Semaglutide

Semaglutide, a Food and Drug Administration (FDA)-approved long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has transformed the management of type 2 diabetes mellitus (T2DM) and obesity. By mimicking the natural incretin hormone GLP-1, it improves metabolic control through multiple glucose-regulating mechanisms.[1,2]

Pharmacological class: GLP-1 receptor agonist

It is indicated:

1. As an add-on to lifestyle modification (exercise and diet) for improving glycemic control in adults with T2DM.[3]
2. As an add-on to decreased calorie diet and elevated physical activity for chronic weight management in:
(a) Adults with an initial body mass index (BMI) ≥30 kg/m² (obesity), or BMI ≥27 kg/m² (overweight) when a minimum of one weight-related condition is present, such as hypertension, T2DM, or dyslipidemia.
(b) Adolescents aged 12 years and above with an initial BMI at or above the 95th percentile for age and sex, consistent with obesity.[4]
3. For adults with established cardiovascular (CV) disease and overweight or obesity to lower the likelihood of major adverse cardiovascular events (MACE), including non-fatal stroke, CV death, and non-fatal myocardial infarction/heart attack.
4. For adults with T2DM and chronic kidney disease to decrease the likelihood of sustained drop in estimated glomerular filtration rate (eGFR), transition to end-stage renal disease, and CV death.
5. For adults with established CV disease and a BMI ≥27 kg/m² to reduce the chances of heart attack (non-fatal myocardial infarction).

Note: Semaglutide has also received accelerated approval from the FDA in August 2025 for the treatment of adults with metabolic-associated steatohepatitis (MASH) and moderate-to-advanced liver fibrosis.[5]

1. Mechanism of glycemic control

GLP-1, a natural hormone, plays a fundamental role in governing blood glucose levels. It improves glycemic control by slowing gastric emptying, improving insulin secretion, and minimizing glucagon release after meals. Normal glucose balance also depends on pancreatic beta-cell hormones such as insulin and amylin.

Semaglutide, a GLP-1 receptor agonist that shares about 94% structural similarity with human GLP-1, mimics this physiological hormone. It selectively binds to GLP-1 receptors on pancreatic islet cells, enhancing insulin synthesis and suppressing glucagon secretion. These effects occur in a glucose-dependent way, helping lower blood glucose while diminishing the risk of excessive hypoglycemia.

2. Mechanism of CV benefit and weight loss

Beyond glycemic control, semaglutide may contribute to CV protection. In conditions such as hypercholesterolemia, it is thought to slow the progression of atherosclerosis by decreasing intestinal permeability and inflammatory processes. The medication also promotes weight loss primarily by diminishing appetite and food cravings, resulting in lower calorie intake.[5]

1. For T2DM and CV disease

• Initiation: Start with 0.25 mg once weekly.
• Dose escalation: Increase to 0.5 mg once weekly following 4 weeks.
• Further adjustment: If additional glycemic monitoring is needed after at least 4 weeks, raise to 1 mg once weekly.
• Administration: Offer once weekly at any time of the day, irrespective of food consumption.
• Missed dose: If a dose is missed, give within 5 days of the scheduled dosage.
• Route: Subcutaneous injection in the upper arm, thigh, or abdomen.[3]
• Switching from oral semaglutide 14 mg daily: Commence 0.5 mg subcutaneously once weekly, beginning the day following the final oral dose.
• Switching from oral semaglutide 7 mg daily: 0.5 mg once weekly may be considered, starting the day after the last oral dose, as no exact equivalent oral-to-injectable dose is specified.[2]

2. For chronic weight management

• Administration: Inject once weekly, on the same day each week, at any convenient time, regardless of meals.
• Route: Subcutaneous injection in the upper arm, thigh, or abdomen.
• Monitoring: In patients with T2DM, check blood glucose before starting and during treatment.
• Initiation: Commence with 0.25 mg once weekly for 4 weeks.
• Dose escalation: Increase the dose every 4 weeks until attaining 2.4 mg weekly.
• Adult maintenance dose: 2.4 mg once weekly (suggested) or 1.7 mg once weekly.
• Pediatric maintenance dose (≥12 years): 2.4 mg once weekly.[4]

Absorption

• The maximum plasma concentration (Cmax) reaches 10.9 nmol/L
• The area under the concentration–time curve (AUC) is approximately 3123.4 nmol h/L.
• Peak concentration (Tmax) is typically reached at about 56 hours, generally within 1–3 days after administration.
• The absolute bioavailability is about 89%.
• Steady-state (oral formulation) plasma concentrations are achieved within 4–5 weeks of regular dosing.
• At doses of 0.5–1 mg, mean steady-state plasma concentrations range from 16 to 30 nmol/L.

