Investigational and unapproved. Findings below describe what trials and reports have observed. Nothing here is an endorsement, a claim of safety or effectiveness, or a clinical recommendation.
Semaglutide
INVESTIGATIONAL
anti-activin type II receptor (ActRII) antibody; muscle-preserving combo with GLP-1RA
123
graded findings
21
effect domains
Evidence spread
High evidence 53Moderate evidence 28Low evidence 31Very low evidence 11
Semaglutide is shown as an investigational or pipeline evidence record. Findings describe what studies and reports observed; they do not endorse use or establish personal suitability.
SemaglutideMARKETED
Safety signalsNo change
High evidence
EMA PRAC concluded its class review and found no evidence of a causal association with suicidal/self-injurious thoughts/actions; no product-information update...
SourceEMA PRAC, Meeting highlights 8-11 April 2024Source
Full findingEMA PRAC concluded its class review and found no evidence of a causal association with suicidal/self-injurious thoughts/actions; no product-information update warranted. Triggered by Icelandic case reports (initially 3), ~150 reports analysed.
PopulationRegulatory review of non-clinical, clinical-trial, post-marketing and observational data; Jul 2023-Apr 2024
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsNo-signal pole. EMA-commissioned final study report (16 Feb 2024) informed the conclusion.
SemaglutideMARKETED
Safety signalsMixed
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.
Comparatorsplacebo; empagliflozin; active comparators
SemaglutideMARKETED
Safety signalsNot 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).
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Safety signalsIncrease
High evidence
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)
Scope limitsReview opened Jan 2025, concluded Jun 2025. UK MHRA Drug Safety Update 5 Feb 2026. 'Very rare' sits between high-HR signal studies and null cohorts.
SemaglutideMARKETED
Safety signalsIncrease
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.
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Safety signalsIncrease
Moderate evidence
In a PCOS RCT, semaglutide improved menstrual-cycle recovery - a weight-loss-mediated effect.
SourceSemaglutide+metformin in PCOS (open-label RCT, n=100), Reprod Biol Endocrinol 2025Source
PopulationPCOS open-label RCT (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)
Scope limitsWEIGHT-MEDIATED PCOS menstrual recovery; does NOT isolate a drug-intrinsic abnormal-uterine-bleeding mechanism - the drug-intrinsic AUB signal remains spontaneous-report-only. DEEPENS the menstrual signal row.
SemaglutideMARKETED
Safety signalsIncrease
Moderate evidence
GLP-1 RA randomisation associated with increased composite of gallbladder/biliary disease (cholelithiasis, cholecystitis, biliary disease); higher at higher doses,...
Full findingGLP-1 RA randomisation associated with increased composite of gallbladder/biliary disease (cholelithiasis, cholecystitis, biliary disease); higher at higher doses, longer durations, and in weight-loss trials.
Fundingacademic-Chinese public (NSFC / Beijing NSF / CAMS)
Scope limitsCartographic anchor for class biliary signal; dose/duration/weight-loss interaction reported.
Comparatorsplacebo; non-GLP-1 RA drugs
SemaglutideMARKETED
Safety signalsIncrease
Moderate evidence
NET VERDICT (NAION, non-arteritic anterior ischaemic optic neuropathy) - a REAL but DEBATED and rare class signal: observational cohorts split (some ~doubled risk,...
SourceNatividade GR et al., JAMA Ophthalmol, 2025 (RCT-level ocular meta) consolidating observa...Source
Full findingNET VERDICT (NAION, non-arteritic anterior ischaemic optic neuropathy) - a REAL but DEBATED and rare class signal: observational cohorts split (some ~doubled risk, others null/protective); the 2025 RCT-level meta-analysis found a significant NAION Peto OR 3.92 but TSA judged the data insufficient for a definitive conclusion; EMA/PRAC added NAION to the semaglutide label (frequency 'unknown'/very rare). Absolute incidence is small throughout.
PopulationAdults with T2D and overweight/obesity; signal strongest in T2D, longer follow-up (>=2 yr) and with hypertension. RCT meta n=73,640; observational cohorts range single-centre to nationwide.
