{"doi":"10.1161/circulationaha.122.063716","title":"Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial","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.","journal":"Circulation","year":2023,"id":332222,"datarank":0.9008462239921378,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.4121317432889154,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.4121317432889154,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":22,"citers_with_citation_signal":18,"citers_with_endowment":18,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT03496298"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1058295,"name":"Zhuoru Li","orcid":"0000-0001-8992-6616","position":1,"is_corresponding":false},{"id":1058296,"name":"Chinthanie Ramasundarahettige","orcid":"0009-0004-3705-8879","position":2,"is_corresponding":false},{"id":1058297,"name":"Seung Jae Baek","orcid":"0000-0003-3385-2077","position":3,"is_corresponding":false},{"id":108439,"name":"Kelley R. Branch","orcid":"0000-0003-2362-6498","position":4,"is_corresponding":false},{"id":40678,"name":"Stefano Del Prato","orcid":"0000-0002-5388-0270","position":5,"is_corresponding":false},{"id":49640,"name":"Carolyn S.P. Lam","orcid":"0000-0003-1903-0018","position":6,"is_corresponding":false},{"id":55170,"name":"Renato D. Lópes","orcid":"0000-0003-2999-4961","position":7,"is_corresponding":false},{"id":231670,"name":"Richard E. Pratley","orcid":"0000-0002-2912-1389","position":8,"is_corresponding":false},{"id":320000,"name":"Julio Rosenstock","orcid":"0000-0001-8324-3275","position":9,"is_corresponding":false},{"id":42051,"name":"Naveed Sattar","orcid":"0000-0002-1604-2593","position":10,"is_corresponding":false},{"id":63109,"name":"Hertzel C. 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