High evidence 48Moderate evidence 25Low evidence 22Very low evidence 4
Semaglutide has a current marketed status in the scoped regulatory record below. Results describe observations and do not provide treatment advice.
Dated status sources
MARKETED
United States; Chronic weight management; Subcutaneous injection; as of 2026-07-13.
US Food and Drug Administration
The grade rates how strong the evidence is, not how good or safe the drug is. A low or very-low grade means the evidence is thin, not that an effect is harmful or ruled out.
SemaglutideMARKETED
safety-otherMixed
High evidence
NET VERDICT (early-worsening diabetic retinopathy): SUSTAIN-6 found retinopathy complications significantly MORE frequent with semaglutide than placebo (HR 1.76),...
SourceMarso SP et al. (SUSTAIN-6), NEJM, 2016Source
Full findingNET VERDICT (early-worsening diabetic retinopathy): SUSTAIN-6 found retinopathy complications significantly MORE frequent with semaglutide than placebo (HR 1.76), widely attributed to RAPID glucose-lowering ('early worsening') in those with pre-existing retinopathy - a KNOWN phenomenon, not necessarily a direct drug effect. At RCT level the 2025 meta found NO overall DR increase (OR 1.04, TSA-sufficient), and a post-hoc RCT showed CRT change explained by glycaemic change rather than drug-specific toxicity.
PopulationT2D at high CV risk with variable baseline retinopathy (SUSTAIN-6, n=3297, 104 wk); pooled RCT n=73,640; post-hoc mechanistic substudy n=40.
Fundingindustry - Novo Nordisk
Comparatorsplacebo; empagliflozin; active comparators
SemaglutideMARKETED
safety-otherNot directional
High evidence
Semaglutide is contraindicated in the US for personal/family history of MTC or MEN 2 (also a boxed warning) and for serious hypersensitivity; the EU contraindication...
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingSemaglutide is contraindicated in the US for personal/family history of MTC or MEN 2 (also a boxed warning) and for serious hypersensitivity; the EU contraindication is hypersensitivity only (the MTC/MEN2 boxed warning is a US construct).
Regulatory: EMA PRAC concluded its review and recommended adding NAION to semaglutide product information as a 'very rare' side effect; WHO issued a confirmatory...
SourceEMA PRAC highlights 2-5 June 2025; WHO safety communication 27 June 2025Source
Full findingRegulatory: EMA PRAC concluded its review and recommended adding NAION to semaglutide product information as a 'very rare' side effect; WHO issued a confirmatory signal.
PopulationEU regulatory review of all NAION data for semaglutide
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
SemaglutideMARKETED
safety-otherIncrease
High evidence
FDA boxed warning: in mice and rats semaglutide caused dose- and treatment-duration-dependent thyroid C-cell tumours (adenomas/carcinomas) at clinically relevant...
SourceOzempic/Wegovy (semaglutide) US Prescribing Information, FDASource
Full findingFDA boxed warning: in mice and rats semaglutide caused dose- and treatment-duration-dependent thyroid C-cell tumours (adenomas/carcinomas) at clinically relevant exposures; contraindicated with personal/family history of MTC or MEN 2. Human relevance not determined.
Diabetic retinopathy complications significantly more frequent with semaglutide than placebo in SUSTAIN-6 (early-worsening signal).
SourceMarso SP et al. (SUSTAIN-6), NEJM, 2016Source
PopulationSUSTAIN-6 RCT; 3297 T2D at high CV risk; semaglutide 0.5/1.0 mg vs placebo, 104 weeks
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
safety-otherIncrease
High evidence
In the cardiovascular-outcomes trial, Wegovy-treated patients aged >=75 reported numerically more hip/pelvis fractures than placebo (2.4% vs 0.6%); small numerators,...
SourceWegovy (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingIn the cardiovascular-outcomes trial, Wegovy-treated patients aged >=75 reported numerically more hip/pelvis fractures than placebo (2.4% vs 0.6%); small numerators, post-hoc, causality NOT established.
Full findingIn obesity without diabetes, semaglutide increased gallbladder disorders (esp. cholelithiasis) >2.6-fold, whereas tirzepatide showed no significant biliary risk; neither significantly increased hepatic or pancreatic AEs.
Population13 RCTs, 26,894 obese participants without diabetes; meta-analysis
Fundingacademic/independent - no funding (None)
Comparatorsplacebo
SemaglutideMARKETED
safety-otherIncrease
Moderate evidence
SIGNAL-confirming meta-analysis (T2D-restricted): semaglutide associated with increased NAION risk vs non-GLP-1RAs, persisting across follow-up windows.
SourceLampsas S et al., Graefes Arch Clin Exp Ophthalmol 2026Source
PopulationMeta-analysis; 8 retrospective cohorts (14,255,247 participants), mean age 59.3 yr
Fundingacademic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)
Comparatorsnon-GLP-1 RA medications
SemaglutideMARKETED
safety-otherNo change
Moderate evidence
Across the STEP programme (RCT data), depression-symptom endorsement on PHQ-9 similar/lower for semaglutide 2.4 mg vs placebo; pooled analysis found no clinically...
SourceWadden TA et al., JAMA Intern Med 2024 (STEP 1/2/3/5 psychiatric post hoc)Source
Full findingAcross the STEP programme (RCT data), depression-symptom endorsement on PHQ-9 similar/lower for semaglutide 2.4 mg vs placebo; pooled analysis found no clinically meaningful difference in incident significant depressive symptoms and no PHQ-9 worsening.
PopulationPost-hoc analysis of the pooled STEP 1/2/3/5 placebo-controlled RCTs in adults with obesity (PHQ-9 psychiatric-safety endpoints).
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
safety-otherDecrease
Low evidence
In 51 people with type-2 diabetes, 10 weeks of semaglutide attenuated (did not abolish) the post-oral-iron-load serum iron rise, consistent with reduced intestinal...
SourceMelis M et al. Effect of semaglutide on intestinal iron absorption in type-2 diabetes: a ...Source
Full findingIn 51 people with type-2 diabetes, 10 weeks of semaglutide attenuated (did not abolish) the post-oral-iron-load serum iron rise, consistent with reduced intestinal iron absorption on the drug.
Population51 people with type-2 diabetes; single-arm uncontrolled observational pre-post study (no control arm), 10 weeks; post-oral-iron-load serum-iron and TSAT measurement (NCT06629688).
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
Comparatorswithin-subject baseline (no control arm)
SemaglutideMARKETED
safety-otherDecrease
Low evidence
The authors attribute the reduced iron absorption (author-hedged 'may') to delayed gastric emptying / altered GI motility, warn it could contribute to iron deficiency...
