Patients who have obesity but don’t have diabetes may now reap the benefits of using a GLP-1 receptor agonist, semaglutide, for weight management.
The STEP study examined using Semaglutide 2.4 mg once weekly for weight management. In the Phase 1 trial, researchers conducted a post hoc analysis of questions that looked at changes in body weight and energy intake post 20 weeks. In Phase 2, 957 participants were evaluated for drug safety, drug tolerability, and weight loss. The study included data from individuals with a BMI >30, age >18 years, >1 failed weight loss attempt, no T1D/T2D, and A1C <6.5%. The primary outcome was a change in percent body weight at week 52. The secondary outcomes included changes in weight, A1C, FBG, and safety. Varying doses ranging from 0.05 mg to 3 mg were tested. Liraglutide and Semaglutide placebo was also compared. In global Phase 3a, individuals were assessed for weight management (STEP 1, N=1,961), weight management in T2D (STEP 2, N=1,210), weight management with intensive behavioral therapy (STEP 3, N=611), sustained weight management (STEP 4, N=813), weight management in adolescents (STEP TEENS, N=200). In regional phase 3a, researchers conducted an East Asian trial (STEP 6, N=400) and a China multi-regional clinical trial (STEP 7, N=375). In Phase 3b, they assessed long term weight management (STEP 5, N=300), head-to-head versus Liraglutide (STEP 8, N=336), Semaglutide in knee osteoarthritis (STEP 9, N=375), Semaglutide in HFpEF (STEP HFpEF, N=478), and cardiovascular outcomes trial (SELECT, N=17,500).
In Phase 1 to Phase 2, Semaglutide 2.4 mg lowered body weight by 10.4 kg compared to 0.4 kg of the placebo. Over 80% of patients in the treatment group lost >5% of their body weight compared to 30% in the placebo. Energy intake was 35% lower when compared to placebo (p<0.01) and 47% lower when compared to baseline (p<0.01). Following a standardized breakfast, participants reported less hunger and prospective food consumption with increased fullness, satiety, and appetite suppression (P<0.01). Liraglutide 3 mg lowered body weight by 7.8% compared to 2.3% of the placebo. With Semaglutide, there was a dose-dependent weight reduction ranging from 6% to 13.8%.
In Phase 3, Semaglutide 2.4 mg coupled with brief monthly lifestyle counseling resulted in a mean weight loss of 15%. Adding a low-calorie diet and Intensive behavioral therapy did not increase weight loss at week 68. In STEP 2, patients with T2D saw a dose-dependent weight reduction of 7% to 9.6% (Semaglutide 1 mg and 2.4 mg). There was a more significant reduction in A1C with patients who had >10% weight loss. In STEP 4, patients that continued treatment saw continued weight loss while the placebo saw weight gain. Overall, the treatment group saw a five mmHg reduction in systolic Bp and a three mmHg reduction in diastolic BP compared to placebo. There was also a 21% decrease in VLDL cholesterol, a 22% decrease in triglycerides, a 16% reduction in free fatty acids, and a 7% reduction in HDL. No significant change was seen in total cholesterol or LDL. There was a 42%-49% reduction with treatment with C-reactive protein and a 17% reduction with placebo. Patients on Semaglutide 2.4 mg saw a 10 cm waist circumference reduction compared to 7 cm with Semaglutide 1 mg and 5 cm with placebo. A1C was reduced by 1.5-1.6 with treatment and by 0.4 with placebo.
Based on results from the STEP trial, Semaglutide 2.4 mg once weekly was approved by the FDA in 2021 for weight loss. It may be an adjunct to diet and exercise in adults with an initial BMI >30. It may also be used in those with an initial BMI >27 if the patient had at least one weight-related comorbidity. Weaknesses of the study included participant dropout due to medication-related adverse effects. In addition, approximately 4% of individuals discontinued Semaglutide due to gastral intestinal discomfort. In the future, the SELECT trial will assess cardiovascular outcomes in patients who do not have T2D.
- Patients with T2D saw a dose-dependent weight reduction of 7% to 9.6% when taking Semaglutide 1 mg and 2.4 mg. There was a more significant reduction in A1C with patients who had >10% weight loss.
- Semaglutide 2.4 mg coupled with brief monthly lifestyle counseling resulted in a mean weight loss of 15%. Adding a low-calorie diet and Intensive behavioral therapy did not increase weight loss at week 68.
- Semaglutide 2.4 mg once weekly was recently approved by the FDA for weight loss. It is used as an adjunct to diet and exercise in adults with an initial BMI >30. It may also be used in those with an initial BMI >27 if the patient had at least one weight-related comorbidity.
Davies, Melanie, et al. “Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial.” Lancet (London, England) vol. 397,10278 (2021): 971-984. doi:10.1016/S0140-6736(21)00213-0
Lee, K. et al. (2021, June). “STEP” against Obesity—Once-Weekly Semaglutide 2.4 mg Clinical Development Program for Weight Management. Copenhagen; Denmark. (Requires ADA Symposium login.
Kornelia Ilias, Pharm.D. Candidate, Creighton University School of Pharmacy and Health Professions