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Research information only. Not medical advice. 18+ only. Not FDA-approved for human therapeutic use.

Semaglutide

Also known as: Ozempic, Wegovy, Rybelsus, GLP-1 analogue, GLP-1 receptor agonist

Glucagon-like peptide-1 receptor agonist (GLP-1 RA)

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What it is

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that binds and activates the GLP-1 receptor (GLP-1R), a class B G protein-coupled receptor (PMID 34260945, PMID 53269530). Cryo-EM structures show semaglutide engages the GLP-1R similarly to native GLP-1 but with distinct receptor dynamics. Proposed mechanisms include: (1) reducing appetite and increasing satiety, decreasing dietary intake and free fatty acid export to the liver; (2) reducing insulin resistance and improving insulin sensitivity; (3) reducing de novo lipogenesis by downregulating ChREBP and SREBP-1c signaling; (4) reducing weight of white and brown adipose tissue; (5) reducing inflammation by decreasing pro-inflammatory markers in GLP-1-expressing macrophages and favorably altering gut microbiota. In the cardiovascular context, semaglutide restores RKIP expression and inhibits the downstream TBK1-NF-κB pathway through Sirt3-dependent signaling, with cAMP/PKA signaling contributing to the anti-inflammatory effect. In adipose and vascular tissue, semaglutide modulates the GLP-1R/PPARG/ACSL1 pathway in macrophages and increases antithrombotic gelsolin secretion from epicardial fat (PMID 39908200, PMID 38172989). The lack of confirmed GLP-1 receptor expression in human and mouse liver suggests liver-related benefits are likely indirect.

Class: Glucagon-like peptide-1 receptor agonist (GLP-1 RA)

