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Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial.

Publication ,  Journal Article
Gerstein, HC; Li, Z; Ramasundarahettige, C; Baek, S; Branch, KRH; Del Prato, S; Lam, CSP; Lopes, RD; Pratley, R; Rosenstock, J; Sattar, N
Published in: Circulation
March 28, 2023

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 χ2 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.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

March 28, 2023

Volume

147

Issue

13

Start / End Page

1004 / 1013

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Renal Insufficiency
  • Hypoglycemic Agents
  • Humans
  • Glucagon-Like Peptide-1 Receptor
  • Diabetes Mellitus, Type 2
  • Cardiovascular System & Hematology
  • Cardiovascular System
  • Cardiovascular Diseases
  • 4207 Sports science and exercise
 

Citation

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Gerstein, H. C., Li, Z., Ramasundarahettige, C., Baek, S., Branch, K. R. H., Del Prato, S., … Sattar, N. (2023). Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial. Circulation, 147(13), 1004–1013. https://doi.org/10.1161/CIRCULATIONAHA.122.063716
Gerstein, Hertzel C., Zhuoru Li, Chinthanie Ramasundarahettige, Seungjae Baek, Kelley R. H. Branch, Stefano Del Prato, Carolyn S. P. Lam, et al. “Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial.Circulation 147, no. 13 (March 28, 2023): 1004–13. https://doi.org/10.1161/CIRCULATIONAHA.122.063716.
Gerstein HC, Li Z, Ramasundarahettige C, Baek S, Branch KRH, Del Prato S, et al. Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial. Circulation. 2023 Mar 28;147(13):1004–13.
Gerstein, Hertzel C., et al. “Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial.Circulation, vol. 147, no. 13, Mar. 2023, pp. 1004–13. Pubmed, doi:10.1161/CIRCULATIONAHA.122.063716.
Gerstein HC, Li Z, Ramasundarahettige C, Baek S, Branch KRH, Del Prato S, Lam CSP, Lopes RD, Pratley R, Rosenstock J, Sattar N. Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial. Circulation. 2023 Mar 28;147(13):1004–1013.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

March 28, 2023

Volume

147

Issue

13

Start / End Page

1004 / 1013

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Renal Insufficiency
  • Hypoglycemic Agents
  • Humans
  • Glucagon-Like Peptide-1 Receptor
  • Diabetes Mellitus, Type 2
  • Cardiovascular System & Hematology
  • Cardiovascular System
  • Cardiovascular Diseases
  • 4207 Sports science and exercise