Contents
Key findings
- 1Semaglutide 2.4 mg produced ~15% mean weight loss over 68 weeks (STEP 1); tirzepatide up to ~21% over 72 weeks (SURMOUNT-1) and beat semaglutide head-to-head (SURMOUNT-5).
- 2Semaglutide reduced major adverse cardiovascular events by 20% in adults with CVD and overweight/obesity without diabetes (SELECT), earning a cardiovascular indication.
- 3Emerging uses with positive phase 3 data include kidney outcomes in T2D (FLOW), MASH (ESSENCE), heart failure with preserved EF (STEP-HFpEF, SUMMIT) and sleep apnoea (SURMOUNT-OSA, now approved).
- 4Alzheimer's disease is the prominent negative: the evoke/evoke+ trials of oral semaglutide did not slow cognitive decline (reported November 2025).
- 5Open questions are real — weight regain after stopping (roughly two-thirds within a year), lean-mass loss, and the safety of compounded and counterfeit products.
Evidence level
For type 2 diabetes, chronic weight management and (semaglutide) cardiovascular risk reduction, the evidence is established — large, long, randomised placebo-controlled trials with hard endpoints. Emerging uses range from established (kidney, sleep apnoea) to negative (Alzheimer's).
Regulatory status
Semaglutide and tirzepatide are FDA-approved for type 2 diabetes and chronic weight management; semaglutide for cardiovascular risk reduction; tirzepatide for obstructive sleep apnoea with obesity. Shortage-based compounding ended in late 2024 (tirzepatide) and February 2025 (semaglutide).
If you want to see what strong peptide evidence looks like, look at the incretin drugs. Semaglutide and tirzepatide have been tested in tens of thousands of people in randomised trials lasting years, with endpoints that matter. That makes them the benchmark for every other peptide on this site — and it also makes it easy to blur the line between what they are proven to do and what is still being studied.
The question readers ask
What are GLP-1 peptides proven to do, and what is still speculative? Proven: glycaemic control in type 2 diabetes, substantial weight loss, and (semaglutide) fewer cardiovascular events in high-risk adults. Emerging: kidney, liver, heart failure and sleep apnoea, several with positive phase 3 trials. Negative: Alzheimer's disease. Open: what happens after stopping, and how much of the loss is muscle.
What they are
GLP-1 is a gut hormone released after eating that boosts insulin secretion when glucose is high, suppresses glucagon, slows gastric emptying and signals satiety in the brain. Semaglutide is human GLP-1 with two amino-acid changes and a fatty-acid chain that binds albumin, giving it a week-long half-life. Tirzepatide is a 39-amino-acid peptide engineered to activate both the GLP-1 receptor and the receptor for a second incretin, GIP.
Established: the trials behind the approvals
Weight management. In STEP 1, 1,961 adults with overweight or obesity (no diabetes) lost a mean 14.9% of body weight on semaglutide 2.4 mg over 68 weeks versus 2.4% on placebo[1]. In SURMOUNT-1, 2,539 adults lost 15–21% on tirzepatide over 72 weeks versus 3.1% on placebo[2]. SURMOUNT-5 then compared them directly: 20.2% versus 13.7% at 72 weeks, favouring tirzepatide[3].
Study details: Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)
- Study type
- rct
- Population
- Adults with obesity without diabetes
- Sample size
- 2539
- Primary result
- −15.0% to −20.9% vs −3.1% at 72 weeks.
- Year
- 2022
- Source
- New England Journal of Medicine(link not yet independently re-verified)
Cardiovascular outcomes. SELECT randomised 17,604 adults with established cardiovascular disease and BMI ≥27 but no diabetes to semaglutide 2.4 mg or placebo and followed them for a mean of 3.3 years. Major adverse cardiovascular events fell by 20%[4]. This is the study that turned a weight-loss drug into a cardiovascular drug and the basis of the 2024 indication.
Study details: Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)
- Study type
- rct
- Population
- Adults ≥45 with CVD and BMI ≥27, no diabetes
- Sample size
- 17604
- Primary result
- MACE HR 0.80 (20% relative reduction).
