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Efpeglenatide (LY3298176-class exendin-based GLP-1 receptor agonist)
An investigational once-weekly injectable, exendin-based (exenatide-lineage) GLP-1 receptor agonist most famous for the AMPLITUDE-O cardiovascular-outcomes trial — the first to show that an EXENDIN-based (rather than human-GLP-1-based) agonist reduces major adverse cardiovascular events AND kidney-outcome events in high-risk type 2 diabetes. Honest framing: in AMPLITUDE-O (NEJM 2021, n=4,076) efpeglenatide cut MACE by ~27% and a composite kidney outcome by ~32% versus placebo, and across its phase-2/3 program it lowered HbA1c (up to ~1.0-1.2%) and bodyweight (placebo-adjusted up to ~7 kg in obesity without diabetes). BUT it is INVESTIGATIONAL and not FDA-approved or marketed anywhere; the proven benefits are metabolic and cardiorenal (HbA1c, weight, MACE, kidney) — NOT a demonstrated lifespan/longevity outcome. It carries the full GLP-1-class GI side-effect burden (very common dose-dependent nausea, vomiting, diarrhea). It is a prescription-pathway investigational drug, not a dietary supplement, and grey-market 'efpeglenatide' is especially risky.
Prescription medication — not a dietary supplement
Efpeglenatide is a prescription (or investigational) drug, not a supplement. It is included here for reference because people research and discuss it (often used off-label) — not as a recommendation. Take it only under a qualified clinician's supervision and only as prescribed; do not source it from grey-market vendors, where identity, purity, and dosing are unverified. The evidence below reflects its clinical trials.
What the evidence says
Efpeglenatide doesn't have enough studies with structured effect-size data yet to pool a verdict. Browse the studies below for individual findings.
Most evidence is from high-quality meta-analyses and randomised trials published 2019–2026 with a typical study size of 3,983 participants.
Based on 21 studies · 8 meta-analyses · 11 RCTs · 31,255 total participants
Confidence
High confidenceBy outcome
Efpeglenatide has unusually strong human cardiorenal evidence for an investigational drug — the pivotal AMPLITUDE-O trial showed reduced MACE and kidney-outcome events plus consistent HbA1c and weight benefit across its phase-2/3 program — but it is NOT approved or marketed anywhere, its proven benefits are metabolic/cardiorenal rather than a demonstrated longevity outcome, and it carries the full GLP-1-class GI side-effect burden, so it stays Emerging.
11 randomised trials
every one checked individually
Every randomised or controlled trial of Efpeglenatide indexed in PubMed, not a hand-picked subset. Meta-analyses and systematic reviews are deliberately excluded from this count: most of them cover many compounds at once, so counting them would inflate it.
PubMed · as of Jul 2026
No trials currently enrolling · 1 completed on ClinicalTrials.gov
1 of the completed trials have posted results
Registered trials show research momentum for Efpeglenatide, not proof of effect — a registration is a plan, and posted results are sponsor-reported, not peer-reviewed. They are never counted toward the evidence rating above.
Browse these trials on ClinicalTrials.govClinicalTrials.gov · as of Nov 2026
Efpeglenatide (development codes LY3298176 / HM11260C) is a long-acting, once-weekly subcutaneous glucagon-like peptide-1 (GLP-1) receptor agonist developed by Hanmi Pharmaceutical and Sanofi.
It is mechanistically distinct from the dominant GLP-1 drugs in one important way: semaglutide, liraglutide, and dulaglutide are structurally modelled on human GLP-1, whereas efpeglenatide is EXENDIN-based — an exendin-4 (exenatide-lineage) backbone fused to a human IgG4 Fc fragment via a flexible linker (Hanmi's 'LAPSCOVERY' technology), which extends its half-life to support weekly dosing.
That distinction is the entire reason efpeglenatide matters scientifically: it was widely assumed that the cardiovascular benefit of GLP-1 agonists might be limited to the human-GLP-1-based agents, and AMPLITUDE-O was the trial that tested — and refuted — that hypothesis for an exendin-based drug.
