GLP-1 Medications: How They Work and What the Trials Actually Show

Over the past five years, glucagon-like peptide-1 (GLP-1) receptor agonists have moved from niche diabetes therapies to among the most-discussed drugs in medicine. Two agents in particular — semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound) — now have large, well-powered trial programs behind them. Understanding the mechanism and the actual numbers from those trials matters for anyone trying to evaluate these medications clearly.

This article is educational information, not medical advice. GLP-1 medications are prescription drugs that require a clinician's evaluation. Do not start, adjust, or stop any medication without guidance from a licensed healthcare provider.

How GLP-1 Receptor Agonists Work

The gut hormone GLP-1 is released after a meal and acts on multiple organ systems simultaneously. When a synthetic GLP-1 analogue is present at pharmacologic doses, several things happen in parallel:

• Pancreatic beta cells increase insulin secretion in a glucose-dependent manner — meaning the effect is largely blunted when blood glucose is already normal, which limits hypoglycemia risk relative to older agents.
• Glucagon release from alpha cells is suppressed, reducing hepatic glucose output.
• Gastric emptying slows, dampening the post-meal glucose spike.
• Hypothalamic satiety circuits are engaged, reducing appetite and caloric intake — the mechanism that drives weight loss in people without diabetes as well as in those with it.

Tirzepatide adds a second mechanism: it is a dual GIP/GLP-1 receptor agonist, activating both the glucose-dependent insulinotropic polypeptide receptor and the GLP-1 receptor. Whether the GIP component amplifies weight loss via a complementary hypothalamic pathway or via peripheral fat metabolism is an active area of research, but the additive effect on body weight appears real across the trial data.

What the SUSTAIN and STEP Programs Found

Semaglutide's cardiovascular and metabolic profile was established across two major trial programs. The SUSTAIN program (multiple phase-3 trials, 2016–2019) tested weekly subcutaneous semaglutide (0.5 mg and 1.0 mg) in adults with type-2 diabetes and demonstrated HbA1c reductions of 1.2–1.8 percentage points and body-weight reductions of 4–6 kg versus placebo. The SUSTAIN-6 cardiovascular outcomes trial showed a 26% relative reduction in the composite of cardiovascular death, nonfatal MI, and nonfatal stroke in a high-cardiovascular-risk population.

The STEP program (four phase-3 trials published 2021–2022 in The New England Journal of Medicine and affiliated journals) tested higher-dose weekly semaglutide (2.4 mg) in adults with obesity or overweight plus a weight-related comorbidity. Headline findings:

• STEP 1 (2021, NEJM): 68 weeks of 2.4 mg semaglutide produced a mean weight loss of 14.9% versus 2.4% on placebo in adults without diabetes.
• STEP 2: adults with type-2 diabetes lost a mean of 9.6% of body weight.
• STEP 4: participants who reached steady state on semaglutide and then switched to placebo regained roughly two-thirds of the lost weight by 48 weeks — underscoring that these medications appear to work for as long as they are taken.

The SURMOUNT Program and Tirzepatide's Numbers

The SURMOUNT trial program evaluated tirzepatide for obesity. SURMOUNT-1 (2022, NEJM) randomized adults with obesity or overweight plus comorbidities (excluding diabetes) to 5 mg, 10 mg, or 15 mg weekly. At 72 weeks:

• The 15 mg dose arm achieved a mean weight loss of 20.9% — a magnitude not previously seen in a pharmacotherapy trial of this scale.
• More than a third of participants on the highest dose lost ≥25% of body weight.

The SURPASS program covered tirzepatide in type-2 diabetes and showed consistent superiority over semaglutide 1.0 mg (SURPASS-2) on both HbA1c reduction and weight loss at 40 weeks, though head-to-head comparisons at obesity doses are ongoing.

Side Effects, Limitations, and What the Trials Do Not Settle

The most common adverse events across both programs are gastrointestinal — nausea, vomiting, diarrhea, and constipation — and are most prominent during dose escalation. Serious adverse events (pancreatitis, gallbladder disease) were rare but more frequent in drug arms than placebo. Long-term cardiovascular outcomes data for tirzepatide specifically in an obesity-primary population are expected from the SURMOUNT-MMO trial but are not yet reported.

Several questions remain at the level of tier B or lower evidence (observational, mechanistic, or underpowered): effects on lean mass preservation with resistance training, optimal duration of therapy, and cardiometabolic outcomes in people with normal glucose tolerance at baseline.

Key Takeaways

• GLP-1 receptor agonists suppress appetite via hypothalamic pathways and slow gastric emptying, producing weight loss beyond glycemic effects.
• The STEP program showed ~15% mean weight loss with high-dose semaglutide; the SURMOUNT program showed ~21% with tirzepatide 15 mg — both in adults without diabetes.
• Weight regain after stopping is substantial, suggesting these are long-term therapies rather than short courses.
• Cardiovascular risk reduction has been demonstrated for semaglutide in high-risk diabetic populations; equivalent data for obesity-primary populations are maturing.
• These are prescription medications requiring individualized clinical evaluation — not supplements or lifestyle adjuncts available without medical supervision.

References

1. Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021.
2. Davies M et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2). The Lancet, 2021.
3. Rubino DM et al. Effect of continued weekly subcutaneous semaglutide vs. placebo on weight loss maintenance in adults with overweight or obesity (STEP 4). JAMA, 2021.
4. Marso SP et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). New England Journal of Medicine, 2016.
5. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine, 2022.
6. Frías JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). New England Journal of Medicine, 2021.
7. American Diabetes Association. Standards of Medical Care in Diabetes — Pharmacologic Approaches to Glycemic Treatment. Diabetes Care, 2024.