This GLP-1 receptor agonist also reduced hemoglobin, eGFR

In patients with type 2 diabetes with either a history of cardiovascular disease (CVD) or current kidney disease, weekly treatment with efpeglenatide, an investigational agent, lowered the risk of having a first major adverse cardiovascular event (MACE) by 27% and the risk of a composite renal outcome event by 32%, according to results from the AMPLITUDE-O trial published in The New England Journal of Medicine.

“Efpeglenatide, a GLP-1 receptor agonist administered weekly by means of subcutaneous injection, has been shown to lower glucose levels without causing hypoglycemia. The drug consists of a modified exendin-4 molecule conjugated with an IgG4 Fc fragment. Its mechanism of action is akin to that of GLP-1 receptor agonists that are structurally similar to human GLP-1, which have been shown to reduce the risk of adverse cardiovascular events. This similarity and an acceptable safety profile suggest that efpeglenatide may also have cardiovascular and renal benefits in patients with diabetes and concomitant cardiovascular disease, kidney disease, or both,” wrote the AMPLITUDE-O Trial Investigators, led by Hertzel C. Gerstein, MD, of the Population Health Research Institute, Hamilton Health Sciences, and McMaster University, Hamilton, Ontario, Canada.

They conducted the randomized, placebo-controlled AMPLITUDE-O study at 344 sites throughout 28 countries to assess the efficacy of efpeglenatide in patients with type 2 diabetes who had a history of cardiovascular or kidney disease and at least one other cardiovascular risk factor.

Gerstein et al randomized 4,076 patients to treatment with either efpeglenatide (once-weekly subcutaneous injections of 4 or 6 mg) or placebo, whom they followed for a median of 1.81 years. Mean patient age was 64.5 years, and 47.9% were younger than 65; 33.0% were women and 86.7% White; 89.6% had a history of CVD, 31.6% had an estimated glomerular filtration rates (eGFR) of less than 60 ml/minute/173 m2, 21.8% had both CVD and low eGFR. Most patients were being treated with statins (80.8%), metformin (73.2%), and either an ACE inhibitor, ARB, or ARN inhibitor (80%) at baseline. Only 15.2% were being treated with an SGLT2 inhibitor.

The incidence of MACE was lower in patients treated with efpeglenatide compared with placebo (7.0% versus 9.2%, respectively; 3.9 versus 5.3 events per 100 person-years; HR: 0.73; 95% CI: 0.58-092; P˂0.001 for noninferiority; P=0.007 for superiority). Researchers also assessed a composite renal outcome event, defined as a decrease in kidney function or macroalbuminuria, which occurred in 13.0% of patients treated with efpeglenatide, compared with 18.4% of those treated with placebo (HR: 0.68; 95% CI: 0.57-0.79; P˂0.001).

Patients treated with efpeglenatide also had a significantly lower incidence of the following:

  • At least one expanded MACE composite even (HR: 0.79; 95% CI: 0.65-0.96; P=0.02).
  • A renal composite outcome event (HR: 0.68; 95% CI: 0.57-0.79; P<0.001).
  • A MACE or death from non-cardiovascular causes (HR: 0.73; 95% CI: 0.59-0.91; P=0.004).

Compared with placebo, continuous variables in patients treated with efpeglenatide also demonstrated the following (in least-squares mean differences compared with placebo):

  • Lower glycated hemoglobin levels (1.24% lower).
  • Lower BMI (0.9 lower).
  • Lower body weight (2.6 kg lower).
  • Lower systolic/diastolic BPS (1.5 and 0.6 mmHg lower, respectively).
  • Lower pulse pressure (2.1 mmHg lower).
  • Higher heart rate (3.9 bpm higher).
  • Lower LDL cholesterol level (2.7 mg/dL lower).
  • Lower urinary albumin-to-creatinine ratio (21% lower).
  • Higher mean eGFR (0.9 ml/min/1.73 m2 higher).

Severe gastrointestinal adverse effects were more common in patients treated with efpeglenatide compared with placebo (P=0.009), as were side effects, including diarrhea, constipation, nausea, vomiting, and bloating were more common in patients treated with (P=0.03). Gerstein and colleagues added, however, that they found no evidence of retinal, pancreatic, or thyroid-related events.

More patients treated with efpeglenatide discontinued treatment due to adverse events compared with placebo (5.4% versus 3.6%, respectively; P=0.02).

“A variety of possibilities may account for the protective effects of efpeglenatide on the heart and the kidneys. The drug significantly reduced several risk factors for both cardiovascular and kidney disease, including glycated hemoglobin level, blood pressure, body-mass index, low-density lipoprotein cholesterol level, eGFR, and the albumin-to-creatinine ratio,” wrote Gerstein et al.

“Other possible mechanisms include anti-inflammatory, antifibrotic, anti-atherosclerotic, vasodilatory, and other hemodynamic effects, as noted in studies of other GLP-1 receptor agonists,” they added.

Limitations included the short duration of follow-up, a lower incidence of a primary outcome than originally planned, and selection for previous CVD or kidney disease that limits generalizability to patients with type 2 diabetes who are at lower risk.

  1. Once-weekly treatment with efpeglenatide lowered the risk of having a first major adverse cardiovascular event (MACE) and a composite renal outcome event in patients with type 2 diabetes with either a history of cardiovascular disease (CVD) or current kidney disease.

  2. Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was funded by Sanofi.

Gerstein is an advisory board member for Abbott Canada and Abbott Laboratories, Eli Lilly and Company, Novo Nordisk, Pfizer, and Sanofi; and has received support from AstraZeneca, Boehringer Ingelheim, DKSH, Covance, Eli Lilly and Co., KOWA Company, Ltd., Merck, Novo Nordisk, and Sanofi.

Cat ID: 12

Topic ID: 76,12,730,446,447,914,12,182,187,127,411,192,669,918,925,181