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GLP-1 Agonists

GMJ News knowledge hub · last reviewed August 2026 · Georgian Medical Journal

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GLP-1 receptor agonists — semaglutide (Ozempic for type 2 diabetes; Wegovy for obesity) and tirzepatide (Mounjaro for T2DM; Zepbound for obesity, a dual GLP-1 plus GIP agonist) — represent the most transformative drug class in medicine since the statins, achieving 15-22% body weight loss in clinical trials (STEP and SURMOUNT programmes), with the 2023 SELECT trial demonstrating that semaglutide reduces major adverse cardiovascular events by 20% in obese adults with established CVD — the first weight-loss drug ever to demonstrate cardiovascular mortality benefit and forcing a complete reconceptualisation of obesity as a treatable cardiometabolic disease rather than a lifestyle choice (WHO). The 2024 FLOW trial (NEJM) further demonstrated semaglutide reduces the composite kidney outcome by 24% in diabetic CKD — and emerging data suggest GLP-1 receptors in the brain’s reward centres (VTA, nucleus accumbens) may also reduce cravings for alcohol, nicotine and opioids, hinting at far broader therapeutic potential than weight loss alone.

Key messages

Semaglutide — 15-17% weight loss, and CVD mortality benefit (SELECT 2023)
Semaglutide 2.4mg weekly (Wegovy) achieved 15-17% mean body weight loss in the STEP phase 3 trials over 68 weeks. The 2023 SELECT trial (NEJM, 17,604 participants) demonstrated 20% reduction in MACE in overweight/obese adults with established CVD — the first weight-loss drug to reduce cardiovascular mortality. This repositioned GLP-1 RAs as cardiovascular drugs as much as weight-loss drugs.
Tirzepatide — 20-22% weight loss — the new ceiling
Tirzepatide (Mounjaro/Zepbound, Eli Lilly) is a dual agonist at GLP-1 and GIP (glucose-dependent insulinotropic peptide) receptors. SURMOUNT-1 trial: 20% mean weight loss at 72 weeks (highest dose). SURMOUNT-4: 22% weight loss with continued treatment. This surpasses semaglutide and approaches bariatric surgery outcomes (~25-30%) pharmacologically — a paradigm shift.
Kidney protection — FLOW trial 2024 (NEJM)
FLOW trial (2024, NEJM) — semaglutide vs placebo in patients with T2DM and CKD: 24% reduction in the composite primary endpoint (sustained ≥50% eGFR decline, ESKD, death from kidney or CVD causes). Trial stopped early for overwhelming efficacy. GLP-1 RAs now join SGLT-2 inhibitors as the two drug classes with proven kidney-protective effects in diabetic CKD — beyond glucose control.
Mechanism — appetite, satiety, and the reward system
GLP-1 receptors are expressed in: pancreatic beta cells (increased insulin secretion, glucose-dependent); alpha cells (reduced glucagon); stomach (delayed gastric emptying — slows digestion, prolongs satiety); hypothalamus (appetite suppression, satiety signalling); VTA and nucleus accumbens (dopamine reward circuits — reduces food reward and cravings). The brain reward effect explains emerging evidence that GLP-1 RAs reduce cravings for alcohol, tobacco, opioids and gambling — potentially far broader than weight loss.
GLP-1 agonists and addiction — the emerging signal
Multiple observational studies and a 2024 Nature Medicine paper reported that GLP-1 RA users have significantly lower rates of: alcohol use disorder; smoking relapse; opioid overdose; cannabis use. Several clinical trials are now actively investigating semaglutide for alcohol use disorder, nicotine dependence and opioid use disorder. The mechanism: GLP-1 receptors in the mesolimbic dopamine reward pathway reduce incentive salience (the reward value) of addictive substances — a fundamentally new pharmacological principle.
Ethical and equity concerns
Cost: Wegovy approximately $1,300/month in the USA without insurance (approximately £200/month in UK on NHS for selected patients). Global demand has created chronic supply shortages, leaving T2DM patients unable to access Ozempic for their primary indication. The concept of pharmacological weight loss raises profound questions about medicalisation of body weight, body autonomy, weight stigma and who deserves treatment. The drugs are dramatically more effective than lifestyle intervention — but lifestyle intervention must not be abandoned.