Fundingacademic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty); full JAMA COI disclosures paywalled
Scope limitssingle-centre/referral-enriched
Comparatorsplacebo; non-GLP-1RA antidiabetics; SGLT2i; active comparators
SemaglutideMARKETED
Safety signalsMixed
Moderate evidence
In obesity without diabetes, semaglutide increased gallbladder disorders (esp. cholelithiasis) >2.6-fold, whereas tirzepatide showed no significant biliary risk;...
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)
Scope limitsNotable divergence: biliary signal attached to semaglutide but not tirzepatide in obesity-only; why left open.
Comparatorsplacebo
SemaglutideMARKETED
Safety signalsIncrease
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)
Scope limitsVery high 1-yr heterogeneity (I2 97%). Tensioned against the null class meta-analysis (same year, opposite conclusion, differing inclusion).
Comparatorsnon-GLP-1 RA medications
SemaglutideMARKETED
Safety signalsMixed
Moderate evidence
A randomised-trials network meta-analysis found intestinal-obstruction risk not elevated for most GLP-1 agents (liraglutide possibly protective), corroborating the...
SourceChen JJ et al. Risk of intestinal obstruction with GLP-1 receptor agonists: a randomised-...Source
Full findingA randomised-trials network meta-analysis found intestinal-obstruction risk not elevated for most GLP-1 agents (liraglutide possibly protective), corroborating the weak/very-low post-marketing spontaneous-report obstruction signal.
PopulationRCT network meta-analysis (Chen et al., Int J Mol Sci 2026; the anchor source) of intestinal-obstruction risk across GLP-1 agents, read against the weaker post-marketing spontaneous-report signal.
Fundingacademic/independent - no external funding
Scope limitsnetwork meta-analysis of RCTs for a rare event; obstruction risk not elevated for most agents
Comparatorsplacebo/active comparators in RCTs; post-marketing spontaneous-report background
SemaglutideMARKETED
Safety signalsNo 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
Scope limitspost-hoc (not prespecified)
Comparatorsplacebo
SemaglutideMARKETED
Safety signalsIncrease
Low evidence
In fasting patients undergoing endoscopy under anaesthesia, GLP-1RA therapy associated with markedly higher residual gastric contents, posing additional...
Full findingIn fasting patients undergoing endoscopy under anaesthesia, GLP-1RA therapy associated with markedly higher residual gastric contents, posing additional pulmonary-aspiration risk.
PopulationRetrospective cohort, single US institution (MGH) 2019-2023, EGD under anaesthesia, 90 vs 102
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsfew events/wide CI
Comparatorspatients starting GLP-1RA after procedure (control)
SemaglutideMARKETED
Safety signalsMixed
Low evidence
In T2D, GLP-1RAs associated with lower risk of 10/13 obesity-associated cancers vs insulin; NO reduction for postmenopausal breast or thyroid cancer; vs metformin,...
Full findingIn T2D, GLP-1RAs associated with lower risk of 10/13 obesity-associated cancers vs insulin; NO reduction for postmenopausal breast or thyroid cancer; vs metformin, INCREASED kidney cancer.
PopulationRetrospective cohort, US nationwide EHR (113M), 1,651,452 T2D, 2005-2018, 15-yr follow-up, matched
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsPer PubMed. Breast/thyroid 'no reduction' and metformin-comparator kidney-cancer increase are the contested poles. Note pancreatic/gallbladder CANCER (distinct from pancreatitis/cholecystitis) lower vs insulin.
Comparatorsinsulin; metformin
SemaglutideMARKETED
Safety signalsIncrease
Low evidence
Multi-database active-comparator emulation (GLP-1RA vs SGLT2i): GLP-1RA associated with ~85% higher presumed-NAION risk, absolute risk small.
SourceTesfaye H, Patorno E et al., Diabetes Obes Metab 2025Source
Population482,912 propensity-matched pairs GLP-1RA vs SGLT2i, three US claims databases 2016-2024
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsTarget-trial emulation; signal-confirming but small absolute risk.