Distribution

• The apparent volume of distribution is 12.5 L after subcutaneous dosing and 8 L after oral administration.
• Semaglutide shows very high plasma protein binding, with >99% bound to plasma albumin. This strong albumin binding enhances drug stability and extends its circulation time in the bloodstream.

Metabolism

• Semaglutide is metabolized via peptide backbone cleavage. This is followed by β-oxidation of the fatty acid side chain.
• Structural modifications make it more resistant to degradation by dipeptidyl peptidase-4 (DPP-4) compared with natural GLP-1.
• Metabolism also encompasses neutral endopeptidase and DPP-4–mediated peptide cleavage.
• The drug is slowly and extensively metabolized, with ~83% of the circulating drug remaining unchanged in plasma.
• Overall, 6 metabolites have been detected in human plasma.
• The major metabolite (P3) accounts for ~7.7% of the administered dose.

Elimination

• Semaglutide is chiefly excreted via the kidneys, with excretion occurring in both urine and feces.
• About 53% of a radiolabeled dose is recovered in the urine.
• Approximately 18.6% of the administered dose is excreted in the feces.
• A small proportion (~3.2%) is eliminated through exhaled air.
• Liver dysfunction does not markedly alter clearance, so dose modification is generally not needed.
• Semaglutide has a long elimination half-life of about 168 hours (≈7 days). Extensive albumin binding minimizes renal clearance and shields the drug from rapid metabolic degradation.
• Reported systemic clearance is about 0.039 L/h, while ~0.05 L/h has been observed in patients with T2DM.[2,5]

Semaglutide is contraindicated in:

• Those with a personal or family past history of multiple endocrine neoplasia syndrome type 2 or medullary thyroid carcinoma.
• Those with known hypersensitivity to semaglutide.[3,4]

• Semaglutide slows gastric emptying, which might retard the absorption of oral drugs. While studies show no major clinical impact, careful monitoring is recommended, especially for medications with a narrow therapeutic range.
• Concomitant administration with insulin or insulin-releasing agents may raise hypoglycemia chances. Decreasing the dosage of insulin or the insulin secretagogue may help lower this risk.
• Semaglutide must not be utilized together with other GLP-1 receptor agonists or tirzepatide due to overlapping mechanisms and safety concerns.
• Agents such as beta-blockers, monoamine oxidase inhibitors, quinolones, salicylates, selective serotonin reuptake inhibitors, and additional antidiabetic drugs may intensify glucose-lowering effects when used with semaglutide.
• Diuretics, including loop and thiazide agents, as well as ritodrine, may reduce glucose-lowering effectiveness.
• Semaglutide may raise circulating levels of levothyroxine; thyroid function monitoring is recommended during combined use.[2]

• Gastrointestinal: Nausea, eructation (belch or burp), diarrhea, constipation, abdominal pain, dyspepsia, abdominal distension, flatulence, vomiting.
• Neurologic/Systemic: Headache, dizziness, fatigue.
• Metabolic: Hypoglycemia in patients with T2DM.
• Infectious/Other: Gastroenteritis, Gastroesophageal reflux disease, Nasopharyngitis.[3,4]

• Pancreatitis: Cases of acute pancreatitis have been witnessed. Discontinue semaglutide promptly if pancreatitis is suspected. Do not restart therapy if confirmed.
• Diabetic retinopathy: Complications of diabetic retinopathy have been observed in patients with T2DM receiving semaglutide. Monitor patients with a prior history of retinopathy.
• Hypoglycemia risk: Concomitant use with insulin or insulin secretagogues may elevate hypoglycemia risk. Consider dose reduction of these agents and counsel patients on symptom recognition.
• Renal effects: Acute kidney injury has been observed, often connected with severe gastrointestinal adverse reactions. Monitor renal function in those with kidney impairment.
• Hypersensitivity reactions: Serious allergic reactions, including angioedema and anaphylaxis, have been reported. Discontinue treatment if hypersensitivity is suspected.
• Gallbladder disease: Semaglutide may increase the risk of gallbladder-related events. Evaluate patients presenting with symptoms suggestive of cholelithiasis.
• Heart rate increase: Modest increases in heart rate have been observed. Periodic monitoring is recommended in at-risk patients.
• Psychiatric effects: Monitor for mood changes, depression, or suicidal ideation. Discontinue therapy if clinically significant behavioral changes occur.
• Injection safety: Injection pens must not be shared between patients, regardless of needle replacement, due to the risk of infection transmission.[3,4]

1. Evidence from the STEP 1 trial

In a double-blind trial involving 1961 adults with obesity or overweight without diabetes, once-weekly semaglutide 2.4 mg combined with lifestyle intervention produced substantially greater weight loss than placebo over 68 weeks. Mean body weight decreased by 14.9% with semaglutide versus 2.4% with placebo, corresponding to a treatment difference of −12.4 percentage points. In absolute terms, participants receiving semaglutide lost 15.3 kg compared with 2.6 kg in the placebo group.

