Fpeglenatide reduces the progression of CKD, a CV event in high-risk type 2 diabetes

The new GLP-1 receptor agonist increases the risk of cardiovascular events by 27% and the progression of renal disease by 32% compared to placebo in high-risk adults with type 2 diabetes, with or without background SGLT2 inhibitor therapy. % Reduced.

Hertzel C. Gerstein

Data from the AMPLITUDE-O trial were presented at a scientific session of the American Diabetes Association and at the same time. New England Journal of Medicine MEdiciIs an exendin-4-based GLP-1 receptor agonist in clinical trials, weekly epeglenatide is safe for high-risk patients, and other human-based GLP-1 receptor agonists in the class of CV and renal benefits Showed to be similar to. Hertzel C. Gerstein, MD, MSc, FRCPCIn a virtual presentation, McMaster University in Ontario, Canada, and Hamilton Health Sciences Professor of Diabetes Research and Chairman of the Institute for Population and Health said. The study was also the first large-scale CV outcome study to evaluate the use of GLP-1 receptor agonists in the population receiving background SGLT2 inhibitor therapy, and 15% of study participants, he said. Stated.

“We know that SGLT2 inhibitors have cardioprotective effects and GLP-1 receptor agonists have cardioprotective effects,” Gerstein told Healio. “There has never been a study investigating the effects of both together. I’m happy that there is no difference with or without SGLT2 inhibitors. It’s encouraging and a CV perspective. Shows that these drugs can be used together, and the benefits are probably additive. “

Effects of non-human GLP-1

Four GLP-1 receptor agonists with a structure based on human GLP-1 have been shown to reduce the risk of CV events in adults with type 2 diabetes. The effect of epeglenatide, an exendin-4-based GLP-1 receptor agonist, on CV and renal outcomes in high-risk adults with type 2 diabetes is unknown.

Gerstein et al. Analyzed data from 4,076 adults with at least one CV risk factor (mean age 65 years, 33% female, 87% white) in addition to a history of type 2 diabetes and CVD or kidney disease, and found 28 Adopted from 344 sites. Country. Within the cohort, the mean diabetic duration was 15.4 years, 90% had previously undergone CVD, and 32% had an estimated glomerular filtration rate of less than 60 mL / min / 1.73 m.².. Researchers randomly assigned participants subcutaneous epegrenatide 4 mg or 6 mg (n = 2,717) or placebo (n = 1,359) weekly, and randomization was stratified using SGLT2 inhibitors (n = 618). ..

“This trial was designed with the knowledge that many people use SGLT2 inhibitors, so we layered the randomization to balance the use of SGLT2 inhibitors,” Gerstein told Helio. Told. “This allowed us to assess whether there were any differences due to the use of baseline SGLT2 inhibitors.”

The main result was the first major adverse CV event, a combination of non-fatal myocardial infarction, non-fatal stroke, or death from CV or unexplained death.

Median follow-up of 1.81 years, 189 participants (7%) assigned epeglenatide (3.9 events per 100 person-years), and 125 participants assigned placebo (9.2%) A serious harmful CV event occurred (5.3 events per 100 people). -Year), HR 0.73 (95% CI, 0.58-0.92; P .0001 for non-inferiority. P = For superiority .0069). The HR for the major adverse CV event, coronary blood circulation reconstruction, or secondary extended outcome of unstable angina was 0.79 for epeglenatide vs. placebo (95% CI, 0.65-0.96).

Kidney results

Richard E. Prattley

Data from the entire large CV outcome trial show consistent CV benefits in the GLP-1 receptor agonist class. However, less information is available regarding the benefits of the kidneys. Richard E. Prattley, MD, Samuel E, Director of Diabetes Research and Medical Care at the Advent Health Diabetes Institute. Chair Crockett said in a presentation on kidney outcomes. AMPLITUDE participants had the highest prevalence of renal disease compared to all other GLP-1 receptor agonist trials.

According to Prattley, study data showed that epeglenatide significantly reduced the incidence of albuminuria, macroalbuminuria, and the rate of reduction in eGFR. In addition, epeglenatide significantly reduced the incidence of new macroalbuminuria complex renal outcomes, reduced eGFR by more than 40%, renal replacement therapy, or eGFR below 15 mL / min / 1.73 m.².. A complex renal outcome event, defined as decreased renal function or the development of macroalbuminuria, occurred in 353 participants (13%) who were assigned epeglenatide and 250 participants (18.4%) who were assigned placebo. It occurred and the HR was 0.68 (95% CI, 0.57). -0.79).

According to Prattley, the effects were similar in all subgroups, including those who were prescribed SGLT2 inhibitors.

“As we have already pointed out, SGLT2 inhibitors are one of the highest background uses, and as we have seen, SGLT2 inhibitors are associated with kidney benefit,” said Pratley. I am. “I asked if SGLT2 inhibitor use affects renal benefit. The answer here is that it wasn’t. Regardless of SGLT2 inhibitor use, there is a significant difference between the two groups. There was not.”

Diarrhea, constipation, nausea, vomiting and bloating were more commonly reported among participants assigned epeglenatide vs. placebo, consistent with the expected adverse event profile of the GLP-1 receptor agonist class. It was.

“Clear” CV risk reduction

“This is the first outcome trial to show a reduction in CV outcomes with exendin-4-based GLP-1,” Gerstein told Healio. “Prior to this, people said that only human GLP-1 reduces CV results …. This study says it’s not true. GLP-1 receptor agonists are in the class. It doesn’t matter if one of them is structurally similar to the other. “

From a cardiac protection perspective, AMPLITUDE data show that epeglenatide is liraglutide (Victoza, Saxenda; Novo Nordisk), semaglutide (Ozempic, Rybelsus, Wegovy; Novo Nordisk), or duraglutide (Trulicity, Eli Lilly).

“This is not a direct study and I don’t know which is worse or better,” Gerstein told Healio. “Because of the benefits of cardiac protection, epeglenatide is consistent with the class as a whole. Primary CV results, secondary CV results, and renal results are clearly and clearly reduced. It is exciting and most for me. The important message is to provide more confidence and peace of mind about the GLP-1 receptor agonist class. This is yet another example of a drug that works. “

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David drum, MD

This study reports the use of the new GLP-1 receptor agonist epeglenatide in patients with established CVD or established renal disease with CV risk factors, the first major adverse CV event and renal outcome complex. I will report on. Interestingly, trial randomization used SGLT2 inhibitors to stratify patients. This is another class of drug that has shown a reduced risk of CV and renal outcomes. Patients receiving epegrenatide have been reported to have a lower risk of combined CV and renal outcomes. The reduced risk of CV is similar to the results reported by other members of the GLP-1 receptor agonist class.

Expert Association guidelines require providers to consider the underlying patient-specific risk factors when deciding on treatment and to consider a drug class with additional CV or renal benefits. This study adds to the growing data on GLP-1 receptor agonists, the benefits of CV and renal outcomes, and how to integrate them into the patient’s treatment regimen.

David drum, MD

Clinical Diabetes Institute Medical Director

Mount Sinai Health System

Associate Professor in Medicine, Endocrinology, Diabetes and Bone Diseases

Mount Sinai School of Medicine

Disclosure: Ram has not reported disclosure of relevant financial information.

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