SourceMelis M et al. Effect of semaglutide on intestinal iron absorption in type-2 diabetes: a ...Source
Full findingThe authors attribute the reduced iron absorption (author-hedged 'may') to delayed gastric emptying / altered GI motility, warn it could contribute to iron deficiency or anaemia in susceptible patients, and suggest monitoring iron status.
Population51 people with type-2 diabetes; single-arm uncontrolled observational pre-post study (no control arm), 10 weeks; post-oral-iron-load serum-iron and TSAT measurement (NCT06629688).
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
Comparatorswithin-subject baseline (no control arm)
SemaglutideMARKETED
safety-otherIncrease
Low evidence
Index signal-raising cohort: patients on semaglutide had markedly higher cumulative NAION incidence than those on non-GLP-1 RA medications, in both T2D and...
SourceHathaway JT et al., JAMA Ophthalmol 2024Source
Full findingIndex signal-raising cohort: patients on semaglutide had markedly higher cumulative NAION incidence than those on non-GLP-1 RA medications, in both T2D and overweight/obese populations.
PopulationRetrospective matched cohort, single neuro-ophthalmology registry (Mass Eye and Ear); 710 T2D, 979 overweight/obese; Dec 2017-Nov 2023
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsnon-GLP-1 RA antidiabetics; non-GLP-1 RA weight-loss meds
PopulationTriNetX; 174,584 semaglutide vs 174,584 non-GLP-1 RA with diabetes; Oct 2019-Dec 2023
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsnon-GLP-1 RA antidiabetics
SemaglutideMARKETED
safety-otherDecrease
Low evidence
REFUTING/NULL pole: in a large racially diverse Military Health System cohort, semaglutide associated with LOWER odds of NAION in T2D and no significant difference in...
Full findingREFUTING/NULL pole: in a large racially diverse Military Health System cohort, semaglutide associated with LOWER odds of NAION in T2D and no significant difference in overweight/obesity.
PopulationMilitary Health System beneficiaries; 973,529 T2D + 239,246 overweight/obese; Dec 2017-Sep 2023
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsnon-GLP-1 RA medications; PDE-5 inhibitors (subset)
SemaglutideMARKETED
safety-otherDecrease
Low evidence
Real-world propensity-matched cohort (TriNetX EHR): semaglutide associated with LOWER risk of incident and recurrent suicidal ideation vs non-GLP1R anti-obesity meds;...
SourceWang W, Volkow ND, Berger NA, Davis PB, Kaelber DC, Xu R. Nat Med 2024;30(1):168-176Source
Full findingReal-world propensity-matched cohort (TriNetX EHR): semaglutide associated with LOWER risk of incident and recurrent suicidal ideation vs non-GLP1R anti-obesity meds; replicated in T2DM.
One year after withdrawal of semaglutide 2.4 mg plus lifestyle intervention, participants regained about two-thirds of lost weight and cardiometabolic improvements...
SourceWilding JPH et al., Diabetes Obes Metab 2022Source
Full findingOne year after withdrawal of semaglutide 2.4 mg plus lifestyle intervention, participants regained about two-thirds of lost weight and cardiometabolic improvements reverted towards baseline.
VigiBase disproportionality identified a potential signal between semaglutide and bile-duct cancer (cholangiocarcinoma); pancreatic cancer was the most frequent...
SourceKaur RJ et al., Indian J Gastroenterol 2026Source
Full findingVigiBase disproportionality identified a potential signal between semaglutide and bile-duct cancer (cholangiocarcinoma); pancreatic cancer was the most frequent neoplasm reported.
PopulationVigiBase ICSRs 1 Jan 2009-31 Jul 2023; disproportionality
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
ComparatorsVigiBase background
SemaglutideMARKETED
safety-otherIncrease
Very low evidence
FAERS flagged unexpected signals for semaglutide incl. pancreatic cancer, intestinal obstruction (ileus), cholecystitis and polycystic ovary.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
ComparatorsFAERS background
SemaglutideMARKETED
pharmacologyNot directional
High evidence
For Ozempic, a missed dose should be administered as soon as possible within 5 days after the missed dose; if more than 5 days have elapsed, skip the missed dose and...
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingFor Ozempic, a missed dose should be administered as soon as possible within 5 days after the missed dose; if more than 5 days have elapsed, skip the missed dose and resume at the next regularly scheduled dose.
For Wegovy, if a dose is missed and the next scheduled dose is more than 2 days (48 hours) away, administer it as soon as possible; if the next scheduled dose is less...
SourceWegovy (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingFor Wegovy, if a dose is missed and the next scheduled dose is more than 2 days (48 hours) away, administer it as soon as possible; if the next scheduled dose is less than 2 days away, skip the missed dose and resume on the regularly scheduled day.
Oral semaglutide must be taken fasting in the morning with a small sip of water and a 30-minute wait before food, other drinks or other oral medicines.
SourceRybelsus (oral semaglutide) US Prescribing Information, Novo NordiskSource
Semaglutide delays gastric emptying and can theoretically affect oral-drug absorption, but did not alter the absorption of orally administered medications to a...
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingSemaglutide delays gastric emptying and can theoretically affect oral-drug absorption, but did not alter the absorption of orally administered medications to a clinically relevant degree.
Oral semaglutide increased levothyroxine exposure by about 33% in a drug-interaction study; this is an oral-semaglutide (SNAC co-formulation) interaction, not stated...
SourceRybelsus (oral semaglutide) US Prescribing Information, Novo NordiskSource
Full findingOral semaglutide increased levothyroxine exposure by about 33% in a drug-interaction study; this is an oral-semaglutide (SNAC co-formulation) interaction, not stated for the injectable products.
Semaglutide does not reduce the effectiveness of combined oral contraceptives to a clinically relevant degree; no additional contraceptive method is required.
SourceOzempic (semaglutide) EU Summary of Product Characteristics (EMA)Source
Oral semaglutide (Rybelsus) has a very low absolute bioavailability (~0.4-1%) and requires the SNAC absorption enhancer; absorption is highly sensitive to...
SourceRybelsus (oral semaglutide) US Prescribing Information, Novo NordiskSource
Full findingOral semaglutide (Rybelsus) has a very low absolute bioavailability (~0.4-1%) and requires the SNAC absorption enhancer; absorption is highly sensitive to fasting/water conditions.
Semaglutide is cleared mainly by metabolism via proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty-acid side chain, not by CYP enzymes.
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
A small 12-week single-arm study in 15 type-2-diabetes patients found semaglutide changed gut-microbiota composition (e.g. more Bifidobacterium, less Firmicutes), but...
SourceChen Y, Shan Y, Wang T, Liu Z, Zhao Z, He Y. The Effect of Semaglutide on Gut Microbiota ...Source
Full findingA small 12-week single-arm study in 15 type-2-diabetes patients found semaglutide changed gut-microbiota composition (e.g. more Bifidobacterium, less Firmicutes), but with no control group and an appetite/diet confound the authors themselves say causation cannot be established.
