How Long Have These Drugs Actually Been Studied? 10 Papers (2026)

The two-year randomized read on semaglutide 2.4 mg, extending the STEP-1 design to 104 weeks in 304 adults. Nothing new appeared in year two: gastrointestinal effects stayed dominant (82.2% against 53.9% on placebo), mild to moderate for the most part and clustered around dose escalation, with serious adverse events at 11.2% against 6.6%. ★ The useful finding is the absence of one — side effects did not accumulate with continued dosing, which is the premise chronic use rests on.

PMID 36216945 ↗NCT03693430 ↗

The largest and longest safety dataset at the obesity dose: 17,604 adults followed a mean 39.8 months. Semaglutide produced fewer serious adverse events (33.4% against 36.4%), while twice as many people stopped over side effects (16.6% against 8.2%), almost entirely gastrointestinal. Gallstones were slightly more frequent (2.8% against 2.3%). No excess in pancreatitis, in thyroid cancer, or in psychiatric events. ★ Both halves matter: fewer serious problems, more people quitting.

PMID 37952131 ↗NCT03574597 ↗DOI 10.1056/NEJMoa2307563 ↗

The reference safety dataset for the class, and the one FDA labeling still leans on: 9,340 patients on liraglutide over a median 3.8 years. Serious adverse events came out even (49.7% against 50.4%), gallstone disease was more common on the drug (3.1% against 1.9%), pancreatitis was numerically lower, and neither pancreatic cancer nor medullary thyroid carcinoma showed an excess. ⚠ It is a diabetes population at a diabetes dose — the closest thing to a long safety record in this class, and not a direct read on Wegovy.

PMID 27295427 ↗NCT01179048 ↗DOI 10.1056/NEJMoa1603827 ↗

The trial that produced the one long-term signal in this class that clinical practice actually changed for. Across 3,297 high-risk patients over 104 weeks, retinopathy complications ran 3.0% against 1.8% — a 76% relative increase — concentrated in patients who already had retinopathy and whose blood sugar dropped fast. ⚠ The mechanism is thought to be the speed of glycemic improvement rather than the drug itself, a phenomenon known from insulin. It is why eye screening before starting is now standard in patients with existing retinopathy.

PMID 27633186 ↗NCT01720446 ↗DOI 10.1056/NEJMoa1607141 ↗

The longest randomized follow-up anywhere in the class: 9,901 patients on dulaglutide over a median 5.4 years, and the only long dataset drawn mostly from people who had not already had a cardiac event. Serious adverse events matched placebo at 45%, the three conditions that carry class warnings — pancreatitis, pancreatic cancer, medullary thyroid carcinoma — came out balanced, and 6% stopped for gastrointestinal reasons. ★ Five and a half years is the current outer edge of randomized evidence for this drug class. Everything beyond it is observational.

PMID 31189511 ↗NCT01394952 ↗DOI 10.1016/S0140-6736(19)31149-3 ↗

88 weeks of tirzepatide exposure in 670 adults — a 36-week open-label run-in followed by 52 weeks randomized to continue or switch to placebo. Continued dosing was well tolerated, with serious adverse events at 4.7% against 5.0%, and gastrointestinal effects were milder than in the original escalation phase because everyone had already titrated up. ⛔ The other half of the result is the reason it is quoted so often: stopping produced 14% weight regain over the year.

PMID 38078870 ↗NCT04660643 ↗DOI 10.1001/jama.2023.24945 ↗

The paper that made 'indefinite' the default framing. 327 STEP-1 completers were followed for a year after everything stopped. Having lost 17.3%, they regained 11.6 percentage points of it — two-thirds — ending at 5.6% below where they started, with blood pressure, lipids, A1C and inflammatory markers drifting back toward baseline alongside. ★ No new adverse events appeared off the drug. Its significance is not a safety signal but a cost one: it is the evidence insurers are shown when the question is whether to cover treatment that never ends.

PMID 35441470 ↗NCT03548935 ↗

The most-cited post-marketing safety signal, drawn from a claims database of roughly 16 million US patients and comparing semaglutide and liraglutide against a non-GLP-1 weight drug rather than against no treatment. Pancreatitis, bowel obstruction and gastroparesis were all substantially more frequent; biliary disease was not. ★ Two things are true at once — the relative increases are large and the absolute rates stay low. This analysis is what produced the 2023 label update adding ileus.

PMID 37796527 ↗DOI 10.1001/jama.2023.19574 ↗

The check on the 2023 suicidality scare. After US adverse-event reports raised a signal, this analysis went looking for it in the World Health Organization's global database, comparing against other weight and diabetes drugs — and did not find it, with reporting ratios below 1 in most comparisons. ⚠ Spontaneous reports cannot establish a rate in either direction, so this is a failure to replicate rather than an exoneration. It is a substantial part of why European regulators concluded no causal link could be shown.

PMID 39433133 ↗

The strongest evidence against the boxed warning. Danish, Norwegian and Swedish national registries plus a large US database, comparing more than 200,000 GLP-1 users against DPP-4 inhibitor users — a comparator chosen because it is prescribed to similar patients — over a mean 3.9 years. Thyroid cancer risk came out at 0.93, with a confidence interval running 0.66 to 1.31 and consistent results by drug and dose. ★ The warning originates in rodent toxicology. This is the best available human evidence that it does not carry across, and it is still not a randomized answer.

PMID 39772758 ↗