Mechanistically efpeglenatide hits the same GLP-1 receptor cascade as the rest of the class: glucose-dependent insulin secretion with glucagon suppression in the pancreas (lowering HbA1c with low intrinsic hypoglycemia risk), central appetite suppression and satiety (driving weight loss), and slowed gastric emptying (blunting post-meal glucose and contributing to the dose-dependent nausea).
The clinical evidence is genuinely strong but the drug never reached market.
The pivotal trial is AMPLITUDE-O (Gerstein et al., N Engl J Med 2021; n=4,076), a randomized placebo-controlled cardiovascular-outcomes trial in people with type 2 diabetes who had a history of cardiovascular disease or kidney disease plus another risk factor: weekly efpeglenatide (4 or 6 mg) reduced the primary MACE outcome (nonfatal MI, nonfatal stroke, or cardiovascular/undetermined death) by 27% (HR 0.73, 95% CI 0.58-0.92; P=0.007 for superiority) and reduced a composite kidney outcome (worsening kidney function or new macroalbuminuria) by 32% (HR 0.68, 95% CI 0.57-0.79; P<0.001) — and a prespecified epidemiological analysis (Gerstein et al., Diabetes Obes Metab 2024) showed the cardiorenal benefit held across the full spectrum of baseline kidney disease (all interaction P≥0.26).
The earlier dose-finding and efficacy program established the metabolic signal: in early type 2 diabetes referenced to liraglutide (Rosenstock et al., Diabetes Care 2019; 'EXCEED 203', n≈254) efpeglenatide ≥1 mg lowered HbA1c by a placebo-adjusted 0.6-1.2% and was noninferior to open-label liraglutide at the 4 mg dose in an exploratory comparison; in obesity WITHOUT diabetes (Pratley et al., Diabetes Obes Metab 2019, phase-2, n=297) it produced placebo-adjusted weight loss of about 6.3-7.2 kg over 20 weeks; and AMPLITUDE-M (Frias et al., Diabetes Care 2022, phase-3 monotherapy) showed dose-dependent HbA1c reductions up to ~1.0% placebo-adjusted with weight loss.
A 2024 systematic review and meta-analysis (Qazi et al., 11 studies) pooled HbA1c -0.84%, bodyweight -2.24 kg and BMI -1.61 kg/m2 versus placebo, with a moderate increase in GI adverse events, and a GLP-1-class network meta-analysis (Vosoughi et al., EClinicalMedicine 2021, 64 RCTs) placed efpeglenatide's weight effect within the class (point estimate -3.2 kg over placebo with a 95% CI of -6.53 to 0.15 that crosses zero, while semaglutide 2.4 mg led at -9.9 kg).
The honest counterweight is decisive on regulatory status: despite this strong cardiorenal dataset, efpeglenatide is INVESTIGATIONAL — it is not FDA-approved or marketed anywhere (its development was not carried through to approval), so it is not a treatment you can be prescribed.
Its proven effects are metabolic and cardiorenal (HbA1c, weight, MACE, kidney) — there is NO demonstrated lifespan/healthspan or longevity outcome; framing it as a longevity drug would be reading a cardiovascular/renal endpoint as something it is not.
Adverse effects are class-typical: dose-related gastrointestinal events (nausea, vomiting, diarrhea, constipation, bloating were more frequent than placebo in AMPLITUDE-O and drove some discontinuation), the GLP-1-class thyroid C-cell (medullary carcinoma) warning is expected to apply, and the usual incretin cautions around pancreatitis, gallbladder events, and lean-mass loss alongside fat loss are unresolved by long-term data.
Because it is an unapproved investigational drug, grey-market 'efpeglenatide' sold online carries serious identity, purity, sterility, and dosing risks with no clinical oversight. It is an unapproved drug, not a supplement, and is sandboxed out of goal-based and stack recommendations.
An exendin-4 (exenatide-lineage) GLP-1 receptor agonist fused to a human Fc fragment for a long half-life and weekly dosing — mechanistically distinct from the human-GLP-1-based agents (semaglutide, liraglutide). The single upstream target driving all downstream metabolic and cardiorenal effects; AMPLITUDE-O is notable because it proved an exendin-based agonist also lowers cardiovascular events.
