{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:42:07Z","timestamp":1792730527234,"version":"4.5.0"},"reference-count":38,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>In CARMELINA\u00ae, linagliptin demonstrated cardiovascular and renal safety in patients with type 2 diabetes (T2D) with high renal and cardiovascular disease (CVD) risk. We investigated safety and efficacy of this dipeptidyl peptidase\u20104 inhibitor in older participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>Subjects aged \u226518\u2009years with T2D and established CVD with urinary albumin\u2010to\u2010creatinine ratio (UACR) &gt;30\u2009mg\/g, and\/or prevalent kidney disease, were randomized to linagliptin or placebo added to usual care. The primary endpoint (time to first occurrence of 3P\u2010MACE: cardiovascular death, non\u2010fatal myocardial infarction or non\u2010fatal stroke) and other outcomes were evaluated across age groups &lt;65 (n = 2968), 65 to &lt;75 (n = 2800) and\u2009\u226575\u2009years (n = 1211).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mean age was 65.9\u2009years (17.4% and 5.9% aged \u226575 and 80, respectively) and median follow\u2010up was 2.2\u2009years. The hazard ratio (HR) for 3P\u2010MACE with linagliptin versus placebo was 1.02 [95% confidence interval (CI) 0.89, 1.17] with no significant interaction between age and treatment effect (\n                      <jats:italic>P<\/jats:italic>\n                      =\u20090.0937). HRs for participants aged &lt;65, 65 to &lt;75 and\u2009\u226575\u2009years were 1.11 (95% CI 0.89, 1.40), 1.09 (0.89, 1.33) and 0.76 (0.57, 1.02), respectively. Linagliptin did not increase the risk of adverse kidney outcomes or hospitalization for heart failure across age groups. The incidence of adverse events, including hypoglycaemia, increased with age but was similar with linagliptin and placebo despite glycated haemoglobin A1c reduction with linagliptin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Linagliptin did not increase risk for cardiovascular events or hypoglycaemia and kidney function remained stable in older people with T2D and established CVD with albuminuria and\/or kidney disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.13995","type":"journal-article","created":{"date-parts":[[2020,2,9]],"date-time":"2020-02-09T23:13:37Z","timestamp":1581290017000},"page":"1062-1073","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Cardiovascular and kidney outcomes of linagliptin treatment in older people with type 2 diabetes and established cardiovascular disease and\/or kidney disease: A prespecified subgroup analysis of the randomized, placebo\u2010controlled CARMELINA\u00ae trial"],"prefix":"10.1111","volume":"22","author":[{"given":"Mark E.","family":"Cooper","sequence":"first","affiliation":[{"name":"Department of Diabetes, Central Clinical School Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-3275","authenticated-orcid":false,"given":"Julio","family":"Rosenstock","sequence":"additional","affiliation":[{"name":"Dallas Diabetes Research Center at Medical City  Dallas Texas"},{"name":"University of Texas, Southwestern Medical Center  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Department of Prevention of Diabetes and Lifestyle\u2010related Diseases, Graduate School of Medicine University of Tokyo  Tokyo Japan"},{"name":"Department of Metabolism and Nutrition, Mizonokuchi Hospital, Faculty of Medicine Teikyo University  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1099-7989","authenticated-orcid":false,"given":"Yutaka","family":"Seino","sequence":"additional","affiliation":[{"name":"Kansai Electric Power Medical Research Institute  Osaka Japan"},{"name":"Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Wanner","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine W\u00fcrzburg University Clinic  W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Schnaidt","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Clark","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH, Ingelheim  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2470-0530","authenticated-orcid":false,"given":"Odd Erik","family":"Johansen","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Norway KS, Asker  Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"CARMELINA investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"IDF Diabetes Atlas","author":"International Diabetes Federation","year":"2017"},{"key":"e_1_2_8_3_1","volume-title":"National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011","year":"2011"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-2890-4"},{"key":"e_1_2_8_5_1","first-page":"61","article-title":"The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies","volume":"8","author":"Davies M","year":"2016","journal-title":"Clin Pharmacol"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/00325481.2018.1457397"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1262-3636(11)70962-4"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamda.2012.04.012"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.12035"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-0413"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.12514"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2014.03.005"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(14)70176-7"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13340-016-0293-8"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14283\/jfa.2017.39","article-title":"An international position statement on the management of frailty in diabetes mellitus: Summary of recommendations 2017","volume":"7","author":"Sinclair AJ","year":"2018","journal-title":"J Frailty Aging"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/dme.13644"},{"issue":"1","key":"e_1_2_8_17_1","first-page":"S283","article-title":"Diabetes in older people","volume":"42","author":"Diabetes Canada Clinical Practice Guidelines Expert Committee","year":"2018","journal-title":"Can J Diabetes"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2019-00198"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/dme.13859"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-S012"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.2165\/11630900-000000000-00000"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/MJT.0b013e31826232dc"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61500-7"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12321"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.18269"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.038352"},{"key":"e_1_2_8_27_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12933-018-0682-3","article-title":"Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA[R]): a randomized, double\u2010blind, placebo\u2010controlled clinical trial in patients with type 2 diabetes and high cardio\u2010renal risk","volume":"17","author":"Rosenstock J","year":"2018","journal-title":"Cardiovasc Diabetol"},{"key":"e_1_2_8_28_1","unstructured":"International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. 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