What it's studied for

  • Type 2 diabetes mellitus — glycemic control Human RCT
    • Once-weekly subcutaneous semaglutide 2.0 mg reduced HbA1c by -2.2 percentage points vs -1.9 pp with 1.0 mg at 40 weeks (ETD -0.23%; p=0.0003). Body weight reduced -6.9 kg vs -6.0 kg. PMID 34293304 Frías et al. SUSTAIN FORTE, Lancet Diabetes Endocrinol. 2021
    • Oral semaglutide 7 mg and 14 mg once-daily reduced HbA1c by -1.23% and -1.47% respectively from baseline 8.3% at 52 weeks. Orforglipron was superior to both doses. PMID 41765029 Rosenstock et al. ACHIEVE-3, Lancet 2026
    • Oral semaglutide approved for T2DM; HbA1c reduction -0.5% to -1.5% absolute; weight reductions -1 to -4.7 kg. Noninferior to placebo for cardiovascular safety. PMID 31744308 Cowart, Ann Pharmacother. 2020
    • Across SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA1c by 1.5–1.8% after 30–56 weeks, superior to sitagliptin, liraglutide, exenatide ER, dulaglutide, canagliflozin, and insulin glargine. PMID 34248838 Meier, Front Endocrinol. 2021
  • Obesity and overweight management — weight loss Human RCT
    • Once-weekly subcutaneous semaglutide 2.4 mg achieved -9.6% body weight change vs -3.4% with placebo at 68 weeks in adults with overweight/obesity and T2D (ETD -6.2 pp; p<0.0001); 68.8% vs 28.5% achieved ≥5% weight reduction. PMID 33667417 Davies et al. STEP 2, Lancet 2021
    • Semaglutide 2.4 mg once-weekly reduced body weight by -13.2% vs -2.1% with placebo at 68 weeks in East Asian adults with obesity (ETD -11.1 pp; p<0.0001); abdominal visceral fat reduced by 40.0% vs 6.9%. PMID 35131037 Kadowaki et al. STEP 6, Lancet Diabetes Endocrinol. 2022
    • Meta-analysis of 4 RCTs (3,613 individuals, obesity without diabetes): mean weight difference -11.85% favoring subcutaneous semaglutide vs placebo; GI adverse events 1.59x more likely with semaglutide. PMID 36578889 Tan et al., J ASEAN Fed Endocr Soc. 2022
    • Once-daily oral semaglutide 50 mg reduced ad libitum energy intake by 39.2% and body weight by 9.8% vs 1.5% with placebo at 20 weeks in adults with obesity. PMID 39082206 Gabe et al., Diabetes Obes Metab. 2024
  • Cardiovascular risk reduction — major adverse cardiovascular events (MACE) Human RCT
    • SUSTAIN-6 trial: 26% MACE reduction (HR 0.74; 95% CI 0.58–0.95; p=0.02) with semaglutide 0.5 or 1.0 mg weekly in high CV-risk T2D patients. SELECT trial: 20% MACE reduction (HR 0.80; 95% CI 0.72–0.90; p<0.001) with semaglutide 2.4 mg weekly in overweight/obese individuals with CVD but without T2D. PMID 40458885 MacIsaac, Future Cardiol. 2025
    • SELECT trial (17,604 adults with CVD and obesity): 20% MACE risk reduction with weekly 2.4 mg semaglutide vs placebo (double-blind, placebo-controlled). PMID 37640171 Irfan, Curr Probl Cardiol. 2024
  • Heart failure with preserved ejection fraction (HFpEF) Human observational
    • In 58,333 patients with cardiometabolic HFpEF, semaglutide vs sitagliptin showed HR 0.58 (95% CI 0.51–0.65) for composite of HF hospitalization or all-cause mortality. Tirzepatide showed no meaningfully lower risk vs semaglutide (HR 0.86; 95% CI 0.70–1.06). PMID 40886075 Krüger et al., JAMA 2025
  • Chronic kidney disease (CKD) progression reduction Human RCT
    • FLOW trial: 24% reduction in major kidney disease events (HR 0.76; 95% CI 0.66–0.88; p=0.002) with weekly 1.0 mg semaglutide in T2D patients with CKD. PMID 40458885 MacIsaac, Future Cardiol. 2025
  • Metabolic dysfunction-associated steatohepatitis (MASH/MASLD) — liver fibrosis and steatohepatitis Human RCT
