{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:57:27Z","timestamp":1791273447479,"version":"4.1.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,3,28]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              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 \u03c7\n              <jats:sup>2<\/jats:sup>\n              statistic for trend.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              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\u20130.86];\n              <jats:italic>P<\/jats:italic>\n              =0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63\u20131.06];\n              <jats:italic>P<\/jats:italic>\n              =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,\n              <jats:italic>P<\/jats:italic>\n              =0.011; HR, 0.85 for 4 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a \u226540% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001; HR, 0.73 for 4 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.0009), MACE or any death (HR, 0.67 for 6 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.0021; HR, 0.81 for 4 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.08), a kidney function outcome comprising a sustained \u226540% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.0072; HR, 0.97 for 4 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.0002; HR, 0.81 for 4 mg,\n              <jats:italic>P<\/jats:italic>\n              =0.067). A clear dose-response was noted for all primary and secondary outcomes (all\n              <jats:italic>P<\/jats:italic>\n              for trend \u22640.018).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT03496298.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.122.063716","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T10:02:06Z","timestamp":1676887326000},"page":"1004-1013","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial"],"prefix":"10.1161","volume":"147","clinical-trial-number":[{"clinical-trial-number":"nct03496298","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8072-2836","authenticated-orcid":true,"given":"Hertzel C.","family":"Gerstein","sequence":"first","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G., Z.L., C.R.)."},{"name":"Department of Medicine, McMaster University, Hamilton, Ontario, Canada (H.C.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8992-6616","authenticated-orcid":true,"given":"Zhuoru","family":"Li","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G., Z.L., C.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinthanie","family":"Ramasundarahettige","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G., Z.L., C.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-2077","authenticated-orcid":true,"given":"Seungjae","family":"Baek","sequence":"additional","affiliation":[{"name":"Hanmi Pharmaceutical, Songpa-gu, Seoul, Korea (S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2362-6498","authenticated-orcid":true,"given":"Kelley R.H.","family":"Branch","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Washington, Seattle (K.R.H.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5388-0270","authenticated-orcid":true,"given":"Stefano","family":"Del Prato","sequence":"additional","affiliation":[{"name":"Department of Clinical &amp; Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Italy (S.D.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-0018","authenticated-orcid":true,"given":"Carolyn S.P.","family":"Lam","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore and Duke-National University of Singapore (C.S.P.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2999-4961","authenticated-orcid":true,"given":"Renato D.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2912-1389","authenticated-orcid":true,"given":"Richard","family":"Pratley","sequence":"additional","affiliation":[{"name":"AdventHealth Translational Research Institute, Orlando, FL (R.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Rosenstock","sequence":"additional","affiliation":[{"name":"Velocity Clinical Research at Medical City, Dallas TX (J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-2593","authenticated-orcid":true,"given":"Naveed","family":"Sattar","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom (N.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)30431-9"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1310799"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(14)70219-0"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(21)00203-5"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dsx.2021.102382"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab722"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31149-3"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2020.07.008"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.0078"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14032"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14223"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2108269"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-022-01594-6"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509225"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1612917"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901118"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.17925\/EE.2022.18.1.10"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02188-7"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14666"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-021-01386-4"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-2251"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv083"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.02.043"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8060"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.122.063716","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T08:11:41Z","timestamp":1715587901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.122.063716"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,28]]},"references-count":24,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,3,28]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.122.063716"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.122.063716","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,28]]},"assertion":[{"value":"2022-12-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}