Efpeglenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist based on the structure of exendin-4, delivered solid improvements in cardiovascular (CV) and renal outcomes in what may be the least well-controlled type 2 diabetes population ever treated in a randomized controlled trial. The efficacy and safety outcomes of efpeglenatide are similar to the outcomes seen in trials of other GLP-1 receptor agonists, according to research presented at the Scientific Sessions.

“Efpeglenatide safely reduces major cardiovascular and renal outcomes in low- and high-risk people with type 2 diabetes whilst lowering glucose, blood pressure, and weight,” said Naveed Sattar, MD, PhD, Professor of Metabolic Medicine, University of Glasgow Institute of Cardiovascular and Medical Science, United Kingdom.

Dr. Sattar and the other trial investigators presented First Results of the Effects of Efpeglenatide on Cardiovascular Outcomes (AMPLITUDE-O) Trial on Monday, June 28, at the Scientific Sessions. The session can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

AMPLITUDE-O was designed to determine if the effects of an exendin-4 based GLP-1 receptor agonist are similar to other agents in the class. Six previous trials (LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, REWIND, PIONEER 6) had clearly demonstrated the benefits in CV and renal outcomes for other types of GLP-1 receptor agonists, noted Stefano del Prato, MD, Professor of Clinical and Experimental Medicine, University of Pisa, Italy. But the results of ELIXA [Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide)], the only other phase 3 trial of an exendin-4 mimetic prior to AMPLITUDE-O, were neutral, leaving questions about the efficacy and safety of efpeglenatide.

AMPLITUDE-O was designed to assess the CV and renal effects of efpeglenatide in people with type 2 diabetes who had a high A1C at baseline, as well as a high prevalence of cardiovascular disease (CVD) and renal disease with moderate use of a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

Compared to the previous trials of GLP-1 receptor agonists, AMPLITUDE-O participants had the longest duration of diabetes, 15 years; the lowest estimated glomerular filtration rate (eGFR), 72; the highest A1C, 8.9;  and the highest rate of insulin use, 62%, noted Kelley Branch, MD, MSc, Professor of Cardiology, University of Washington. Study participants’ mean age was 54.5 years, mean body max index (BMI) was 32.7, and mean blood pressure was 135/77 mmHg. Participants were 33% female and 87% were white.

Most study participants, 90%, had prior CVD and 91% had hypertension appropriately treated with ACEI/ARB/ARNI (angiotensin converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor) agents, beta blockers, statins, fibrates, aspirin, and other antiplatelet drugs., Dr. Branch noted. Only 2% of participants were not on at least one glucose-lowering drug, including insulin, metformin, sulfonylureas, and/or SGLT2 inhibitors.

A total of 4,076 participants were enrolled across 344 sites in 28 countries between February 2018 and April 2019, and then randomized 1:1:1 to placebo, 4 mg weekly efpeglenatide, or 6 mg weekly efpeglenatide, said Carolyn S.P. Lam, MBBS, PhD, Senior Consultant Cardiologist, National Heart Centre Singapore, and Professor of Medicine, Duke-National University of Singapore Medical School, Singapore.

The primary outcome was non-inferiority of efpeglenatide 4 mg and 6 mg to placebo for major adverse cardiac events (MACE), a composite of non-fatal myocardial infarction (MI) or stroke or death from cardiovascular or undetermined causes. The trial was not powered to compare the two separate doses of efpeglenatide to each other, or to placebo. Results from the two efpeglenatide doses were combined and reported as a single cohort.

Six secondary outcomes were a hierarchy assessed for superiority versus placebo until non-significance was reached: MACE; MACE plus coronary revascularization or hospitalization for unstable angina; new or worsening neuropathy; MACE or non-CV death; renal function; and MACE, non-cardiovascular death, heart failure, or renal function.

Clinical outcomes

After a mean follow up of 1.8 years, the efpeglenatide group had 1.24 lower A1C—7.5 versus 8.4—compared to placebo.

“This is despite increased use of glucose-lowering medications in the placebo group,” said Julio Rosenstock, MD, Director of the Dallas Diabetes Research Center and Clinical Professor of Medicine, University of Texas Southwestern Medical Center.

Efpeglenatide showed the expected changes in body weight and BMI—2.59 kg lower weight and a 0.92 BMI reduction versus placebo.

Blood pressure improved more in the efpeglenatide group—1.48 mmHg lower systolic and 0.59 mmHg lower diastolic versus placebo. Pulse pressure fell 2.05 mmHg lower with efpeglenatide and the heart rate increased 3.89 beats per minute versus placebo.

There were no significant differences in prespecified adverse events, such as cancer, pancreatic events, severe hypoglycemia, diabetic retinopathy, acute renal failure, or severe immune complex disease. And there was no increase in spontaneously reported adverse events.

Cardiovascular and neuropathy outcomes

The hazard ratio (HR) for MACE was 0.73 for efpeglenatide, with p-values of <0.001 for non-inferiority and  0.0069 for superiority.

“There are clearly lower events in efpeglenatide, with the curves beginning to diverge in the first three months,” said Hertzel C. Gerstein, MD, MSc, FRCPC, Population Health Institute Chair in Diabetes Research, McMaster University, Hamilton, Canada. “There is very clear superiority, with a 27% reduction in risk for MACE.”

Efpeglenatide also showed superiority for MACE or coronary revascularization/unstable angina hospitalization (HR 0.79, p=0.020), MACE or non-cardiovascular death (HR 0.73, p=0.0040), and neuropathy (HR 0.57, p<0.0001).

Efpeglenatide was not superior to placebo for MACE, non-cardiovascular death, heart failure, or renal function.

An exploratory comparison between the two efpeglenatide doses shows a hazard ratio of 0.82 for the 4 mg dose and 0.65 for the 6 mg dose, Dr. Gerstein noted. Other exploratory outcomes show benefit for efpeglenatide, including fatal or nonfatal MI (HR 0.75), fatal or nonfatal stroke (HR 0.74), cardiovascular death (HR 0.72), all-cause mortality (HR 0.78), and heart failure hospitalization (HR 0.61).

Renal outcomes

The renal effects of efpeglenatide were uniformly positive. The urine albumin:creatinine ratio was 21% lower versus placebo (p<0.001), and eGFR was 0.87 mL/min/1.73m² higher (p=0.0005). The efpeglenatide HR for a composite kidney outcome was 0.68. Efpeglenatide had a HR of 0.77 for kidney function with no differences by sex, age, ancestry, geography, or baseline clinical factors.

“There is an early and marked difference between the two groups,” said Richard E. Pratley, MD, Medical Director, AdventHealth Diabetes Institute, and Diabetes Program Lead, AdventHealth Translational Research Institute. “We saw no SGLT2 inhibitor effect on renal benefits, no differences by SGLT2 inhibitor use or not.”