ComparatorsSGLT2 inhibitors
SemaglutideMARKETED
Safety signalsNo change
Low evidence
Propensity-weighted population-based cohort (Diabetologia): assessed GLP-1 RA association with suicidal ideation/self-injury in diabetes and obesity; part of the...
Full findingPropensity-weighted population-based cohort (Diabetologia): assessed GLP-1 RA association with suicidal ideation/self-injury in diabetes and obesity; part of the cohort evidence body informing regulators.
PopulationIndividuals with diabetes and obesity; propensity-weighted population-based cohort
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsAdditional cohort-pole data point. Exact HRs not extracted this pass (PMC11519213 available); recorded with confirmed DOI.
Comparatorsactive comparators
SemaglutideMARKETED
Safety signalsNo change
Low evidence
Periconceptional GLP-1 RA exposure NOT associated with a large increased major-congenital-malformation risk vs insulin, in a multinational cohort of pregnant women...
Full findingPericonceptional GLP-1 RA exposure NOT associated with a large increased major-congenital-malformation risk vs insulin, in a multinational cohort of pregnant women with T2D.
PopulationCohort, 4 Nordic + US MarketScan + Israeli Maccabi, 2009-2021; T2D pregnancies, infants to 1 yr
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsPer PubMed. Estimates imprecise/confounded by maternal T2D; no glycaemic-control data. Reassuring but not exonerating.
Comparatorsinsulin; sulfonylureas; DPP-4i; SGLT2i
SemaglutideMARKETED
Safety signalsIncrease
Low evidence
GLP-1 RAs may improve ovulatory function/menstrual regularity (esp. obesity/PCOS), potentially increasing conception and unintended pregnancy; human pregnancy-exposure...
Full findingGLP-1 RAs may improve ovulatory function/menstrual regularity (esp. obesity/PCOS), potentially increasing conception and unintended pregnancy; human pregnancy-exposure safety data remain limited.
PopulationNarrative review 2020-2025, reproductive-age women
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
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)
Scope limitsSmall single-arm pilot, no control, 10 weeks; absorption attenuated not abolished. MANDATORY: do NOT assert the mechanism is proven to be genuine malabsorption rather than an acute-phase effect - that stronger restatement was REFUTED 0-3 in adversarial review; hepcidin and inflammation were not measured.
Comparatorswithin-subject baseline (no control arm)
SemaglutideMARKETED
Safety signalsDecrease
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)
Scope limitsAuthor interpretation, hedged. Same small single-arm pilot; mechanism attribution is hypothesis, not proven.
Comparatorswithin-subject baseline (no control arm)
SemaglutideMARKETED
Safety signalsIncrease
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)
Scope limitssingle-centre/referral-enriched
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)
Scope limitsNull early, significant from 2 yr; follow-up length drives the signal. Risk also raised with concomitant hypertension.
Comparatorsnon-GLP-1 RA antidiabetics
SemaglutideMARKETED
Safety signalsDecrease
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)
Scope limitsDirectly contradicts the signal cohorts; authors conclude NAION risk should not preclude use.
Comparatorsnon-GLP-1 RA medications; PDE-5 inhibitors (subset)
SemaglutideMARKETED
Safety signalsDecrease
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.
Scope limitsPer PubMed; numbers CONFIRMED via metadata. Frames obesity as chronic relapsing. Weight-regain straddles safety-other and weight-loss domains.
Comparatorsplacebo
SemaglutideMARKETED
Safety signalsNo change
Very low evidence
FAERS disproportionality found only WEAK / non-significant intestinal-obstruction signals across GLP-1RAs; no clear class signal for mechanical obstruction.
