Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial
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abstract
Background:In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain.Methods:
Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ
2
statistic for trend.
Results:
During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5–0.86];
P
=0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63–1.06];
P
=0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg,
P
=0.011; HR, 0.85 for 4 mg,
P
=0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg,
P
<0.0001; HR, 0.73 for 4 mg,
P
=0.0009), MACE or any death (HR, 0.67 for 6 mg,
P
=0.0021; HR, 0.81 for 4 mg,
P
=0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg,
P
=0.0072; HR, 0.97 for 4 mg,
P
=0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg,
P
=0.0002; HR, 0.81 for 4 mg,
P
=0.067). A clear dose-response was noted for all primary and secondary outcomes (all
P
for trend ≤0.018).
Conclusions:The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits.Registration:
URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03496298.
