8 hours long, although periods up to roughly 10 hours may provide some benefits. Results from multiple studies document that TRE produces modest but consistent weight loss of less than 5% in many people. A recent meta-analysis of 17 randomized controlled studies involving 899 people showed an overall incremental weight loss, compared with controls of 1.60 kg on a TRE regimen.
The more limited data collected so far in people with type 2 diabetes show additional metabolic benefits from TRE, including improved beta-cell responsiveness, increased insulin sensitivity, nonoxidative glucose disposal, increased time in glycemic range, and virtually no hypoglycemic events, Courtney Peterson, PhD, said at the annual scientific sessions of the American Diabetes Association.
said Dr. Peterson, a researcher in the department of nutrition sciences at the University of Alabama, Birmingham.
‘Eating earlier is better’
An advantage of TRE is that it is “agnostic to food preferences and quality,” said Lisa S. Chow, MD, during a separate session at the meeting. TRE “may have benefits beyond calorie restriction” that appear related to “the timing of eating and the extent of the eating window restriction. Eating earlier [in the day] is better” for markers of metabolic health regardless of how much weight a person may lose on a TRE regimen, noted Dr. Chow, an endocrinologist and professor at the University of Minnesota Medical School, Minneapolis.
But the TRE paradigm seems amenable to some flexibility on the timing for the eating window while still having benefit.
“Self-selected eating windows are usually late,” Dr. Chow observed, and because compliance with a constrained eating window matters, it may be worth allowing people to choose whichever time window for eating works best for them.
“If you let people pick their eating window, they typically include dinner,” said Dr. Chow, who has run a small TRE study that showed this.
“To maximize the effects [of TRE] people should use the eating window that best fits their life,” agreed Kelsey Gabel, PhD, who also gave a TRE talk during the meeting. “Eating most of your [daily] calories first thing in the morning would have the best cardiometabolic benefit, but reduced adherence would mitigate the benefit,” said Dr. Gabel, a nutrition researcher at the University of Illinois.
‘Meeting people where they’re at’
“We can have a larger public health impact by meeting people where they’re at. People should position their eating window where it best fits so they can achieve calorie restriction without even knowing it,” Dr. Gabel advised.
She cited a report as evidence that most people prefer a later eating window. The report reviewed observational data from nearly 800,000 people who used either of two different TRE phone apps. The data showed that most people opted to start their daily eating during 11:00 AM-1:00 PM, and then stop during 6:00 PM-8:00 PM.
“TRE will not solve all of our obesity problems, but it’s a good place to start,” Dr. Gabel declared.
For people who include dinner at a typical evening time in their TRE window, a key message is that “dinner is your last food of the day. There’s no snacking later,” said Dr. Chow.
“The biggest challenge is adherence,” said Dr. Peterson. “Fewer people want to do TRE than you think. We know that calorie restriction works. We just need a way for people to do it,” and for at least some people, TRE is that way. While no evidence clearly shows that 8 hours is the best eating-window duration, “we think 8 hours is a good sweet-spot for motivated people,” she said.
Sparser data on TRE in people with T2D
Fewer studies have examined the impact of TRE on glycemic control, insulin sensitivity, and related effects in people with type 2 diabetes. According to Dr. Peterson, published reports currently include two randomized controlled studies and three single-arm studies in people with type 2 diabetes and an additional two studies in people with prediabetes.
The largest of these reports randomized 120 adults in China with type 2 diabetes and overweight to TRE using a 10-hour eating window (8:00 AM-6:00 PM) or unrestricted eating for 12 weeks. By the end of the study, those on the TRE regimen had an average reduction in their hemoglobin A1c from baseline that was 0.88 percentage points greater than among the controls, and the TRE arm had also lost an average of nearly 2.15 kg more from baseline than the controls.
Dr. Peterson highlighted the importance of expanding research using TRE in people with type 2 diabetes.
Dr. Peterson and Dr. Gabel report no relevant financial relationships. Dr. Chow has received research support from Dexcom.
A version of this article first appeared on Medscape.com.
Time-restricted eating (TRE) can be a practical, easy-to-follow way for some people to control their daily food intake and lose weight. It precludes a person’s need to pay close attention to how much they eat as long as they confine consumption to a limited time window. Plus, results from several recent studies show TRE can further benefit people with type 2 diabetes as well as obesity via mechanisms beyond weight loss.