SourceGI Safety Assessment of GLP-1 RAs from FAERS, Diagnostics (MDPI) 2024Source
PopulationFAERS 2007-2023, US reports, 16,568 GI AE reports (tirzepatide not included)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Full findingFOLK-CLAIM VERDICT ('menstrual changes - intermenstrual/heavy/irregular bleeding'): MIXED / EMERGING - no longer pure self-report. Two independent low-grade signals now converge (online self-report + a semaglutide-specific FAERS reproductive signal), but it is NOT trial-grade: FAERS cannot establish incidence/causation (reporting bias, no denominator, and weight loss itself shifts cycles). Notably the pharmacovigilance signal is AGENT-SPECIFIC (semaglutide), with tirzepatide/dulaglutide trending the opposite way.
PopulationOnline self-report cohort + FAERS disproportionality; no dedicated RCT endpoint.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
FAERS disproportionality (2018-2022): no signal of disproportionate reporting for suicidal/self-injurious behaviours; co-medication analysis flagged...
Full findingFAERS disproportionality (2018-2022): no signal of disproportionate reporting for suicidal/self-injurious behaviours; co-medication analysis flagged psychiatric-comorbidity proxies.
FAERS disproportionality (2005-2023): no overall disproportionate increase in suicide/self-injury; a marginal ROR elevation in children was NOT confirmed by EBGM05.
SourceChen C et al., Eur Psychiatry 2023;66(1):e99Source
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsidentifier not fully verified
Comparatorsfull database background
SemaglutideMARKETED
Safety signalsIncrease
Very low evidence
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)
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)
Scope limitsidentifier not fully verified; no outcome data yet (ongoing)
Comparatorsplacebo
SemaglutideMARKETED
Pharmacology and mechanismNot 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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNot directional
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNot directional
High evidence
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
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNot directional
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismIncrease
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNot directional
High evidence
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
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNot directional
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNot directional
High evidence
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
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
Pharmacology and mechanismNo change
Low evidence
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)
Scope limitssmall sample (n=15); single-arm (no control); short duration (12wk); appetite/diet confound
Comparatorsbaseline (pre-treatment)
SemaglutideMARKETED
Pharmacology and mechanismNo 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)
Scope limitsin-vitro receptor assay; human relevance via pharmacology only
Comparatorsbroad receptor panel
SemaglutideMARKETED
Pharmacology and mechanismNo 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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
special-populationsNot directional
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
special-populationsIncrease
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
special-populationsNot directional
High evidence
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
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
special-populationsNot directional
High evidence
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.
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
SemaglutideMARKETED
special-populationsIncrease
Moderate evidence
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)
Scope limitsWEIGHT/OVULATION-MEDIATED in a PCOS-anovulatory population (a channel absent in already-ovulatory women); open-label, small. Context-distinct from the general fertility-care cohort - the honest compendium statement is that the effect on fertility is context-dependent, not one-way.
SemaglutideMARKETED
special-populationsDecrease
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
Scope limitsCONTEXT-DISTINCT, both-poled with the PCOS conception-up RCT (different population). This cohort signal is confounded by required washout/discontinuation timing and indication - NOT a demonstrated direct anti-fertility drug effect. Do not state a one-way 'GLP-1 harms fertility'.
SemaglutideMARKETED
special-populationsNot directional
Low evidence
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.
Scope limitsUPGRADES the label-only lactation rows. Caveats: n=8, single-dose sampling, no infant plasma levels or long-term outcomes. Non-semaglutide agents (tirz, lira, reta) remain never-measured for milk transfer.
SemaglutideMARKETED
Cardiovascular outcomesDecrease
High evidence
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
Scope limitsDEEPENS the prior one-line SELECT row with the HR and event rates. First GLP-1RA CVOT in a non-diabetic obesity population. Weight-independence framing carried in companion analysis (C-SEMA-CARDIO-05). Cross-ref the T2D sema CVOTs.
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesDecrease
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.
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
Scope limitsBOTH-POLES: a non-inferiority (NOT superiority) oral-sema result; the design was CV-safety. Definitive oral-sema superiority came later in SOUL (C-SEMA-CARDIO-04). DEEPENS prior row with HR and CI-crossing-1 detail.
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesDecrease
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
Scope limitskidney confirmatory-secondary not met
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesNo change
High 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
Scope limitsBOTH-POLED: the point estimate (0.85) is protective-leaning within a positive trial. The CV-death HR is from the SELECT supplementary appendix, not the primary abstract.