- Year
- 2023
- Source
- New England Journal of Medicine(link not yet independently re-verified)
Type 2 diabetes. Both drugs have large phase 3 programmes (SUSTAIN and PIONEER for semaglutide; SURPASS for tirzepatide) showing HbA1c reduction and weight loss versus placebo and active comparators.
Every one of these is a randomised, controlled, adequately powered trial with a hard or validated endpoint. That is what established means on this site.
Emerging: real trials, newer results
- Kidney disease. FLOW randomised 3,533 people with type 2 diabetes and chronic kidney disease to semaglutide 1 mg or placebo and found a 24% reduction in major kidney events[5]; an indication followed.
- Liver disease (MASH). ESSENCE reported histological improvement with semaglutide in metabolic-associated steatohepatitis, leading to a 2025 approval.
- Heart failure with preserved ejection fraction. STEP-HFpEF (semaglutide) and SUMMIT (tirzepatide) reported improved symptoms and, for tirzepatide, fewer heart-failure events.
- Obstructive sleep apnoea. SURMOUNT-OSA showed large reductions in apnoea-hypopnoea index with tirzepatide, and the FDA approved that indication in December 2024.
- Alcohol, addiction, inflammation, neurodegeneration. Observational signals and small trials abound; nothing yet at phase 3 quality — with one large exception below.
The negative result that matters: Alzheimer's disease
Observational data and animal work suggested GLP-1 agonists might protect the brain, and Novo Nordisk ran two large phase 3 trials, evoke and evoke+, of oral semaglutide in early Alzheimer's disease. In November 2025 the company reported that neither trial met its primary endpoint of slowing decline on the CDR-SB scale[9]. It is a clean lesson: plausible mechanism plus encouraging observational signals still failed the definitive test. On this site, semaglutide is graded unsupported for cognition — while its metabolic and cardiovascular grades are unaffected.
The open questions
Regain after stopping. In the STEP 1 extension, participants regained about two-thirds of their lost weight within a year of stopping semaglutide[6]. In SURMOUNT-4, people switched from tirzepatide to placebo regained about 14% of body weight over a year while those who continued kept losing[7]. These drugs treat a chronic condition chronically; the trials say so.
Lean-mass loss. DEXA substudies show a meaningful share of lost weight is lean tissue — as with any large weight loss. Whether the proportion differs from diet-induced loss, and whether resistance training and protein intake mitigate it, is being studied; muscle-preserving co-therapies are in trials.
Compounded and counterfeit products. During the 2022–2024 shortages, compounded semaglutide and tirzepatide became widely available. The FDA declared the tirzepatide shortage resolved in late 2024 and semaglutide in February 2025, ending the shortage-based allowance, and has reported adverse events — including dosing errors with vial-and-syringe products — and counterfeit pens[8]. Compounded products are not FDA-approved or reviewed for safety, effectiveness or quality.
Safety profile. Gastrointestinal effects are common and drive most discontinuations; the labels carry a boxed warning for thyroid C-cell tumours based on rodent studies, plus pancreatitis, gallbladder disease, ileus, hypoglycaemia with insulin or sulfonylureas, and (semaglutide) diabetic retinopathy complications. These are known and monitored risks in approved products — the point of a label.
Grades by claim
| Claim | Best evidence | Grade |
|---|---|---|
| Weight loss (both drugs) | STEP 1, SURMOUNT-1, SURMOUNT-5 | Established evidenceLarge phase 3 RCTs |
| Cardiovascular risk reduction (semaglutide) | SELECT, n=17,604 | Established evidenceOutcomes trial |
| Kidney protection in T2D (semaglutide) | FLOW | Established evidenceOutcomes trial |
| Sleep apnoea (tirzepatide) | SURMOUNT-OSA; approved | Established evidencePhase 3 RCTs |
| MASH / heart failure | ESSENCE, STEP-HFpEF, SUMMIT | Promising evidencePhase 3, newer |
| Slows Alzheimer's disease | evoke/evoke+ negative | Unsupported evidenceFailed phase 3 |
| Weight stays off after stopping | STEP 1 ext., SURMOUNT-4 | Unsupported evidenceContradicted by trials |
Where to go next
- Semaglutide profile and tirzepatide profile.
