Efpeglenatide
A long-acting exendin-4 analogue whose outcomes trial cut cardiovascular and kidney events, then stalled without approval
Efpeglenatide is exendin-4 attached to an antibody fragment that stretches its half-life to about a week, allowing weekly or even monthly injections. Its AMPLITUDE-O outcomes trial found fewer heart and kidney events in type 2 diabetes, but it has not been approved anywhere this page could verify, and the US lists no application.
What is it?
Efpeglenatide belongs with exenatide and the other GLP-1 receptor agonists, but its carrier gives a geometric-mean half-life of 135 to 180 hours. In AMPLITUDE-O, people with type 2 diabetes and cardiovascular or kidney disease had fewer major cardiovascular events and fewer kidney outcomes on weekly efpeglenatide than on placebo.
The benefit tracked the dose. Major cardiovascular events occurred in 9.2% on placebo, 7.7% on 4 mg and 6.2% on 6 mg, and only the higher dose was significant on its own. It held whether or not people were also on an SGLT2 inhibitor, and lower LDL cholesterol and urinary albumin together explained only about 30% of it.
Glucose and weight effects followed the class: HbA1c fell by more than a percentage point on monotherapy and 0.6 to 1.2 points more than placebo in dose-ranging, with the usual gastrointestinal side effects; 4 mg matched liraglutide and later doses matched dulaglutide. Monthly dosing worked but let glucose and side effects rise and fall between doses.
It was also tested for weight. In BALANCE, adults with obesity but without diabetes lost 6.3 to 7.2 kg more than on placebo over 20 weeks, and among those with pre-diabetes up to 64% returned to normal glucose. Development for obesity is described as ongoing in a 2025 pharmacokinetic analysis. It is approved nowhere.
Mechanism of Action
Efpeglenatide is a GLP-1 receptor agonist attached to a carrier that stretches its half-life to about a week.
GLP-1 receptor
Activates the GLP-1 receptor, the same target as exenatide and the rest of the class.
Long half-life
Geometric-mean half-life of 135 to 180 hours across dose-finding studies, allowing weekly or even monthly dosing.
Cardiorenal effects
Lowered cardiovascular and kidney events in AMPLITUDE-O; LDL and albuminuria changes explained only part of that.
Published Research
Trials read from their PubMed abstracts; efpeglenatide has no label.
AMPLITUDE-O
In 4,076 people with type 2 diabetes and cardiovascular or kidney disease, a major cardiovascular event occurred in 7.0% on efpeglenatide 4 or 6 mg weekly against 9.2% on placebo over a median 1.8 years, and the kidney composite in 13.0% against 18.4% (hazard ratio 0.68).
Monotherapy
In adults with type 2 diabetes on diet and exercise alone, HbA1c fell from 8.1% to 6.9%, 6.6% and 6.4% on 2, 4 and 6 mg weekly by week 30, all superior to placebo, with mostly transient gastrointestinal events.
Once a month
After weekly titration, monthly dosing brought more patients below 7% HbA1c than placebo (48.7% against 30.6%) and 2.0 kg of placebo-corrected weight loss, with effects and GI events fluctuating between peak and trough.
Pharmacokinetics
Across the dose-finding studies the geometric-mean half-life was 135 to 180 hours, and glucose stayed below baseline for at least 3 weeks after a single dose.
Against liraglutide
Monthly efpeglenatide 16 mg slowed gastric emptying less than liraglutide (non-inferiority was not shown), with comparable or better glucose effects and mild, transient GI events.
AMPLITUDE-D, -L and -S
In type 2 diabetes, once-weekly efpeglenatide 4 or 6 mg was non-inferior to dulaglutide 1.5 mg for HbA1c at 56 weeks, with similar weight loss of about 3 kg; in two placebo-controlled trials it lowered HbA1c and weight numerically more than placebo.
What explains the heart benefit?
In a post hoc AMPLITUDE-O analysis, changes in LDL cholesterol and urinary albumin together accounted for about 30% of efpeglenatide's effect on major cardiovascular events; weight change did not.
Liver fibrosis score and benefit
In 4,059 AMPLITUDE-O participants, efpeglenatide's effect on cardiovascular events did not vary with the FIB-4 liver fibrosis score.
AMPLITUDE-O: does dose matter?
Major cardiovascular events occurred in 9.2% on placebo, 7.7% on 4 mg (hazard ratio 0.82, not significant) and 6.2% on 6 mg (0.65); kidney outcomes also fell more on the higher dose.
With or without an SGLT2 inhibitor
In AMPLITUDE-O, effects on cardiovascular events (hazard ratio 0.74 without and 0.70 with an SGLT2 inhibitor) and on kidney outcomes did not differ by SGLT2 inhibitor use, and neither did adverse events.
Dose-ranging in type 2 diabetes
From a baseline HbA1c near 8%, weekly doses of 1 mg or more lowered HbA1c 0.6 to 1.2 points more than placebo; 4 mg was non-inferior to liraglutide, and no neutralising antibodies were found.
BALANCE: weight in adults without diabetes
Over 20 weeks, efpeglenatide lowered weight by 6.3 to 7.2 kg more than placebo, with better glucose and lipids; 5% to 19% stopped for adverse events, mostly gastrointestinal.
