Semaglutide Side Effects: What Studies Report

This page is for educational purposes only and is not medical advice; consult a licensed physician or another qualified clinician about any medicine, symptom or health decision. Semaglutide is a prescription glucagon-like peptide-1 (GLP-1) receptor agonist, and everything below describes what published trials and reviews reported rather than what any individual should do.

Evidence tier: Established — semaglutide has been examined in multiple large, randomised, placebo-controlled phase 3 trials, in cardiovascular outcome trials and in systematic reviews, so its adverse-event profile is characterised in the peer-reviewed literature rather than inferred from preliminary work.

Where the safety data come from

A review of semaglutide in obesity described the compound as a GLP-1 receptor agonist developed for weight management alongside its earlier use in type 2 diabetes (PMID 34942372). The phase 3 diabetes programme began with placebo-controlled monotherapy work: SUSTAIN 1 was a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial of once-weekly semaglutide monotherapy in patients with type 2 diabetes (PMID 28110911). In the obesity programme, STEP 2 was a randomised, double-blind, double-dummy, placebo-controlled phase 3 trial of semaglutide 2.4 mg once a week in adults with overweight or obesity and type 2 diabetes (PMID 33667417), and STEP 5 reported two-year effects of semaglutide in adults with overweight or obesity (PMID 36216945).

Because adverse events are counted differently in short trials, long trials and case reports, the sections below separate what randomised trials recorded from what narrative reviews and case-level publications discussed.

Trials and reviews cited on this page

Gastrointestinal Effects: What Studies Report

Gastrointestinal complaints dominate the adverse-event tables of GLP-1 receptor agonist trials. A dedicated safety review of semaglutide reported that gastrointestinal events — including nausea, vomiting, diarrhoea and constipation — were the most frequently recorded adverse effects across the clinical programme and were generally described as mild to moderate and transient (PMID 34305810). A systematic review and meta-analysis of semaglutide for weight loss in obesity without diabetes likewise reported that gastrointestinal adverse events occurred more often with semaglutide than with placebo while pooling efficacy outcomes (PMID 36578889).

The same pattern appeared in individual trials. Researchers in STEP 2 reported gastrointestinal disorders as the most common adverse events with semaglutide 2.4 mg once a week in adults with overweight or obesity and type 2 diabetes (PMID 33667417), and the two-year STEP 5 report described gastrointestinal events as the most frequent adverse events over the longer treatment period (PMID 36216945). In the oral formulation trial OASIS 1, researchers reported that adverse events with oral semaglutide 50 mg once per day were mostly gastrointestinal and mostly mild to moderate (PMID 37385278).

Discontinuation and Tolerability: What Studies Report

Tolerability is usually measured by how many participants stopped treatment. In OASIS 1, the study recorded adverse events leading to treatment discontinuation more often in the semaglutide group than in the placebo group, with gastrointestinal events the main reason (PMID 37385278). The SELECT cardiovascular outcomes trial in obesity without diabetes also reported that discontinuation of the trial product because of adverse events was more common with semaglutide than with placebo (PMID 37952131).

Reviews have framed this as a tolerability rather than a toxicity signal: the safety review of semaglutide reported that most discontinuations were driven by gastrointestinal intolerance rather than by serious organ-level events (PMID 34305810).

Gallbladder, Pancreas and Thyroid Signals: What Studies Report

Beyond gastrointestinal symptoms, the semaglutide safety review discussed gallbladder-related events, pancreatitis case reports, and the thyroid C-cell tumour findings originally observed in rodent studies of GLP-1 receptor agonists, noting that these have not been established as human effects in the clinical trial record (PMID 34305810). The review also addressed diabetic retinopathy, a signal that emerged in the diabetes trial programme and has been attributed in part to the speed of glycaemic improvement (PMID 34305810).

The obesity-focused review in Trends in Cardiovascular Medicine similarly summarised semaglutide's safety considerations alongside its weight-management data (PMID 34942372).

Kidney-Related Reports: What Studies Report

A 2024 publication in Clinical Kidney Journal described semaglutide-associated kidney injury, discussing cases in which acute kidney injury followed marked gastrointestinal fluid losses and volume depletion during treatment (PMID 39258261). The authors framed this as a reason for clinical attention to hydration and renal monitoring rather than as a common trial-level outcome (PMID 39258261). Case-level reports of this kind describe possible associations; they do not quantify incidence the way randomised trials do.

Hypoglycaemia and Diabetes-Specific Findings: What Studies Report

In type 2 diabetes, hypoglycaemia risk depends heavily on background therapy. SUSTAIN 1 studied once-weekly semaglutide as monotherapy against placebo and reported its safety profile in that setting (PMID 28110911), while STEP 2 examined semaglutide 2.4 mg once a week in participants with type 2 diabetes who were also receiving glucose-lowering treatment and reported adverse events in that mixed-therapy context (PMID 33667417). The semaglutide safety review discussed hypoglycaemia as an event more closely tied to concomitant insulin or sulfonylurea use than to semaglutide alone (PMID 34305810).