Population15 Chinese type-2-diabetes patients poorly controlled on metformin; 12-week single-arm semaglutide; 16S rRNA, n=15 (no control arm).
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsbaseline (pre-treatment)
SemaglutideMARKETED
pharmacologyNo change
Low evidence
FDA Ozempic Pharm/Tox review confirms semaglutide does not bind the human glucagon receptor, and a broad receptor-profile assay showed no greater-than-50% activity at...
Full findingFDA Ozempic Pharm/Tox review confirms semaglutide does not bind the human glucagon receptor, and a broad receptor-profile assay showed no greater-than-50% activity at any other receptor. The GLP-1 monoagonist comparator is GCGR-negative, completing (with the tirzepatide GCGR-silence datum) the receptor-level elimination: the glucagon arm is the sole added pharmacology in retatrutide versus both characterised duals.
Fundingindustry - Novo Nordisk (applicant/manufacturer; FDA Pharm/Tox review of Novo's NDA 209637 submission)
Comparatorsbroad receptor panel
SemaglutideMARKETED
pharmacologyNo change
Very low evidence
In obese mice, semaglutide reversed diet-induced gut-microbiota changes (16S), with the shifted taxa correlating with lower inflammation - but this is a...
SourceFeng J, Teng Z, Yang Y, Liu J, Chen S. Effects of semaglutide on gut microbiota, cognitiv...Source
Full findingIn obese mice, semaglutide reversed diet-induced gut-microbiota changes (16S), with the shifted taxa correlating with lower inflammation - but this is a compositional/correlational rodent finding, not evidence that the microbiome mediates semaglutide's effects.
US labelling states there are no data on the presence of semaglutide in human milk; in lactating rats it was detected in milk at 3-12-fold lower levels than maternal...
SourceWegovy (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingUS labelling states there are no data on the presence of semaglutide in human milk; in lactating rats it was detected in milk at 3-12-fold lower levels than maternal plasma, and advises weighing breastfeeding benefits against clinical need.
Animal reproduction studies show embryofetal mortality, structural abnormalities and growth alterations across rat, rabbit and monkey at exposures at or below the...
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingAnimal reproduction studies show embryofetal mortality, structural abnormalities and growth alterations across rat, rabbit and monkey at exposures at or below the human dose; the label states human data are insufficient to establish a drug-associated risk and to discontinue when pregnancy is recognised.
No overall difference in effectiveness was observed between older (>=65) and younger adults; greater sensitivity of some older individuals cannot be ruled out.
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
US labelling specifies no dose adjustment for renal impairment including ESRD (no clinically relevant PK change). 'No dose adjustment' is a label instruction, not a...
SourceOzempic (semaglutide) US Prescribing Information, Novo NordiskSource
Full findingUS labelling specifies no dose adjustment for renal impairment including ESRD (no clinically relevant PK change). 'No dose adjustment' is a label instruction, not a measured null.
In a PCOS RCT, adding semaglutide to metformin raised the natural pregnancy rate (35% vs 15%) in anovulatory women.
SourceSemaglutide+metformin in PCOS (open-label RCT, n=100), Reprod Biol Endocrinol 2025Source
PopulationPCOS open-label RCT (NCT not stated; Reprod Biol Endocrinol 2025): 100 overweight/obese women with PCOS (Rotterdam criteria), prospective randomised controlled open-label trial of semaglutide 1 mg weekly plus metformin vs metformin alone, 16 weeks.
Fundingacademic/government - Chinese government and institutional grants (Chongqing Health Commission/Science & Technology Bureau; NSFC; not industry)
SemaglutideMARKETED
Specific groups of peopleDecrease
Low evidence
In a matched real-world cohort, semaglutide pretreatment before fertility care was associated with reduced and delayed conception, with miscarriage unchanged.
SourceSemaglutide pretreatment and fertility-care outcomes (PSM cohort), Reprod Biol Endocrinol...Source
A measured human-milk PK study found subcutaneous semaglutide undetectable in breast milk, with a worst-case relative infant dose of 1.26% - converting the lactation...
SourceSemaglutide human breast-milk transfer study (n=8), Nutrients 2024Source
Full findingA measured human-milk PK study found subcutaneous semaglutide undetectable in breast milk, with a worst-case relative infant dose of 1.26% - converting the lactation question from never-measured to measured-negligible FOR SEMAGLUTIDE.
In adults aged >=45 with pre-existing CVD and overweight/obesity (BMI >=27) but WITHOUT diabetes, once-weekly s.c. semaglutide 2.4 mg reduced 3-point MACE (CV death,...
SourceLincoff AM et al. (SELECT), NEJM, 2023Source
Full findingIn adults aged >=45 with pre-existing CVD and overweight/obesity (BMI >=27) but WITHOUT diabetes, once-weekly s.c. semaglutide 2.4 mg reduced 3-point MACE (CV death, non-fatal MI, non-fatal stroke) versus placebo.
PopulationSELECT: N=17,604; established CVD + overweight/obesity, no diabetes; multicentre double-blind placebo-controlled event-driven superiority RCT; mean follow-up 39.8 months.
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationDecrease
High evidence
In T2D at high CV risk, s.c. semaglutide reduced first MACE versus placebo, meeting non-inferiority then superiority; reduction driven mainly by non-fatal stroke and...
SourceMarso SP et al. (SUSTAIN-6), NEJM, 2016Source
Full findingIn T2D at high CV risk, s.c. semaglutide reduced first MACE versus placebo, meeting non-inferiority then superiority; reduction driven mainly by non-fatal stroke and MI, with CV death unchanged.
PopulationSUSTAIN-6: N=3297; T2D high CV risk; double-blind placebo-controlled pre-approval CV-safety RCT; median 2.1 years.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationNo change
High evidence
In T2D at high CV risk, once-daily oral semaglutide was non-inferior to placebo for MACE but did NOT demonstrate superiority (CV-safety trial, underpowered for...
SourceHusain M et al. (PIONEER 6), NEJM, 2019Source
Full findingIn T2D at high CV risk, once-daily oral semaglutide was non-inferior to placebo for MACE but did NOT demonstrate superiority (CV-safety trial, underpowered for superiority).
PopulationPIONEER 6: N=3183; T2D high CV risk; double-blind placebo-controlled CV-safety RCT; median 15.9 months.
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationDecrease
High evidence
In T2D with established ASCVD, CKD, or both, oral semaglutide 14 mg reduced MACE versus placebo in a dedicated superiority CVOT; the kidney composite did not differ.
