Clinician Article

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.

  • Gerstein HC
  • Sattar N
  • Rosenstock J
  • Ramasundarahettige C
  • Pratley R
  • Lopes RD, et al.
N Engl J Med. 2021 Sep 2;385(10):896-907. doi: 10.1056/NEJMoa2108269. Epub 2021 Jun 28. (Original)
PMID: 34215025
Read abstract
  • Cardiology
    Relevance - 6/7
    Newsworthiness - 6/7
  • Endocrine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 6/7
  • Nephrology
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 5/7
    Newsworthiness - 4/7


BACKGROUND: Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.

METHODS: In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m2 of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).

RESULTS: A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.

CONCLUSIONS: In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).

Clinical Comments


So many meds are beneficial in diabetes.


It should be noted that this paper shows the importance of the baseline prevalence of established CVD and why one cannot compare HRs between studies to evaluate the effectiveness of different GLP-1 agonists. All of the patients had established CVDs (and a lower HR than in the studies of other GLP-1 agonists); in the other studies, baseline established CVDs were less.

Family Medicine (FM)/General Practice (GP)

Another medication that can mimimize MACE in patients with DM type II. However, it is injectable, there were only 4K patients in the study, and cost is most certainly an issue.

General Internal Medicine-Primary Care(US)

It's good to know that another GLP-1 with a different chemical structure protects against adverse cardiac and renal outcomes.

Internal Medicine

This drug is not on the market.

Internal Medicine

Perhaps I’m too cynical: I do not find this study of interest. We already know these drugs lower risk. We also know the risk reduction is modest. We know that the target population is “nearly every adult." We know that they are expensive and that guidelines will exert pressure for them to be used in addition to all the other risk reduction drug classes. What we don’t know is how patients and prescribers will have the capacity to incorporate yet another “breakthrough" in their lives.

Internal Medicine

Another potential GLP-1 that has cardiovascular and kidney benefits.


This RCT examines a newer GLP-1 receptor agonist, efpeglenatide, given as a weekly subcutaneous injection. It confirms the cardiac and renal benefits seen in other studies of GLP-1 analogues. Most of the renal benefit was driven by a decrease in incident albuminuria, rather than "hard" clinical outcomes.


Another well-conducted RCT using a GLP-1 agonist that showed benefits for MACE and renal outcomes in patients with type 2 DM and either CVD, CKD, or CVD risk factors. Half of patients had albuminuria. It's unclear how many of the renal events were driven by proteinuria reduction as opposed to eGFR reduction or ESRD. This adds to evidence that GLP-1 agonists should be used earlier and more often in this group of patients.

Register for free access to all Professional content

Want the latest in aging research? Sign up for our email alerts.

Support for the Portal is largely provided by the Labarge Optimal Aging Initiative. AGE-WELL is a contributing partner. Help us to continue to provide direct and easy access to evidence-based information on health and social conditions to help you stay healthy, active and engaged as you grow older. Donate Today.

© 2012 - 2020 McMaster University | 1280 Main Street West | Hamilton, Ontario L8S4L8 | +1 905-525-9140 | Terms Of Use