Clinically meaningful weight reduction was achieved by a remarkably higher proportion of participants treated with semaglutide: 86.4% lost ≥5% of body weight, 69.1% lost ≥10%, and 50.5% lost ≥15%, compared with 31.5%, 12.0%, and 4.9% in the placebo group, respectively. Treatment with semaglutide also resulted in better improvements in physical functioning and cardiometabolic risk determinants.[6]

2. Evidence from the STEP 2 trial

The STEP 2 trial investigated once-weekly semaglutide 2.4 mg for weight control in adults with overweight or obesity and T2DM. After 68 weeks of treatment, participants receiving semaglutide 2.4 mg experienced a mean body weight reduction of 9.6%, compared with 3.4% with placebo, corresponding to a −6.2 percentage-point treatment difference. A substantially greater proportion of participants treated with semaglutide 2.4 mg achieved ≥5% weight loss than those receiving placebo (68.8% vs 28.5%).[7]

3. Evidence from the STEP 4 trial

In a 68-week randomized withdrawal trial involving adults with obesity or overweight without T2D, continued treatment with semaglutide 2.4 mg once weekly markedly improved long-term weight-loss maintenance. Following a 20-week run-in phase, participants achieved a mean weight reduction of 10.6% before randomization.

Over the subsequent 48 weeks, participants who continued semaglutide experienced an additional mean weight loss of 7.9%, whereas those switched to placebo regained 6.9% of body weight, resulting in a significant −14.8 percentage-point treatment difference. Continued semaglutide therapy also produced greater reductions in waist circumference (−9.7 cm) and systolic blood pressure (−3.9 mm Hg) and improved physical functioning scores when compared with placebo.[8]

4. Evidence from SUSTAIN trials
Across multiple phase 3 trials (SUSTAIN 1–6 and additional studies), semaglutide consistently produced greater reductions in glycated hemoglobin (HbA1c; up to 1.8%) and body weight compared with placebo and several active treatments, including sitagliptin, exenatide (extended-release), dulaglutide, and insulin glargine.In the SUSTAIN 6 trial, semaglutide also demonstrated CV safety and significantly reduced MACE compared with placebo, confirming its noninferiority while suggesting potential CV protection.[9]

5. Pooled evidence from SOUL, SUSTAIN-6, and PIONEER-6 trials

A systematic review and meta-analysis explored the CV effects of semaglutide in patients with T2DM. Three trials—SOUL Trial, SUSTAIN-6 Trial, and PIONEER-6 Trial—including 16,130 participants were analyzed. The pooled results showed that semaglutide reduced MACE—CV death, nonfatal myocardial infarction, and nonfatal stroke—with a hazard ratio of 0.83, representing a 17% relative risk reduction and low heterogeneity (I² = 25%). Adverse events were comparable between the semaglutide and placebo groups. Overall, semaglutide remarkably lowers CV risk in T2DM, supporting its use for both glycemic control and CV risk reduction.[10]

1. Pawar SS, Rasal PB, Kulkarni KH, Pawar SB. Semaglutide: A Comprehensive Review of its Pharmacology, Clinical Applications, and Future Therapeutic Potential. Journal of Drug Delivery & Therapeutics. 2025 Dec 1;15(12).
2. Kommu S, Whitfield P. Semaglutide. [Updated 2024 Feb 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK603723/. Bookshelf ID: NBK603723, PMID: 38753931.
3. OZEMPIC (semaglutide) injection. FDA label. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf
4. WEGOVY (semaglutide) injection. FDA label. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215256s007lbl.pdf
5. Semaglutide. Drug Bank [DB13928]. Available from:
https://go.drugbank.com/drugs/DB13928
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7. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021 Mar 13;397(10278):971-984.
8. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1414-1425.
9. Goldenberg RM, Steen O. Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes. Canadian Journal of Diabetes. 2019 Mar;43(2):136-145.
10. Adinolfi G, Milia V, Dinkov B, Stavreva G. Cardiovascular Outcomes Associated with Semaglutide in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Endocrines. 2026 Mar 4;7(1):9.