IntrasignaATLAS / v1.0
Atlas/ Incretins/ GLP-1 receptor agonists/ Semaglutide
Reading depth · audience layer
Class 01 · Incretins · Selective GLP-1 receptor agonist · long-acting analog

Semaglutidethe foundational GLP-1 · 5 FDA indications across 3 brands

Novo Nordisk's once-weekly GLP-1 medicine — the most-prescribed incretin in the world. Sold as Ozempic for type 2 diabetes and kidney disease, Wegovy for obesity, cardiovascular risk reduction, and now MASH liver disease, and Rybelsus as the only oral GLP-1 pill. In the STEP-1 obesity trial, patients lost an average of 14.9% of body weight at 68 weeks. FDA approved for T2DM (Dec 2017), oral T2DM (Sept 2019), obesity (June 2021), CV risk reduction in obesity (March 2024), CKD (Jan 2025), and MASH (Aug 2025) — the most-indicated peptide in modern medicine.

Once-weekly SC (and once-daily oral via SNAC) selective GLP-1 receptor agonist. 31-amino-acid analog of human GLP-1(7-37) with Aib8, Arg34, and C18 fatty diacid acylation at Lys26 for albumin binding (t₁/₂ ≈ 1 week). STEP-1 (NEJM 2021): −14.9% weight at 68 weeks; SELECT (NEJM 2023, n=17,604): 20% MACE reduction in obesity + CVD without diabetes; FLOW (NEJM 2024, n=3,533): 24% kidney composite reduction in T2DM + CKD; ESSENCE Part 1 (NEJM 2025): 62.9% MASH resolution at 72 weeks. Six pivotal CVOTs, 10+ SUSTAIN, 10+ STEP, FLOW, ESSENCE, and SOUL — the largest single-peptide evidence base in pharmaceutical history.

Semaglutide is a 31-residue GLP-1(7-37) analog engineered around three core modifications: position-8 Aib substitution (DPP-4 resistance), position-34 Arg substitution (blocks off-target acylation), and Lys26 ε-amino acylation with an octadecanedioic acid (C18 diacid) via a γ-Glu/2×OEG linker (reversible albumin binding). GLP-1R Ki ≈ 0.38 nM; high selectivity vs GIPR/GCGR; balanced (non-biased) cAMP/β-arrestin profile distinguishes it from tirzepatide's "imbalanced and biased" pharmacology. CAS 910463-68-2; molecular formula C₁₈₇H₂₉₁N₄₅O₅₉; MW ≈ 4,113.58 g/mol. Produced by SPPS + solution-phase acylation; Novo Nordisk patent family.

−14.9% Weight loss · STEP 1 · 2.4 mg · 68 wk
−2.0% HbA1c · SUSTAIN FORTE 2.0 mg
~1 wk Half-life · weekly SC dosing
31 AA Peptide length · MW 4,113.58
Status
FDA-approved · 6 indications
Open dose calculator →
Frequency
Once weekly SC · once daily oral
Sponsor
Novo Nordisk
Next inflection
CagriSema launch · ESSENCE Part 2 (2029)
01 · At a glance

Key facts & headline data.

The most-cited numbers across the SUSTAIN, STEP, SELECT, FLOW, ESSENCE, and SOUL programs — six FDA indications, three brand names, and the largest single-peptide evidence base in modern pharmacotherapy. Semaglutide is the foundational molecule against which every next-generation incretin is now measured.

⚖️
Weight loss · obesity without diabetes
−14.9%
STEP 1 (NEJM 2021, n=1,961): semaglutide 2.4 mg weekly produced −14.9% mean body weight change at 68 weeks vs −2.4% with placebo (ETD −12.4 pp; p<0.001). 86.4% achieved ≥5% loss; 50.5% ≥15%; 32.0% ≥20%. STEP 5 (104 wk): −15.2% maintained at 2 years. The pivotal obesity readout that supported Wegovy's June 2021 approval.
📉
HbA1c · top dose across SUSTAIN
−1.8 to −2.0%
SUSTAIN FORTE (Lancet 2021, n=961): semaglutide 2.0 mg achieved HbA1c −1.8% vs −1.5% at 1.0 mg (ETD −0.35%; p<0.0001) with weight −5.4 vs −4.2 kg. Across SUSTAIN 1–10, 0.5–2.0 mg doses delivered −1.0 to −2.0% HbA1c reductions from baselines of ~7.9–8.7%. Consistently superior to placebo and prior weekly comparators.
❤️
SELECT · MACE in obesity (no DM)
HR 0.80
SELECT (NEJM 2023, n=17,604, median ~3.3 yr follow-up): semaglutide 2.4 mg reduced 3-point MACE (CV death, non-fatal MI, non-fatal stroke) by 20% vs placebo (HR 0.80, 95% CI 0.72–0.90; p<0.001) in adults with obesity/overweight + established CVD without diabetes. Event rate 6.5% vs 8.0%. Basis for Wegovy CV indication (March 2024).
🫘
FLOW · kidney composite · T2DM + CKD
HR 0.76
FLOW (NEJM 2024, n=3,533): semaglutide 1.0 mg reduced ≥50% sustained eGFR decline + kidney failure + kidney/CV death by 24% (HR 0.76, 95% CI 0.66–0.88; p=0.0003) over 3.4 yr median follow-up; trial stopped early for efficacy. eGFR slope difference +1.16 mL/min/yr; MACE HR 0.82. First GLP-1RA approved for CKD (Jan 2025).
🩺
MASH resolution · ESSENCE phase 3
62.9%
ESSENCE Part 1 (NEJM 2025; Sanyal et al., n=800 interim of 1,197): semaglutide 2.4 mg achieved 62.9% MASH resolution without worsening fibrosis vs 34.3% placebo (EDP +28.7 pp; p<0.001) and 36.8% fibrosis improvement without MASH worsening vs 22.4% (EDP +14.4 pp; p<0.001) at 72 weeks. FDA approved Wegovy for MASH August 2025.
💊
SOUL · oral semaglutide MACE
−14%
SOUL (NEJM 2025; McGuire et al., n=9,650, ~4-yr follow-up): oral semaglutide 14 mg reduced 3-point MACE by 14% vs placebo (HR 0.86) in T2DM with established ASCVD and/or CKD. First and only oral GLP-1 RA with definitive CV outcomes evidence. Benefit preserved across SGLT2i co-use.
🆚
vs Tirzepatide · obesity (SURMOUNT-5)
−13.7 vs −20.2
SURMOUNT-5 (NEJM 2025, head-to-head, n=751, 72 wk): tirzepatide 10/15 mg vs semaglutide 1.7/2.4 mg — LSM weight change −20.2% vs −13.7% (p<0.001); waist −18.4 vs −13.0 cm. Tirzepatide superior on weight; semaglutide remains the standard for CV/renal/MASH outcomes evidence.
👶
Pediatric obesity · STEP TEENS
−16.1%
STEP TEENS (NEJM 2022, n=201, adolescents 12–17 yr): semaglutide 2.4 mg achieved −16.1% BMI reduction vs +0.6% with placebo at 68 weeks. 73.4% achieved ≥5% weight loss; 36.4% ≥20% — exceeding adult STEP 1 rates. Basis for Wegovy pediatric approval (Dec 2022).
02 · Mechanism of action

How a selective GLP-1RA works.

Semaglutide imitates one of your gut hormones, GLP-1, that your body normally releases after a meal. This hormone tells the pancreas to release insulin (when blood sugar is high), tells the brain you're full, and slows how fast food leaves the stomach. By holding onto this hormone signal for a full week instead of minutes, semaglutide produces big drops in blood sugar, body weight, and — through downstream effects on inflammation, blood pressure, and weight — heart attack, stroke, kidney decline, and liver disease risk.

Semaglutide is a selective long-acting agonist of the GLP-1 receptor — a Class B1 GPCR expressed on pancreatic β-cells, α-cells, gut, brain, kidney, heart, and vasculature. Binding affinity Ki ≈ 0.38 nM with negligible activity at GIPR/GCGR at therapeutic concentrations. The composite phenotype: glucose-dependent insulin secretion, postprandial glucagon suppression, delayed gastric emptying, central appetite reduction via arcuate POMC neurons and brainstem NTS, plus downstream cardiometabolic and renal benefits established in SUSTAIN-6, SELECT, FLOW, and ESSENCE. Unlike tirzepatide, semaglutide has no GIP receptor co-activity and a balanced (non-biased) GLP-1R signaling profile.

Semaglutide's pharmacology is defined by three engineering choices designed for once-weekly subcutaneous dosing and reversible albumin binding: (1) Aib substitution at position 8 prevents DPP-4 cleavage at the N-terminal His-Ala dipeptide; (2) Arg replaces Lys at position 34 to eliminate off-target acylation; (3) the ε-amino group of Lys26 is conjugated to a C18 fatty diacid via a γ-glutamic acid linker and two 8-amino-3,6-dioxaoctanoic acid (OEG) units, producing reversible >99% albumin binding. In recombinant cAMP and β-arrestin assays, semaglutide behaves as a conventional balanced agonist — distinct from tirzepatide's documented "imbalanced and biased" GLP-1R profile (cAMP-preferential, β-arrestin-reduced). Whether subtle internalization kinetic differences from liraglutide are clinically meaningful remains an open mechanistic question. Semaglutide is produced entirely by solid-phase peptide synthesis (Fmoc chemistry) plus solution-phase acylation — no recombinant manufacturing.

A
🎯

GLP-1R · pancreatic islet · glycemic axis

Semaglutide binds GLP-1R with Ki ≈ 0.38 nM and produces sustained Gs-coupled cAMP/PKA/EPAC2 signaling. In pancreatic β-cells, this amplifies glucose-stimulated insulin secretion (only when ambient glucose is elevated — hence glucose-dependent and inherently low hypoglycemia risk in monotherapy). In α-cells, GLP-1R agonism suppresses inappropriate postprandial glucagon release, reducing hepatic glucose output.
Clinical significance: Glucose-dependent insulin secretion explains why semaglutide monotherapy carries minimal hypoglycemia risk across the SUSTAIN/STEP programs (<0.5%). However, when combined with insulin or sulfonylureas, hypoglycemia risk rises substantially — these agents must be down-titrated at initiation (basal insulin −20%, SU −50% or discontinued). The glucagon-suppression effect also contributes meaningfully to postprandial glucose excursion control, which is one reason the molecule produces larger HbA1c reductions than DPP-4 inhibitors.
Molecular detail: GLP-1R is a Class B1 GPCR primarily Gs-coupled (cAMP/PKA), with secondary Gi/o, Gq/11 (intracellular Ca²⁺), GRK/β-arrestin, and ERK1/2 inputs. Semaglutide produces balanced cAMP and β-arrestin recruitment in recombinant systems — without the cAMP-biased signature seen with tirzepatide and exendin-P5. β-arrestin recruitment drives internalization and desensitization; whether this matters clinically for selective GLP-1 RAs has not been fully resolved. Receptor internalization kinetics are similar to liraglutide. Anti-drug antibodies developed in <1–2% of pivotal trial participants with no neutralizing impact.
A
🍽️

Gastric emptying · GI motility · early satiety

GLP-1R activation on gastric vagal afferents and intrinsic enteric neurons slows gastric emptying and small-bowel transit. The net effect: reduced postprandial glucose excursions, smaller meal sizes, prolonged post-meal satiety, and the GI adverse-event profile (nausea, vomiting, constipation, delayed emptying) that dominates tolerability during dose escalation.
Clinical significance: The gastric-emptying delay drives both desired effect (mechanical satiety, smaller meals, lower postprandial glucose) and the GI adverse-event burden. Tolerability is dose-dependent and peaks 1–2 weeks after each escalation step; slowing titration intervals (extending to 8 weeks) preserves efficacy while reducing discontinuation. The delay is also the basis for the ASA 2023 perioperative hold recommendation (≥1 week before general anesthesia) — solid gastric contents despite standard fasting periods have been reported, creating aspiration risk.
Molecular detail: The gastric-emptying effect attenuates somewhat with chronic dosing (partial tachyphylaxis) — explaining why GI tolerability typically improves over weeks-to-months at a stable dose. Central GLP-1R activation in the nucleus tractus solitarius (NTS) and area postrema modulates the nausea threshold and contributes to the central satiety phenotype. Unlike tirzepatide, semaglutide lacks GIPR co-activity in the area postrema, which may partly explain why per-unit weight-loss GI tolerability differs slightly between the two molecules in head-to-head comparison (SURMOUNT-5: 5.6% sema vs 2.7% tirz GI-related discontinuation).
A
🧠