- Semaglutide vs tirzepatide — the head-to-head detail.
- Metabolic health hub — how the rest of the "metabolic peptides" compare.
- FDA-approved, off-label, investigational and unapproved peptides — the compounding story in context.
Frequently asked questions
- Are GLP-1 drugs peptides?
- Yes. Semaglutide is a modified 31-amino-acid GLP-1 analogue; tirzepatide is a 39-amino-acid dual GIP/GLP-1 agonist. They are the best-evidenced peptides in this publication.
- Which is better, semaglutide or tirzepatide?
- For weight loss, tirzepatide produced more in a head-to-head trial (about 20% vs 14%). Semaglutide has a completed cardiovascular outcomes trial in obesity without diabetes; tirzepatide's dedicated obesity CVOT is ongoing.
- Do you regain the weight after stopping?
- Most of it, in trials — about two-thirds within a year of stopping semaglutide, and about 14% of body weight over a year after switching from tirzepatide to placebo.
- Is compounded semaglutide safe?
- It is not FDA-approved or reviewed, and the shortage-based allowance to compound it ended in February 2025. The FDA has reported adverse events including dosing errors and warned about counterfeit products.
References
Numbered in order of first use. Study type is shown for every source; see our methodology for how we rank evidence.
- 1.
Wilding JPH, Batterham RL, Calanna S, et al.. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1) New England Journal of Medicine, 2021.
Randomized controlled trialAdults with overweight/obesity without diabetesn = 1961
Result: −14.9% vs −2.4% body weight at 68 weeks.
↑ back to text - 2.
Jastreboff AM, Aronne LJ, Ahmad NN, et al.. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) New England Journal of Medicine, 2022.
Randomized controlled trialAdults with obesity without diabetesn = 2539
Result: −15.0% to −20.9% vs −3.1% at 72 weeks.
↑ back to text - 3.
Aronne LJ, Horn DB, le Roux CW, et al.. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5) New England Journal of Medicine, 2025.
Randomized controlled trialAdults with obesity without diabetesn = 751
Result: −20.2% (tirzepatide) vs −13.7% (semaglutide) at 72 weeks.
Limitations: Open-label.
↑ back to text - 4.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT) New England Journal of Medicine, 2023.
Randomized controlled trialAdults ≥45 with CVD and BMI ≥27, no diabetesn = 17604
Result: MACE HR 0.80 (20% relative reduction).
↑ back to text - 5.
Perkovic V, Tuttle KR, Rossing P, et al.. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW) New England Journal of Medicine, 2024.
Randomized controlled trialAdults with T2D and CKDn = 3533
Result: 24% relative reduction in major kidney disease events.
↑ back to text - 6.
Wilding JPH, Batterham RL, Davies M, et al.. Weight regain and cardiometabolic effects after withdrawal of semaglutide — the STEP 1 trial extension Diabetes, Obesity and Metabolism, 2022.
Randomized controlled trialSTEP 1 participants one year off treatmentn = 327
Result: About two-thirds of prior weight loss regained.
↑ back to text - 7.
Aronne LJ, Sattar N, Horn DB, et al.. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (SURMOUNT-4) JAMA, 2024.
Randomized controlled trialAdults with obesity after 36-week lead-inn = 670
Result: ~14% regain on placebo vs further loss on tirzepatide over 52 weeks.
↑ back to text - 8.
FDA's concerns with unapproved GLP-1 drugs used for weight loss U.S. Food and Drug Administration, 2025.
Regulatory source
Result: Shortage resolutions, adverse-event reports with compounded products, enforcement.
↑ back to text - 9.
Novo Nordisk announces results from evoke and evoke+ trials of oral semaglutide in early Alzheimer's disease Novo Nordisk (company announcement), 2025.
Source
Result: Trials did not meet primary endpoint of slowing progression on CDR-SB (November 2025 announcement).
Limitations: Company press release; full publication pending at our last check.
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Review status: Editorially reviewed against primary sources. This article was fact-checked against the primary sources listed in the references by our editorial team, and it has not been reviewed by a licensed clinician. It is educational content, not medical advice. Read our editorial policy and methodology. Spotted an error? Tell us.
