Efpeglenatide Cuts Risk of CV Events and Kidney Disease in High-risk T2D Patients, Regardless of SGLT2 Status

Sanofi gave up rights to develop the glucagon-like peptide 1 receptor agonist last year after a change in strategy.

Efpeglenatide, a long-acting exendin-4–based glucagon-like peptide-1 receptor agonist (GLP-1 RA), offered significant benefits in cardiovascular (CV) and renal outcomes for some of the highest-risk patients ever studied, in findings presented Monday during the 81st Scientific Sessions of the American Diabetes Association.

But in a surprise, the findings of AMPLITUDE-O showed that the 15% of patients in the trial who were taking sodium-glucose co-transporter 2 (SGLT2) inhibitors, which reduces blood glucose through a separate mechanism of action, did not have better outcomes than others in the trial. This finding comes despite recommendations from some diabetes experts that some high-risk patients with type 2 diabetes (T2D) should take a drug in each class; their benefits are seen as complementary.

Results were simultaneously published in The New England Journal of Medicine (NEJM).

Nearly all patients with T2D have at least 1 other chronic condition: 24% have kidney disease, 22% have cardiovascular disease, and 82% have hypertension. Thus, patients taking medication to control blood sugar are almost always taking other therapy to treat these comorbid conditions, and clinicians have been encouraged by the rise of modern T2D drug classes that could treat multiple conditions at once.

SGLT2 inhibitors had been shown to reduce the risk of heart failure hospitalization and chronic kidney disease progression, while GLP-1 RAs were seen as beneficial in preventing CV events, including stroke; earlier trials also showed that GLP-1 RA drugs based on human GLP-1 could reduce kidney events. AMPLITUDE-O was designed to evaluate the effects of weekly injections of efpeglenatide on CV and renal outcomes in patients with or without an SGLT2 inhibitor.

The trial involved 4076 patients in 28 countries randomized 1:1:1 to receive either a 4-mg or 6-mg dose of the study drug, or placebo. Most patients were treated for 1.8 years. Patients in AMPLITUDE-O had a mean glycated hemoglobin level of 8.91%, a mean age of 64.5 years, and a mean duration of diabetes of 15.4 years; 86.7% of the study participants and 87% of those taking the study drug were White.

Results showed:

  • Patients taking efpeglenatide had a 27% reduction in major adverse cardiovascular events, which included heart attack, stroke, or CV death; the HR compared with placebo was 0.73 (95% CI, 0.58-0.92; P = .0069 for superiority)
  • Patients taking efpeglenatide saw a 32% reduction in a composite of renal events (decreased kidney function or macroalbuminuria), for an HR of 0.68 (95% CI, 0.57-0.79; P < . 001)
  • The most common adverse events were diarrhea, constipation, and nausea, and they were more common with the study drug than with placebo and consistent with the GLP-1 RA class
  • Although the results were exploratory, the findings did show a more pronounced benefit for efpeglantide at the higher dose

Hertzel C. Gerstein, MD, MSc, professor at McMaster University and Hamilton Health Sciences, and deputy director, Population Health Research Institute, in Ontario, Canada, said the findings establish efpeglenatide as a safe, effective cardioprotective drug for T2D in patients with cardiovascular or kidney disease.

He noted the lack of differentiation among patients taking the study drug with and without an SGLT2 inhibitor; there were 618 who took both.

“When we look at the effect, you're seeing no evidence whatsoever of any difference in effect of the combination of SGLT2 inhibitor plus a GLP-1 receptor agonist,” Gerstein said, as he demonstrated the trajectory of the curves from baseline to through the course of the study.

The NEJM paper stated, “The results suggest that these cardiovascular and renal benefits occurred independently of the baseline use of SGLT2 inhibitors, the baseline use of metformin, and the baseline [estimated glomerular filtration rate].”

The study authors listed strengths as the high retention rate of trial participants, the inclusion of patients taking SGLT2 inhibitors, and the fact that all patients were taking guideline-recommended therapies for comorbid conditions.

Limitations included the short follow-up period and that a primary outcome event occurred in a lower number of participants than planned: 314 vs 330. Also, the authors listed as a limitation, “selection for previous cardiovascular or kidney disease, which limit the power of our trial and its generalizability to lower-risk persons with type 2 diabetes.”

Sanofi had funded the trial, but last year returned the marketing rights for the drug to developer Hanmi after announcing a dramatic shift away from its long-term focus on diabetes and CV care.


Gerstein HC, Sattar N, Rosenstock J, et al. for the AMPLITUDE-O investigators. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. Published online June 28, 2021. doi:10.1056/NEJMoa2108269

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