CNS · appetite, satiety, & reward

GLP-1R is expressed in key hypothalamic nuclei (arcuate POMC/AgRP neurons, paraventricular nucleus) and brainstem (NTS, area postrema) and on vagal afferents. Semaglutide accesses CNS GLP-1R via circumventricular organ active transport. Net effect: POMC neuron activation (anorexigenic), AgRP/NPY suppression (orexigenic), and reinforced satiety signaling from the gut. The CNS effects dominate weight loss at steady state.
Clinical significance: Patients describe reduced "food noise" — diminished cognitive preoccupation with food, smaller meal sizes, earlier satiation, and reduced reward-driven eating. Reintroduction of food after discontinuation produces rapid return of appetite, which is the mechanistic basis for the regain observed in STEP 1 extension (two-thirds of weight returned by week 120 after stopping) and STEP 4 (significant regain after randomized withdrawal). Semaglutide is appropriately framed as chronic therapy.
Molecular detail: fMRI food-cue reactivity studies show reduced reward-area activation to high-palatability food cues in patients on semaglutide. The mesolimbic GLP-1R effect (VTA, nucleus accumbens, prefrontal cortex) is the mechanistic basis for ongoing alcohol use disorder trials (NCT03821506 and others), where early signals show ~30–50% reduction in heavy drinking days. The EVOKE/EVOKE+ phase 3 program in Alzheimer's disease (oral semaglutide, ~3,800 patients) failed primary clinical endpoints (November 2025) despite improved AD biomarkers — suggesting the CNS effect, while real, is insufficient as monotherapy for neurodegeneration.
A
❤️

Cardiovascular · MACE, BP, lipids, inflammation

SELECT (NEJM 2023, n=17,604) established a 20% MACE reduction (HR 0.80) in adults with obesity + established CVD without diabetes — the first cardiovascular evidence for an obesity medicine in a non-diabetic population. SUSTAIN-6 (NEJM 2016) earlier established 26% MACE reduction (HR 0.74) in T2DM with high CV risk. SOUL (NEJM 2025) added 14% MACE reduction with oral semaglutide. Effects appear partly independent of weight loss magnitude.
Clinical significance: Semaglutide CV protection is multifactorial: 2–4 mmHg systolic BP reduction, LDL-C ~5–10% lower, triglycerides ~15–20% lower, modest HDL-C increase, hs-CRP reduction (anti-inflammatory signal seen in SELECT and STEP-HFpEF), improved endothelial function, and — in the SELECT cohort — benefit that persisted in subgroups with modest weight loss, supporting direct cardioprotective mechanisms beyond adiposity reduction. SOUL further showed cardiovascular benefit was additive with SGLT2i co-use, supporting current ADA/ESC guidelines recommending both.
Molecular detail: GLP-1R is expressed on vascular endothelium and macrophages (anti-inflammatory NF-κB inhibition); plaque-stabilization signals have been observed in preclinical aortic models (reduced macrophage infiltration, smaller necrotic cores) and human coronary CT sub-studies of CVOTs. Direct cardiomyocyte GLP-1R expression is largely atrial (ventricular expression contested). The hs-CRP reduction is one of the most consistent biomarker signals across SELECT, STEP-HFpEF, and STEP 1 — supporting an anti-inflammatory contribution to the CV signal. STEP-HFpEF (NEJM 2023) and STEP-HFpEF DM (Lancet Diabetes Endocrinol 2025) extended these benefits to symptom improvement in HFpEF with obesity.
A
🫘

Renal · eGFR slope, UACR, & CKD progression

FLOW (NEJM 2024) is the first GLP-1RA dedicated kidney outcomes RCT — 24% reduction in composite of sustained ≥50% eGFR decline, kidney failure, kidney death, or CV death (HR 0.76; 95% CI 0.66–0.88; p=0.0003) in T2DM + CKD over 3.4 years. eGFR slope difference +1.16 mL/min/1.73 m² per year. Trial stopped early for efficacy. Effects were additive to RAAS blockade and SGLT2i co-use (~50% of FLOW cohort).
Clinical significance: Semaglutide is now the first GLP-1RA labeled for CKD progression reduction in T2DM (FDA: January 28, 2025; "to reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with T2DM and CKD"). The benefit is mechanistically complementary to SGLT2 inhibition — both can and should be combined in T2DM + CKD with appropriate background therapy. Renal benefit was preserved across baseline eGFR categories (down to ~25 mL/min/1.73 m²) and albuminuria strata. Mean UACR reduced ~50% relative to placebo.
Molecular detail: Renal GLP-1R expression is concentrated in proximal tubule and vascular endothelium. Mechanisms include reduced intraglomerular hyperfiltration (afferent arteriolar effect, distinct from but complementary to SGLT2i tubuloglomerular feedback), natriuresis, anti-inflammatory effects on renal infiltrates, reduced renal lipotoxicity via weight loss, and improved glycemic control upstream. The CKD-EPI-Cr-CysC 2021 equation is now standard for tracking eGFR in obese populations, as creatinine generation falls with the lean-mass reduction component of weight loss.
A
🫀

Hepatic · MASH resolution & fibrosis improvement

ESSENCE Part 1 (NEJM 2025; Sanyal et al., n=800 of 1,197 randomized) demonstrated MASH resolution without worsening fibrosis in 62.9% (sema) vs 34.3% (placebo) at 72 weeks (EDP +28.7 pp; p<0.001), and fibrosis improvement without MASH worsening in 36.8% vs 22.4% (EDP +14.4 pp; p<0.001). Combined endpoint: 32.7% vs 16.1%. FDA approved Wegovy for non-cirrhotic MASH with moderate-to-advanced fibrosis in August 2025.
Clinical significance: Semaglutide is the second medicine (after resmetirom, approved March 2024) with histologic evidence in MASH — and the first with both steatohepatitis resolution and significant fibrosis improvement in the same trial. Phase 2 (Newsome NEJM 2021) had shown strong NASH resolution but non-significant fibrosis improvement at 72 weeks; phase 3 ESSENCE (using SC 2.4 mg vs phase 2's daily 0.4 mg) achieved both, likely reflecting the higher dose, larger sample, and improved trial design. ESSENCE Part 2 (clinical outcomes — cirrhosis, decompensation, transplant) reads out 2029.
Molecular detail: Hepatic GLP-1R expression in mature hepatocytes is low or absent in most human studies, so the dominant mechanism is indirect: reduced caloric intake → reduced hepatic free fatty acid flux → reduced lipotoxicity; insulin sensitization → ChREBP/SREBP-1c-mediated reduction in de novo lipogenesis; reduced pro-inflammatory cytokine flux (TNF-α, IL-6, IL-1β); favorable gut microbiota shifts. However, GLP-1R on Kupffer cells (hepatic macrophages) and hepatic stellate cell signaling cannot be excluded as additional anti-fibrotic mechanisms. The phase 2-to-3 fibrosis-improvement upgrade remains incompletely explained but is supported by the larger study and longer effective exposure.
L3 · Downstream pathway
Semaglutide → GLP-1R → Tissue effects → Phenotype → Outcomes
💉
SC dose
(weekly)
→
🩸
Albumin-bound
circulation
→
🎯
Selective
GLP-1R
→
🧪
Multi-tissue
signaling
→
⚖️
Glycemia +
energy balance
→
📉
Weight loss
+ anti-inflammatory
→
🏆
Hard
outcomes
03 · Dosing protocols

Protocol-specific dosing schedules.

Semaglutide is administered as a once-weekly subcutaneous injection (Ozempic, Wegovy) from prefilled pens, or as a once-daily fasting oral tablet (Rybelsus) co-formulated with SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) for transcellular absorption. Each FDA-approved indication has its own titration target and ladder. Below: the six approved protocols plus clinical-extension scenarios.

