{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:43:41Z","timestamp":1790009021049,"version":"4.0.1"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,1,15]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Individuals with type 2 diabetes mellitus are at increased risk for heart failure (HF), particularly those with coexisting atherosclerotic cardiovascular disease and\/or kidney disease. Some but not all dipeptidyl peptidase-4 inhibitors have been associated with increased HF risk. We performed secondary analyses of HF and related outcomes with the dipeptidyl peptidase-4 inhibitor linagliptin versus placebo in CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), a cardiovascular outcomes trial that enrolled participants with type 2 diabetes mellitus and atherosclerotic cardiovascular disease and\/or kidney disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Participants in 27 countries with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and\/or kidney disease were randomized 1:1 to receive once daily oral linagliptin 5 mg or placebo, on top of standard of care. All hospitalization for HF (hHF), cardiovascular outcomes, and deaths were prospectively captured and centrally adjudicated. In prespecified and post hoc analyses of HF and related events, Cox proportional hazards models adjusting for region and baseline history of HF were used. Recurrent hHF events were analyzed using a negative binomial model. In a subset of participants with left ventricular ejection fraction captured within the year before randomization, HF-related outcomes were assessed in subgroups stratified by left ventricular ejection fraction &gt; or \u226450%.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      CARMELINA enrolled 6979 participants (mean age, 65.9 years; estimated glomerular filtration rate, mL\/min per 1.73m\n                      <jats:sup>2<\/jats:sup>\n                      ; hemoglobin A1c, 8.0%; 62.9% men; diabetes mellitus duration, 14.8 years), including 1873 (26.8%) with a history of HF at baseline. Median follow-up was 2.2 years. Linagliptin versus placebo did not affect the incidence of hHF (209\/3494 [6.0%] versus 226\/3485 [6.5%], respectively; hazard ratio [HR], 0.90; 95% CI, 0.74\u20131.08), the composite of cardiovascular death\/hHF (HR, 0.94; 95% CI, 0.82\u20131.08), or risk for recurrent hHF events (326 versus 359 events, respectively; rate ratio, 0.94; 95% CI, 0.75\u20131.20). There was no heterogeneity of linagliptin effects on hHF by history of HF at baseline, baseline estimated glomerular filtration rate or urine albumin-creatinine ratio, or prerandomization left ventricular ejection fraction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>In a large, international cardiovascular outcome trial in participants with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and\/or kidney disease, linagliptin did not affect the risk of hHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous left ventricular ejection fraction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial 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: NCT01897532.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.118.038352","type":"journal-article","created":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T14:03:44Z","timestamp":1547474624000},"page":"351-361","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":150,"title":["Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA"],"prefix":"10.1161","volume":"139","author":[{"given":"Darren K.","family":"McGuire","sequence":"first","affiliation":[{"name":"University of Texas Southwestern Medical Center, Dallas (D.K.M., R.D.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke Health, Durham, NC (J.H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odd Erik","family":"Johansen","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Norway, Asker (O.E.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlado","family":"Perkovic","sequence":"additional","affiliation":[{"name":"The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia (V.P.)."}],"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"}]},{"given":"Mark E.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia (M.E.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Wanner","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, W\u00fcrzburg University Clinic, Germany (C.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Kahn","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans\u2019 Administration Puget Sound Health Care System and University of Washington, Seattle (S.E.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Toto","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center, Dallas (D.K.M., R.D.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Zinman","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Division of Endocrinology, University of Toronto, Canada (B.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Baanstra","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim, Alkmaar, The Netherlands (D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egon","family":"Pfarr","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. Ingelheim, Germany (E.P., S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Schnaidt","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. Ingelheim, Germany (E.P., S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Meinicke","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH, Biberach, Germany (T.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyothis T.","family":"George","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International, Ingelheim, Germany (J.T.G., M.v.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"von Eynatten","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International, Ingelheim, Germany (J.T.G., M.v.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Marx","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Aachen, Rheinisch-Westf\u00e4lische Technische Hochschule Aachen University, Germany (N.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"On behalf of the CARMELINA Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1608664"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.01.030"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2016.0103"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-018-9685-0"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(14)70031-2"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/dme.12859"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.4.421"},{"key":"e_1_3_4_9_2","unstructured":"US Department of Health and Human Services Food and Drug Administration. Guidance for Industry. Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. www.fda.gov\/downloads\/drugs\/guidancecomplianceregulatoryinformation\/guidances\/ucm071627.pdf. Accessed October 16 2018."},{"key":"e_1_3_4_10_2","unstructured":"European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012. http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2012\/06\/WC500129256.pdf. 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Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk. The CARMELINA Randomized Clinical Trial. JAMA. 2018; In press. doi: 10.1001\/jama.2018.18269","DOI":"10.1001\/jama.2018.18269"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000156"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.08.021"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0410"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.2337\/db15-1224"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.06.009"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1146"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.022281"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.118.038352","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T03:56:52Z","timestamp":1715572612000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.118.038352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,15]]},"references-count":24,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,1,15]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.118.038352"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.118.038352","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.734768755.793560747","asserted-by":"object"}]},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,15]]},"assertion":[{"value":"2018-10-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}