BALANCE: people with pre-diabetes
Among BALANCE participants with pre-diabetes, 40.6% to 64.3% on efpeglenatide returned to normal glucose against 10.0% on placebo, and weight fell 5.6 to 7.3 kg more.
Population pharmacokinetics
Pooling six studies in type 2 diabetes and obesity, body weight and disease affected absorption and clearance, but exposure differences were within bioequivalence limits, supporting one dosing scheme without routine adjustment.
Dosing Data
There is no approved dose. The outcomes trial used 4 or 6 mg once weekly under the skin; obesity trials used up to 6 mg weekly.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the trials.
Contraindications & Cautions
No label exists.
Legal Status
Not approved in the US.
Frequently Asked Questions
?Why was it not approved after a positive outcomes trial?
The trial results are public; why no application followed is not something its PubMed record explains, and this page does not guess.
?How is it different from semaglutide?
Both act on the GLP-1 receptor; efpeglenatide is built on exendin-4 with an antibody fragment, semaglutide on human GLP-1 with a fatty acid chain.
?Could it be taken monthly?
A 2020 trial tested monthly doses after weekly titration and found HbA1c benefits with peak-to-trough swings.
?Does it help with weight?
In the phase 2 BALANCE trial, adults with obesity but without diabetes lost 6.3 to 7.2 kg more than on placebo over 20 weeks, and many with pre-diabetes returned to normal glucose.
?Can it be combined with an SGLT2 inhibitor?
In AMPLITUDE-O its effects on heart and kidney outcomes, blood pressure, weight and albuminuria were the same whether or not people were also taking an SGLT2 inhibitor, and adverse events did not differ.
?Did the dose matter for the heart benefit?
It seemed to. Major cardiovascular events were 6.2% on 6 mg against 9.2% on placebo, a significant reduction; on 4 mg they were 7.7%, which on its own did not reach significance.
References
- [clinical-trial] Gerstein HC, et al. "Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes." N Engl J Med, 2021;385(10):896-907. PMID: 34215025.
- [clinical-trial] Frias JP, et al. "Efficacy and Safety of Once-Weekly Efpeglenatide Monotherapy Versus Placebo in Type 2 Diabetes: The AMPLITUDE-M Randomized Controlled Trial." Diabetes Care, 2022;45(7):1592-1600. PMID: 35671039.
- [clinical-trial] Del Prato S, et al. "Efficacy and safety of once-monthly efpeglenatide in patients with type 2 diabetes: Results of a phase 2 placebo-controlled, 16-week randomized dose-finding study." Diabetes Obes Metab, 2020;22(7):1176-1186. PMID: 32128957.
- [clinical-trial] Yoon KH, et al. "Pharmacokinetic and dose-finding studies on efpeglenatide in patients with type 2 diabetes." Diabetes Obes Metab, 2020;22(8):1292-1301. PMID: 32175655.
- [clinical-trial] Hompesch M, et al. "Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study." BMJ Open Diabetes Res Care, 2021;9(1). PMID: 34172436.
- [clinical-trial] Aroda VR, et al. "Efficacy and safety of once-weekly efpeglenatide in people with suboptimally controlled type 2 diabetes: The AMPLITUDE-D, AMPLITUDE-L and AMPLITUDE-S randomized controlled trials." Diabetes Obes Metab, 2023;25(8):2084-2095. PMID: 37013892.
- [pubmed] Raaschou-Oddershede D, et al. "Potential Mediators of Efpeglenatide's Cardiovascular Benefit: An Exploratory Analysis of the AMPLITUDE-O Trial." Diabetes Obes Metab, 2026;28(9):8552-8559. PMID: 42387302.
- [pubmed] Del Prato S, et al. "Impact of baseline FIB-4 score on efpeglenatide benefits on cardiovascular outcomes in people with type 2 diabetes: a participant-level exploratory analysis of the AMPLITUDE-O trial." Cardiovasc Diabetol, 2024;23(1):352. PMID: 39342203.
- [pubmed] Gerstein HC, et al. "Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial." Circulation, 2023;147(13):1004-1013. PMID: 36802715.
- [pubmed] Lam CSP, et al. "Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial." Circulation, 2022;145(8):565-574. PMID: 34775781.
- [pubmed] Rosenstock J, et al. "Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide." Diabetes Care, 2019;42(9):1733-1741. PMID: 31320446.
- [pubmed] Pratley RE, et al. "Body weight management and safety with efpeglenatide in adults without diabetes: A phase II randomized study." Diabetes Obes Metab, 2019;21(11):2429-2439. PMID: 31264757.
- [pubmed] Pratley RE, et al. "Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline." BMJ Open Diabetes Res Care, 2022;10(1). PMID: 35042751.
- [pubmed] Choi S, et al. "Population pharmacokinetics of efpeglenatide in individuals with obesity and with type 2 diabetes." Front Pharmacol, 2025;16:1715585. PMID: 41403449.
Sources & Citations
Studies were read from their PubMed abstracts; there is no approved label. Read October 6, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.