    • Phase 2 RCT: Semaglutide 2.4 mg QW achieved fibrosis improvement without MASH worsening in 30% vs 16% placebo (EDP 14.05; 95% CI 1.88–26.23; p=0.024, nominally significant) in patients with F2–F4c fibrosis at 52 weeks. PMID 42456707 Loomba et al., Lancet Gastroenterol Hepatol. 2026
    • Review of preclinical and clinical studies: semaglutide effectively improves MASH but does not confer histological fibrosis resolution; mechanisms are likely indirect given lack of GLP-1R expression in liver. PMID 40538007 Ezhilarasan, J Gastroenterol Hepatol. 2025
  • Alzheimer's disease risk reduction / neuroprotection Human observational
    • Target trial emulation in 1,094,761 T2DM patients: semaglutide associated with 40–70% reduced risk of first-time AD diagnosis vs other antidiabetic medications, including insulin (HR 0.33; 95% CI 0.21–0.51) and other GLP-1RAs (HR 0.59; 95% CI 0.37–0.95) over 3-year follow-up. PMID 39445596 Wang et al., Alzheimers Dement. 2024
    • In APP/PS1 mice and human AD brain organoids, semaglutide improved cognition, reduced amyloid plaque deposition, reduced GFAP/Iba1 expression, and upregulated oxytocin. PMID 39405916 Zhang et al., Biomed Pharmacother. 2024
  • Diabetic retinopathy — attenuation of progression Mixed
    • Meta-analysis of 23 RCTs (22,096 T2DM patients): overall semaglutide not associated with increased DR risk (RR 1.14; 95% CI 0.98–1.33). Subgroup vs placebo showed increased risk (RR 1.24; 95% CI 1.03–1.50). Increased risk in patients ≥60 years or diabetes duration ≥10 years. PMID 34894326 Wang et al., Clin Drug Investig. 2022
    • Streptozotocin-induced DR rat model: semaglutide 100 μg/kg/week for 5 weeks reduced blood glucose, improved retinal function, alleviated vascular lesions and neuronal apoptosis, and reduced inflammation in vivo. In HRMECs (5 nM), semaglutide inhibited oxidative stress and downregulated VEGFA. PMID 40931416 Cheng et al., Diabetes Obes Metab. 2025
  • Diabetic cardiomyopathy — cardiac protection Animal studies only
    • In HFD/STZ diabetic mice, semaglutide ameliorated myocardial fibrosis, improved cardiac function, antagonized oxidative stress, suppressed cardiomyocyte apoptosis, and attenuated cardiac inflammation via Sirt3-dependent RKIP-TBK1-NF-κB pathway. PMID 39710830 Lin et al., Br J Pharmacol. 2025
    • In C57BL/6J mice, semaglutide ameliorated doxorubicin-induced cardiac dysfunction via PI3K/AKT pathway by reducing BNIP3 expression in mitochondria, improving mitochondrial function. PMID 38574433 Li et al., Redox Biol. 2024
  • Papillary thyroid carcinoma — anti-tumor macrophage reprogramming Animal studies only
    • In PTC xenograft mouse models and coculture systems, semaglutide reduced tumor size and inhibited PTC cell proliferation by increasing M1 and decreasing M2 macrophages via GLP-1R/PPARG/ACSL1 signaling pathway. No direct effect on PTC cell proliferation. PMID 39908200 Wang et al., J Clin Endocrinol Metab. 2025
  • Atherosclerosis/thrombosis risk reduction — vascular and immune modulation Human observational
    • In patients treated with semaglutide for 6 months: 20% statistically significant reduction in FABP4 levels and 80% increase in neutrophil CD88; increased antithrombotic gelsolin secretion from epicardial fat; modulation of neutrophil migration and endothelial adhesion. PMID 38172989 García-Vega et al., Cardiovasc Diabetol. 2024
  • Pediatric obesity management Human RCT
    • Review of one large RCT in youth: once-weekly subcutaneous semaglutide effectively reduces BMI and improves hyperglycemia, elevated ALT, hyperlipidemia, and quality of life over 68 weeks. Long-term safety data limited. PMID 38774967 Bensignor et al., Curr Opin Pediatr. 2024