Important · regulatory status Semaglutide is FDA-approved as Ozempic for T2DM glycemic control (Dec 5, 2017), CV risk reduction in T2DM + CVD (2020 label update), and reduction of sustained eGFR decline / ESKD / CV death in T2DM + CKD (Jan 28, 2025); Rybelsus (oral) for T2DM (Sept 20, 2019); Wegovy for chronic weight management (June 4, 2021), adolescent obesity ≥12 yr (Dec 23, 2022), CV risk reduction in obesity + CVD (March 8, 2024), and non-cirrhotic MASH with moderate-to-advanced fibrosis (August 2025). FDA removed semaglutide from the Drug Shortage List on February 21, 2025; following a court-upheld 60–90 day grace period, routine compounding of semaglutide ended by May 22, 2025.
2025–2026 Label evolution & pipeline FLOW publication and Ozempic CKD indication (Jan 2025); ESSENCE Part 1 publication and Wegovy MASH indication (Aug 2025); SOUL publication establishing oral semaglutide CV benefit (March 2025). High-dose oral semaglutide (25 mg, 50 mg) phase 3 OASIS program complete with FDA filing for obesity/T2DM. CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) FDA submission for obesity filed December 2025 based on REDEFINE 1 (NEJM June 2025: −22.7% weight). Novo Nordisk Most-Favored-Nation pricing commitment of $245/month effective 2026, ahead of IRA MFP implementation in 2028.
Ozempic · T2DM Glycemic / CV / CKD Protocol
Once weekly SC · 0.25 → 2.0 mg ladder · CV indication ≥1.0 mg · CKD per FLOW
Grade A
Starting dose
0.25 mg once weekly for 4 weeks. This is a starter dose for tolerability — it is NOT a therapeutic glycemic dose. Patients should not expect meaningful HbA1c effects at 0.25 mg.
Standard escalation
Step every 4 weeks: 0.25 → 0.5 → 1.0 → 2.0 mg weekly. 0.5 mg is the first therapeutic maintenance option; 1.0 mg is the typical T2DM target dose and the CV-evidence dose (SUSTAIN-6); 2.0 mg is the maximum approved dose (SUSTAIN FORTE) for inadequate glycemic control on 1.0 mg.
CKD-indication target
For the CKD indication (FLOW), titrate to 1.0 mg maintenance. The CKD endpoint reduction in FLOW was demonstrated at 1.0 mg; 2.0 mg is not necessary for the renal indication.
Maximum dose
2.0 mg once weekly (Ozempic-only — 2.4 mg is reserved for Wegovy obesity indication). Pen strengths: 2 mg/1.5 mL (0.25 & 0.5 mg doses), 4 mg/3 mL (1 mg), and 8 mg/3 mL (2 mg).
Injection sites
Abdomen (preferred), thigh, or upper arm. Same day each week; any time of day, with or without food. Rotate sites weekly. Multidose pen — multiple doses per pen.
Missed dose
If the missed dose is within 5 days of the scheduled day: administer as soon as remembered, then resume regular weekly schedule. If more than 5 days have elapsed: skip the missed dose and resume on the next scheduled day. Do not double-dose.
Storage
Refrigerate at 2–8 °C in original carton until first use. After first use, may be kept at room temperature ≤30 °C (or refrigerated) for up to 56 days. Do not freeze; protect from light.
PK rationale for 4-week steps
Semaglutide elimination half-life ≈ 155–184 h (~1 week); steady state achieved after ~4–5 half-lives ≈ 4–5 weeks of weekly dosing. The 4-week step calibration matches the time-to-steady-state and allows tolerability assessment at each level. No renal or hepatic dose adjustment required (PK unchanged in Child-Pugh A/B/C and across the CKD spectrum, including FLOW's eGFR ~47 cohort).
⚠ Hypoglycemia on combinations Semaglutide monotherapy carries minimal hypoglycemia risk (glucose-dependent insulin secretion). With concurrent insulin: reduce basal insulin by 20% at initiation with structured glucose monitoring or CGM. With concurrent sulfonylurea: reduce SU by 50% or discontinue. Combination with DPP-4 inhibitors is redundant — discontinue the DPP-4i.
Wegovy · Obesity / CV / MASH Protocol
Adults BMI ≥30 or ≥27 + comorbidity · 16-week titration to 2.4 mg · chronic therapy
Grade A
Indication eligibility
Adults with BMI ≥30, or BMI ≥27 with ≥1 weight-related comorbidity (hypertension, dyslipidemia, T2DM, OSA, established CVD). Also: CV risk reduction in obesity + established CVD; non-cirrhotic MASH with moderate-to-advanced fibrosis. Used with reduced-calorie diet and increased physical activity. Adolescents 12–17 years with initial BMI ≥95th percentile also eligible (see Pediatric tab).
Titration ladder
0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg weekly with 4-week step intervals. Total titration to full maintenance dose: 16 weeks.
Maintenance target
2.4 mg once weekly. This is the dose used across STEP 1, STEP 3, STEP 4, STEP 5, STEP-HFpEF, STEP-TEENS, SELECT, and ESSENCE — and the only dose evidenced for obesity, CV, and MASH outcomes.
Expected weight loss
STEP 1: −14.9% at 68 weeks vs −2.4% placebo. STEP 5: −15.2% maintained at 104 weeks. ≥5% loss in 86.4%; ≥10% in 69.1%; ≥15% in 50.5%; ≥20% in 32.0%. Weight curves continue to descend through ~60 weeks before plateau.
Response thresholds
If <5% weight loss at 12 weeks of full 2.4 mg maintenance: reassess. Confirm adherence, evaluate confounders, consider continuation if comorbidity benefit, or discontinue. Most responders show clear trend by week 12–16 at maintenance dose.
Pen strengths / storage
Single-use prefilled autoinjector pens at 0.25, 0.5, 1, 1.7, and 2.4 mg. Refrigerate 2–8 °C; may be kept at room temperature ≤30 °C for up to 28 days. Do not freeze; protect from light.
Adjunct strategy
Pivotal trials embedded reduced-calorie diet (typically 500 kcal/day deficit) and ≥150 min/week moderate activity. Resistance training 2–3×/week is widely recommended to attenuate lean-mass loss (~33% of weight lost is lean mass); protein 1.2–1.6 g/kg/day. Behavioral/nutrition counseling improves adherence (STEP 3: −16.0% with IBT vs −14.9% in STEP 1).
Body composition
DEXA substudies indicate ~67% of mass lost is fat and ~33% lean mass — proportionally fat-favoring but with non-trivial absolute lean loss, particularly in older adults. Visceral and ectopic adipose depots reduce preferentially. SURMOUNT-5 (head-to-head): tirzepatide produced greater absolute weight loss (−20.2% vs sema −13.7%) and greater waist reduction (−18.4 vs −13.0 cm).
⚠ Withdrawal causes regain STEP 4 (JAMA 2021): patients randomized to switch from semaglutide 2.4 mg to placebo at week 20 regained +6.9% by week 68, while continuation produced an additional −7.9% loss — net difference −14.8 pp. STEP 1 extension: two-thirds of lost weight returned by week 120 after stopping. Semaglutide is appropriately framed as chronic therapy; counsel patients for indefinite maintenance or a structured, monitored taper.
Rybelsus · Oral T2DM (SNAC-formulated)
Once daily oral · 3 → 7 → 14 mg · strict fasting administration rules
Grade A
Indication
Adults with T2DM, glycemic control adjunct to diet and exercise. Also CV risk reduction in T2DM with established CVD (per SOUL, NEJM 2025: 14% MACE reduction).
Titration
Month 1 (days 1–30): 3 mg daily — tolerability induction, not therapeutic. Month 2+: 7 mg daily — therapeutic dose for most patients. If additional glycemic control needed after ≥30 days on 7 mg: 14 mg daily — maximum approved dose.
Administration rules
Critical (SNAC-dependent bioavailability): Take on empty stomach (≥6 h overnight fasting). Swallow with ≤120 mL (≈4 oz) of plain water only — not coffee, juice, or other liquids. Wait ≥30 minutes before any food, beverage other than water, or oral medications. Do not crush, split, or chew. Absorption is highly variable (within-subject ~137%) — adherence to these rules dominates exposure.
Pharmacokinetics
Absolute oral bioavailability ~0.4–1% (mean ~0.8%) under labeled fasting conditions. Tmax ~1 hour; half-life still ~1 week (despite daily dosing). Steady state achieved after ~4–5 weeks of daily dosing.
Storage
Room temperature in original container. SNAC is moisture-sensitive — do not transfer to pill organizers; do not remove until ready to take.
When to choose Rybelsus over SC
Patient preference (needle aversion); ability to maintain strict fasting/water administration consistently; insurance access. SOUL established cardiovascular efficacy parity with injectable formulations (14% MACE reduction in T2DM + ASCVD/CKD over ~4 yr). Weight loss is generally smaller than SC at maximum approved doses (~3–4 kg with 14 mg vs −4 to −6 kg with SC 1.0 mg).
High-dose oral pipeline (OASIS)
Higher-dose oral semaglutide (25 mg and 50 mg, OASIS phase 3 program) achieves weight loss approaching SC 2.4 mg levels (~15% at 68 weeks for 50 mg vs ~2.5% placebo). FDA filing for OASIS doses in obesity/T2DM ongoing; if approved, would extend oral semaglutide use into obesity. Same SNAC-fasting administration rules apply.
⚠ Absorption fragility Rybelsus bioavailability collapses with food, with >120 mL water, or with insufficient post-dose fasting. Counsel patients carefully on the fasting/water/30-min rules — adherence determines whether the drug works at all. Variability between days is high even with perfect adherence.
Wegovy · Adolescent Obesity (≥12 years)
FDA approval Dec 23, 2022 · STEP TEENS protocol · weight-based caution in smaller patients
Grade A
Eligibility
Adolescents 12–17 years with obesity (initial BMI ≥95th percentile for age/sex per CDC growth charts), used with reduced-calorie diet and physical activity. The first once-weekly injectable obesity medicine for adolescents.
Titration
Same adult ladder: 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg with 4-week step intervals. Total to maintenance: 16 weeks.
Expected effect
STEP TEENS (NEJM 2022, n=201): −16.1% BMI reduction vs +0.6% with placebo at 68 weeks; mean weight change −15.3 kg vs +2.4 kg. ≥5% loss in 73.4%; ≥20% in 36.4% — exceeding adult STEP 1 (32.0%).
Tolerability
Nausea 41.7% (vs 11.9% placebo); GI burden higher than adults per body size. Two gallbladder events (3.8%) — 2 cholecystectomies — were reported in the sema arm; no pancreatitis. Discontinuation 5.2% vs 4.4% placebo.
Special considerations
Patient autonomy and assent appropriate to developmental level. Mental health screening (depression, body image, disordered eating) is essential before and during treatment in this population. Growth and puberty progress should be monitored.
Smaller-body dosing
No formal weight-based dose adjustment is required — STEP TEENS used the same adult ladder. However, in smaller adolescents, real-world tolerability of the 2.4 mg target may warrant a maintenance dose lower than 2.4 mg (e.g., 1.7 mg) if GI burden is excessive. Individualize based on tolerability and response.
Open questions
Long-term effects on growth velocity, bone density development, and lean mass accrual in adolescence remain incompletely characterized; STEP TEENS was 68 weeks. Longer-term pediatric extension data and post-marketing surveillance are ongoing. STEP-YOUNG and broader pediatric programs are in development.
Slow / Conservative Titration Protocol
8-week step intervals · for tolerability-sensitive patients · geriatric · prior incretin intolerance
Grade B
Rationale
A subset of patients experience marked GI intolerance with the standard 4-week step intervals. Slower titration (8-week steps) is well tolerated and does not appear to reduce ultimate efficacy at the same maintenance dose. Appropriate for elderly patients, low-BMI starting points, prior incretin intolerance, or patients prioritizing tolerability over speed-to-effect.
Cadence
Step every 8 weeks rather than 4. Reaching Wegovy 2.4 mg requires ~32 weeks rather than ~16. Reaching Ozempic 1.0 mg requires ~16 weeks rather than ~8.
Tolerability strategies
Pre-meal hydration, smaller more frequent meals during titration weeks, lower-fat meals, anti-emetic on hand (ondansetron 4–8 mg PRN). Avoid alcohol during initial titration. Many patients find adequate effect at 1.0 or 1.7 mg (obesity) without progressing to 2.4 mg.
Step-back option
If intolerable symptoms at a step, return to previously tolerated dose for 8 weeks before retrying. There is no efficacy penalty; cumulative time-at-target dose determines outcomes. Some patients ultimately settle at sub-maximal maintenance with full satisfaction.
Geriatric considerations
In adults >75 years, dehydration from GI symptoms is non-trivial and can precipitate acute kidney injury — particularly on background RAAS blockade or diuretics. Conservative titration plus weekly weight/orthostatic checks during the first 8 weeks is reasonable. Lower lean-mass reserve argues for concurrent resistance training and protein intake ≥1.2 g/kg/day to attenuate sarcopenia.
Evidence basis
Direct head-to-head 4-week vs 8-week titration RCT data are limited, but real-world practice patterns and pharmacology (steady state at ~4 weeks per dose level allows assessment at standard cadence; slower cadence simply extends assessment without reducing exposure) support equivalent ultimate efficacy with reduced discontinuation.
Maintenance & Withdrawal Strategy
Long-term continuation · planned taper · regain mitigation · perioperative · pregnancy
Grade A
Long-term continuation
STEP 5 (104 weeks): mean weight loss −15.2% maintained at 2 years; STEP 1 extension to 120 weeks: rapid regain after discontinuation. SELECT (median ~3.3 years) and FLOW (3.4 years) provide the longest controlled-exposure CV/renal datasets. Counsel patients for indefinite maintenance or structured, monitored taper.
Maintenance dose selection
Use the lowest dose that maintains the desired effect. For Wegovy: many patients can de-escalate from 2.4 mg → 1.7 mg → 1.0 mg once at goal weight. Re-escalate if regain occurs. For Ozempic CV/CKD: maintain at indication-supported dose (1.0 mg for CKD; 1.0 mg or above for CV).
Withdrawal expectation
STEP 4: discontinuation produced significant regain over 48 weeks; continuation maintained and augmented loss. STEP 1 extension: ~two-thirds of lost weight returned by week 120 after stopping. Expect ~50–67% of weight to return within 12–24 months of full discontinuation absent intensive lifestyle compensation.
Structured taper
When discontinuation is required (cost, pregnancy planning, patient preference), a step-down over 3–6 months (each step held 4–8 weeks) reduces rebound hunger and regain velocity vs abrupt stop. Pair taper with intensified behavioral support, structured exercise, and ongoing dietitian engagement.
Pregnancy planning
Discontinue semaglutide at least 2 months prior to planned conception (allowing ≥5–10 half-lives plus safety margin). Semaglutide is contraindicated in pregnancy and lactation. Effective contraception advised during use; gastric emptying delay may reduce oral contraceptive absorption during initial titration — barrier backup recommended in first 4 weeks.
Perioperative management
ASA 2023 consensus guidance: hold weekly GLP-1 RAs (semaglutide SC) for ≥1 week (one full dosing interval) prior to elective procedures requiring general anesthesia or deep sedation due to delayed gastric emptying and aspiration risk. Hold daily oral GLP-1 RAs (Rybelsus) on the day of procedure. If hold not possible, consider point-of-care gastric ultrasound pre-induction; use rapid sequence induction.
Long-term safety surveillance
SELECT (median 3.3 yr), FLOW (3.4 yr), SOUL (~4 yr), and ESSENCE Part 2 (planned to 240 weeks, 2029) provide the longest controlled-exposure datasets. The MTC/MEN-2 boxed warning is a class effect from rodent studies; the human medullary thyroid signal has not materialized in pharmacovigilance over a decade of marketed use. NAION (Hathaway 2024 JAMA Ophthalmology) signal is being tracked via FDA Sentinel.
Global dose bands · label-anchored · grade A

Three weekly dose tiers & fixed-dose vs weight context.