SourceMcGuire DK, Marx N, Buse JB et al., N Engl J Med, 2025Source
PopulationSOUL: N=9650; T2D age >=50, HbA1c 6.5-10.0%, with ASCVD and/or CKD; double-blind placebo-controlled event-driven superiority RCT; mean follow-up 47.5 months.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationDecrease
Moderate evidence
Prespecified SELECT analysis: semaglutide produced sustained weight loss across every baseline BMI category to 4 years (208 weeks). The trial's headline 20% MACE...
SourceRyan DH, Lingvay I, Deanfield J et al., Nat Med, 2024Source
Full findingPrespecified SELECT analysis: semaglutide produced sustained weight loss across every baseline BMI category to 4 years (208 weeks). The trial's headline 20% MACE reduction is restated as context; this paper reports weight-by-BMI, not a per-subgroup MACE analysis.
PopulationSELECT prespecified weight/BMI secondary analysis (prespecified secondary of the N=17,604 double-blind RCT); up to 208 weeks.
Fundingindustry - Novo Nordisk (SELECT sponsor)
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationDecrease
Moderate evidence
CROSS-DOMAIN (kidney trial with CV components): in T2D with CKD, s.c. semaglutide 1.0 mg reduced the major-kidney-disease composite (which includes CV death) and...
Full findingCROSS-DOMAIN (kidney trial with CV components): in T2D with CKD, s.c. semaglutide 1.0 mg reduced the major-kidney-disease composite (which includes CV death) and separately reduced CV death, MACE and all-cause death.
PopulationFLOW: N=3533; T2D with CKD (eGFR 25-75, raised UACR); double-blind placebo-controlled RCT; median 3.4 years (stopped early at interim).
Fundingindustry - Novo Nordisk (FLOW sponsor)
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationDecrease
Moderate evidence
In the prespecified SELECT mediation analysis, semaglutide's cardiovascular benefit was largely INDEPENDENT of baseline adiposity and of the amount of weight lost -...
SourceDeanfield J, Lincoff AM, Kahn SE et al. Semaglutide and cardiovascular outcomes by baseli...Source
Full findingIn the prespecified SELECT mediation analysis, semaglutide's cardiovascular benefit was largely INDEPENDENT of baseline adiposity and of the amount of weight lost - roughly two-thirds of the MACE reduction was not explained by waist-circumference change - indicating mechanisms of CV benefit beyond adiposity reduction. CRITICAL: this is the evidence the popular 'works even without weight loss' claim rests on, and it is SEMAGLUTIDE-SPECIFIC; there is NO equivalent tirzepatide mediation analysis, so the weight-independent CV claim must NOT be transferred to tirzepatide (the SURMOUNT-MMO obesity CV trial is ongoing).
PopulationPrespecified analysis of SELECT (NCT03574597): n=17,604 adults >=45 y, BMI >=27, with established CVD and WITHOUT diabetes; semaglutide 2.4 mg weekly vs placebo; 41 countries; primary outcome time-to-first MACE (CV death, non-fatal MI, non-fatal stroke). Mediation via time-varying adjustment for waist/weight change + week-20 and week-104 landmarks.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationNo change
Moderate evidence
In SELECT, semaglutide's cardiovascular-death component did not independently reach significance, despite a positive composite MACE and a significant...
SourceLincoff AM et al. (SELECT), NEJM, 2023Source
Full findingIn SELECT, semaglutide's cardiovascular-death component did not independently reach significance, despite a positive composite MACE and a significant all-cause-mortality reduction - a component null, NOT evidence that semaglutide fails to reduce CV death.
PopulationPeer-reviewed RCT (measured null)
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart and circulationNo change
Moderate evidence
In PIONEER-6, oral semaglutide showed no significant effect on the individual non-fatal MI or stroke components; the MACE 'non-superiority' is a design feature of a...
SourceHusain M et al. (PIONEER 6), NEJM, 2019Source
Full findingIn PIONEER-6, oral semaglutide showed no significant effect on the individual non-fatal MI or stroke components; the MACE 'non-superiority' is a design feature of a non-inferiority safety trial, not a measured efficacy null.
PopulationPeer-reviewed RCT (measured null)
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart failureIncrease
High evidence
STEP-HFpEF: in HFpEF with obesity but without diabetes, semaglutide improved HF symptoms/physical limitations (KCCQ-CSS) versus placebo at 52 weeks.
SourceKosiborod MN et al. (STEP-HFpEF), NEJM, 2023;389:1069-1084Source
PopulationN=529, HFpEF (EF >=45%), BMI >=30, no T2D; 52 weeks; RCT vs placebo.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart failureIncrease
High evidence
STEP-HFpEF DM: in HFpEF with obesity AND T2D, semaglutide improved KCCQ-CSS, weight, 6MWD and inflammation versus placebo at 52 weeks.
SourceKosiborod MN et al. (STEP-HFpEF DM), NEJM, 2024;390:1394-1407Source
PopulationN=616, HFpEF with BMI >=30 and T2D; 52 weeks; RCT vs placebo.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart failureDecrease
Moderate evidence
Pooled post-hoc (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM): in participants with HFpEF history, semaglutide reduced the composite of CV death or worsening HF events,...
SourceKosiborod MN et al., Lancet, 2024;404:949-961Source
Full findingPooled post-hoc (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM): in participants with HFpEF history, semaglutide reduced the composite of CV death or worsening HF events, and worsening HF events alone; no significant effect on CV death alone.
PopulationN=3,743 with HFpEF history pooled from four RCTs; 1914 sema vs 1829 placebo; ITT.
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Heart failureDecrease
Moderate evidence
In a secondary analysis of the STEP-HFpEF programme, inflammation (CRP >=2 mg/L) was present in 71% of obesity-related HFpEF patients; semaglutide reduced CRP more...
SourceVerma S et al., J Am Coll Cardiol 2024;84(17):1646-1662 (STEP-HFpEF inflammation analysis)Source
Full findingIn a secondary analysis of the STEP-HFpEF programme, inflammation (CRP >=2 mg/L) was present in 71% of obesity-related HFpEF patients; semaglutide reduced CRP more than placebo across all baseline CRP strata, and the CRP fall was largely INDEPENDENT of the magnitude of weight loss.
Populationsecondary analysis of pooled STEP-HFpEF programme, HFpEF + obesity
Fundingindustry - Novo Nordisk (trial sponsor; sponsor-authored)
Comparatorsplacebo
SemaglutideMARKETED
Heart failureDecrease
Moderate evidence
In a prespecified echocardiography substudy of the pooled STEP-HFpEF programme (491 of 1145 participants), semaglutide 2.4 mg attenuated left-atrial remodelling (LA...