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesNo change
High 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
Scope limitsMEASURED component nulls (wide CIs, both-poled). The MACE-superiority is NEVER-MEASURED-AT-POWER and is already recorded in C-SEMA-CARDIO-03 - this row adds only the component detail.
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesDecrease
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)
Scope limitssurrogate/exploratory endpoint
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesDecrease
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)
Scope limitsstopped early for efficacy (may inflate estimate)
Comparatorsplacebo
SemaglutideMARKETED
Cardiovascular outcomesDecrease
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
Scope limitsno outcome data yet (ongoing); possible confounding by indication
Comparatorsplacebo
SemaglutideMARKETED
Body compositionMixed
Moderate evidence
BELIEVE phase-2b (Eli Lilly/Versanis) tested bimagrumab alone or added to semaglutide. The combination drove fat-selective weight loss with lean-mass preservation;...
SourceHeymsfield et al., Nat Med 2026; presented ADA 2025Source
Full findingBELIEVE phase-2b (Eli Lilly/Versanis) tested bimagrumab alone or added to semaglutide. The combination drove fat-selective weight loss with lean-mass preservation; bimagrumab monotherapy GAINED lean while semaglutide alone lost it. Now PEER-REVIEWED (Heymsfield et al., Nat Med 2026).
PopulationBELIEVE phase-2b RCT, N=507, 48-week treatment (results to wk72), randomised double-blind placebo-controlled, 9 arms; bimagrumab IV q12w +/- semaglutide sc weekly; adults overweight/obese with >=1 comorbidity.
Fundingindustry - Eli Lilly (trial sponsor)
Scope limitsDEEPENED (D2): upgraded from landscape note to the peer-reviewed BELIEVE result. VALIDATOR: PMID 41772149 RESOLVED (Heymsfield et al., Nat Med 2026;32(3):869-882, NCT05616013) - status verified, no fallback needed. The per-arm lean DXA percentages (mono +2.5%, sema -7.4%, 92.8% fat fraction, fat -45.7%) are SECONDARY results not in the Nat Med abstract; design-consistent but flagged as not-abstract-verified. Distinguishes lean GAIN (bimagrumab mono) from lean PRESERVATION (combo). Surrogate DXA/BIA, phase-2b, 9 arms dilute per-arm N -> moderate; Lilly-sponsored.
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)
Scope limitssmall sample (N~115)
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
Scope limitssmall sample (N~178)
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
Full findingCOURAGE phase-2 (Regeneron, NCT06299098) tests trevogrumab (anti-myostatin) +/- garetosmab (anti-activin A) added to semaglutide. Interim results show dose-ordered lean preservation, with the triplet most lean-preserving but least tolerated. Final readout pending.
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
Scope limitsconference/abstract-level; no outcome data yet (ongoing)
Comparatorssemaglutide 2.4 mg alone; placebo
SemaglutideMARKETED
Body compositionMixed
Very low evidence
Muscle-preserving combination landscape: bimagrumab (ActRII blockade) is reported to add lean mass while reducing fat, and is being combined with semaglutide to...
SourceNunn E et al., Mol Metab, 2024 (preclinical); Kaiser M et al., Cardiol Rev, 2025 (review)Source
Full findingMuscle-preserving combination landscape: bimagrumab (ActRII blockade) is reported to add lean mass while reducing fat, and is being combined with semaglutide to counter GLP-1-associated lean-mass loss; preclinical work shows combination preserves muscle while enhancing fat loss vs semaglutide alone.
PopulationPreclinical (diet-induced obese mice) plus clinical-development narrative/review; combination under clinical study
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorssemaglutide
SemaglutideMARKETED
cns-neuropsychiatricNo 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.
FOLK-CLAIM VERDICT ('vivid/bizarre Ozempic dreams'): UNPROVEN / essentially anecdotal. There is no randomised-trial endpoint, no sleep-architecture (PSG) study, and...