Stimulates pancreatic insulin release in a glucose-dependent manner and suppresses glucagon, lowering blood glucose and HbA1c with low intrinsic hypoglycemia risk (few hypoglycemia events in the trials).
Acts on central appetite-regulating circuits to increase satiety and reduce food intake — the primary driver of the weight loss seen in the obesity and diabetes trials.
Beyond glucose lowering, efpeglenatide reduced major adverse cardiovascular events and a composite kidney outcome (worsening kidney function / new macroalbuminuria) in AMPLITUDE-O — the GLP-1-class cardiorenal benefit, here demonstrated for an exendin-based agent across the spectrum of baseline kidney disease.
Delays gastric emptying, blunting post-meal glucose excursions and prolonging fullness — and the mechanism behind much of the dose-dependent nausea seen early in treatment.
How Efpeglenatide works — from molecular targets to health outcomes. Click an edge to see supporting research.This visualization is in beta — pathways are being refined and expanded.
There is no approved or marketed use; obtaining or using grey-market 'efpeglenatide' means taking an unapproved investigational drug with no clinical oversight, dosing standard, or product-quality guarantee. Strongly discouraged.
Higher hypoglycemia risk if combined; only relevant under trial-level medical supervision with secretagogue adjustment.
Expected to be contraindicated — the GLP-1 class carries a thyroid C-cell tumor warning.
Contraindicated — weight loss and an investigational drug are not appropriate in pregnancy or breastfeeding.
GLP-1 agonism slows gastric emptying, which can reduce the rate/extent of absorption of co-administered oral drugs — relevant for time-critical or narrow-therapeutic-index oral medicines.
Combining a glucose-lowering incretin agonist with insulin or sulfonylureas increases hypoglycemia risk; dose reduction of the secretagogue is typically required in supervised use. Efpeglenatide alone showed few hypoglycemia events.
Stacking efpeglenatide with another GLP-1/incretin agonist (semaglutide, liraglutide, dulaglutide, tirzepatide) compounds gastrointestinal toxicity and glucose-lowering with no evidence of added benefit; this combination is not studied and is dangerous.
Tip: Dose-related and more common than placebo; mitigated by a lower starting dose and slow escalation. Generally transient, concentrated during titration.
Tip: Class-typical GI effects (more frequent than placebo in AMPLITUDE-O); generally transient and dose-related; a reason for some discontinuation.
Tip: In the 20-week weight-management trial, 5% to 19% of efpeglenatide-treated participants stopped because of adverse events, and gastrointestinal effects were the most common adverse events. The abstract gives no placebo figure to compare. Slower titration may help.
Tip: Rapid weight loss and incretin-class effects are associated with gallbladder events; report severe abdominal pain.
Tip: A class concern for incretin drugs; discontinue and seek care for persistent severe abdominal pain. Long-term incidence not established.
Efpeglenatide has an evidence score of 4.3/10 — emerging evidence based on 21 indexed studies, including 2 meta-analyses. An investigational once-weekly injectable, exendin-based (exenatide-lineage) GLP-1 receptor agonist most famous for the AMPLITUDE-O cardiovascular-outcomes trial — the first to show that an EXENDIN-based (rather than human-GLP-1-based) agonist reduces major adverse cardiovascular events AND kidney-outcome events in high-risk type 2 diabetes. Honest framing: in AMPLITUDE-O (NEJM 2021, n=4,076) efpeglenatide cut MACE by ~27% and a composite kidney outcome by ~32% versus placebo, and across its phase-2/3 program it lowered HbA1c (up to ~1.0-1.2%) and bodyweight (placebo-adjusted up to ~7 kg in obesity without diabetes). BUT it is INVESTIGATIONAL and not FDA-approved or marketed anywhere; the proven benefits are metabolic and cardiorenal (HbA1c, weight, MACE, kidney) — NOT a demonstrated lifespan/longevity outcome. It carries the full GLP-1-class GI side-effect burden (very common dose-dependent nausea, vomiting, diarrhea). It is a prescription-pathway investigational drug, not a dietary supplement, and grey-market 'efpeglenatide' is especially risky. Representative study: PMID 34877513.