SourceSolomon SD et al., J Am Coll Cardiol 2024;84(17):1587-1602 (STEP-HFpEF echo substudy)Source
Full findingIn a prespecified echocardiography substudy of the pooled STEP-HFpEF programme (491 of 1145 participants), semaglutide 2.4 mg attenuated left-atrial remodelling (LA volume difference -6.13 mL, p=0.0013) and right-ventricular enlargement and improved diastolic indices, with no change in LV mass or systolic function; greater weight loss correlated with greater LA-volume reduction.
Populationprespecified echo substudy of pooled STEP-HFpEF + STEP-HFpEF DM, 491 of 1145 participants, HFpEF + obesity, 52 wk
Fundingindustry - Novo Nordisk (trial sponsor; sponsor-authored)
Comparatorsplacebo
SemaglutideMARKETED
appetite-intakeDecrease
High evidence
Semaglutide 2.4 mg reduces food cravings and improves control of eating on the VALIDATED Control of Eating Questionnaire, with improvements sustained to 2 years - the...
SourceWharton S et al. Two-year effect of semaglutide 2.4 mg on control of eating (STEP 5 CoEQ)...Source
Full findingSemaglutide 2.4 mg reduces food cravings and improves control of eating on the VALIDATED Control of Eating Questionnaire, with improvements sustained to 2 years - the instrument-grade evidence underlying the lay 'food noise' claim for semaglutide.
PopulationSTEP-5 CoEQ subgroup (n=174, 104 wk) + mechanism-of-action RCT (n=72, 20 wk); adults with overweight/obesity; semaglutide 2.4 mg vs placebo.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
appetite-intakeDecrease
Moderate evidence
Once-weekly semaglutide 2.4 mg reduced ad libitum energy intake at an unrestricted lunch by 35% vs placebo at week 20; also reduced hunger and prospective food...
SourceFriedrichsen M et al., Diabetes Obes Metab 2021;23(3):754-762Source
Full findingOnce-weekly semaglutide 2.4 mg reduced ad libitum energy intake at an unrestricted lunch by 35% vs placebo at week 20; also reduced hunger and prospective food consumption, increased fullness/satiety, and improved Control of Eating with fewer/weaker cravings. The same study found NO delayed gastric emptying at week 20 (paracetamol AUC0-5h +8%, NS once body-weight corrected, P=0.12), attributing the intake drop to central appetite suppression rather than gastric slowing.
PopulationAdults with obesity; randomised placebo-controlled, week 20
Fundingindustry - Novo Nordisk (trial sponsor)
Comparatorsplacebo
SemaglutideMARKETED
appetite-intakeDecrease
Moderate evidence
Once-weekly semaglutide (escalated to 1.0 mg, 12 wk) reduced total ad libitum energy intake across all meals by 24% vs placebo, with less hunger and fewer food...
SourceBlundell J et al., Diabetes Obes Metab 2017;19(9):1242-1251Source
Full findingOnce-weekly semaglutide (escalated to 1.0 mg, 12 wk) reduced total ad libitum energy intake across all meals by 24% vs placebo, with less hunger and fewer food cravings, better control of eating, and a lower preference for high-fat/energy-dense foods; resting metabolic rate adjusted for lean mass did not differ (i.e. weight loss is intake-driven, not expenditure-driven).
PopulationSubjects with obesity, n=30 crossover, 12 weeks
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
appetite-intakeDecrease
Moderate evidence
Oral semaglutide (escalated to 14 mg, 12 wk) reduced total daily ad libitum energy intake by 38.9% vs placebo in type 2 diabetes, with increased satiety/fullness after...
SourceGibbons C et al., Diabetes Obes Metab 2021;23(2):581-588Source
Full findingOral semaglutide (escalated to 14 mg, 12 wk) reduced total daily ad libitum energy intake by 38.9% vs placebo in type 2 diabetes, with increased satiety/fullness after a fat-rich breakfast, fewer cravings and better eating control.
PopulationSubjects with T2D, n=15 (13 evaluable), crossover, 12 weeks
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
appetite-intakeDecrease
Moderate evidence
Once-daily oral semaglutide 50 mg (20 wk) reduced ad libitum energy intake by 39.2 percentage points vs placebo in adults with obesity, with reduced hunger, increased...
SourceGabe MBN et al., Diabetes Obes Metab 2024;26(10):4480-4489Source
Full findingOnce-daily oral semaglutide 50 mg (20 wk) reduced ad libitum energy intake by 39.2 percentage points vs placebo in adults with obesity, with reduced hunger, increased fullness/satiety, fewer cravings and better control of eating, and no statistically significant difference in gastric emptying at week 20.
PopulationAdults with obesity, 20 weeks
Fundingindustry - Novo Nordisk (with Steno Diabetes Center Copenhagen)
Comparatorsplacebo
SemaglutideMARKETED
Brain and moodNo change
High evidence
In two fully-powered phase-3 trials, oral semaglutide did NOT slow clinical progression of early Alzheimer's disease versus placebo (primary endpoint CDR-SB) - a...
SourceCummings et al., Oral semaglutide in early symptomatic Alzheimer's disease (evoke and evo...Source
Full findingIn two fully-powered phase-3 trials, oral semaglutide did NOT slow clinical progression of early Alzheimer's disease versus placebo (primary endpoint CDR-SB) - a measured null that reverses the optimistic epidemiological GLP-1/dementia-association literature.
Populationevoke and evoke+ (NCT04777396, NCT04777409): 3808 participants with early symptomatic Alzheimer's disease, oral semaglutide up to 14 mg once daily vs placebo; two multicentre randomised double-blind placebo-controlled phase-3 trials across 566 sites in 40 countries.
FundingNovo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Brain and moodDecrease
Low evidence
ADDICTION (alcohol) - the key RCT: in adults with alcohol use disorder, once-weekly low-dose semaglutide reduced alcohol consumed in a laboratory self-administration...
Full findingADDICTION (alcohol) - the key RCT: in adults with alcohol use disorder, once-weekly low-dose semaglutide reduced alcohol consumed in a laboratory self-administration task and reduced craving, drinks-per-drinking-day and heavy drinking versus placebo, but did NOT change overall drinking frequency. A within-trial smoker subsample also cut cigarettes/day.
PopulationHendershot AUD RCT (NCT05520775): N=48 non-treatment-seeking adults with AUD; phase-2 double-blind RCT, 9 weeks; semaglutide titrated to 1.0 mg vs placebo; single US centre.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsplacebo
SemaglutideMARKETED
Brain and moodDecrease
Low evidence
ADDICTION (alcohol) - the largest real-world signal: in an EHR cohort, semaglutide vs other anti-obesity medications was associated with substantially lower risk of...
SourceWang W, Volkow ND, Berger NA et al., Nat Commun, 2024 (Author Correction PMID 38890337)Source
Full findingADDICTION (alcohol) - the largest real-world signal: in an EHR cohort, semaglutide vs other anti-obesity medications was associated with substantially lower risk of incident and recurrent alcohol use disorder, consistent across subgroups and replicated in T2D. ASSOCIATION ONLY (LOW): confounding-by-indication is unresolved and the signal is NOT corroborated by the semaglutide AUD RCT, which was null on real-world drinking frequency.