Community-reported dosing

RouteDoseFrequency / DurationPopulation / contextSource tier
Subcutaneous injection2.4 mg once weekly; also 1.0 mg once weekly as comparator68 weekshumanResearch PMID 33667417
Subcutaneous injection2.4 mg once weekly; also 1.7 mg once weekly68 weekshumanResearch PMID 35131037
Subcutaneous injection2.0 mg once weekly vs 1.0 mg once weekly40 weekshumanResearch PMID 34293304
Subcutaneous injection2.4 mg once weekly52 weekshumanResearch PMID 42456707
Subcutaneous injection0.5 or 1.0 mg weekly (SUSTAIN-6); 1.0 mg weekly (FLOW); 2.4 mg weekly (SELECT)Not specified per trial in abstracthumanResearch PMID 40458885
Subcutaneous injection2.4 mg weeklyNot statedhumanResearch PMID 37640171
Subcutaneous injection (SUSTAIN); oral (PIONEER)1.0 mg once weekly (SUSTAIN); 14 mg once daily (PIONEER)30–56 weeks (SUSTAIN); 26 weeks (PIONEER)humanResearch PMID 34248838
Oral50 mg once daily (dose-escalated)20 weekshumanResearch PMID 39082206
Oral3 mg escalating to 14 mg once daily12 weekshumanResearch PMID 38808476
Oral7 mg or 14 mg once daily52 weekshumanResearch PMID 41765029
Oral3 mg escalating to 7 mg to 14 mg once daily12 weekshumanResearch PMID 33184979
Subcutaneous injection and oralVarious subcutaneous (0.5 mg, 1.0 mg) and oral formulations assessed across SUSTAIN and PIONEER phase 3 programsVarioushumanResearch PMID 34305810
Not explicitly stated (administered to rats in STZ model)100 μg/kg/week5 weeksanimalResearch PMID 40931416
In vitro (cell culture)5 nMNot statedin_vitroResearch PMID 40931416
Not specified (varied)Not specified (observational studies; doses varied across included cohorts)Up to 36 months follow-uphumanResearch PMID 42612051
Subcutaneous injection1 mg weekly (prescribed); patient self-injected full monthly supply (4x weekly dose) at once as overdose1 year prior to overdose eventhumanResearch PMID 40849680
subcutaneous injection0.25 mgonce weeklyindividuals beginning semaglutide for weight loss or metabolic health, often sourcing compounded or research-grade peptide[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection0.5 mgonce weeklyindividuals who have completed 4-week 0.25 mg titration without intolerable side effects[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection1 mgonce weeklyintermediate users who have titrated through 0.25 mg and 0.5 mg phases[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection1.7 mgonce weeklyindividuals titrating toward the 2.4 mg Wegovy weight-loss ceiling dose[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection2.4 mgonce weeklyindividuals seeking maximum GLP-1-driven weight loss, often those with significant obesity or metabolic dysfunction[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection0.5 mgonce weeklylean biohackers and longevity-focused adults using semaglutide for metabolic optimization rather than significant weight loss[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection0.25 mgonce weeklylean biohackers, longevity-focused adults, or individuals highly sensitive to GLP-1 side effects who use minimal dosing for metabolic benefits[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection1 mgonce weeklyindividuals who have completed titration and find 1 mg to be their sweet spot for appetite suppression without escalating GI side effects[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection2 mgonce weeklyindividuals seeking high-end weight loss outcomes using compounded or research-grade semaglutide[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection0.5 mgonce every 2 weeksfirst-time users who are highly cautious about GI side effects or who have had prior GI sensitivity to GLP-1 agonists[S] Claude Sonnet 4.6 — synthesized from aggregate training data
subcutaneous injection0.1 mgonce weeklyhighly GI-sensitive individuals or biohackers experimenting with sub-clinical dosing, particularly using compounded semaglutide[S] Claude Sonnet 4.6 — synthesized from aggregate training data