SourceWadden TA et al., JAMA Intern Med 2024 (STEP 1/2/3/5 psychiatric post hoc)Source
Full findingFOLK-CLAIM VERDICT ('vivid/bizarre Ozempic dreams'): UNPROVEN / essentially anecdotal. There is no randomised-trial endpoint, no sleep-architecture (PSG) study, and only a sub-0.1/100-patient-year uncoded spontaneous-report trickle with an explicit no-causation caveat; post-marketing spontaneous-report screening is dream-silent. More parsimonious benign explanations (REM rebound from improved sleep/OSA resolution, nocturnal hypoglycaemia in the diabetic subset, recall/attention bias and social contagion around a viral named phenomenon) are unproven but more likely than a direct dream-generating drug effect.
PopulationPooled STEP 1/2/3/5 semaglutide psychiatric-safety post-hoc analysis (Wadden 2024, the anchor source); corroborated by a post-marketing spontaneous-report screen and the manufacturer spontaneous-report rate.
Fundingindustry-Novo Nordisk
Scope limitspost-hoc (not prespecified)
Comparatorsplacebo
SemaglutideMARKETED
cns-neuropsychiatricDecrease
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)
Scope limitsanimal data; human relevance uncertain; small sample (N~48); surrogate/exploratory endpoint
Comparatorsplacebo
SemaglutideMARKETED
cns-neuropsychiatricDecrease
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)
Scope limitspossible confounding by indication
Comparatorsother anti-obesity medications
SemaglutideMARKETED
cns-neuropsychiatricDecrease
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)
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)
Scope limitsidentifier not fully verified; no outcome data yet (ongoing)
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
Scope limitsidentifier not fully verified; magnitude web/secondary-sourced
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
Scope limitsKCCQ-CSS gain numerically smaller than non-diabetic STEP-HFpEF. PMID/DOI verified.
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
Scope limitspost-hoc (not prespecified)
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)
Scope limitssurrogate/exploratory endpoint; sponsor-authored COI (Novo Nordisk)
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)
Scope limitssurrogate/exploratory endpoint; sponsor-authored COI (Novo Nordisk)
Comparatorsplacebo
SemaglutideMARKETED
Appetite and food 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
Scope limitssmall sample (N~174)
Comparatorsplacebo
SemaglutideMARKETED
Appetite and food 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)
Scope limitsSponsor-authored (Novo Nordisk); COI-flag. Reused from corpus T9-GLP1R-01 (validated 2026-06-20). Central-vs-peripheral mechanism: intake reduction without persistent gastric-emptying delay.
Comparatorsplacebo
SemaglutideMARKETED
Appetite and food 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
Scope limitssmall sample (N~30)
Comparatorsplacebo
SemaglutideMARKETED
Appetite and food 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
Scope limitssmall sample (N~15)
Comparatorsplacebo
SemaglutideMARKETED
Appetite and food 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)
Scope limitsSponsor-authored; COI-flag. Reused from corpus T9-GLP1R-04. Reinforces central (not gastric) mechanism at steady state.
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
health-economics-adherenceNot directional
Low evidence
In a real-world US commercially insured cohort of obese adults WITHOUT diabetes newly initiating GLP-1 therapy for weight loss, only 32.3% remained persistent at 1...
SourceGleason PP, Urick BY, Marshall LZ, Friedlander N, Qiu Y, Leslie RS. Real-world persistenc...Source
Full findingIn a real-world US commercially insured cohort of obese adults WITHOUT diabetes newly initiating GLP-1 therapy for weight loss, only 32.3% remained persistent at 1 year and only 27.2% were adherent (PDC>=80%) - far below the >85% adherence reported in pivotal obesity trials. (Note: this is the diabetes-free obesity stratum, which persists worse than type 2 diabetes; cf. ADHERENCE-02.)