PopulationWang/Xu EHR cohort: N=83,825 obesity (+598,803 T2D replication); 12-month retrospective cohort; semaglutide vs other anti-obesity meds.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsother anti-obesity medications
SemaglutideMARKETED
Brain and moodDecrease
Low evidence
ADDICTION (tobacco): in a target-trial-emulation EHR study of T2D + tobacco use disorder, semaglutide was associated with lower TUD-related healthcare measures versus...
SourceWang W, Volkow ND, Berger NA et al., Ann Intern Med, 2024Source
Full findingADDICTION (tobacco): in a target-trial-emulation EHR study of T2D + tobacco use disorder, semaglutide was associated with lower TUD-related healthcare measures versus seven other antidiabetes classes, including other GLP-1RAs.
PopulationWang/Xu target-trial emulation (US EHR): N=222,942 new antidiabetes users incl. 5,967 semaglutide with T2D+TUD; 12 months; vs 7 comparator classes.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
The lower-dose (25 mg) registrational oral-semaglutide obesity trial gave ~14% weight loss.
SourceOral semaglutide 25 mg for obesity (OASIS-4), NEJM 2025Source
PopulationOASIS-4 (NCT05564117): 307 adults without diabetes, BMI >=30 (or >=27 with an obesity-related complication), oral semaglutide 25 mg vs placebo 2:1; 71-week registrational randomised double-blind placebo-controlled RCT at 22 sites in four countries.
FundingNovo Nordisk
SemaglutideMARKETED
weight-lossDecrease
High evidence
Once-weekly subcutaneous semaglutide 2.4 mg produced a mean body-weight change of -14.9% vs -2.4% with placebo at week 68 (treatment-policy estimand; -17.3% vs -2.0%...
SourceWilding JPH et al., NEJM 2021 (STEP 1)Source
Full findingOnce-weekly subcutaneous semaglutide 2.4 mg produced a mean body-weight change of -14.9% vs -2.4% with placebo at week 68 (treatment-policy estimand; -17.3% vs -2.0% on the trial-product estimand); 86.4% reached >=5% weight loss vs 31.5% placebo.
PopulationSTEP 1: 1961 adults, BMI >=30 (or >=27 with comorbidity), without diabetes, 68 weeks, randomised double-blind vs placebo, adjunct to lifestyle
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
weight-lossDecrease
High evidence
Once-daily oral semaglutide 50 mg produced a mean body-weight change of -15.1% vs -2.4% placebo at week 68 (treatment-policy; -17.4% trial-product). In T2D (PIONEER...
Full findingOnce-daily oral semaglutide 50 mg produced a mean body-weight change of -15.1% vs -2.4% placebo at week 68 (treatment-policy; -17.4% trial-product). In T2D (PIONEER PLUS) oral 50 mg gave ~2.0 percentage-point HbA1c reduction.
PopulationOASIS 1: adults with overweight/obesity without T2D, 9 countries, 68 weeks, randomised double-blind vs placebo; PIONEER PLUS: T2D, baseline HbA1c >=8%
Fundingindustry - Novo Nordisk (disclosed in publication)
Comparatorsplacebo
SemaglutideMARKETED
energy-expenditure-thermogenesisDecrease
Moderate evidence
FDA Ozempic Clinical Pharmacology review: in obese non-diabetics semaglutide weight loss was driven by ~24% lower energy intake, NOT energy expenditure - resting...
SourceFDA Ozempic NDA 209637 Clinical Pharmacology Review, Reference ID 4142722, Study NN9535-3685Source
Full findingFDA Ozempic Clinical Pharmacology review: in obese non-diabetics semaglutide weight loss was driven by ~24% lower energy intake, NOT energy expenditure - resting metabolic rate was significantly lower on semaglutide (-601.9 kJ/24h), and the reviewer concluded weight loss is more related to appetite/intake than to expenditure. Supports 'EE not demonstrably raised (chronic GLP-1-mono)', NOT a causal EE-suppression claim: the post-hoc lower RMR is mass-confounded (lower RMR is the trivial consequence of lower mass).
Fundingindustry - Novo Nordisk (applicant/manufacturer; FDA Clinical Pharmacology review of Novo's NDA 209637 submission)
Comparatorsplacebo
SemaglutideMARKETED
energy-expenditure-thermogenesisIncrease
Moderate evidence
In a small human study (T2DM, subcutaneous fat biopsy before and after 6-month semaglutide), therapy restored adipose-derived stem cell proliferation and increased...
SourceStafeev I, Agareva M, Michurina S, et al. Semaglutide 6-months therapy of type 2 diabetes...Source
Full findingIn a small human study (T2DM, subcutaneous fat biopsy before and after 6-month semaglutide), therapy restored adipose-derived stem cell proliferation and increased both white and beige adipogenesis ex vivo, with lipid-droplet fragmentation in beige adipocytes. Newly formed beige adipocytes used glucose for canonical thermogenesis; both white and beige adipocytes showed 2-3 fold higher glucose uptake. Insulin sensitivity (HOMA-IR, M-index) was unchanged.
PopulationT2DM patients, N=8, subcutaneous adipose biopsy at baseline and after 6 months semaglutide; adipose-derived stem cells studied ex vivo
Fundingacademic-Russian Science Foundation (grant 22-15-00365)
Comparatorswithin-subject baseline
SemaglutideMARKETED
energy-expenditure-thermogenesisIncrease
Very low evidence
In diet-induced obese rats with a pair-fed (intake-matched) control, semaglutide produced weight loss beyond caloric restriction alone and, across adipose depots,...
SourceByun S, Sotzen MR, Knappenberger MA, et al. Advantage of Semaglutide: Comprehensive Analy...Source
Full findingIn diet-induced obese rats with a pair-fed (intake-matched) control, semaglutide produced weight loss beyond caloric restriction alone and, across adipose depots, promoted white adipose tissue browning, smaller adipocytes and enhanced sympathetic innervation - changes largely absent in pair-fed rats. Semaglutide rescued caloric-restriction-associated hypothermia, reduced the small fall in circulating thyroid hormones, potentiated local thyroid input, and sustained increased locomotor activity. Effects were more potent in females.
PopulationDiet-induced obese rats; semaglutide vs ad libitum control vs intake-matched (pair-fed); sex-stratified
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsad libitum control; pair-fed control
SemaglutideMARKETED
body-compositionDecrease
Moderate evidence
SEMALEAN prospective study: semaglutide 2.4 mg reduced total fat mass with an initial lean-mass decline that stabilised after 7 months; handgrip strength improved and...
