GLP-1 weight-loss drugs: what the evidence shows

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1. 1

   Once-weekly semaglutide in adults with overweight or obesity (STEP 1)

   New England Journal of Medicine (Wilding et al.)Published Mar 18, 2021Checked Sep 30, 2026

   “Among 1,961 adults, mean body weight fell 14.9% with semaglutide 2.4 mg versus 2.4% with placebo over 68 weeks. Gastrointestinal side effects were the most common adverse events.”

2. 2

   Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1)

   New England Journal of Medicine (Jastreboff et al.)Published Jul 21, 2022Checked Sep 30, 2026

   “Over 72 weeks, mean weight fell 15.0%, 19.5% and 20.9% with 5, 10 and 15 mg tirzepatide, versus 3.1% with placebo.”

3. 3

   Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT)

   New England Journal of Medicine (Lincoff et al.)Published Dec 14, 2023Checked Sep 30, 2026

   “In 17,604 patients with cardiovascular disease and overweight or obesity but no diabetes, semaglutide reduced major adverse cardiovascular events by 20% (6.5% vs 8.0%).”

4. 4

   Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension

   Diabetes, Obesity and Metabolism (Wilding et al.)Published May 19, 2022Checked Sep 30, 2026

   “One year after stopping semaglutide, participants regained two-thirds of their prior weight loss, and cardiometabolic improvements largely reverted.”

5. 5

   FDA's concerns with unapproved GLP-1 drugs used for weight loss

   US Food and Drug AdministrationPublished Jan 1, 2025Checked Sep 30, 2026

   “FDA has received reports of adverse events, some requiring hospitalisation, related to dosing errors with compounded semaglutide and tirzepatide, and warns against counterfeit and unapproved products.”

6. 6

   Persistence in GLP-1-Based Therapy Among Adults with Obesity and Type 2 Diabetes: A Narrative Review of Definitions, Real-World Outcomes, and Determinants.

   Current diabetes reports (Wang & Shiyanbola)Published Aug 15, 2026Checked Oct 4, 2026

   “Persistence generally declined over time and often fell below 60% by 12 to 24 months, although estimates varied by refill-gap definitions and analytic approaches. Discontinuation reached 64.1% at 2 years in one large cohort, and treatment interruption with reinitiation was common. Persistence varied by age, income, gastrointestinal adverse events, weight reduction, body mass index-related measures, GLP-1 agent, formulation, and dosing schedule. Only two studies reported patient-level reasons for discontinuation, most commonly adverse effects, and none described structured behavioral or supportive strategies. Persistence with GLP-1-based therapies among adults with obesity and type 2 diabetes is variable and often declines within the first one to two years. More consistent definitions, closer attention to patient experiences, and routine-care support strategies are needed to improve long-term continuation.”

7. 7

   Weight regain following discontinuation of glucagon-like peptide-1 receptor agonists in adults who are overweight or obese: a systematic review and meta-analysis.

   PeerJ (Qi et al.)Published Sep 8, 2026Checked Oct 4, 2026

   “Eventually, six studies involving 8,993 patients were included in the quantitative analysis, comprising 5,553 patients in the discontinuation group and 3,440 in the continued treatment group. The results of the meta-analysis showed that, compared with the continued treatment group, the weight difference in the discontinuation group was mean difference (MD) = 17.90%, 95% confidence interval (CI) [14.11-21.69], P P = 0.0082). Subgroup analysis further revealed that the weight rebound amplitude after discontinuation of tirzepatide was significantly higher than that of semaglutide. This result suggests that the differences in the mechanism of action of different GLP-1RAs may be the reason for the differences in weight changes after discontinuation. In addition, the percentage difference in body weight between after and before drug withdrawal was MD = 9.11%, 95% CI [7.91-10.30], P ConclusionThere is a significant weight rebound phenomenon after discontinuation of GLP-1RAs, and the rebound magnitudes vary among different types of drugs. At the same time, there is a risk of adverse reactions during the use of such drugs.”

8. 8

   Comparative efficacy and safety of glucagon-like peptide 1 based drugs for weight loss in adults with overweight or obesity without diabetes: network meta-analysis of randomised controlled trials.

   BMJ medicine (Chen et al.)Published Aug 27, 2026Checked Oct 4, 2026

   “Compared with placebo, weight loss was greatest with retatrutide (-22.10%, 95% confidence interval -25.60% to -18.60%), followed by tirzepatide (-19.28%, -20.39% to -18.16%), and CagriSema (a combination of cagrilintide and semaglutide, -17.32%, -19.32% to -15.32%). Conventional GLP-1 receptor agonists showed more modest effects. Similar patterns were seen for waist circumference and lipid outcomes. Treatment rankings suggested a probabilistic hierarchy favouring next generation incretin based treatments, although confidence intervals overlapped for several comparisons. Low certainty evidence suggested higher rates for discontinuing treatment with danuglipron and retatrutide, whereas mazdutide showed better tolerability.ConclusionsIn adults with overweight or obesity without diabetes, next generation incretin based treatments achieved greater weight loss than conventional GLP-1 receptor agonists. Differences in tolerability, limited head-to-head evidence, and residual uncertainty, however, should be considered when interpreting comparative treatment effects.Study registrationPROSPERO CRD420261279841.”

9. 9

   Comparative Efficacy of Tirzepatide Versus Semaglutide for Weight Loss in Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis of Head-to-Head Studies.

   Clinical obesity (Paccola et al.)Published Oct 1, 2026Checked Oct 4, 2026

   “Secondary outcomes included absolute weight change, weight-loss thresholds, HbA1c and safety outcomes. Ten studies including 41 381 participants were analysed. Tirzepatide was associated with greater percentage weight reduction than semaglutide (MD -4.28 percentage points; 95% CI -5.28 to -3.28; p < 0.00001) and greater absolute weight loss (MD -4.43 kg; 95% CI -5.56 to -3.30; p < 0.00001). Tirzepatide was also associated with a higher likelihood of achieving ≥ 10%, ≥ 15% and ≥ 20% weight loss, with no difference at ≥ 5%. HbA1c reduction was greater with tirzepatide (MD -0.29%; p = 0.0002). Subgroup analyses by study design and type 2 diabetes status yielded consistent findings. There was no significant difference in treatment discontinuation due to adverse events (RR 1.28; p = 0.54), whereas serious adverse events were more frequent with tirzepatide (RR 1.83; p = 0.007). Overall and gastrointestinal adverse events were similar between groups. Tirzepatide was associated with greater weight reduction, greater glycaemic benefit and a higher likelihood of achieving weight-loss thresholds than semaglutide, but with a higher risk of serious adverse events.”