Efpeglenatide is Safe, Effective in Treatment-naïve Patients with Type 2 Diabetes: AMPLITUDE-M Findings

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Monotherapy with once-weekly efpeglenatide significantly improved glycemic control and reduced body weight among treatment-naïve patients with type 2 diabetes (T2D) inadequately controlled with diet and exercise alone, according to findings from the phase 3 AMPLITUDE-M study.

The study authors, writing in the journal Diabetes Care, report that efpeglenatide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), demonstrated a safety and tolerability profile similar to that of other GLP-1 RA.

GLP-1 RA are guideline-recommended as the first injectable agent for T2D patients with hyperglycemia poorly controlled on oral glucose-lowering medications, the authors write. The class is noted for its glycemic efficacy, minimal risk of hypoglycemia, and weight-reduction properties. Further, GLP-1 RA in clinical trials also have demonstrated significant cardiorenal protection properties

Efpeglenatide, according to senior author Juan Pablo Frias, MD, medical director and principal investigator of the National Research Institute, in Los Angeles, CA, and colleagues, proved superior to placebo for reduction of HbA1c and body weight in earlier phase 2 studies with T2D patients either treatment-naïve or on maximally tolerated metformin therapy.

In the more recent phase 3 AMPLITUDE-O cardiovascular outcomes trial, efpeglenatide compared with placebo significantly reduced the risk of composite cardiovascular (CV) and renal events in patients with T2D and either a history of atherosclerotic CVD or current kidney disease plus at least one additional CV risk factor.

AMPLITUDE-M, a multicenter, 56-week, randomized, double-blind, placebo-controlled phase 3 trial, was designed to provide data on the safety and efficacy of efpeglenatide and to demonstrate its superiority vs placebo in a population of patients withT2D who had no history of medical therapy for hyperglycemia and whose HbA1c remained inadequately controlled (HbA1c ≥7 and ≤10%) on a regimen of dietary change and increased physical activity.

The primary objective was to demonstrate the superiority of a once-weekly injection of efpeglenatide 2, 4, or 6 mg vs placebo for HbA1c reduction at 30 weeks.

Key secondary objectives included superiority of the same measure at 56 weeks; achievement of target HbA1c (<7%) at week 30; change in fasting plasma glucose (FPG) at week 30; and change in body weight at weeks 30 and 56.

Investigators designated 4 study periods: a 3-week screening, a 30-week, “core” treatment period to evaluate the key efficacy endpoint, a 26-week treatment extension period, and a 6-week safety follow-up period.

Patients were randomized in 1:1:1 fashion to receive 1 once weekly subcutaneous doses of either 2, 4, or 6 mg of efpeglenatide; all patients were initiated on a 2 mg dose and the dose was titrated in 2-mg increments every 2 weeks until the other 2 randomized doses were reached.

Patients were recruited from Germany, Poland, the UK, the US, and Ukraine. Patient visits began in 2017 and ended in 2020. After screening, the final cohort numbered 900; average age was 58 years; more than half (~56%) were men; and the majority (~90%) were White. Of the total, 304 were randomized to efpeglenatide (2 mg dose, N = 100; 4 mg dose, N = 101; 6 mg dose, N = 103) and 102 to placebo.

Findings

At week 30, HbA1c was reduced from a mean baseline of 8.1% to 6.9% in the efpeglenatide 2mg group; to 6.6% in the 4 mg group; and to 6.4% in the 6 mg group.

Least squares mean HbA1c reductions from baseline were statistically superior for each efpeglenatide dose versus placebo:

• 2 mg −0.5% (95% CI −0.9, −0.2; P =.0054)
• 4 mg −0.8% (−1.2, −0.5; P <.001)
• 6 mg −1.0% (−1.4, −0.7; P <.001)

Among efpeglenatide-treated patients at all doses, Frias et al report a greater proportion achieved the target HbA1c of <7% vs placebo at week 30 (P <.001 for all). Specifically, the majority in each active treatment group achieved the target—60–74% at week 30 and 54–57% at week 56. Further, they report, approximately one-half (44–58%) of patients across all efpeglenatide dose groups reached the more stringent target of HbA1c ≤6.5%.

...approximately one-half (44–58%) of patients across all efpeglenatide dose groups reached the more stringent target of HbA1c ≤6.5%.

Researchers also observed significant reductions in body weight and FPG for patients treated with efpeglenatide (4 and 6 mg doses) compared with placebo-treated participants at week 30 (P <.05 for all).

The authors write that there were very few cases of hypoglycemia reported and that adverse events were consistent with the GLP-1 RA class and gastrointestinal events were reported most commonly.

Frias and colleagues point out that the HbA1c reductions seen in AMPLITUDE-M compare favorably with those reported elsewhere and are “aligned with previous reports of other once-weekly GLP-1 RAs as monotherapy” in the treatment-naïve population.

They add that the efpeglenatide pharmacokinetic/pharmacodynamic profile may permit even more flexible dosing from once-weekly to potentially once-monthly.

Study strengths they point out include the double-blind randomized design and study duration while limitations include the potential departure from real-world clinical results inherent in clinical trial structure.

Reference: Frias JP, Cho JD, Rosenstock J, et al. Efficacy and safety of once-weekly efpeglenatide monotherapy versus placebo in type 2 diabetes: the AMPLITUDE-M randomised controlled trial. Diabetes Care 2022;45(7):1592–1600. https://doi.org/10.2337/dc21-2656