GLP-1 signaling is powerful target for obesity
Presenters: Melanie J. Davies, CBE, FMedSci, Robert F. Kushner, MD, John Wilding, DM, and Lee M. Kaplan, MD, PhD
Semaglutide, 2.4 mg/week, was approved for weight management by the U.S. Food and Drug Administration on June 4, 2021. Per the FDA approval, it is indicated as an adjunct to diet and exercise in adults with obesity (initial body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) with at least one weight-related comorbidity. The approval was based on the phase 3a STEP program, which was the subject of a symposium.
The four pivotal trials in the STEP program were STEP 1, examining weight management in overweight or obese adults1; STEP 2, focusing on weight management in patients with type 2 diabetes mellitus not on insulin2; STEP 3, focusing on weight management with intensive behavioral therapy3; and STEP 4, assessing sustained weight management.4 An overview of the STEP program findings was presented.
Semaglutide acts directly in the hypothalamus and the hindbrain to reduce appetite and food cravings, said Melanie J. Davies, CBE, FMedSci, professor of diabetes medicine, University of Leicester. Energy intake is 35% lower in semaglutide recipients compared with placebo, and 47% lower compared with baseline.
In people with obesity, across all STEP programs, reductions in body, waist circumference, and systolic blood pressure were realized with semaglutide, 2.4 mg, along with an improvement in physical function, reported Robert F. Kushner, MD, professor of medicine and medical education, Northwestern University, Chicago.
Data from STEP 3 suggest that semaglutide with monthly brief lifestyle counseling is sufficient to produce a mean weight loss of 15%. Initial weight loss is accelerated by the lifestyle and behavioral counseling components but does not provide additive weight loss at week 68. Weight loss is slightly greater in patients without type 2 diabetes (mean loss: 15 to 17%) than in those with type 2 diabetes (mean loss: 10%). In patients with type 2 diabetes in STEP 2, the mean decrease in HbA1c from baseline with semaglutide, 2.4 mg, was 1.6%, compared with a decline of 0.4% with placebo.
Cardiometabolic outcomes were improved in individuals treated with semaglutide, 2.4 mg, in STEP 1 and STEP 3, said John Wilding, DM, professor of endocrinology, University of Liverpool, United Kingdom. Mean reductions in systolic blood pressure from baseline were 6.2 and 5.6 mm Hg in the two trials, respectively, compared with reductions of 1.1 and 1.6 mm Hg, respectively, in placebo recipients. The proportion of individuals with normoglycemia improved from 55% at baseline to 84% at week 68 in patients assigned to semaglutide, 2.4 mg, in STEP 1, compared with a decrease in this proportion from 60% to 48% in those assigned to placebo. The proportion of participants without metabolic syndrome also improved from 46.7% to 75.4% in the semaglutide arm while declining from 53.3% to 48.0% in the placebo arm.
The mean change in waist circumference in STEP 2 was ─9.4 cm in patients assigned to semaglutide, 2.4 mg, compared with 4.5 cm in those assigned to placebo.
The weight loss obtained with semaglutide shows typical patient-to-patient variability, said Lee M. Kaplan, MD, PhD, director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Boston. In the STEP 1 program, 35% of patients treated with semaglutide, 2.4 mg, lost more than 20% of body weight and 11% lost more than 30%, “but some patients fail to respond as well,” he said. Some 7 to 13% of patients overall, and 31% of patients with type 2 diabetes, lost less than 5% of body weight.
“The superior efficacy of semaglutide, 2.4 mg, demonstrates that GLP-1 signaling is a powerful and effective target for obesity therapy. It provides new clinical opportunity for the control of obesity and its medical complications,” said Dr. Kaplan. “But to be effective, semaglutide needs to be used. Obesity needs to be recognized as a disease in its own right, as well as a risk factor for numerous other diseases.”
References
- Wilding JPH, Batterham RL, Calana S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989-1002.
- Davies M, Faerch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971-984.
- Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021;325:1403-1413.
- Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021;325:1414-1425.
Disclosures
Dr. Davies discloses the following relationships. Advisory panel: Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Speaker’s bureau: AstraZeneca Pharma India Ltd, Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Inc., Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim Singapore Pte.Ltd, Boehringer Ingelheim Sp.Z o.o., Eli Lilly and Company, Napp Pharmaceuticals, Novo Nordisk, Novo Nordisk A/S, S.C.Sanofi Romania SRL, Sanofi K.K. Other Relationship: AstraZeneca, NIHR Leicester Biomedical Research Centre, Novo Nordisk.
Dr. Wilding discloses the following relationships. Consultant: AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Mundipharma International, Napp Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Inc., Saniona, Sanofi, Research support: AstraZeneca, Novo Nordisk. Speaker’s bureau: AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Napp Pharmaceuticals.
Dr. Kaplan discloses the following relationships. Advisory panel: Eli Lilly and Company, Gelesis, GI Dynamics, Novo Nordisk, Pfizer Inc., Consultant; Self; Eli Lilly and Company, Gelesis, Intellihealth, Johnson & Johnson, Novo Nordisk, Pfizer Inc., Rhythm Pharmaceuticals, Inc., Stock/shareholder: Gelesis.