Key statistics

15-17%
mean body weight loss with semaglutide 2.4mg (Wegovy) — STEP trials 68 weeks
NEJM 2021
20-22%
mean body weight loss with tirzepatide (Zepbound) — SURMOUNT trials
NEJM 2022-23
20%
reduction in MACE (major CVD events) with semaglutide — SELECT trial 2023
NEJM 2023
24%
reduction in composite kidney outcome — FLOW trial 2024 (stopped early)
NEJM 2024
2005
year first GLP-1 RA (exenatide, Byetta) approved — 20 years of GLP-1 development
FDA 2005
Addiction
emerging evidence GLP-1 RAs reduce alcohol, tobacco and opioid cravings
Nature Medicine 2024

GLP-1 agonist weight loss — comparison across drug classes and trials (%)

Source: STEP/SURMOUNT trials. GLP-1 RAs now approach bariatric surgery outcomes pharmacologically.

Glossary of key terms

GLP-1 (glucagon-like peptide-1)
EndocrinologyAn incretin hormone secreted by L-cells in the ileum and colon in response to nutrient ingestion. Actions: stimulates pancreatic insulin secretion (glucose-dependent — only when blood glucose is elevated, eliminating hypoglycaemia risk); inhibits glucagon secretion; slows gastric emptying (prolongs satiety); acts on hypothalamic receptors to suppress appetite; stimulates beta-cell proliferation and inhibits apoptosis. Native GLP-1 is rapidly degraded by DPP-4 enzyme (half-life 2 minutes). GLP-1 receptor agonists (GLP-1 RAs) are structural analogues engineered for longer half-life.
SELECT trial (2023)
NEJM 2023Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity: 17,604 adults with overweight/obesity (BMI ≥27) and established CVD but without type 2 diabetes, randomised to semaglutide 2.4mg weekly vs placebo. Primary endpoint: first MACE (cardiovascular death, non-fatal MI, non-fatal stroke). Result: 20% risk reduction (6.5% vs 8.0%, HR 0.80, p<0.001). This was groundbreaking: the first time any weight-loss drug demonstrated cardiovascular event reduction independent of glucose lowering — proving obesity itself as a modifiable cardiovascular risk factor.
FLOW trial (2024)
NEJM 2024Evaluate Renal Function with Semaglutide Once Weekly: 3,533 patients with T2DM and CKD (eGFR 24-75 mL/min/1.73m²) randomised to semaglutide 1mg weekly vs placebo. Primary composite: sustained ≥50% eGFR decline, ESKD, death from kidney or cardiovascular causes. Result: 24% risk reduction (HR 0.76, p=0.0001). Trial stopped 18 months early by Independent Data Monitoring Committee for overwhelming efficacy. GLP-1 RAs join SGLT-2 inhibitors as the two drug classes with proven cardiorenal protection in diabetic CKD.
Tirzepatide — dual GIP and GLP-1 agonism
PharmacologyTirzepatide (Mounjaro for T2DM, Zepbound for obesity — Eli Lilly) simultaneously activates both the GLP-1 receptor and the GIP (glucose-dependent insulinotropic polypeptide) receptor. GIP is the other main incretin hormone — secreted by K-cells in the duodenum. The dual agonism is more effective than GLP-1 agonism alone. SURMOUNT-1 trial (2022): tirzepatide 15mg achieved 20.9% weight loss vs 3.1% placebo at 72 weeks. SURMOUNT-4: 22.0% from randomisation. The drug also demonstrates superior HbA1c reduction vs semaglutide for T2DM.
GLP-1 and reward circuits
Neuroscience/PharmacologyGLP-1 receptors are expressed in the VTA (ventral tegmental area — dopamine neurons) and nucleus accumbens (striatal dopamine target) — the core of the mesolimbic reward pathway. GLP-1 receptor activation in these areas reduces the incentive salience (reward value) of food cues. The same mechanism appears to reduce reward value of other stimuli: alcohol, nicotine, opioids, gambling. Mechanistic studies in rodents confirm this. Multiple large observational studies in humans show GLP-1 RA users have significantly lower rates of alcohol use disorder, smoking, opioid overdose and drug-seeking behaviour. Clinical trials actively in progress (2024-2026).
The "Ozempic face" — cosmetic consequence
Dermatology/Aesthetics"Ozempic face" is a colloquial term for the facial changes observed in some patients on GLP-1 RAs: rapid facial fat loss → facial lipoatrophy; reduced subcutaneous volume of cheeks, temples and periorbital areas → hollow appearance, accentuated jowls, more pronounced nasolabial folds — making the face appear older despite overall weight loss. Not a medical complication — a cosmetic consequence of rapid fat redistribution. Plastic surgeons report increased demand for facial fillers in GLP-1 RA users. Speed of weight loss and genetic fat distribution determine who develops it.

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Related health topics

ObesityType 2 diabetesCardiovascular disease (SELECT trial)CKD (FLOW trial)NAFLD (GLP-1 benefit)Addiction (emerging GLP-1 data)

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