Semaglutide - Informational Research Article: Scientific & Clinical Overview

Regulatory status

Semaglutide is an active pharmaceutical substance with one of the most extensive clinical development programs in metabolic medicine. Regulatory authorization applies to specific medicinal products, manufacturers, formulations, indications, and jurisdictions — not to every material that contains semaglutide.

In the European Union, three centrally authorized medicines have semaglutide as their active substance, all with Novo Nordisk A/S as marketing authorization holder: Ozempic (once-weekly injection; authorized 8 February 2018) for insufficiently controlled type 2 diabetes and, in later label updates, cardiovascular and kidney risk reduction in defined populations; Rybelsus (once-daily tablet; authorized 3 April 2020) for type 2 diabetes; and Wegovy (once-weekly injection; authorized 6 January 2022) for weight management in adults with a BMI of at least 30 kg/m², or at least 27 kg/m² with a weight-related comorbid condition, alongside diet and physical activity. In the United States, the FDA has additionally approved semaglutide-containing medicines for cardiovascular risk reduction in overweight/obesity with established cardiovascular disease (2024, following the SELECT trial), for chronic kidney disease in type 2 diabetes (2025, following FLOW), for metabolic dysfunction-associated steatohepatitis under accelerated approval (August 2025, following ESSENCE), for cardiovascular risk reduction with the oral form (October 2025, following SOUL), and — in December 2025 — a 25 mg once-daily oral formulation for weight management, the first oral GLP-1 medicine authorized for that indication. Authorized indications and product names differ between jurisdictions; current EMA and FDA labeling should be consulted.

Important regulatory distinction. The existence of marketing authorizations for branded medicines containing a given active substance does not establish the approval, equivalence, quality, safety, or efficacy of any other material that happens to contain the same substance.

Clinical research

Major published Phase 3 trials are summarized below. Doses named describe how the trials were designed; they are not dosing instructions.

SUSTAIN-6 — cardiovascular safety in type 2 diabetes (Phase 3). A randomized, placebo-controlled cardiovascular outcome trial in 3,297 adults with type 2 diabetes at elevated cardiovascular risk, over about 2 years. Major adverse cardiovascular events occurred less often with semaglutide (hazard ratio 0.74), driven mainly by fewer strokes and myocardial infarctions; the trial also flagged an increase in diabetic retinopathy complications that subsequent research has continued to examine. Marso SP, et al. N Engl J Med. 2016;375:1834–1844.

STEP 1 — obesity, without diabetes (Phase 3). A 68-week, randomized, double-blind, placebo-controlled trial in 1,961 adults with obesity (or overweight with a complication), without diabetes, testing semaglutide 2.4 mg once weekly. Reported mean body-weight change was approximately −14.9% versus −2.4% with placebo; about one third of semaglutide-treated participants lost at least 20% of body weight. Wilding JPH, et al. N Engl J Med. 2021;384:989–1002.

STEP-HFpEF — heart failure with preserved ejection fraction and obesity (Phase 3). A 52-week, randomized, placebo-controlled trial in 529 participants with HFpEF and obesity, without diabetes. Semaglutide 2.4 mg improved heart-failure-related symptoms and physical limitations (KCCQ-CSS) and reduced body weight versus placebo. Kosiborod MN, et al. N Engl J Med. 2023;389:1069–1084.

SELECT — cardiovascular outcomes in overweight/obesity without diabetes (Phase 3). A randomized, placebo-controlled outcome trial in 17,604 adults with established cardiovascular disease and overweight or obesity, without diabetes, over a mean of about 3 years. Major adverse cardiovascular events occurred in fewer semaglutide-treated participants (hazard ratio 0.80; 95% CI 0.72–0.90) — the first demonstration that a weight-management medicine can reduce cardiovascular events in this population. Lincoff AM, et al. N Engl J Med. 2023;389:2221–2232.

FLOW — chronic kidney disease in type 2 diabetes (Phase 3). A randomized, placebo-controlled kidney outcome trial in 3,533 participants with type 2 diabetes and chronic kidney disease, stopped early for efficacy. The composite of major kidney disease events occurred less often with semaglutide 1 mg (hazard ratio 0.76), with slower kidney-function decline and fewer cardiovascular deaths. Perkovic V, et al. N Engl J Med. 2024;391:109–121.

ESSENCE — metabolic dysfunction-associated steatohepatitis (Phase 3). A randomized, placebo-controlled trial of semaglutide 2.4 mg in MASH with moderate-to-advanced fibrosis (part 1 analysis at 72 weeks). Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% versus 34.3% with placebo, and fibrosis improvement without worsening of steatohepatitis in 36.8% versus 22.4%. Sanyal AJ, Newsome PN, et al. N Engl J Med. 2025;392:2089–2099.

SOUL — cardiovascular outcomes with oral semaglutide (Phase 3). A randomized, placebo-controlled outcome trial in 9,650 adults with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease, testing once-daily oral semaglutide up to 14 mg. Major adverse cardiovascular events occurred in 12.0% versus 13.8% with placebo (hazard ratio 0.86; 95% CI 0.77–0.96). McGuire DK, et al. N Engl J Med. 2025 (DOI 10.1056/NEJMoa2501006).

OASIS 4 — oral semaglutide 25 mg in weight management (Phase 3). A randomized, placebo-controlled trial of a once-daily 25 mg oral formulation in adults with obesity or overweight with comorbidity. Reported mean weight reduction was about 16.6% when treatment was adhered to, with roughly one in three participants reaching at least 20%; the trial supported the December 2025 U.S. authorization of the first oral GLP-1 medicine for weight management.

Clinical evidence matrix

Figures are as reported in the primary publications and should be verified against those sources.

Clinical development timeline

• 2016 — SUSTAIN-6 cardiovascular safety results in type 2 diabetes published.
• 2017–2020 — first authorizations: Ozempic (FDA 2017; EMA 8 February 2018) and the oral formulation Rybelsus (FDA 2019; EMA 3 April 2020).
• 2021–2022 — STEP program in weight management published; Wegovy authorized (FDA June 2021; EMA 6 January 2022).
• 2023 — SELECT cardiovascular outcomes in overweight/obesity and STEP-HFpEF published.
• 2024 — FLOW kidney outcomes published; U.S. cardiovascular indication added after SELECT.
• 2025 — ESSENCE (MASH) and SOUL (oral, cardiovascular) published; U.S. approvals for MASH (August, accelerated), oral cardiovascular indication (October) and oral 25 mg weight management (December).

Limitations and interpretation

• Trials use specific inclusion/exclusion criteria; results do not necessarily generalize to everyone.
• Interventions were regulated pharmaceutical products made to defined standards; data do not establish equivalence of other materials.
• Trial durations are finite; long-term outcomes beyond the studied periods are not established by these trials alone.
• Secondary and exploratory outcomes carry less certainty than primary endpoints; accelerated approvals are contingent on confirmatory evidence.
• Because many secondary metabolic outcomes accompany substantial weight loss, direct drug effects are difficult to isolate.
• Most trials were industry-sponsored, which should be disclosed when interpreting the results.

How incretin mechanisms differ

This comparison is mechanistic and informational; it is not advice on which agent to use. Semaglutide is a GLP-1 receptor agonist acting on a single incretin pathway and is the active substance of authorized medicines with dedicated cardiovascular, kidney and liver outcome evidence. Tirzepatide is a dual agonist of the GIP and GLP-1 receptors. Retatrutide adds glucagon receptor agonism to the incretin pathways and remains investigational. Cagrilintide acts on the amylin pathway and is studied, including in combination regimens, as a separate mechanistic approach.