The most tested and recommended eating window is 8 hours long, although periods up to roughly 10 hours may provide some benefits. Results from multiple studies document that TRE produces modest but consistent weight loss of less than 5% in many people. A recent meta-analysis of 17 randomized controlled studies involving 899 people showed an overall incremental weight loss, compared with controls of 1.60 kg on a TRE regimen.
The more limited data collected so far in people with type 2 diabetes show additional metabolic benefits from TRE, including improved beta-cell responsiveness, increased insulin sensitivity, nonoxidative glucose disposal, increased time in glycemic range, and virtually no hypoglycemic events, Courtney Peterson, PhD, said at the annual scientific sessions of the American Diabetes Association.
said Dr. Peterson, a researcher in the department of nutrition sciences at the University of Alabama, Birmingham.
‘Eating earlier is better’
An advantage of TRE is that it is “agnostic to food preferences and quality,” said Lisa S. Chow, MD, during a separate session at the meeting. TRE “may have benefits beyond calorie restriction” that appear related to “the timing of eating and the extent of the eating window restriction. Eating earlier [in the day] is better” for markers of metabolic health regardless of how much weight a person may lose on a TRE regimen, noted Dr. Chow, an endocrinologist and professor at the University of Minnesota Medical School, Minneapolis.
But the TRE paradigm seems amenable to some flexibility on the timing for the eating window while still having benefit.
“Self-selected eating windows are usually late,” Dr. Chow observed, and because compliance with a constrained eating window matters, it may be worth allowing people to choose whichever time window for eating works best for them.
“If you let people pick their eating window, they typically include dinner,” said Dr. Chow, who has run a small TRE study that showed this.
“To maximize the effects [of TRE] people should use the eating window that best fits their life,” agreed Kelsey Gabel, PhD, who also gave a TRE talk during the meeting. “Eating most of your [daily] calories first thing in the morning would have the best cardiometabolic benefit, but reduced adherence would mitigate the benefit,” said Dr. Gabel, a nutrition researcher at the University of Illinois.
‘Meeting people where they’re at’
“We can have a larger public health impact by meeting people where they’re at. People should position their eating window where it best fits so they can achieve calorie restriction without even knowing it,” Dr. Gabel advised.
She cited a report as evidence that most people prefer a later eating window. The report reviewed observational data from nearly 800,000 people who used either of two different TRE phone apps. The data showed that most people opted to start their daily eating during 11:00 AM-1:00 PM, and then stop during 6:00 PM-8:00 PM.
“TRE will not solve all of our obesity problems, but it’s a good place to start,” Dr. Gabel declared.
For people who include dinner at a typical evening time in their TRE window, a key message is that “dinner is your last food of the day. There’s no snacking later,” said Dr. Chow.
“The biggest challenge is adherence,” said Dr. Peterson. “Fewer people want to do TRE than you think. We know that calorie restriction works. We just need a way for people to do it,” and for at least some people, TRE is that way. While no evidence clearly shows that 8 hours is the best eating-window duration, “we think 8 hours is a good sweet-spot for motivated people,” she said.
Sparser data on TRE in people with T2D
Fewer studies have examined the impact of TRE on glycemic control, insulin sensitivity, and related effects in people with type 2 diabetes. According to Dr. Peterson, published reports currently include two randomized controlled studies and three single-arm studies in people with type 2 diabetes and an additional two studies in people with prediabetes.
The largest of these reports randomized 120 adults in China with type 2 diabetes and overweight to TRE using a 10-hour eating window (8:00 AM-6:00 PM) or unrestricted eating for 12 weeks. By the end of the study, those on the TRE regimen had an average reduction in their hemoglobin A1c from baseline that was 0.88 percentage points greater than among the controls, and the TRE arm had also lost an average of nearly 2.15 kg more from baseline than the controls.
Dr. Peterson highlighted the importance of expanding research using TRE in people with type 2 diabetes.
Dr. Peterson and Dr. Gabel report no relevant financial relationships. Dr. Chow has received research support from Dexcom.
A version of this article first appeared on Medscape.com.