PopulationRetrospective cohort, Prime Therapeutics integrated pharmacy + medical claims (~16.5M monthly commercially insured members); 4,066 obese adults WITHOUT type 2 diabetes initiating GLP-1 in 2021; mean age 46, 81% female; obesity (weight-loss) indication; USA.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitspossible confounding by indication
SemaglutideMARKETED
health-economics-adherenceNot directional
Low evidence
In a nationwide T2D real-world database, adherence and persistence to GLP-1 RA were significantly higher for once-weekly than daily formulations and were...
SourceKassem S, Khalaila B, Stein N, Saliba W, Zaina A. Efficacy, adherence and persistence of ...Source
Full findingIn a nationwide T2D real-world database, adherence and persistence to GLP-1 RA were significantly higher for once-weekly than daily formulations and were socio-economically patterned (better adherence with higher socio-economic status), showing real-world persistence varies markedly by agent/dosing schedule and by access, even within type 2 diabetes.
PopulationRetrospective cohort, Clalit Health Services EMR (Israel, nationwide HMO); 70,654 adults with T2D purchasing any GLP-1 RA 2009-2021; 51% female; T2D indication.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitspossible confounding by indication
Comparatorsonce-weekly vs daily GLP-1 RA
SemaglutideMARKETED
health-economics-adherenceNot 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; COI-flagged per Constitution 1.8)
Scope limitsWI-3 NEW-GATHER (cost-effectiveness / QALY, CV-disease obesity setting). Context-only modelling study, not an efficacy/mechanism claim or recommendation. GRADE low by rule (cost-effectiveness model). COI / sponsor-authorship flag (Constitution 1.8): sponsor (Novo Nordisk) authored, advancing the sponsor-favourable 'cost-effective at list price' conclusion - down-weighted at point of use and deliberately paired with the INDEPENDENT competing null (C-TIRZEPATIDE-HEALTHECON-CEA-01, academic, which finds semaglutide NOT cost-effective at net price, ICER $467,676/QALY in the general-obesity setting). The two are not in direct contradiction (different populations: SELECT CV-disease cohort with modelled CV-event savings vs general obesity; different WTP thresholds $150k vs $100k; list vs net price) - record both poles and the price-assumption dependence per Constitution 1.10. scope_limits: model assumptions, list-price sensitivity (rebate scenario swings the ICER ~4x), sponsor COI, generalisability of SELECT to broader population (authors' own caveat).
Comparatorsplacebo; standard of care
SemaglutideINVESTIGATIONAL
comparative-efficacyIncrease
High evidence
ACTIVE-CONTROLLED head-to-head within trial (REDEFINE 1, obesity without T2D). CagriSema (cagri 2.4 mg + sema 2.4 mg) gave -20.4% weight vs placebo -3.0% (difference...
SourceGarvey WT, Blüher M, et al. N Engl J Med 2025 (REDEFINE 1)Source
Full findingACTIVE-CONTROLLED head-to-head within trial (REDEFINE 1, obesity without T2D). CagriSema (cagri 2.4 mg + sema 2.4 mg) gave -20.4% weight vs placebo -3.0% (difference -17.3 pp) at 68 weeks; trial also contained semaglutide 2.4 mg monotherapy (N=302) and cagrilintide 2.4 mg monotherapy (N=302) arms enabling within-trial comparison of the combination against each component.
Population3417 adults with overweight/obesity without diabetes, double-blind placebo- and active-controlled phase 3a, 68 weeks; randomised 21:3:3:7 (combo:sema:cagri:placebo)
ACTIVE/placebo-controlled (REDEFINE 2, overweight/obesity WITH T2D). CagriSema -13.7% vs placebo -3.4% weight at 68 weeks (difference -10.4 pp). HbA1c <=6.5% reached...
SourceDavies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2)Source
Full findingACTIVE/placebo-controlled (REDEFINE 2, overweight/obesity WITH T2D). CagriSema -13.7% vs placebo -3.4% weight at 68 weeks (difference -10.4 pp). HbA1c <=6.5% reached by 73.5% (CagriSema) vs 15.9% (placebo).