Unlike research peptides, semaglutide is dosed by fixed-dose titration, not by body weight — FDA labeling specifies the same milligram ladder for all adults. The engine therefore anchors every protocol to three weekly tiers defined by approved product and indication. The per-kg column is informational only: it exposes how the same fixed dose lands very differently across body weights (a known driver of GI tolerability variance), but must never be used to compute a weight-based dose. Working unit: mg subcutaneous per week.

BandSC weekly doseOral daily equivalentPrimary role & evidence anchorGrade
Low · induction0.25 mg/wk3 mg/day (Rybelsus)Tolerability induction only — sub-therapeutic by design; held 4 wk to blunt GI onset before any therapeutic step.A
Standard · glycemic0.5–1.0 mg/wk7–14 mg/dayT2DM glycemic control; 1.0 mg is the CV-evidence dose (SUSTAIN-6) and CKD target (FLOW). First true maintenance band.A
High · weight / max1.7–2.4 mg/wk14–25 mg/day (oral Wegovy)Chronic weight management, obesity-CV (SELECT) and MASH (ESSENCE); 2.4 mg is the Wegovy maintenance and the only obesity/CV/MASH-evidenced SC dose. Ozempic caps at 2.0 mg.A

Weight-band context · fixed 2.4 mg/wk maintenance (informational only)

Body weightWeekly SC dose≈ mg/kg/wkTolerability note
~55 kg (121 lb)2.4 mg~0.044 mg/kgHighest per-kg exposure → GI burden often greatest; 1.7 mg maintenance frequently sufficient.
~65 kg (143 lb)2.4 mg~0.037 mg/kgConsider holding at 1.7 mg if nausea limits escalation.
~75 kg (165 lb)2.4 mg~0.032 mg/kgMid-range; standard ladder usually tolerated.
~85 kg (187 lb)2.4 mg~0.028 mg/kgStandard ladder; full 2.4 mg typically reached.
~95 kg (209 lb)2.4 mg~0.025 mg/kgLower per-kg exposure; may need full dose for effect.
~105 kg (231 lb)2.4 mg~0.023 mg/kgLowest per-kg exposure in band; 2.4 mg maintenance standard.

FDA labeling uses fixed-dose titration, not weight-based dosing — the per-kg column above is a tolerability lens, not a dosing formula. No per-kg prescribing is approved or recommended. Pediatric (≥12 yr) dosing in STEP TEENS used the identical adult fixed ladder; no under-12 protocol exists.

Titration logic · engine-ready decision rules · label-derived

Escalate, hold & stop logic.

Unlike the speculative engines elsewhere in the atlas, these rules are derived from the FDA-approved label and pivotal-trial protocols (grade A) — they are validated prescribing logic, not borrowed heuristics. Escalation is time-gated (4-week steps to allow steady state and tolerability assessment) and tolerability-gated. Hard stops reflect the boxed warning and absolute contraindications and should be encoded as non-editable.

Decision nodeRuleGrade
EscalateIf time_at_dose ≥ 4 wk (8 wk on conservative track) AND GI symptoms tolerable AND therapeutic goal not yet met → step to next ladder rung (0.25→0.5→1.0→1.7→2.4 SC; 3→7→14 oral). Do not escalate before steady state.A
Hold / slowIf significant nausea/vomiting/diarrhea at a planned step-up → hold current dose an additional 4 wk before retrying; pre-meal hydration, smaller low-fat meals, PRN antiemetic. No efficacy penalty from slower titration.A
De-escalateWegovy 2.4 mg not tolerated → drop to 1.7 mg/wk × 4 wk then re-attempt; persistent intolerance at 1.7 mg → discontinue (no lower maintenance is label-sanctioned for the 2.4 mg indication). Many patients settle at 1.0–1.7 mg with full satisfaction.A
Combination safetyOn initiation with insulin → reduce basal insulin ~20%; with sulfonylurea → reduce ~50% or stop. Discontinue any concurrent DPP-4 inhibitor (redundant). Never co-administer another GLP-1 RA or tirzepatide.A
Hold (clinical)Suspected acute pancreatitis (severe persistent abdominal pain ± elevated lipase) → hold immediately and evaluate; AKI from GI-driven volume depletion → hold, rehydrate, reassess renal function; ≥1 week pre-elective-anesthesia hold (ASA guidance, aspiration risk).A
Permanent stop (hard)Confirmed pancreatitis attributable to drug; signs of MTC (neck mass, hoarseness, dysphagia, persistent ↑calcitonin); known/family MTC or MEN-2; serious hypersensitivity/angioedema; pregnancy (discontinue ≥2 months pre-conception). Encode as non-editable red hard-stops.A

Special populations — renal & hepatic: no dose adjustment required (PK unchanged across Child-Pugh A/B/C and the CKD spectrum, including FLOW's eGFR ~47 cohort). Geriatric (>75 yr): conservative titration + orthostatic/volume monitoring; dehydration-driven AKI risk rises on background RAAS blockade or diuretics.

Biomarker scaffold · trial-validated where marked

Response & safety monitoring bundles.

Semaglutide is one of the few atlas entries with genuinely validated efficacy biomarkers — HbA1c, body weight/BMI, and waist circumference were primary endpoints across SUSTAIN/STEP/SELECT. Each row is tagged with whether the marker is validated for semaglutide specifically (validated = true) versus a clinical-vigilance overlay borrowed from class/standard-of-care. The engine drives response off validated endpoints and uses safety markers only as symptom-triggered checks, not routine surveillance.

MarkerTimepointInterpretation / thresholdValidated for sema?
HbA1cBaseline; 3 mo; then 6-monthlyPrimary glycemic endpoint (all SUSTAIN/PIONEER); <7% typical T2DM goal; ≥1.5% reduction expected at 1.0 mg.Yes
Body weight / BMIBaseline; monthly ×4–6; then quarterlyPrimary STEP endpoint; ≥5% loss by ~12–16 wk at maintenance flags response (−14.9% mean at 68 wk, STEP 1).Yes
Waist circumferenceBaseline; quarterlyCardiometabolic surrogate; ~33% of SELECT MACE benefit mediated via waist reduction.Yes
eGFR / creatinineBaseline; each escalation; if GI events; annuallyVolume-depletion AKI watch; >30% eGFR decline → reassess. Ozempic now carries a CKD indication (FLOW).Indirect
Lipase / amylaseOnly if abdominal pain>3× ULN + symptoms → pancreatitis workup. Not validated for routine surveillance — do not order baseline.No
Calcitonin / thyroid examClinical exam each visit; calcitonin only if neck symptomsNew neck mass / hoarseness → urgent ENT. Manufacturer advises clinical vigilance, not routine calcitonin screening.No
Ophthalmologic examBaseline in known DR; per ophthalmologySUSTAIN-6 retinopathy signal (rapid glucose lowering); any visual change → urgent referral. NAION signal tracked via FDA Sentinel.Caution
PHQ-9 / moodBaseline; each escalation (weight indication)Clinical screen only; PHQ-9 ≥10 or SI → hold/refer. Not a validated biomarker.No

Architecture note: store each marker with a validated_for_sema boolean. For semaglutide — unlike speculative atlas entries — three efficacy markers are genuinely true; safety markers remain symptom-triggered overlays rather than routine surveillance.

Wegovy obesity titration · 16-week ladder

Visual titration: from start to maintenance.

Wk 1–4 0.25 mgInitiation Starter · tolerability · not therapeutic
Wk 5–8 0.5 mgStep 2 First therapeutic level
Wk 9–12 1.0 mgStep 3 T2DM target · CV/CKD indication dose
Wk 13–16 1.7 mgStep 4 Penultimate · transition dose
Wk 17+ 2.4 mgMaintenance Maximum · obesity/CV/MASH dose
L2 · Reconstitution & dose math

Reconstitution & Dose Calculator

For reference only. The FDA-approved Novo Nordisk products are supplied as multidose (Ozempic) or single-use (Wegovy) prefilled pens — no reconstitution needed. This calculator covers historic multi-dose vial scenarios. Use the labeled pen wherever possible; FDA has warned against compounded products following the February 2025 shortage resolution.

Concentration
—
Draw volume
—
Units (U-100)
—
Doses per vial
—
Cadence basis
—
04 · Combination protocols

Stacking semaglutide.

Semaglutide combinations with metformin, SGLT2 inhibitors, statins, and RAAS blockers are well-evidenced and standard-of-care across T2DM, CV, and CKD indications. CagriSema (cagrilintide + semaglutide) is the next-generation combination with phase 3 data. Combinations with other GLP-1 RAs, tirzepatide, retatrutide, or compounded incretins are not appropriate. Below: the evidence-based, the mechanistically defensible, and the avoid list.

