Investigational GLP-1 RA Cuts Heart, Renal Risk in Vulnerable Diabetes Patients

An investigational glucagon-like peptide-1 (GLP-1) receptor agonist had significant heart and kidney benefits in an already compromised population with diabetes, the AMPLITUDE-O study found.

In the randomized controlled trial of people with type 2 diabetes and a pre-existing history of cardiovascular disease or kidney disease, those on once-weekly efpeglenatide saw a 27% reduced risk for an incident major cardiovascular adverse event (MACE) compared with placebo (HR 0.73, 95% CI 0.58-0.92, P<0.001), reported Hertzel C. Gerstein, MD, of Hamilton Health Sciences in Ontario, Canada, and colleagues.

Of note, the injectable agent met statistical significance for both non-inferiority (P<0.001) and superiority (P=0.007) compared with placebo for MACE reduction — which included a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined cause — during a median 1.81-year follow-up period.

In total, 7% (n=189) of patients on efpeglenatide experienced a MACE (3.9 events per 100 person-years) versus 9.2% (n=125) of those on placebo (5.3 events per 100 person-years).

The findings were presented at the virtual American Diabetes Association (ADA) Scientific Sessions and simultaneously published in the New England Journal of Medicine.

Beyond a heart benefit, the GLP-1 receptor agonist also showed a significant renal benefit in these patients. Compared with placebo, efpeglenatide yielded a 32% reduced risk for a composite renal outcome, including a decrease in kidney function or macroalbuminuria (HR 0.68, 95% CI 0.57-0.79, P<0.001).

Specifically, this composite outcome occurred in 13% (n=353) on efpeglenatide versus 18.4% (n=250) on placebo.

Although this investigational agent falls into the GLP-1 receptor agonist class of antidiabetics, what separates it is that it acts as an exendin-4-based GLP-1 receptor agonist rather than a human-based one, which include liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), and semaglutide (Ozempic, Rybelsus, Wegovy).

The agent was first developed by South Korean-based Hanmi Pharmaceutical, but was later licensed out to Sanofi during clinical testing. Last year, Sanofi returned all rights for efpeglenatide back to Hanmi.

Also presented at the meeting, the treatment met the primary efficacy endpoint in a phase III clinical trial, demonstrating a significant reduction in HbA1c versus placebo over 30 weeks in the AMPLITUDE-M trial. Tested at 2 mg, 4 mg, and 6 mg doses, efpeglenatide showed a 1.06%, 1.39%, and 1.59% HbA1c change from baseline at week 30, respectively.

The agent plus lifestyle intervention also showed an additional benefit on weight loss as well, meeting a secondary endpoint. Specifically, there was a significant 3.47 kg (7.65 lb) and 3.37 kg (7.45 lb) change from baseline at week 30 with the 4 mg and 6 mg doses, respectively.

Hanmi announced plans to combine efpeglenatide with other treatments in its pipeline, like the investigational long-acting glucagon analog HM15136.

AMPLITUDE-O, which took place across 344 clinical sites in 28 countries, recruited 4,076 adults with type 2 diabetes with a history of cardiovascular disease or kidney disease — defined as an eGFR of 25.0 to 59.9 mL/min/1.73 m² — in addition to another cardiovascular risk factor. Some exclusion criteria included gastroparesis, uncontrolled reflux, prolonged nausea or vomiting, severe retinal disease, pancreatitis, or use of a GLP-1 receptor agonist or a dipeptidyl peptidase (DPP)-4 inhibitor within the past 3 months.

Randomized in a 1:1:1 fashion, participants were assigned to either 4 mg of efpeglenatide, 6 mg of efpeglenatide, or placebo.

Of note, about 15% of participants were also on an SGLT-2 inhibitor at baseline, which was continued through the trial. Around 63% of the total cohort was on any type of insulin, 73% were on metformin, and around a quarter were on a sulfonylurea.

“This trial has the most number of people with baseline SGLT-2 inhibitor use and provides the ability to assess the combined effect of an SGLT-2 inhibitor and a GLP-1 receptor agonist on cardiovascular outcomes,” Gerstein explained during a presentation of the findings. “When we look at the effect, you see no evidence whatsoever of any difference in effect of the combination of SGLT-2 inhibitor plus the GLP-1 receptor agonist efpeglenatide versus no efpeglenatide and an SGLT-2 inhibitor.”

• SGLT-2 inhibitor at baseline: HR 0.70 (95% CI 0.37-1.30)
• No SGLT-2 inhibitor at baseline: HR 0.74 (95% CI 0.58-0.94)

“You see that the effect size of baseline SGLT-2 inhibitor or no baseline SGLT-2 inhibitor are essentially overlapping completely,” he said.

As is expected with a GLP-1 receptor agonist, gastrointestinal side effects occurred in the treatment group — the most common of which included diarrhea, constipation, nausea, vomiting, and bloating. Severe gastrointestinal events occurred in 3.3% of the treatment group versus 1.8% of the placebo group (P=0.009).