{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:24:12Z","timestamp":1792009452362,"version":"4.4.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,2,22]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor\u2013by\u2013treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58\u20130.94] and 0.70 [0.37\u20131.30], respectively), expanded MACEs (0.77 [0.62\u20130.96] and 0.87 [0.51\u20131.48]), renal composite (0.70 [0.59\u20130.83] and 0.52 [0.33\u20130.83]), and MACEs or death (0.74 [0.59\u20130.93] and 0.65 [0.36\u20131.19]) did not differ by baseline SGLT2 inhibitor use (\n                      <jats:italic>P<\/jats:italic>\n                      for all interactions &gt;0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction\n                      <jats:italic>P<\/jats:italic>\n                      \u22650.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes.<\/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.121.057934","type":"journal-article","created":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T08:12:10Z","timestamp":1636877530000},"page":"565-574","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":126,"title":["Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial"],"prefix":"10.1161","volume":"145","clinical-trial-number":[{"clinical-trial-number":"nct03496298","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-0018","authenticated-orcid":true,"given":"Carolyn S.P.","family":"Lam","sequence":"first","affiliation":[{"name":"National Heart Centre Singapore and Duke\u2013National University of Singapore, Singapore (C.S.P.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinthanie","family":"Ramasundarahettige","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, Hamilton Health Sciences, ON, Canada (C.R., H.C.G.)."},{"name":"McMaster University, Hamilton, OH, Canada (C.R., H.C.G.)."}],"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\/0000-0002-1604-2593","authenticated-orcid":true,"given":"Naveed","family":"Sattar","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Rosenstock","sequence":"additional","affiliation":[{"name":"Dallas Diabetes Research Center at Medical City, TX (J.R.)."}],"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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5388-0270","authenticated-orcid":true,"given":"Stefano","family":"Del Prato","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Italy (S.D.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2999-4961","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"}]},{"given":"Elisabeth","family":"Niemoeller","sequence":"additional","affiliation":[{"name":"Sanofi, Frankfurt, Germany (E.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3677-6356","authenticated-orcid":true,"given":"Nardev S.","family":"Khurmi","sequence":"additional","affiliation":[{"name":"Sanofi, Bridgewater, NJ (N.S.K.)."}],"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"}]},{"given":"Hertzel 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