AMPLITUDE-O: Efpeglenatide reduces CV events, CKD progression in high-risk type 2 diabetes
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A novel GLP-1 receptor agonist reduced cardiovascular event risk by 27% and kidney disease progression by 32% compared with placebo for high-risk adults with type 2 diabetes, with or without background SGLT2 inhibitor therapy, data show.
Data from the AMPLITUDE-O trial, presented at the American Diabetes Association Scientific Sessions and simultaneously published in The New England Journal of Medicine, showed that weekly efpeglenatide, an investigational, exendin-4-based GLP-1 receptor agonist, was safe for high-risk patients and CV and renal benefits were similar to other human-based GLP-1 receptor agonists in the class, Hertzel C. Gerstein, MD, MSc, FRCPC, professor and population health institute chair in diabetes research at McMaster University and Hamilton Health Sciences in Ontario, Canada, said during a virtual presentation. The study was also the first large CV outcomes trial to assess the use of a GLP-1 receptor agonist in a population on background SGLT2 inhibitor therapy — 15% of trial participants, he said.
“We know SGLT2 inhibitors are cardioprotective and GLP-1 receptor agonists are cardioprotective,” Gerstein told Healio. “No trial has ever looked at the effects of both taken together. We were pleased to see there were no differences whatsoever with or without concomitant SGLT2 inhibitor use. It is reassuring, and it shows that we can use these drugs together from a CV perspective and the benefits would likely be additive.”
Effects of nonhuman GLP-1
Four GLP-1 receptor agonists with structures based on human GLP-1 have been shown to reduce the risk for CV events among adults with type 2 diabetes. The effect of an exendin-4-based GLP-1 receptor agonist, efpeglenatide, on CV and renal outcomes in among high-risk adults with type 2 diabetes is uncertain.
Gerstein and colleagues analyzed data from 4,076 adults with type 2 diabetes and either a history of CVD or kidney disease plus at least one CV risk factor (mean age, 65 years; 33% women; 87% white), recruited from 344 sites across 28 countries. Within the cohort, mean diabetes duration was 15.4 years and 90% had prior CVD, with 32% having an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2. Researchers randomly assigned participants weekly subcutaneous efpeglenatide 4 mg or 6 mg (n = 2,717) or placebo (n = 1,359), with randomization stratified by use of an SGLT2 inhibitor (n = 618).
“This trial was designed with the knowledge that many would be on an SGLT2 inhibitor, so we stratified randomization to ensure a balance of use of SGLT2s,” Gerstein told Healio. “That allowed us to assess if there was any difference by baseline SGLT2 inhibitor use.”
The primary outcome was the first major adverse CV event, a composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or undetermined causes.
During a median follow-up of 1.81 years, incident major adverse CV events occurred among 189 participants (7%) assigned efpeglenatide (3.9 events per 100 person-years) and among 125 participants (9.2%) assigned placebo (5.3 events per 100 person-years), for an HR of 0.73 (95% CI, 0.58-0.92; P < .0001 for noninferiority; P = .0069 for superiority). HR for the secondary expanded outcome of major adverse CV events, coronary revascularization or unstable angina was 0.79 for efpeglenatide vs. placebo (95% CI, 0.65-0.96).
Renal outcomes
Data across large CV outcomes trials have shown a consistent CV benefit with the GLP-1 receptor agonist class; however, there is less information available regarding renal benefit, Richard E. Pratley, MD, the Samuel E. Crockett chair in diabetes research and medical director of AdventHealth Diabetes Institute, said during a presentation on renal outcomes. Participants in AMPLITUDE had the highest prevalence of kidney disease compared with all other GLP-1 receptor agonist trials.
Study data showed that efpeglenatide significantly decreased albuminuria, development of macroalbuminuria and the rate of decline in eGFR, Pratley said. Additionally, efpeglenatide significantly decreased occurrence of the composite kidney outcome of new macroalbuminuria, an eGFR decline of greater than 40%, renal replacement therapy or an eGFR of less than 15 mL/min/1.73 m2. A composite renal outcome event, defined as a decrease in kidney function or development of macroalbuminuria, occurred in 353 participants (13%) assigned efpeglenatide and among 250 participants (18.4%) assigned placebo, for an HR of 0.68 (95% CI, 0.57-0.79).
The effects were similar across all subgroups, including among those prescribed SGLT2 inhibitor therapy, Pratley said.
“As was already pointed out, we had one of the highest rates of background SGLT2 inhibitor use and as we have seen, SGLT2 inhibitors are associated with renal benefit,” Pratley said. “We asked whether the use of SGLT2 inhibitors impacted renal benefit. The answer here is it did not. Regardless of the use of SGLT2 inhibitors, there was no significant difference in the two groups.”
Diarrhea, constipation, nausea, vomiting and bloating were more commonly reported among participants assigned efpeglenatide vs. placebo, keeping with the expected adverse event profile of the GLP-1 receptor agonist class.
‘Unambiguous’ CV risk reduction
“This is the first outcomes trial to show a reduction in CV outcomes with an exendin-4-based GLP-1,” Gerstein told Healio. “Prior to this, people had said only human GLP-1 reduces CV outcomes. ... This study says that is not true. Whether a GLP-1 receptor agonist is structurally similar to one vs. the other in the class is not important.”
From a cardioprotection standpoint, Gerstein said the AMPLITUDE data show that efpeglenatide is comparable to other GLP-1 receptor agonists like liraglutide (Victoza, Saxenda; Novo Nordisk), semaglutide (Ozempic, Rybelsus, Wegovy; Novo Nordisk), or dulaglutide (Trulicity, Eli Lilly).
“This is not a head-to-head study and we cannot say whether one is worse or better,” Gerstein told Healio. “From a cardioprotective benefit, efpeglenatide is right in line with the class as a whole. We have a clear, unambiguous reduction in primary CV outcomes and in secondary CV outcomes and renal outcomes. That is exciting and, to me, the most important message is it provides even more confidence and reassurance about the GLP-1 receptor agonist class. Here is yet another example of the drug that works.”
Reference:
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David Lam, MD
This study reports on the use of efpeglenatide, a new GLP-1 receptor agonist, in patients with established CVD or established kidney disease with a CV risk factor and reports on first major adverse CV events and a renal outcome composite. Interestingly, the trial randomization stratified patients by the use of SGLT2 inhibitors, another class of medications that has demonstrated reduced risk in CV and renal outcomes. A lower CV and renal composite outcome risk is reported in those who received efpeglenatide. The CV risk reduction is similar to outcomes reported with other members in the GLP-1 receptor agonist class.
Professional society guidelines ask providers to consider underlying, patient-specific risk factors when making treatment decisions and to consider medication classes with added CV or renal benefit. This study adds to the growing body of data regarding GLP-1 receptor agonists, benefits in CV and renal outcomes, and how they can be integrated into their patients’ treatment regimens.
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Gerstein HC, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. Presented at: American Diabetes Association Scientific Sessions; June 25-29, 2021 (virtual meeting).
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