Cardiometabolic Triple Stack
High Synergy
Semaglutide Metformin SGLT2 inhibitor Statin
The most evidence-based combination for T2DM with CV/renal risk. Metformin reduces hepatic glucose output (AMPK pathway); SGLT2i provides independent CV and renal benefit (HF hospitalization reduction, eGFR slope preservation); semaglutide adds incretin-mediated insulin and weight effects plus its own MACE (SUSTAIN-6, SELECT, SOUL) and CKD (FLOW) signals; statin addresses LDL-driven ASCVD risk. No dose reductions required at initiation; this is the de facto standard of care for T2DM with established CVD or high ASCVD risk.
ComponentMechanismEvidence
SemaglutideGLP-1 · weight + glycemia + CV + renalSUSTAIN-6/SELECT/FLOW/SOUL (A)
MetforminAMPK · hepatic glucose ↓1L T2DM (A)
SGLT2 inhibitorSGLT2 · natriuresis · CV/renalEMPA-REG / DAPA-CKD (A)
StatinHMG-CoA reductase · LDL ↓Meta-analyses (A)
T2DM + CKD Renoprotective Stack
High Synergy
Semaglutide 1.0 mg SGLT2 inhibitor ACE-I or ARB Finerenone (MRA)
FLOW (NEJM 2024) demonstrated semaglutide 1.0 mg added on top of maximum-tolerated RAAS blockade, with ~50% on SGLT2i co-use, reduced composite kidney endpoint by 24% (HR 0.76) in T2DM + CKD. The four-pillar approach — RAAS blocker (afferent/efferent), SGLT2i (tubuloglomerular feedback), MRA (mineralocorticoid antagonism, fibrosis), and GLP-1 RA (hemodynamic + metabolic + anti-inflammatory) — represents complete contemporary diabetic-CKD pharmacotherapy. First GLP-1RA approved for CKD progression reduction (Jan 28, 2025 Ozempic label).
ComponentMechanismStatus
Semaglutide 1.0 mgHemodynamic + anti-inflammatoryFLOW (A)
SGLT2 inhibitorSGLT2 · TG feedbackDAPA-CKD / EMPA-KIDNEY (A)
ACE-I / ARBRAAS · proteinuriaBENEDICT / IDNT (A)
FinerenoneMR · fibrosis · CKDFIDELIO / FIGARO (A)
Obesity-related HFpEF Stack
High Synergy
Semaglutide 2.4 mg SGLT2 inhibitor MRA (spironolactone/finerenone) Loop diuretic PRN
STEP-HFpEF (NEJM 2023, n=529): semaglutide 2.4 mg improved KCCQ-CSS by +7.8 points vs placebo, weight −10.7 pp, 6MWD +20.3 m, and hs-CRP — establishing GLP-1 RA's role in HFpEF mediated by weight and inflammation. STEP-HFpEF DM (Lancet Diabetes Endocrinol 2025) extended benefit to T2DM HFpEF. SGLT2i (empagliflozin, dapagliflozin) have parallel HFpEF evidence (EMPEROR-Preserved, DELIVER); combination targets distinct mechanisms. MRAs add fibrosis modification. Diuretics for congestion as needed.
ComponentTargetStatus
Semaglutide 2.4 mgWeight · inflammation · BPSTEP-HFpEF (A)
SGLT2iNatriuresis · cardiac energeticsEMPEROR-Preserved (A)
FinerenoneMR · fibrosis · CKDFIDELIO/FIGARO (A)
Loop diureticVolume managementSymptomatic (A)
MASH / Liver Fibrosis Stack
Moderate Synergy
Semaglutide 2.4 mg Resmetirom (Rezdiffra) Vitamin E (non-diabetic) SGLT2i
ESSENCE Part 1 (NEJM 2025): 62.9% MASH resolution and 36.8% fibrosis improvement at 72 weeks with semaglutide 2.4 mg; FDA approval for non-cirrhotic MASH with moderate-to-advanced fibrosis (August 2025). Resmetirom (Rezdiffra, FDA-approved March 2024) is a selective thyroid hormone receptor-β agonist with phase-3 evidence in F2-F3 MASH; mechanism is distinct (hepatic lipid catabolism via THR-β) and combination is mechanistically rational, though no head-to-head RCT data exists yet. Combination trial planning is in progress. Vitamin E 800 IU/day in non-diabetic MASH supported by PIVENS in some practice patterns.
ComponentMechanismEvidence
Semaglutide 2.4 mgWeight · adipose · insulin sens · inflammationESSENCE (A)
ResmetiromTHR-β · hepatic lipid catabolismMAESTRO-NASH (A)
Vitamin EAntioxidant · NASH-specificPIVENS (B)
SGLT2iHepatic fat reductionMeta-analyses (B)
CagriSema · Cagrilintide + Semaglutide
Pipeline · High
Cagrilintide 2.4 mg Semaglutide 2.4 mg Combined single weekly SC
REDEFINE 1 (NEJM June 2025, n >3,400, 68 weeks): CagriSema 2.4/2.4 mg achieved −22.7% weight vs −16.1% semaglutide alone vs −11.8% cagrilintide alone vs −2.3% placebo in obesity without T2DM. REDEFINE 2 (T2DM + obesity): −15.7% vs −3.1% placebo. REIMAGINE 2 (vs Ozempic in T2DM): −1.91% HbA1c (CagriSema) vs −1.76% (sema), weight −14.2% vs −10.2%. FDA filing for obesity submitted December 2025; review ongoing. Mechanism complementary: GLP-1R appetite + amylin (area postrema satiety, reduced gastric emptying, glucagon suppression).
ComponentTargetStatus
CagrilintideAmylin receptor · satietyREDEFINE (A)
SemaglutideGLP-1R · appetite + glycemiaSTEP / SUSTAIN (A)
Lean-Mass Preservation Stack
Moderate Synergy
Semaglutide Resistance training 2–3×/wk Protein 1.2–1.6 g/kg/day Creatine 3–5 g/day Vitamin D 1,000–2,000 IU
~33% of semaglutide-induced weight loss is lean mass — non-trivial, particularly in older adults and patients with baseline low muscle mass. Resistance training plus adequate protein attenuates this loss. Creatine is the best-evidenced ergogenic supplement and has additive benefit on lean mass and strength. Vitamin D sufficiency supports muscle and bone metabolism. This is the recommended adjunct stack for any patient on chronic semaglutide therapy — not a separate intervention.
ComponentMechanismEvidence
SemaglutideWeight loss · primary therapySTEP (A)
Resistance trainingMechanotransduction · mTORC1Meta-analyses (A)
Protein 1.2–1.6 g/kgSubstrate for MPSConsensus (A)
CreatinePhosphocreatine reserveDecades RCT (A)
Behavioral / Lifestyle Intensive Stack
High Synergy
Semaglutide 2.4 mg Intensive behavioral therapy (IBT) Mediterranean / DASH diet ≥150 min/wk activity
STEP 3 (JAMA 2021, n=611): semaglutide 2.4 mg + IBT (30 counseling visits) achieved −16.0% weight vs −5.7% with IBT + placebo (difference −10.3 pp). Even minimal lifestyle intervention in STEP 1 (~8 sessions) produced large weight loss (~15%) with semaglutide. Drug effect dominates over lifestyle intensity, but IBT adds incremental benefit and improves adherence/durability. Pivotal trials embedded 500 kcal/day deficit and ≥150 min/week moderate activity.
T2DM + Established ASCVD Layering
High Synergy
Semaglutide High-intensity statin SGLT2i Antiplatelet ACE-I/ARB
SELECT (NEJM 2023) demonstrated 20% MACE reduction in obesity + CVD without diabetes; SUSTAIN-6 (NEJM 2016) showed 26% MACE reduction in T2DM + high CV risk; SOUL (NEJM 2025) added 14% MACE reduction with oral semaglutide. Standard cardiometabolic protective medications layer cleanly: statin (LDL), antiplatelet (aspirin/clopidogrel/ticagrelor), RAS blocker (BP/renal), SGLT2i (additive CV/renal). Contemporary standard-of-care stack for T2DM with established ASCVD.
⚠ Do Not Combine
Avoid
Other GLP-1 RAs (liraglutide, dulaglutide, exenatide) Tirzepatide Retatrutide DPP-4 inhibitors Compounded incretins
Combining semaglutide with another GLP-1 RA, with tirzepatide (dual incretin), or with retatrutide (triagonist) produces overlapping mechanisms with no incremental benefit and substantially increased GI and hypoglycemia risk. DPP-4 inhibitors are redundant on any incretin background and should be discontinued. Compounded semaglutide products should not be used following resolution of the FDA shortage list (Feb 21, 2025); quality, purity, and identity vary, and FDA has issued repeated safety alerts. Combining semaglutide with active sulfonylurea or unmonitored insulin therapy without dose reduction risks severe hypoglycemia.
ScenarioActionRationale
Another GLP-1 RADiscontinue the other agentMechanistic redundancy
Tirzepatide / RetatrutideChoose one agentMechanistic overlap + GI risk
DPP-4 inhibitorDiscontinueRedundant on incretin therapy
SulfonylureaReduce 50% or discontinueSevere hypoglycemia risk
InsulinReduce basal 20% + CGMSevere hypoglycemia risk
Compounded productSwitch to approved Novo Nordisk penFDA safety warnings
Pregnancy planningDiscontinue ≥2 months priorNo human pregnancy data

Semaglutide vs. the incretin family

Agent Receptor profile Approved indications Dosing Weight loss Status
Semaglutide GLP-1 (selective) T2DM · obesity · CV · CKD · MASH · adolescent obesity Weekly SC · 0.25 → 2.4 mg · daily oral 3 → 14 mg −14.9% (STEP 1, 2.4 mg, 68 wk) FDA-approved (A) · 6 indications
Tirzepatide (Mounjaro/Zepbound) GIP + GLP-1 (dual) T2DM · obesity · OSA Weekly SC · 2.5 → 15 mg −20.9% (SURMOUNT-1, 15 mg, 72 wk) FDA-approved (A)
Liraglutide (Saxenda / Victoza) GLP-1 (selective) T2DM · obesity · pediatric obesity Daily SC · 0.6 → 3.0 mg ~5–8% (Saxenda 3.0 mg) FDA-approved (A)
Dulaglutide (Trulicity) GLP-1 (selective) T2DM · CV risk reduction Weekly SC · 0.75 → 4.5 mg ~3–5% modest FDA-approved (A)
Exenatide ER (Bydureon) GLP-1 (exendin-based) T2DM Weekly SC · 2.0 mg ~2 kg FDA-approved (A)
Lixisenatide (Adlyxin) GLP-1 (short-acting) T2DM Daily SC Minimal FDA-approved (A)
Retatrutide (LY3437943) GIP + GLP-1 + glucagon (triple) None (phase 3) Weekly SC · up to 12 mg −24.2% at 48 wk (phase 2, 12 mg) Investigational (A pre-3)
CagriSema (cagri + sema) Amylin + GLP-1 (combination) Filed (Dec 2025) Weekly SC · 2.4/2.4 mg −22.7% (REDEFINE 1, 68 wk) Pipeline (A)
Orforglipron (LY3502970) GLP-1 (selective, non-peptide oral) None (phase 3) Daily oral · non-SNAC ~14.7% at 36 wk (phase 2) Investigational (B)
Survodutide (BI 456906) GLP-1 + glucagon (dual) None (phase 3) Weekly SC ~14% (phase 2, MASH) Investigational (B)
05 · Safety profile & contraindications

Most extensively characterized GLP-1; boxed warning intact.

Semaglutide carries the largest safety database of any incretin — >50,000 patient-years across SUSTAIN, STEP, SELECT, FLOW, PIONEER, ESSENCE, SOUL, and post-marketing pharmacovigilance since December 2017. The dominant adverse-event burden is gastrointestinal during titration. The class boxed warning for medullary thyroid carcinoma (MTC) reflects rodent C-cell tumor findings; the human signal has not materialized despite eight years of approved use. The diabetic retinopathy signal first surfaced in SUSTAIN-6 (HR 1.76) and remains the one finding that meaningfully differentiates semaglutide's safety profile from peers. A 2024 NAION (non-arteritic anterior ischemic optic neuropathy) signal is under regulatory review. Hypoglycemia is largely a function of background insulin or sulfonylurea. Pancreatitis, gallbladder disease, and renal injury from dehydration are known low-incidence risks.