SourceAlissou M et al. (SEMALEAN), Diabetes Obes Metab, 2025Source
Full findingSEMALEAN prospective study: semaglutide 2.4 mg reduced total fat mass with an initial lean-mass decline that stabilised after 7 months; handgrip strength improved and prevalence of sarcopenic obesity fell from 49% to 33%; REE normalised to lean mass rose from M7 to M12.
Populationn=115 enrolled / 106 completers with obesity (68.9% female, mean BMI 46.3); DXA + handgrip + REE at M0, M7, M12; prospective single-arm
Fundingacademic/investigator - no external funding declared (NOT industry/Novo Nordisk)
SemaglutideMARKETED
body-compositionDecrease
Moderate evidence
SUSTAIN 8 DXA substudy: semaglutide 1.0 mg vs canagliflozin 300 mg in T2D reduced total fat mass, lean mass and visceral fat; proportion of lean mass rose ~1.2...
SourceMcCrimmon RJ et al., Diabetologia, 2020Source
Full findingSUSTAIN 8 DXA substudy: semaglutide 1.0 mg vs canagliflozin 300 mg in T2D reduced total fat mass, lean mass and visceral fat; proportion of lean mass rose ~1.2 percentage points; changes in visceral fat and fat-to-lean ratio comparable between arms.
Populationn=178 randomised to DXA substudy (sema n=88, cana n=90); 114 with end-of-treatment data; T2D on metformin; 52 weeks; RCT (NCT03136484)
Fundingindustry - Novo Nordisk
Comparatorscanagliflozin
SemaglutideMARKETED
body-compositionDecrease
Moderate evidence
STOP randomised trial (T2D): semaglutide reduced epicardial adipose tissue vs comparator over the trial period (epicardial-fat-specific RCT readout).
SourceManubolu VS et al. (STOP trial), J Am Coll Cardiol, 2024Source
PopulationSTOP (Semaglutide Treatment effect On coronary atherosclerosis Progression) randomised trial in T2D; CT-based epicardial adipose tissue
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
renalDecrease
High evidence
FLOW: in T2D + CKD, semaglutide reduced the primary composite kidney outcome versus placebo; trial stopped early for efficacy. eGFR slope also less steep.
PopulationFLOW: N=3,533 T2D + CKD; median follow-up 3.4 years; double-blind RCT vs placebo.
Fundingindustry - Novo Nordisk (disclosed in publication)
Comparatorsplacebo
SemaglutideMARKETED
renalDecrease
High evidence
SUSTAIN-6 prespecified secondary: lower rate of new or worsening nephropathy with semaglutide versus placebo.
SourceMarso SP et al. (SUSTAIN-6), NEJM, 2016Source
PopulationSUSTAIN-6: N=3,297 T2D; 104 weeks; RCT.
Fundingindustry - Novo Nordisk
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Stomach and gutIncrease
High evidence
GI effects (esp. nausea, vomiting) most frequent AEs across the PIONEER programme; mild-to-moderate, faded with time. PIONEER 1 trial-product discontinuations...
SourceAroda VR et al., Diabetes Care 2019 (PIONEER 1)Source
Full findingGI effects (esp. nausea, vomiting) most frequent AEs across the PIONEER programme; mild-to-moderate, faded with time. PIONEER 1 trial-product discontinuations dose-related.
PopulationPIONEER 1: 703 adults with T2D on diet/exercise; 26 weeks; phase 3a RCT, oral semaglutide 3/7/14 mg vs placebo
Fundingindustry-Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Stomach and gutIncrease
High evidence
Nausea and diarrhoea most common AEs; transient, mild-to-moderate. More semaglutide than placebo participants discontinued for GI events.
SourceWilding JPH et al., NEJM 2021 (STEP 1)Source
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
weight-maintenance-regainIncrease
Moderate evidence
STEP-4 randomised-withdrawal RCT: adults who had lost a mean 10.6% during a 20-week semaglutide run-in were re-randomised (2:1) at week 20 to continue semaglutide 2.4...
SourceRubino D, Abrahamsson N, Davies M et al., JAMA, 2021 (STEP 4)Source
Full findingSTEP-4 randomised-withdrawal RCT: adults who had lost a mean 10.6% during a 20-week semaglutide run-in were re-randomised (2:1) at week 20 to continue semaglutide 2.4 mg or switch to placebo. Those switched to placebo REGAINED weight (+6.9%) while those continuing kept losing (-7.9%); waist/BP gains were preserved only with continued treatment. The headline is regain-on-withdrawal; the continued arm is the maintenance counterpart.
STEP-1 off-treatment extension: after BOTH semaglutide and lifestyle were stopped at week 68, participants regained ~two-thirds of lost weight (11.6 of 17.3 pp) by...
SourceWilding JPH et al., Diabetes Obes Metab 2022Source
Full findingSTEP-1 off-treatment extension: after BOTH semaglutide and lifestyle were stopped at week 68, participants regained ~two-thirds of lost weight (11.6 of 17.3 pp) by week 120, and on-treatment cardiometabolic improvements reverted towards baseline. The clearest class documentation of cardiometabolic REVERSAL on regain.
PopulationSTEP-1 extension (NCT03548935): exploratory subset N=327; adults with obesity without diabetes; off-treatment observational follow-up after the 68-week RCT.
Fundingindustry-Novo Nordisk
Comparatorsplacebo (also withdrawn)
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Liver and MASHDecrease
High evidence
In ESSENCE (the landmark phase-3 registrational MASH trial), once-weekly s.c. semaglutide 2.4 mg met BOTH distinct co-primary histological endpoints at week 72 vs...
SourceSanyal AJ, Newsome PN et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associ...Source
Full findingIn ESSENCE (the landmark phase-3 registrational MASH trial), once-weekly s.c. semaglutide 2.4 mg met BOTH distinct co-primary histological endpoints at week 72 vs placebo: it roughly doubled MASH resolution (62.9% vs 34.3%) AND improved fibrosis by >=1 stage (36.8% vs 22.4%). These are two SEPARATE endpoints, reported separately. Both are histological SURROGATES supporting FDA accelerated (subpart H) approval; the hard clinical-outcome part (part 2, ~240 wk) has not yet read out and is UNPROVEN.
PopulationESSENCE (NCT04822181), phase 3 double-blind placebo-controlled. Part-1 interim of first 800 (semaglutide 534, placebo 266, 2:1). Biopsy MASH fibrosis F2 (31%) or F3 (69%); F0/F1 and F4/CIRRHOSIS EXCLUDED. 55.5% T2D. 72 wk (full trial 240 wk).
Fundingindustry - Novo Nordisk
Comparatorsplacebo
SemaglutideMARKETED
Liver and MASHMixed
Moderate evidence
In the phase 2b NASH trial, semaglutide 0.4 mg/day significantly increased NASH resolution vs placebo, but did NOT significantly improve fibrosis stage (fibrosis pole...