Cardiovascular Outcome Data: What Studies Report

Two large outcome trials contribute long-horizon safety information. SELECT evaluated semaglutide and cardiovascular outcomes in people with obesity without diabetes and reported cardiovascular event results alongside adverse-event and discontinuation data (PMID 37952131). A later analysis of the same trial reported long-term weight-loss effects of semaglutide in obesity without diabetes over the multi-year follow-up (PMID 38740993). In 2025, researchers reported cardiovascular outcomes with oral semaglutide in high-risk type 2 diabetes in the New England Journal of Medicine (PMID 40162642).

Outcome trials matter for safety questions because their size and duration allow rarer events to be counted; the SELECT publication reported adverse events over years of treatment rather than the weeks-to-months windows typical of earlier phase trials (PMID 37952131).

Oral Versus Injectable Formulations: What Studies Report

Semaglutide has been studied as a once-weekly injection and as a daily tablet. OASIS 1 was a randomised, double-blind, placebo-controlled phase 3 trial of oral semaglutide 50 mg taken once per day in adults with overweight or obesity, and the study reported a predominantly gastrointestinal adverse-event profile (PMID 37385278). The 2025 oral semaglutide cardiovascular outcomes trial extended the oral safety record into a high-risk type 2 diabetes population (PMID 40162642). Published comparisons across formulations describe broadly similar adverse-event categories, with differences in administration rather than in event type (PMID 34305810).

Comparisons With Other Incretin Agents: What Studies Report

A 2025 indirect comparative analysis in Diabetes, Obesity and Metabolism examined the efficacy and safety of tirzepatide 10 mg and 15 mg versus semaglutide 2.4 mg for the management of obesity and overweight in patients with type 2 diabetes (PMID 40537987). Indirect comparisons of this type pool results from separate trials rather than randomising participants head to head, and the authors reported both efficacy and safety endpoints under that methodological limitation (PMID 40537987).

Longer-Term Observations: What Studies Report

STEP 5 reported two-year outcomes with semaglutide in adults with overweight or obesity, making it one of the longer randomised windows in the obesity programme (PMID 36216945). The SELECT weight analysis reported long-term weight change in obesity without diabetes across an extended treatment period (PMID 38740993). Longer trials are informative for adverse events that accumulate slowly, and the semaglutide safety review reported that the overall event pattern in longer studies remained dominated by gastrointestinal effects rather than by new organ-specific signals (PMID 34305810).

What the Literature Does Not Settle

• Rare events. Case-level publications such as the kidney injury report describe associations without incidence estimates (PMID 39258261).
• Populations outside trial criteria. The randomised trials cited here enrolled defined populations, such as adults with overweight or obesity and type 2 diabetes in STEP 2 (PMID 33667417) or people with obesity without diabetes in SELECT (PMID 37952131).
• Head-to-head comparisons. The tirzepatide-versus-semaglutide analysis was indirect rather than a direct randomised comparison (PMID 40537987).
• Individual risk. Trial averages do not describe how any one person responds; that judgement belongs to a treating clinician.

Readers looking for a structured walk-through of semaglutide's mechanism, trial programme and outcome measures can follow the linked semaglutide course; this page is limited to what the literature reported about adverse events and tolerability.

Trademark and Affiliation Note

Brand names under which semaglutide is marketed are used in the scientific literature only to identify the medicine studied; each such brand name is a trademark of its owner. PeptideU is an independent educational publisher and is not affiliated with or endorsed by any pharmaceutical manufacturer, trademark holder, prescriber or clinic. Nothing here is an offer, a supply channel or a recommendation, and no regulatory, prescribing or clinical decision should be based on this summary.

References

• Safety of Semaglutide (Frontiers in Endocrinology, 2021)
• Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1) (The Lancet Diabetes & Endocrinology, 2017)
• Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2) (Lancet, 2021)
• Semaglutide for the treatment of obesity (Trends in Cardiovascular Medicine, 2023)
• Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial (Nature Medicine, 2022)
• Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis (Journal of the ASEAN Federation of Endocrine Societies, 2022)
• Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1) (Lancet, 2023)
• Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (New England Journal of Medicine, 2023)
• Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial (Nature Medicine, 2024)
• Semaglutide-associated kidney injury (Clinical Kidney Journal, 2024)
• Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes (New England Journal of Medicine, 2025)
• Indirect comparative efficacy and safety of tirzepatide 10 and 15 mg versus semaglutide 2.4 mg for the management of obesity and overweight in patients with type 2 diabetes (Diabetes, Obesity & Metabolism, 2025)