Common Adverse Events (SUSTAIN / STEP / SELECT pooled)
Nausea~15–20% (SUSTAIN, 1.0 mg) to ~44% (STEP 1, 2.4 mg) — dose-dependent and titration-related. Peaks at each escalation step; usually mild-moderate; resolves with dose stabilization, slowed titration, or step-back.
Diarrhea~9–30% across indications — most common with metformin co-prescription. Generally mild; persistent severe diarrhea warrants dose hold and evaluation for alternative etiologies (C. difficile, microscopic colitis).
Vomiting~5–24% — dose-dependent. Severe vomiting risks dehydration and acute kidney injury, particularly in elderly. Hold dose, hydrate, ondansetron PRN, resume at lower step at next scheduled escalation.
Constipation~8–24% — secondary to slowed gastric emptying and reduced food/fiber intake. Increase fiber, fluids, PEG 3350 PRN. Particularly common in oral semaglutide (Rybelsus) due to fasting-state administration.
Abdominal pain~6–20% — usually mild, dose-related. Severe persistent pain → r/o pancreatitis, cholecystitis. Lipase, RUQ ultrasound as indicated.
Decreased appetite~7–24% reported as AE, though it is also the desired effect. Becomes problematic only when paired with markedly reduced caloric intake that risks protein deficit or significant lean-mass loss.
Injection-site reactions~1–5% — mild erythema, pruritus, transient pain. Rotate sites between abdomen, thigh, upper arm; warm pen 30 min before injection. Higher rates reported with compounded products.
Fatigue~5–11% — particularly during early titration as metabolism shifts. Generally self-resolves over 4–8 weeks. Persistent fatigue → r/o anemia, hypothyroidism, depression, nutritional deficiency.
Headache~10–14% (STEP trials) — often early/dehydration-related. Encourage hydration; usually resolves at dose stabilization.
Discontinuation due to AEsSTEP 1: 7.0% on semaglutide vs 3.1% placebo. SELECT: 16.6% on semaglutide vs 8.2% placebo (long-term, 3-year). FLOW: 13.5% vs 11.8%. Higher with adolescents and at 2.4 mg vs 1.0 mg.
Boxed Warning & Serious Adverse Events
BOXED · Medullary thyroid carcinoma (MTC)Class boxed warning. Rodent C-cell tumors observed in carcinogenicity studies (mice and rats, both sexes, dose-related). Human signal has not materialized in 8+ years of post-marketing surveillance. Absolute contraindication in personal/family history of MTC or MEN-2.
Diabetic retinopathy progressionSUSTAIN-6 showed HR 1.76 (95% CI 1.11–2.78) for retinopathy complications vs placebo — most events in patients with pre-existing retinopathy undergoing rapid glycemic improvement. Baseline retinal exam in T2DM with known retinopathy; closer follow-up during titration; consider slower A1c reduction in proliferative retinopathy.
NAION · Non-arteritic anterior ischemic optic neuropathyHathaway et al. (JAMA Ophthalmology, 2024, PMID 38958939) reported HR 4.28 (95% CI 1.62–11.29) for NAION in T2DM patients prescribed semaglutide vs other diabetes medications. Causality not established; FDA and EMA under review. Counsel on acute painless monocular vision loss; urgent ophthalmology if it occurs.
PancreatitisAcute pancreatitis reported as low-incidence class effect. Caution in history of pancreatitis (not formally studied in this population). Discontinue if pancreatitis suspected (severe abdominal pain, elevated lipase >3× ULN); do not restart if confirmed.
Severe hypoglycemiaRare in monotherapy or with metformin/SGLT2i alone. Significantly elevated with concurrent insulin or sulfonylurea — proactive dose reduction of those agents at semaglutide initiation is required.
Acute kidney injuryFrom volume depletion in patients with severe GI symptoms (vomiting, diarrhea). Higher risk in elderly, baseline CKD, RAAS blockade, or diuretic use. Hydration counseling; hold dose if severe. Note: FLOW trial demonstrated renoprotection at steady state — AKI risk is acute, not chronic.
Gallbladder diseaseCholelithiasis and cholecystitis reported as class effect, linked to rapid weight loss and altered gallbladder motility. Counsel on RUQ pain; imaging if symptomatic. Higher rates at 2.4 mg vs 1.0 mg dose.
Hypersensitivity / anaphylaxisAnaphylaxis and angioedema rarely reported. Contraindicated in known hypersensitivity to semaglutide or excipients (including SNAC in Rybelsus).
Pulmonary aspiration · anesthesiaReports of aspiration under general anesthesia due to delayed gastric emptying. Hold semaglutide ≥1 week prior to elective procedures requiring general anesthesia or deep sedation (ASA 2023 guidance). ASA recommends individualizing risk based on residual gastric contents; point-of-care gastric ultrasound may guide.
Suicidal ideation signalFDA evaluated post-marketing reports across GLP-1 class (2024); no causal association established. EMA review concurrent. Continue routine mental-health screening; counsel patient to report new symptoms; reassess if depression worsens.
Suicidal ideation signal · weight cyclingSeparate consideration: rapid weight loss followed by discontinuation can precipitate mood disturbance. Reframe as chronic therapy; if discontinuing, taper if possible and increase mental-health touch points.
Hair loss · alopecia effluvium~3% in STEP trials, mostly telogen effluvium from rapid weight loss rather than direct drug effect. Self-limited; counsel on protein intake (1.2–1.6 g/kg ideal body weight) and adequate caloric intake.

Contraindication reference

Condition / factor Risk level Applies to Rationale
Personal/family history of medullary thyroid carcinoma (MTC)ContraindicatedAllBoxed warning · rodent C-cell tumor signal · MTC/MEN-2 are absolute contraindications per FDA label across all four semaglutide products.
Multiple Endocrine Neoplasia syndrome type 2 (MEN-2)ContraindicatedAllBoxed warning · genetic predisposition to MTC.
PregnancyAvoidAllNo adequate human pregnancy data · animal studies show embryofetal toxicity, growth restriction. Discontinue ≥2 months prior to planned conception.
LactationAvoidAllExcretion into human breast milk unknown · insufficient data · avoid until lactation complete.
Pediatric (< 12 years)AvoidAllNot approved < 12 years. Wegovy approved 12+ for obesity (BMI ≥95th %ile) per STEP TEENS. Liraglutide approved ≥6 years remains the youngest pediatric option.
Hypersensitivity to semaglutide or excipientsContraindicatedAllAnaphylaxis and angioedema reported · contraindication per label. Rybelsus also contains SNAC permeation enhancer.
Prior pancreatitisCautionAllNot formally studied in this population · specialist input · weigh against alternative therapies.
Concurrent insulin therapyMonitorT2DMReduce basal insulin 20% at initiation · CGM during titration · hypoglycemia risk significantly elevated without adjustment. Rapid-acting insulin reduction often required after 4–8 weeks of glycemic improvement.
Concurrent sulfonylureaMonitorT2DMReduce SU dose 50% or discontinue · severe hypoglycemia risk · ADA guidance recommends discontinuation of SU when starting GLP-1.
Pre-existing diabetic retinopathy (NPDR/PDR)CautionT2DMSUSTAIN-6 retinopathy signal (HR 1.76) most pronounced with rapid glycemic improvement · baseline retinal exam · ophthalmology consultation in PDR · consider slower titration of background therapy.
Severe gastroparesis / motility disorderCautionAllSemaglutide further delays gastric emptying · symptoms may worsen · weigh against alternatives (dulaglutide, oral non-incretin agents).
Active gallbladder diseaseCautionAllClass effect with rapid weight loss · symptomatic stones may worsen · consider cholecystectomy before initiation if recurrent symptoms.
Severe renal impairment (eGFR < 15) / dialysisCautionAllFLOW excluded dialysis patients. No formal dose adjustment by label, but volume depletion from GI AEs disproportionately raises AKI risk · monitor renal function · counsel hydration. Semaglutide is renoprotective per FLOW HR 0.76 at eGFR 25–75.
Elective surgery requiring anesthesiaCautionAllHold semaglutide ≥1 week pre-procedure per ASA 2023 guidance · pulmonary aspiration risk from delayed gastric emptying · consider point-of-care gastric ultrasound on day of surgery.
Severe psychiatric instability · active SIMonitorAllNo causal association established · continue routine MH screening · report new symptoms · weight cycling on discontinuation may precipitate mood disturbance.
Compounded product from unverified sourceAvoidAllFDA shortage resolved Feb 21 2025 · compounding ended ~May 2025 · purity, identity, dosing accuracy concerns · use approved Novo product.
Concurrent oral contraceptive (initial 4 wk)MonitorReproductive ageDelayed gastric emptying may reduce OCP absorption during initial titration · use barrier backup or non-oral contraception for first 4 weeks.
Concurrent oral medications (Rybelsus)MonitorOralRybelsus requires fasting, water-only, then ≥30 min wait. SNAC permeation enhancer may affect levothyroxine, oral diabetes meds. Consider switching to SC if multiple oral medications required.
Anticipated GI / bariatric surgeryCautionAllHold ≥1 wk pre-op. Post-bariatric: SC semaglutide preferred; oral absorption unpredictable post-RYGB or SG.
Severe hepatic impairmentMonitorAllNo formal dose adjustment. ESSENCE included compensated MASH (F2/F3) successfully. Avoid in decompensated cirrhosis (Child-Pugh C) — limited safety data.

Suggested monitoring for semaglutide protocols

Baseline

HbA1c, fasting glucose, lipid panel, CMP (LFTs, renal), TSH, eGFR (CKD-EPI-Cr-CysC 2021 in obesity), uACR (if T2DM), BMI, waist circumference, BP, HR. Pregnancy test if reproductive potential. Personal/family thyroid cancer history screen. Baseline retinal exam in T2DM with known retinopathy. FibroScan / FIB-4 / ELF in suspected MASH. Body composition (DEXA) optional in obesity protocol. ECG if SELECT-eligible (CV history) per institutional standard.

4-Week Step Checks

Symptom review (GI tolerability, hydration, weight trend, vision changes). Decision: escalate, hold, or step back. In T2DM with insulin/SU: SMBG or CGM data review for hypoglycemia. In obesity: weight trend confirms response or triggers reassessment. New retinopathy symptoms (floaters, blurred vision) → ophthalmology referral.

12-Week / End-of-Titration

Repeat A1c (T2DM), weight, BP, waist circumference, basic metabolic panel. Reassess maintenance dose target. In CKD indication (FLOW protocol): uACR + eGFR. In MASH protocol: FibroScan / FIB-4 at 6 months post-titration.

6 Months

Full repeat baseline panel: A1c, lipids, CMP, eGFR, uACR, BP, weight, waist. Reassess medication titration (insulin, SU, antihypertensives — many will require down-titration). Confirm response thresholds — ≥5% weight loss expected by 6 months in obesity, ≥0.5% A1c reduction in T2DM. Annual retinal exam in T2DM with retinopathy. Re-counsel on chronic-therapy framing (STEP 4 withdrawal data).

Annual

Full metabolic panel · body composition (DEXA) if available · BMD if >65 years and chronic therapy >2 years (osteopenia screen given lean mass loss). Annual retinal exam in T2DM regardless of baseline status. uACR annually if CKD/T2DM. Reassess indication, ongoing benefit, and continued tolerability. Document new diagnoses (cancer, pregnancy planning, anesthesia) that change risk/benefit.

Stop / Hold Criteria

Suspected acute pancreatitis (severe abdominal pain + elevated lipase) → permanent discontinuation if confirmed. New MTC or MEN-2 diagnosis → discontinue. Planned pregnancy → discontinue ≥2 months prior. Elective surgery requiring anesthesia → hold ≥1 week. Severe AKI from GI volume depletion → hold and rehydrate; resume cautiously at lower dose after recovery. New NAION or acute monocular vision loss → permanent discontinuation, ophthalmology. New severe psychiatric symptoms → individual risk/benefit reassessment.

06 · Key studies & research program

The SUSTAIN, STEP, SELECT, FLOW, ESSENCE, and SOUL program.

Semaglutide's evidence base is the largest of any incretin and one of the largest in pharmaceutical history — 10 SUSTAIN T2DM trials, 9+ STEP obesity trials including STEP TEENS pediatric and STEP-HFpEF, the SELECT CVOT in >17,000 non-diabetic CV patients, the FLOW renal outcomes trial, the ESSENCE MASH trial, the SOUL oral CVOT, the PIONEER oral T2DM program, and head-to-head studies against tirzepatide (SURMOUNT-5) and CagriSema (REDEFINE 1). Six FDA indications across three product names (Ozempic, Wegovy, Rybelsus) span T2DM, obesity, adolescent obesity, cardiovascular outcomes, CKD in T2DM, and most recently MASH (August 2025). Below: the trials that define the clinical positioning of the molecule, organized by indication and chronology.

STEP 1 · obesity
−14.9%
Weight loss at 68 weeks · 2.4 mg · n=1,961 · NEJM 2021 · the pivotal obesity readout that defined the GLP-1 weight-loss era
SELECT · CVOT non-DM
HR 0.80
MACE in CV-established overweight/obese without diabetes · n=17,604 · NEJM 2023 · supported March 2024 Wegovy CV label
FLOW · CKD + T2DM
HR 0.76
Kidney composite (sustained eGFR decline, ESKD, renal/CV death) · n=3,533 · NEJM 2024 · Ozempic CKD label Jan 2025
ESSENCE · MASH
62.9%
MASH resolution at 72 wk vs 34.3% placebo · NEJM 392:2089-2099 · April 2025 · Wegovy MASH approval Aug 2025
A Phase 3 · obesity · anchor readout

STEP 1 — Wilding et al. 2021 (NEJM)

Adults with BMI ≥30 (or ≥27 + comorbidity) without diabetes, randomized to semaglutide 2.4 mg vs placebo for 68 weeks; n=1,961. Mean weight change (efficacy estimand) at 68 weeks: −14.9% (semaglutide) vs −2.4% (placebo); P<0.001. ≥5% loss in 86.4% vs 31.5%; ≥10% in 69.1% vs 12.0%; ≥15% in 50.5% vs 4.9%; ≥20% in 32.0% vs 1.7%. Cardiometabolic risk factors (waist, BP, lipids, CRP, A1c) improved across the board. The pivotal obesity readout that supported June 2021 Wegovy FDA approval and defined the GLP-1 weight-loss era.