Dosing for Efpeglenatide: SupStack does not provide a self-directed dosing protocol for Efpeglenatide. A dose used in a clinical trial does not establish a safe consumer dose. In trials, efpeglenatide was given as a once-weekly subcutaneous injection, titrated up to 4-6 mg (AMPLITUDE-O used 4 and 6 mg) with gradual escalation to limit GI side effects. Not for self-administration.
Timing is flexible for Efpeglenatide — consistent daily use matters more than the time of day. Trials dosed once weekly subcutaneously with gradual dose escalation to limit gastrointestinal effects; the long half-life supports once-weekly administration.
No consumer dose of Efpeglenatide is endorsed, so there is no dose at which it can be called safe. Talk to a healthcare provider before taking it. Reported side effects include pancreatitis (class concern), treatment discontinuation due to adverse events, gallbladder / biliary events. How often they occur is not established for all of them. Use caution if any of these apply to you: Not a dietary supplement and not an approved/marketed drug — investigational; do not self-source grey-market vials; Personal/family history of medullary thyroid carcinoma or MEN 2 (expected GLP-1-class thyroid C-cell precaution, not a product-label contraindication: this investigational drug has no label, and not every approved GLP-1 product carries the US thyroid boxed warning); History of pancreatitis.
What side effects does Efpeglenatide have?Don't take this if…
Semaglutide
Too few graded studiesAn FDA-approved GLP-1 receptor agonist (Ozempic/Rybelsus for type 2 diabetes, Wegovy for chronic weight management) with genuinely strong, large-RCT evidence for glycemic control and substantial weight loss, plus a cardiovascular-outcomes benefit. Honest appraisal: this is a real prescription medicine with real efficacy AND real risks — a US FDA boxed warning for thyroid C-cell tumors, pancreatitis and gallbladder risk, very common GI side effects, and growing concern about grey-market/compounded versions. It is a prescription drug, not a supplement, and is never auto-recommended.
Liraglutide
Too few graded studiesAn FDA-approved, once-daily GLP-1 receptor agonist (Victoza for type 2 diabetes, Saxenda for chronic weight management). Honest appraisal: a real prescription medicine with genuinely strong large-RCT evidence for glycemic control and moderate weight loss, plus a cardiovascular-outcomes benefit (LEADER). It also carries real risks — a US FDA boxed warning for thyroid C-cell tumors, pancreatitis and gallbladder risk, very common GI side effects, and lean-mass loss with weight loss. It is a prescription medicine, NOT a supplement, and is not auto-recommended.
Tirzepatide
Too few graded studiesAn FDA-approved prescription medication (Mounjaro for type 2 diabetes, Zepbound for obesity and obstructive sleep apnea), not a dietary supplement. Honest appraisal: in head-to-head phase-3 trials it is the most effective approved weight-loss drug to date — up to ~21% body-weight loss over 72 weeks and superior to semaglutide — but it is a real medicine with real risks: a US FDA boxed warning for thyroid C-cell tumors, common GI side effects, and pancreatitis/gallbladder signals. Do not source or use it outside a prescription.
Dulaglutide
Too few graded studiesAn FDA-approved once-weekly GLP-1 receptor agonist (brand Trulicity) for type 2 diabetes, with genuinely strong, large-RCT evidence for lowering HbA1c plus a dedicated cardiovascular-outcomes trial (REWIND) showing a ~12% reduction in major cardiovascular events. Honest appraisal: this is a real prescription medicine with real efficacy AND real risks — a US FDA boxed warning for thyroid C-cell tumors, pancreatitis and gallbladder risk, very common GI side effects, and modest (not semaglutide-tier) weight loss. It is a prescription drug, not a supplement, and is never auto-recommended.
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Reviewed by Dr. Baher Al Hakim · Last reviewed June 2026 · evidence from 21 studies · how we score · editorial policy
This information is for educational purposes only. It is not a substitute for professional medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any supplement or medication.
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