SourceNewsome PN et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic ...Source
Full findingIn the phase 2b NASH trial, semaglutide 0.4 mg/day significantly increased NASH resolution vs placebo, but did NOT significantly improve fibrosis stage (fibrosis pole negative).
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Head-to-head comparisonsIncrease
Moderate evidence
DIRECT head-to-head (SUSTAIN 7, T2D). Semaglutide was superior to dulaglutide at matched low and high doses for both HbA1c and weight at 40 weeks. HbA1c: sema 0.5 mg...
SourcePratley RE, Aroda VR, Lingvay I, et al. Lancet Diabetes Endocrinol 2018 (SUSTAIN 7)Source
Full findingDIRECT head-to-head (SUSTAIN 7, T2D). Semaglutide was superior to dulaglutide at matched low and high doses for both HbA1c and weight at 40 weeks. HbA1c: sema 0.5 mg -1.5 pp vs dula 0.75 mg -1.1 pp (ETD -0.40, p<0.0001); sema 1.0 mg -1.8 pp vs dula 1.5 mg -1.4 pp (ETD -0.41, p<0.0001). Weight: sema 0.5 -4.6 kg vs dula 0.75 -2.3 kg (ETD -2.26 kg); sema 1.0 -6.5 kg vs dula 1.5 -3.0 kg (ETD -3.55 kg, p<0.0001).
Population1201 adults with T2D on metformin, open-label phase 3b, 40 weeks, randomised 1:1:1:1; 16 countries
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
blood-pressureDecrease
Low evidence
Once-weekly semaglutide 2.4 mg reduced office SBP/DBP versus placebo across the STEP 1-5 programme.
SourceAmaro A et al. (STEP cardiometabolic review), Postgrad Med, 2022;134(sup1):18-27Source
PopulationAdults with overweight/obesity, STEP 1-5; most 68 weeks; RCT.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Heart rateIncrease
Low evidence
Semaglutide produces a modest resting heart-rate rise versus placebo (class chronotropic effect).
SourceMarso SP et al. (SUSTAIN-6), NEJM, 2016;375:1834-1844; plus class HR summariesSource
PopulationT2D (SUSTAIN-6) and obesity (STEP) populations; s.c. semaglutide vs placebo.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
lipids-lipoproteinDecrease
Low evidence
Semaglutide 2.4 mg improved the lipid profile (TG, total/LDL cholesterol) versus placebo across the STEP programme.
SourceAmaro A et al. (STEP cardiometabolic review), Postgrad Med, 2022;134(sup1):18-27Source
PopulationAdults with overweight/obesity, STEP 1-5; 68 weeks; RCT.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Cost and sticking with itNot directional
Low evidence
In a MANUFACTURER-SPONSORED (Novo Nordisk) Markov cost-effectiveness model of semaglutide 2.4 mg in the SELECT population (overweight/obese with established CV...
SourceMcEwan P, Bog M, Faurby M, Foos V, Lingvay I, Lubker C, Miller R, Toliver JC, Yeates F, L...Source
Full findingIn a MANUFACTURER-SPONSORED (Novo Nordisk) Markov cost-effectiveness model of semaglutide 2.4 mg in the SELECT population (overweight/obese with established CV disease, no diabetes), semaglutide was reported cost-effective at US list price against a $150,000/QALY willingness-to-pay threshold. Context-only economic observation; the headline result is highly price-assumption-dependent and sponsor-authored, so it is paired here with the independent competing null.
PopulationCohort-level Markov state-transition cost-effectiveness model; simulated 100,000 subjects aligned to SELECT (NCT03574597) baseline; healthcare-sector perspective; USA; sponsor Novo Nordisk (four of ten authors Novo employees, others Novo-commissioned HEOR Ltd).
Fundingindustry - Novo Nordisk (sponsor-authored cost-effectiveness model)
Comparatorsplacebo; standard of care
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Sleep apnoeaNot directional
Low evidence
EVIDENCE GAP: as of this sweep there is NO dedicated semaglutide randomised OSA trial with a polysomnographic AHI primary endpoint - a notable hole given semaglutide...
SourceKutler RB et al. GLP-1 RA Utilization Among Sleep Surgery Clinic Patients. Otolaryngol He...Source
Full findingEVIDENCE GAP: as of this sweep there is NO dedicated semaglutide randomised OSA trial with a polysomnographic AHI primary endpoint - a notable hole given semaglutide is the dominant GLP-1. OSA benefit for semaglutide is inferred from its weight loss (STEP/SELECT, neither using a sleep-apnoea endpoint) on the unproven weight-mediation assumption; available OSA-context data are observational/utilisation.
Populationn/a - gap statement. Supporting observational source: GLP-1 RA utilisation among sleep-surgery clinic patients (retrospective, n=384, single tertiary centre).
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
insulin-beta-cellIncrease
Low evidence
Twelve weeks of once-weekly semaglutide 1.0 mg significantly improved beta-cell function and glycaemic control in T2D: both first- and second-phase insulin secretion...
Full findingTwelve weeks of once-weekly semaglutide 1.0 mg significantly improved beta-cell function and glycaemic control in T2D: both first- and second-phase insulin secretion (IVGTT) increased markedly; the arginine stimulation test showed increased maximal insulin capacity; a graded glucose infusion test restored insulin secretion rate to levels similar to healthy participants; and a 24-h meal test showed reduced fasting/postprandial/overall glucose AND glucagon responses.
PopulationFOCUS RCT, ~1500 T2D with diabetic retinopathy, semaglutide 1.0 mg s.c. weekly vs placebo, ~5 yr
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
Comparatorsplacebo
SemaglutideMARKETED
Brain and moodNo changeREGISTERED, NO RESULTS
Very low evidence
NEURODEGENERATION (Alzheimer's) - the load-bearing NEGATIVE readout: the EVOKE and EVOKE+ phase-3 trials of oral semaglutide in early Alzheimer's did NOT slow disease...
SourceNovo Nordisk topline announcement, 24 Nov 2025 (EVOKE/EVOKE+); CTAD Dec 2025; peer-review...Source
Full findingNEURODEGENERATION (Alzheimer's) - the load-bearing NEGATIVE readout: the EVOKE and EVOKE+ phase-3 trials of oral semaglutide in early Alzheimer's did NOT slow disease progression (CDR-SB primary not met) despite company-reported improvement in AD biomarkers - a biomarker/clinical dissociation. The largest GLP-1-in-AD result to date.
PopulationEVOKE (NCT04777396) + EVOKE+ (NCT04777409): amyloid-positive early AD (MCI / mild dementia), age 55-85; phase-3 double-blind placebo-controlled; ~2 years.
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
The Echo Compendium