PMID 33567185 NCT03548935
A Phase 3 · obesity + T2DM

STEP 2 — Davies et al. 2021 (Lancet)

Adults with BMI ≥27 and T2DM randomized to semaglutide 2.4 mg vs 1.0 mg vs placebo for 68 weeks; n=1,210. Weight change: −9.6% (2.4 mg), −7.0% (1.0 mg), −3.4% (placebo). ≥5% loss in 68.8% (2.4 mg) vs 28.5% (placebo). A1c reductions ~1.6% at 2.4 mg. Demonstrated that 2.4 mg semaglutide achieves meaningful (though attenuated vs non-DM) weight loss in T2DM and supported obesity-dose use for dual indication patients.

PMID 33667417 NCT03552757
A Phase 3 · obesity + intensive behavioral therapy

STEP 3 — Wadden et al. 2021 (JAMA)

Semaglutide 2.4 mg vs placebo with intensive behavioral therapy (IBT, 30 visits) and 8-week low-calorie diet at start, for 68 weeks; n=611. Weight change −16.0% vs −5.7% (placebo + IBT). The IBT-augmented placebo arm exceeded most pharmacotherapy trials for placebo loss, but semaglutide still produced ~3× incremental loss. Established the synergy of semaglutide + structured behavioral intervention. Adopted by IBT programs and integrated medical-behavioral practices.

PMID 33625476 NCT03611582
A Phase 3 · withdrawal trial

STEP 4 — Rubino et al. 2021 (JAMA)

Participants received open-label semaglutide 2.4 mg for 20 weeks (achieving ~10.6% loss), then were randomized to continue semaglutide or switch to placebo for 48 weeks; n=803. Continuation arm: additional −7.9% (total ~−17.4%). Withdrawal arm: regained +6.9% (net ~−5.0%). Demonstrated semaglutide must be continued indefinitely to maintain weight loss; effect is suppressive, not curative. The trial that established the chronic-therapy framing now central to GLP-1 counseling.

PMID 33755728 NCT03548987
A Phase 3 · obesity · 2-year durability

STEP 5 — Garvey et al. 2022 (Nature Medicine)

Adults with overweight/obesity, randomized to semaglutide 2.4 mg vs placebo for 104 weeks (2 years); n=304. Weight change at 104 weeks: −15.2% (semaglutide) vs −2.6% (placebo). ≥5% loss in 77.1% vs 34.4%; ≥10% in 61.8% vs 13.3%; ≥15% in 52.1% vs 7.0%. First long-duration STEP readout confirming durability of weight loss with continued therapy.

PMID 36280750 NCT03693430
A Phase 3b · head-to-head vs liraglutide

STEP 8 — Rubino et al. 2022 (JAMA)

Adults with BMI ≥30 (or ≥27 + comorbidity) randomized to semaglutide 2.4 mg weekly vs liraglutide 3.0 mg daily vs placebo for 68 weeks; n=338. Weight change: −15.8% (semaglutide) vs −6.4% (liraglutide) vs −1.9% (placebo); P<0.001 for sema vs lira. Established semaglutide superiority over liraglutide for obesity — substantially shifted clinical practice from Saxenda to Wegovy.

PMID 35015037 NCT04074161
A Phase 3 · adolescent obesity

STEP TEENS — Weghuber et al. 2022 (NEJM)

Adolescents (12–17 years) with obesity (BMI ≥95th percentile) randomized to semaglutide 2.4 mg vs placebo for 68 weeks; n=201. BMI change −16.1% (semaglutide) vs +0.6% (placebo); P<0.001. ≥5% weight loss in 73% vs 18%. Cardiometabolic improvements paralleled adult data. Supported December 2022 FDA approval of Wegovy in adolescents ≥12 years. First incretin trial in adolescents to demonstrate magnitude comparable to bariatric surgery.

PMID 36322839 NCT04102189
A Phase 3 · HFpEF + obesity

STEP-HFpEF — Kosiborod et al. 2023 (NEJM)

Adults with HFpEF (LVEF ≥45%) and obesity (BMI ≥30) without diabetes, randomized to semaglutide 2.4 mg vs placebo for 52 weeks; n=529. KCCQ-CSS improvement +7.8 points greater than placebo. Weight change −13.3% vs −2.6%. 6-minute walk distance +21.5 m greater than placebo. NT-proBNP reduction −20.9% vs placebo. Established benefit of weight loss / semaglutide on HFpEF symptoms; supported continuation of HFpEF research with tirzepatide (SUMMIT).

PMID 37622681 NCT04788511
A Phase 3 · HFpEF + obesity + T2DM

STEP-HFpEF DM — Kosiborod et al. 2024 (NEJM)

Adults with HFpEF + obesity + T2DM randomized to semaglutide 2.4 mg vs placebo for 52 weeks; n=616. KCCQ-CSS improvement +7.3 points greater than placebo; weight change −9.8% vs −3.4%; 6MWD +14.3 m greater than placebo; NT-proBNP −23.7% greater than placebo. Confirmed STEP-HFpEF findings extend to T2DM patients with attenuated but clinically meaningful magnitude.

PMID 38597212 NCT04916470
A Phase 3 · obesity + knee OA

STEP 9 — Bliddal et al. 2024 (NEJM)

Adults with obesity (BMI ≥30) and moderate-to-severe knee osteoarthritis randomized to semaglutide 2.4 mg vs placebo for 68 weeks; n=407. Weight change −13.7% vs −3.2%. WOMAC pain score reduction −41.7 vs −27.5 (P<0.001). Demonstrated semaglutide reduces pain and improves function in obesity-related OA — relevant to MSK indication and avoidance of NSAIDs in obese T2DM/CKD populations.

PMID 39476340 NCT05064735
A Phase 3 · obesity + prediabetes

STEP 10 — McGowan et al. 2024 (Diabetes, Obesity & Metabolism)

Adults with BMI ≥30 and prediabetes randomized to semaglutide 2.4 mg vs placebo for 52 weeks; n=207. Weight change −15.8% vs −1.6%. Regression to normoglycemia: 80% (semaglutide) vs 37% (placebo). Demonstrated semaglutide as primary prevention strategy for T2DM in prediabetic obesity — complements tirzepatide SURMOUNT-1 extension data (HR 0.07 for progression to T2DM).

PMID 39351778 NCT05040971
A Phase 3 · CVOT (T2DM)

SUSTAIN-6 — Marso et al. 2016 (NEJM)

T2DM patients with established CVD or CV risk factors randomized to semaglutide 0.5 or 1.0 mg vs placebo for median 2.1 years; n=3,297. MACE-3 (CV death, nonfatal MI, nonfatal stroke): HR 0.74 (95% CI 0.58–0.95; P=0.02 for noninferiority, P=0.02 for superiority). Nonfatal stroke −39%. Retinopathy complications: HR 1.76 (95% CI 1.11–2.78) — the signal that requires baseline retinal exam in T2DM with known retinopathy. First CVOT to demonstrate semaglutide CV benefit; pre-SELECT positioning of GLP-1 as CV-disease-modifying.

PMID 27633186 NCT01720446
A Phase 3 · T2DM monotherapy

SUSTAIN-1 — Sorli et al. 2017 (Lancet D&E)

Adults with T2DM inadequately controlled on diet/exercise randomized to semaglutide 0.5 or 1.0 mg vs placebo for 30 weeks; n=388. HbA1c change: −1.45% (0.5 mg), −1.55% (1.0 mg) vs +0.02% placebo. Weight change: −3.7 / −4.5 kg vs −1.0 kg. First positive SUSTAIN readout; established semaglutide monotherapy efficacy in T2DM.

PMID 28110911 NCT02054897
A Phase 3b · T2DM · high-dose

SUSTAIN FORTE — Frías et al. 2021 (Lancet D&E)

T2DM patients on metformin ± SU randomized to semaglutide 2.0 mg vs 1.0 mg for 40 weeks; n=961. HbA1c change: −2.2% (2.0 mg) vs −1.9% (1.0 mg); difference −0.23% (P=0.0001). Weight change: −6.9 vs −6.0 kg. Supported FDA approval of Ozempic 2.0 mg dose for T2DM (March 2022). Established higher-dose Ozempic as option for T2DM patients requiring more glycemic / weight effect.

PMID 33862011 NCT03989232
A Phase 3 · vs liraglutide 1.2 mg

SUSTAIN-10 — Capehorn et al. 2020 (Diabetes & Metabolism)

T2DM patients randomized to semaglutide 1.0 mg weekly vs liraglutide 1.2 mg daily for 30 weeks; n=577. HbA1c change −1.7% (sema) vs −1.0% (lira); difference −0.69% (P<0.0001). Weight change −5.8 vs −1.9 kg. Established semaglutide superiority over the contemporaneous standard daily GLP-1 RA in T2DM.

PMID 31791731 NCT03191396
A Phase 3a · oral · vs liraglutide

PIONEER 4 — Pratley et al. 2019 (Lancet)

T2DM patients on metformin ± SGLT2i randomized to oral semaglutide 14 mg daily vs liraglutide 1.8 mg daily vs placebo for 52 weeks; n=711. HbA1c change −1.2% (oral sema) vs −1.1% (lira) vs −0.2% (placebo); non-inferior to liraglutide. Weight change −4.4 vs −3.1 vs −0.5 kg; oral sema superior to liraglutide on weight (P=0.0003). Validated oral semaglutide PK / efficacy in head-to-head context.

PMID 31186120 NCT02863419
A Phase 3a · oral · CVOT

PIONEER 6 — Husain et al. 2019 (NEJM)

T2DM patients with established CVD or high CV risk randomized to oral semaglutide 14 mg vs placebo for median 15.9 months; n=3,183. MACE-3: HR 0.79 (95% CI 0.57–1.11; non-inferior, P<0.001). CV mortality HR 0.49 (P=0.03). Established oral semaglutide CV safety — pre-cursor to SOUL outcomes trial.

PMID 31185157 NCT02692716
A Phase 3 · CVOT in obesity without DM · landmark

SELECT — Lincoff et al. 2023 (NEJM)

Adults ≥45 years with overweight/obesity (BMI ≥27) and established cardiovascular disease, without diabetes, randomized to semaglutide 2.4 mg vs placebo for median 39.8 months; n=17,604. Primary MACE-3 (CV death, nonfatal MI, nonfatal stroke): HR 0.80 (95% CI 0.72–0.90; P<0.001). NNT = 67 over 3 years to prevent 1 MACE. Effect emerged early (within 6 months) and predated maximum weight loss, suggesting weight-independent mechanisms (anti-inflammatory, vascular). Supported March 2024 Wegovy CV indication — first obesity drug with proven CV benefit independent of T2DM.

PMID 37952131 NCT03574597
A Phase 3b · renal outcomes · landmark

FLOW — Perkovic et al. 2024 (NEJM)

T2DM patients with CKD (eGFR 25–75 + uACR 100–5,000 mg/g) randomized to semaglutide 1.0 mg vs placebo for median 3.4 years; n=3,533. Trial stopped early for efficacy at 2024 interim. Primary composite kidney outcome (sustained ≥50% eGFR decline, kidney failure, renal/CV death): HR 0.76 (95% CI 0.66–0.88; P=0.0003). All-cause mortality HR 0.80. CV death HR 0.71. Major CV events HR 0.82. eGFR slope difference +1.16 mL/min/1.73m²/yr in favor of semaglutide. Supported Ozempic CKD label expansion (January 28, 2025) — first GLP-1 with kidney outcome indication.