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

References

  1. [1] PMID 34293304 — Once-weekly subcutaneous semaglutide 2.0 mg reduced HbA1c by -2.2 percentage points vs -1.9 pp with 1.0 mg at 40 weeks (ETD -0.23%; p=0.0003). Body weight reduc
  2. [2] PMID 41765029 — Oral semaglutide 7 mg and 14 mg once-daily reduced HbA1c by -1.23% and -1.47% respectively from baseline 8.3% at 52 weeks. Orforglipron was superior to both dos
  3. [3] PMID 31744308 — Oral semaglutide approved for T2DM; HbA1c reduction -0.5% to -1.5% absolute; weight reductions -1 to -4.7 kg. Noninferior to placebo for cardiovascular safety.
  4. [4] PMID 34248838 — Across SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA1c by 1.5–1.8% after 30–56 weeks, superior to sitagliptin, liraglutide, exenatide
  5. [5] PMID 33667417 — Once-weekly subcutaneous semaglutide 2.4 mg achieved -9.6% body weight change vs -3.4% with placebo at 68 weeks in adults with overweight/obesity and T2D (ETD -
  6. [6] PMID 35131037 — Semaglutide 2.4 mg once-weekly reduced body weight by -13.2% vs -2.1% with placebo at 68 weeks in East Asian adults with obesity (ETD -11.1 pp; p<0.0001); abdom
  7. [7] PMID 36578889 — Meta-analysis of 4 RCTs (3,613 individuals, obesity without diabetes): mean weight difference -11.85% favoring subcutaneous semaglutide vs placebo; GI adverse e
  8. [8] PMID 39082206 — Once-daily oral semaglutide 50 mg reduced ad libitum energy intake by 39.2% and body weight by 9.8% vs 1.5% with placebo at 20 weeks in adults with obesity.
  9. [9] PMID 40458885 — SUSTAIN-6 trial: 26% MACE reduction (HR 0.74; 95% CI 0.58–0.95; p=0.02) with semaglutide 0.5 or 1.0 mg weekly in high CV-risk T2D patients. SELECT trial: 20% MA
  10. [10] PMID 37640171 — SELECT trial (17,604 adults with CVD and obesity): 20% MACE risk reduction with weekly 2.4 mg semaglutide vs placebo (double-blind, placebo-controlled).
  11. [11] PMID 40886075 — In 58,333 patients with cardiometabolic HFpEF, semaglutide vs sitagliptin showed HR 0.58 (95% CI 0.51–0.65) for composite of HF hospitalization or all-cause mor
  12. [12] PMID 42456707 — Phase 2 RCT: Semaglutide 2.4 mg QW achieved fibrosis improvement without MASH worsening in 30% vs 16% placebo (EDP 14.05; 95% CI 1.88–26.23; p=0.024, nominally
  13. [13] PMID 40538007 — Review of preclinical and clinical studies: semaglutide effectively improves MASH but does not confer histological fibrosis resolution; mechanisms are likely in
  14. [14] PMID 39445596 — Target trial emulation in 1,094,761 T2DM patients: semaglutide associated with 40–70% reduced risk of first-time AD diagnosis vs other antidiabetic medications,
  15. [15] PMID 39405916 — In APP/PS1 mice and human AD brain organoids, semaglutide improved cognition, reduced amyloid plaque deposition, reduced GFAP/Iba1 expression, and upregulated o
  16. [16] PMID 34894326 — Meta-analysis of 23 RCTs (22,096 T2DM patients): overall semaglutide not associated with increased DR risk (RR 1.14; 95% CI 0.98–1.33). Subgroup vs placebo show
  17. [17] PMID 40931416 — Streptozotocin-induced DR rat model: semaglutide 100 μg/kg/week for 5 weeks reduced blood glucose, improved retinal function, alleviated vascular lesions and ne
  18. [18] PMID 39710830 — In HFD/STZ diabetic mice, semaglutide ameliorated myocardial fibrosis, improved cardiac function, antagonized oxidative stress, suppressed cardiomyocyte apoptos
  19. [19] PMID 38574433 — In C57BL/6J mice, semaglutide ameliorated doxorubicin-induced cardiac dysfunction via PI3K/AKT pathway by reducing BNIP3 expression in mitochondria, improving m
  20. [20] PMID 39908200 — In PTC xenograft mouse models and coculture systems, semaglutide reduced tumor size and inhibited PTC cell proliferation by increasing M1 and decreasing M2 macr
  21. [21] PMID 38172989 — In patients treated with semaglutide for 6 months: 20% statistically significant reduction in FABP4 levels and 80% increase in neutrophil CD88; increased antith
  22. [22] PMID 38774967 — Review of one large RCT in youth: once-weekly subcutaneous semaglutide effectively reduces BMI and improves hyperglycemia, elevated ALT, hyperlipidemia, and qua
  23. [23] PMID 38808476 — 3 mg escalating to 14 mg once daily Oral (human)
  24. [24] PMID 33184979 — 3 mg escalating to 7 mg to 14 mg once daily Oral (human)
  25. [25] PMID 34305810 — Various subcutaneous (0.5 mg, 1.0 mg) and oral formulations assessed across SUSTAIN and PIONEER phase 3 programs Subcutaneous injection and oral (human)
  26. [26] PMID 42612051 — Not specified (observational studies; doses varied across included cohorts) Not specified (varied) (human)
  27. [27] PMID 40849680 — 1 mg weekly (prescribed); patient self-injected full monthly supply (4x weekly dose) at once as overdose Subcutaneous injection (human)
  28. [28] PMID 34260945 — in-prose reference
  29. [29] PMID 53269530 — in-prose reference
  30. [30] PMID 33969456 — in-prose reference
  31. [31] PMID 40966636 — in-prose reference
  32. [32] PMID 40631351 — in-prose reference
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