Population1206 adults with T2D and BMI >=27, double-blind, 68 weeks, randomised 3:1 vs placebo
Fundingindustry-Novo Nordisk
Scope limitsT2D companion to REDEFINE 1. Note weight loss in T2D (-13.7%) lower than obesity-only (-20.4%) - the standard T2D weight-loss attenuation pattern, recorded as observation. No active drug comparator (placebo only).
Comparatorsplacebo
SemaglutideMARKETED
comparative-efficacyIncrease
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)
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
Scope limitsRegistrational programme; the NEJM article-type metadata field is mis-tagged at a lower study phase, but this is the registrational 25 mg pivotal trial - graded high on its true double-blind RCT design.
SemaglutideMARKETED
Weight changeDecrease
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
Scope limitsconference/abstract-level
Comparatorsplacebo
SemaglutideMARKETED
Weight changeDecrease
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)
Scope limitsMechanism: same molecule as s.c. semaglutide, formulated with SNAC for oral gastric absorption; oral bioavailability low/variable, hence high mg doses (14/25/50 mg). Original PIONEER programme (3/7/14 mg) marketed as Rybelsus (T2D); oral 25/50 mg obesity dosing later filed. GI AEs ~80% vs 46% placebo (OASIS 1).
Comparatorsplacebo
SemaglutideMARKETED
Energy expenditure and 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).
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)
Scope limitssmall sample (N~8)
Comparatorswithin-subject baseline
SemaglutideMARKETED
Energy expenditure and 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)
Scope limitsanimal data; human relevance uncertain
Comparatorsad libitum control; pair-fed control
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.
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Gastrointestinal tolerabilityIncrease
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
Scope limitsPMID/DOI and discontinuation range CONFIRMED directly via PubMed (corrects fork's earlier review-channel tag). Per-symptom nausea rates (e.g. 16.0% on 14 mg) from broader PIONEER reporting.
Comparatorsplacebo
SemaglutideMARKETED
Gastrointestinal tolerabilityIncrease
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
Maintenance and 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.
Scope limitsCanonical randomised-withdrawal regain figure for semaglutide (+6.9% over 48 wk). Counterpart to the on-treatment weight-loss rows: loss is maintained only while treatment continues. Authors frame as supporting continued treatment for maintenance. Pairs with the STEP-1 extension (longer off-treatment arc + cardiometabolic reversal). VALIDATOR: confirm PMID 33755728 + the +6.9/-7.9 figures.
Comparatorsplacebo (switch from semaglutide)
SemaglutideMARKETED
Maintenance and regainIncrease
Low evidence
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
Scope limitsSource of the widely-cited 'regained ~two-thirds' figure + the explicit cardiometabolic-reversal statement. Graded MODERATE not high: exploratory, non-randomly-selected off-treatment extension where lifestyle was ALSO withdrawn (so regain reflects total withdrawal, not drug alone). Reports TOTAL weight only - no fat-vs-lean composition (see C-CLASS-MAINT-04 gap). VALIDATOR: confirm PMID 35441470 + the 11.6/17.3 figures.
Comparatorsplacebo (also withdrawn)
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
hepatic-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
Scope limitsno outcome data yet (ongoing)
Comparatorsplacebo
SemaglutideMARKETED
hepatic-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).
Scope limitsBoth poles present: resolution positive, fibrosis NOT improved (p=0.48). Imbalance in neoplasms noted (15% semaglutide vs 8% placebo). Daily formulation (vs weekly 2.4 mg in ESSENCE).
Comparatorsplacebo
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)
Scope limitsReview summary, not a dedicated ABPM trial. Magnitude approximate; confirm against individual STEP papers. PMID/DOI verified.
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
heart-rate-chronotropyIncrease
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)
Scope limitsconference/abstract-level
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Lipids and lipoproteinsDecrease
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)
Scope limitsReview summary; semaglutide lipid effects generally milder than glucagon co-agonists (no direct glucagon-driven hepatic TG effect). PMID/DOI verified.
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Obstructive 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)
Scope limitspossible confounding by indication; single-centre/referral-enriched
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
SemaglutideMARKETED
Insulin and beta-cell functionIncrease
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.
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