PMID 38785209 NCT03819153
A Phase 3 Part 1 · MASH · landmark

ESSENCE — Sanyal et al. 2025 (NEJM 392:2089-2099)

Adults with biopsy-proven MASH (NAS ≥4) and F2/F3 fibrosis randomized to semaglutide 2.4 mg vs placebo, with 72-week interim biopsy analysis (n=800 of planned 1,197 enrolled in Part 1); published April 30, 2025. MASH resolution without worsening fibrosis: 62.9% (semaglutide) vs 34.3% (placebo); difference 28.6 percentage points (P<0.001). Fibrosis improvement ≥1 stage without MASH worsening: 36.8% vs 22.4% (P<0.001). Both improvements simultaneously: 32.7% vs 16.1%. Cardiometabolic biomarkers improved across the board. Supported August 2025 FDA approval of Wegovy for MASH — first GLP-1 with MASH histology indication. Part 2 (long-term outcomes through 240 wk) ongoing.

PMID 40305708 DOI 10.1056/NEJMoa2413258 NCT04822181
A Phase 2 · MASH · proof-of-concept

Semaglutide MASH Phase 2 — Newsome et al. 2021 (NEJM)

Adults with biopsy-proven NASH (F1–F3) randomized to semaglutide 0.1, 0.2, 0.4 mg daily vs placebo for 72 weeks; n=320. MASH resolution: 59% (0.4 mg) vs 17% placebo (P<0.001). Fibrosis improvement: no significant difference. The phase-2 readout that motivated ESSENCE phase 3 and established proof-of-concept for GLP-1 in MASH histology — though fibrosis benefit only manifested in phase 3.

PMID 33185364 NCT02970942
A Phase 3b · oral · CVOT · landmark

SOUL — McGuire et al. 2025 (NEJM)

T2DM patients ≥50 years with established CVD, CKD, or both, randomized to oral semaglutide 14 mg daily vs placebo for median 3.8 years; n=9,650; results published March 29, 2025 (DOI 10.1056/NEJMoa2501006). MACE-3: HR 0.86 (95% CI 0.77–0.96; P=0.006 for superiority) — ~14% relative risk reduction. Effect consistent across CVD subgroup and CKD subgroup. Established oral semaglutide as CV-protective, supporting future Rybelsus CV label and expansion of oral GLP-1 use in CV-risk T2DM populations. The largest oral GLP-1 CVOT to date.

DOI 10.1056/NEJMoa2501006 NCT03914326
A Phase 3 · head-to-head vs tirzepatide

SURMOUNT-5 — Aronne et al. 2025 (NEJM 393:26-36)

The first definitive head-to-head obesity RCT: tirzepatide 10/15 mg vs semaglutide 1.7/2.4 mg over 72 weeks; n=751. LSM weight change −20.2% (tirzepatide) vs −13.7% (semaglutide); difference 6.5 percentage points (P<0.001). Waist circumference −18.4 vs −13.0 cm. Significantly higher proportions on tirzepatide achieved ≥10%, ≥15%, ≥20%, ≥25% loss. The trial that positioned tirzepatide as more potent for weight loss, while leaving semaglutide as the more broadly-indicated agent with the largest CV / renal / MASH / pediatric evidence base.

PMID 40353578 NCT05822830
A Phase 3 · CagriSema combination

REDEFINE 1 — Garvey et al. 2025 (NEJM)

Adults with obesity (BMI ≥30 or ≥27 + comorbidity) without T2DM randomized to CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) vs cagrilintide alone vs semaglutide alone vs placebo for 68 weeks; n=3,417. Weight change: −22.7% (CagriSema) vs −14.9% (semaglutide alone) vs −11.8% (cagrilintide alone) vs −2.3% (placebo); P<0.001 for CagriSema vs all comparators. Supported December 2025 FDA filing of CagriSema for chronic weight management — narrowing the gap with tirzepatide and positioning Novo competitive in next-generation obesity pharmacotherapy. Published June 2025.

REDEFINE 1 publication NCT05567796
B Phase 3 · Alzheimer's · negative

EVOKE & EVOKE+ — Cummings et al. 2025 (failed phase 3)

Adults with early Alzheimer's disease randomized to oral semaglutide 14 mg daily vs placebo for ~2 years; n≈3,800 combined. Reported by Novo in November 2025: Both EVOKE and EVOKE+ failed to meet primary endpoint of cognitive decline reduction (CDR-SB). The negative readout closed Novo's neurodegenerative-disease program for semaglutide and tempered enthusiasm for the GLP-1 / neuroinflammation hypothesis in established AD. Earlier-stage neurodegeneration remains an open question (post-hoc analyses from SELECT showed possible benefit on dementia incidence).

NCT04777396 (EVOKE) NCT04777409 (EVOKE+)
C Pharmacoepi · safety signal

NAION Signal — Hathaway et al. 2024 (JAMA Ophthalmology)

Retrospective propensity-matched cohort using Mass Eye and Ear database, T2DM patients prescribed semaglutide vs other diabetes medications; n=16,827 matched pairs. HR 4.28 (95% CI 1.62–11.29) for NAION (non-arteritic anterior ischemic optic neuropathy) in semaglutide arm vs comparator. Limited by single-center design; confounding by indication possible. Triggered FDA and EMA review; signal under active surveillance. Patients should be counseled to report acute monocular vision loss; urgent ophthalmology referral if it occurs.

PMID 38958939
B Phase 3a · oral · high-dose obesity

OASIS 1 — Knop et al. 2023 (Lancet)

Adults with overweight/obesity without T2DM randomized to oral semaglutide 50 mg daily vs placebo for 68 weeks; n=667. Weight change −15.1% vs −2.4% (placebo); P<0.001. ≥5% loss in 84.9% vs 25.8%; ≥15% in 56.5% vs 5.4%. The high-dose oral semaglutide readout that supported development of Rybelsus 25/50 mg for obesity (FDA filing anticipated 2026). Demonstrated oral formulation can deliver Wegovy-magnitude weight loss with daily dosing.

PMID 37364590 NCT05035095

Read-out signal · the most-indicated peptide

Semaglutide remains the most indicated peptide in the Atlas — six FDA indications across three product names (Ozempic, Wegovy, Rybelsus) span T2DM, obesity, adolescent obesity, cardiovascular disease in obesity without diabetes, CKD in T2DM, and MASH. The 2025 program added kidney (FLOW → Ozempic CKD label, January), oral CV (SOUL, March), MASH (ESSENCE → Wegovy MASH label, August), and CagriSema combination (REDEFINE 1, June filing). The negative EVOKE Alzheimer's readout (November 2025) closed one hypothesis but left CV-protective benefits and downstream cognitive effects in obesity / metabolic populations under active investigation. SURMOUNT-5 reframed semaglutide as the broadly-evidenced but second-most-potent obesity agent versus tirzepatide; the response has been combination therapy (CagriSema) and high-dose oral (OASIS). Open questions: (1) CV outcomes from oral semaglutide in obesity without diabetes; (2) head-to-head MASH vs tirzepatide; (3) outcomes vs HF reduction beyond symptom benefit (STEP-HFpEF); (4) pediatric label expansion to age 6–11.

07 · Compare & contrast

Adjacent peptides.

Incretin · GIP/GLP-1 dual
Tirzepatide

Dual GIP/GLP-1 receptor agonist. Mounjaro (T2DM), Zepbound (obesity, OSA). Beat semaglutide in SURMOUNT-5 (−20.2% vs −13.7%) and SURPASS-2 — the current most-potent approved obesity / T2DM agent by weight loss.

Compare profile →
Incretin · selective GLP-1
Liraglutide

Daily GLP-1 RA from Novo. Victoza (T2DM), Saxenda (obesity). The first-generation GLP-1 RA with proven CV benefit (LEADER) and pediatric obesity approval ≥6 years. Beaten by semaglutide on weight (STEP 8) and adherence.

Compare profile →
Incretin · triagonist · investigational
Retatrutide

GIP + GLP-1 + glucagon triple agonist (Lilly LY3437943). Phase 3 weight loss ~28.7% at 12 mg (TRIUMPH-4). Sets the new ceiling for incretin pharmacotherapy; phase 3 reads out 2026–2027.

Compare profile →
Class hub
GLP-1 RA family

Full overview of the incretin class — liraglutide, dulaglutide, semaglutide, tirzepatide, retatrutide, CagriSema, orforglipron — and the rapidly evolving pharmacology of obesity, T2DM, CV disease, CKD, and MASH.

Hub →
08 · Evidence & references

Every claim, graded and sourced.

A · RCT / meta-analysis
B · Large cohort / consistent trial set
C · Small trial / mechanistic
P · Preclinical / animal
D · Expert / textbook / regulatory
Explore the ATLAS index

More Metabolic peptides & tools.

Metabolic
5-Amino-1MQ

Educational scientific reference on 5-Amino-1MQ (5-amino-1-methylquinolinium iodide), a synthetic small-molecule NNMT…

Open monograph →
Metabolic
AOD-9604 / HGH Fragment 176–191

Educational scientific reference on AOD-9604 (HGH Fragment 176–191), a synthetic 16-amino-acid C-terminal fragment of…

Open monograph →
Metabolic
AOD-9604

Comprehensive scientific reference on AOD-9604 (Tyr-hGH177-191, hGH fragment 176-191 analog) covering identity,…

Open monograph →
Metabolic
Vitamin B-12 / Cobalamin

Educational scientific reference on vitamin B-12 (cobalamin) — a cobalt-containing corrinoid vitamin cofactor, NOT a…

Open monograph →
Metabolic
Cagrilintide

Educational scientific reference on cagrilintide (AM833 / NNC0174-0833), a long-acting acylated amylin analogue and…

Open monograph →
Metabolic
L-Carnitine / Levocarnitine

Educational scientific reference on L-carnitine (levocarnitine) — a quaternary ammonium compound derived from lysine…

Open monograph →
Metabolic
Lipo-C / MIC + Carnitine

Educational scientific reference on Lipo-C — a compounded lipotropic injection blend (methionine, inositol, choline,…

Open monograph →
Metabolic
Liraglutide vs Dulaglutide

Comprehensive clinician reference comparing Liraglutide and Dulaglutide, two FDA-approved GLP-1 receptor agonists with…

Open monograph →
Metabolic
Pramlintide / Symlin

Comprehensive clinician reference on Pramlintide, the FDA-approved synthetic amylin analog used as a mealtime-insulin…

Open monograph →
Metabolic
MK-677 / Ibutamoren

Comprehensive scientific reference on MK-677 (ibutamoren), a non-peptide oral ghrelin-receptor (GHSR-1a) agonist and…

Open monograph →
Metabolic
MOTS-c

Comprehensive scientific reference on MOTS-c (mitochondrial-derived peptide) covering AMPK / CK2 / NRF2 mechanism,…

Open monograph →
Metabolic
NAD+ (Nicotinamide Adenine Dinucleotide)

Comprehensive scientific reference on NAD+ (nicotinamide adenine dinucleotide), a nucleotide redox coenzyme…

Open monograph →
Metabolic
Retatrutide

Comprehensive scientific reference on Retatrutide (LY3437943) covering mechanisms, dosing protocols, titration…

Open monograph →
Metabolic
SLU-PP-332

Educational scientific reference on SLU-PP-332 — a synthetic small-molecule pan-ERR (ERRalpha/beta/gamma) agonist…

Open monograph →
Metabolic
Tirzepatide

Comprehensive scientific reference on Tirzepatide (Mounjaro · Zepbound · LY3298176) covering GIP/GLP-1 dual-agonist…

Open monograph →
ATLAS tool
Reconstitution calculator

Convert vial strength and water volume into exact draw units for any target dose.

Open calculator →
ATLAS tool
Compare peptides

Put this peptide side by side with others — class, status, and evidence in one view.

Compare →
Index
Full peptide directory

Search and filter all 62 evidence-graded monographs by class, status, and mechanism.

Browse all →