Time-restricted eating (TRE) can be a practical, easy-to-follow way for some people to control their daily food intake and lose weight. It precludes a person’s need to pay close attention to how much they eat as long as they confine consumption to a limited time window. Plus, results from several recent studies show TRE can further benefit people with type 2 diabetes as well as obesity via mechanisms beyond weight loss.
The most tested and recommended eating window is 8 hours long, although periods up to roughly 10 hours may provide some benefits. Results from multiple studies document that TRE produces modest but consistent weight loss of less than 5% in many people. A recent meta-analysis of 17 randomized controlled studies involving 899 people showed an overall incremental weight loss, compared with controls of 1.60 kg on a TRE regimen.
The more limited data collected so far in people with type 2 diabetes show additional metabolic benefits from TRE, including improved beta-cell responsiveness, increased insulin sensitivity, nonoxidative glucose disposal, increased time in glycemic range, and virtually no hypoglycemic events, Courtney Peterson, PhD, said at the annual scientific sessions of the American Diabetes Association.
said Dr. Peterson, a researcher in the department of nutrition sciences at the University of Alabama, Birmingham.
‘Eating earlier is better’
An advantage of TRE is that it is “agnostic to food preferences and quality,” said Lisa S. Chow, MD, during a separate session at the meeting. TRE “may have benefits beyond calorie restriction” that appear related to “the timing of eating and the extent of the eating window restriction. Eating earlier [in the day] is better” for markers of metabolic health regardless of how much weight a person may lose on a TRE regimen, noted Dr. Chow, an endocrinologist and professor at the University of Minnesota Medical School, Minneapolis.
But the TRE paradigm seems amenable to some flexibility on the timing for the eating window while still having benefit.
“Self-selected eating windows are usually late,” Dr. Chow observed, and because compliance with a constrained eating window matters, it may be worth allowing people to choose whichever time window for eating works best for them.
“If you let people pick their eating window, they typically include dinner,” said Dr. Chow, who has run a small TRE study that showed this.
“To maximize the effects [of TRE] people should use the eating window that best fits their life,” agreed Kelsey Gabel, PhD, who also gave a TRE talk during the meeting. “Eating most of your [daily] calories first thing in the morning would have the best cardiometabolic benefit, but reduced adherence would mitigate the benefit,” said Dr. Gabel, a nutrition researcher at the University of Illinois.
‘Meeting people where they’re at’
“We can have a larger public health impact by meeting people where they’re at. People should position their eating window where it best fits so they can achieve calorie restriction without even knowing it,” Dr. Gabel advised.
She cited a report as evidence that most people prefer a later eating window. The report reviewed observational data from nearly 800,000 people who used either of two different TRE phone apps. The data showed that most people opted to start their daily eating during 11:00 AM-1:00 PM, and then stop during 6:00 PM-8:00 PM.
“TRE will not solve all of our obesity problems, but it’s a good place to start,” Dr. Gabel declared.
For people who include dinner at a typical evening time in their TRE window, a key message is that “dinner is your last food of the day. There’s no snacking later,” said Dr. Chow.
“The biggest challenge is adherence,” said Dr. Peterson. “Fewer people want to do TRE than you think. We know that calorie restriction works. We just need a way for people to do it,” and for at least some people, TRE is that way. While no evidence clearly shows that 8 hours is the best eating-window duration, “we think 8 hours is a good sweet-spot for motivated people,” she said.
Sparser data on TRE in people with T2D
Fewer studies have examined the impact of TRE on glycemic control, insulin sensitivity, and related effects in people with type 2 diabetes. According to Dr. Peterson, published reports currently include two randomized controlled studies and three single-arm studies in people with type 2 diabetes and an additional two studies in people with prediabetes.
The largest of these reports randomized 120 adults in China with type 2 diabetes and overweight to TRE using a 10-hour eating window (8:00 AM-6:00 PM) or unrestricted eating for 12 weeks. By the end of the study, those on the TRE regimen had an average reduction in their hemoglobin A1c from baseline that was 0.88 percentage points greater than among the controls, and the TRE arm had also lost an average of nearly 2.15 kg more from baseline than the controls.
Dr. Peterson highlighted the importance of expanding research using TRE in people with type 2 diabetes.
Dr. Peterson and Dr. Gabel report no relevant financial relationships. Dr. Chow has received research support from Dexcom.
A version of this article first appeared on Medscape.com.
FROM ADA 2023