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 - Journal of the American Medical Association

Volumn 321, Issue 1, 2019, Pages 69-79

  Rosenstock, Julio ^a,b   Perkovic, Vlado ^c   Johansen, Odd Erik ^d   Cooper, Mark E ^e   Kahn, Steven E ^f   Marx, Nikolaus ^g   Alexander, John H ^h   Pencina, Michael ^h   Toto, Robert D ^b   Wanner, Christoph ⁱ   Zinman, Bernard ^j,k   Woerle, Hans Juergen ^l   Baanstra, David ^m   Pfarr, Egon ^m   Schnaidt, Sven ^m   Meinicke, Thomas ^m   George, Jyothis T ^m   Von Eynatten, Maximilian ^m   McGuire, Darren K ^b  

^a Dallas Diabetes and Endocrine Center at Medical City   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c UNIVERSITY OF NEW SOUTH WALES   (Australia)

^d Boehringer Ingelheim Norway KS   (Norway)

^e MONASH UNIVERSITY   (Australia)

^f UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^g UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^h DUKE CLINICAL RESEARCH INSTITUTE   (United States)

ⁱ Würzburg University Clinic ^*  (Germany)

^j MOUNT SINAI HOSPITAL   (Canada)

^k UNIVERSITY OF TORONTO   (Canada)

^l UNIVERSITY OF ULM   (Germany)

^m BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; HEMOGLOBIN A1C; INSULIN; LINAGLIPTIN; METFORMIN; PLACEBO; SULFONYLUREA; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLYCOSYLATED HEMOGLOBIN;

ACUTE PANCREATITIS; AGED; ANGIONEUROTIC EDEMA; ARTICLE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; CHRONIC PANCREATITIS; COLON CANCER; CONTROLLED STUDY; DEATH; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG WITHDRAWAL; END STAGE RENAL DISEASE; ESTIMATED GLOMERULAR FILTRATION RATE; FEMALE; FOLLOW UP; HEART INFARCTION; HIGH RISK PATIENT; HUMAN; HYPOGLYCEMIA; KIDNEY DISEASE; KIDNEY FAILURE; MAJOR CLINICAL STUDY; MALE; MICROALBUMINURIA; MULTICENTER STUDY; NON INSULIN DEPENDENT DIABETES MELLITUS; NON-INFERIORITY TRIAL; PANCREAS CANCER; PEMPHIGOID; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SKIN DEFECT; TREATMENT OUTCOME; VASCULAR DISEASE; CHEMICALLY INDUCED; CHRONIC KIDNEY FAILURE; CLINICAL TRIAL; COMBINATION DRUG THERAPY; COMPARATIVE STUDY; COMPLICATION; MIDDLE AGED; MORTALITY; PROPORTIONAL HAZARDS MODEL; RISK FACTOR;

AGED; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; FEMALE; GLYCATED HEMOGLOBIN A; HUMANS; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; KIDNEY FAILURE, CHRONIC; LINAGLIPTIN; MALE; MIDDLE AGED; PROPORTIONAL HAZARDS MODELS; RISK FACTORS;

EID: 85056408909     PISSN: 00987484     EISSN: 15383598     Source Type: Journal    
DOI: 10.1001/jama.2018.18269     Document Type: Article

References (33)

1. Rawshani A, Rawshani A, Franzén S, Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017; 376 (15): 1407-1418. doi: 10.1056/NEJMoa1608664 28402770
2. Wen CP, Chang CH, Tsai MK, Diabetes with early kidney involvement may shorten life expectancy by 16 years. Kidney Int. 2017; 92 (2): 388-396. doi: 10.1016/j.kint.2017.01.030 28577854
3. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; 356 (24): 2457-2471. doi: 10.1056/NEJMoa072761 17517853
4. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005; 294 (20): 2581-2586. doi: 10.1001/jama.294.20.joc50147 16239637
5. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007; 370 (9593): 1129-1136. doi: 10.1016/S0140-6736(07)61514-1 17905165
6. US Food and Drug Administration. Guidance for Industry. Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed August 31, 2018.
7. Committee for Medicinal Products for Human Use. Guideline on Clinical Investigation of Medicinal Products in the Treatment or prevention of Diabetes Mellitus. London, England: European Medicines Agency; 2012. https://www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2012/06/WC500129256.pdf. Accessed August 31, 2018.
8. Scirica BM, Bhatt DL, Braunwald E,; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369 (14): 1317-1326. doi: 10.1056/NEJMoa1307684 23992601
9. White WB, Cannon CP, Heller SR,; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013; 369 (14): 1327-1335. doi: 10.1056/NEJMoa1305889 23992602
10. Green JB, Bethel MA, Armstrong PW,; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015; 373 (3): 232-242. doi: 10.1056/NEJMoa1501352 26052984
11. Boehringer Ingelheim. Tradjenta (linagliptin) tablets prescribing information. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf. Accessed August 31, 2018.
12. Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012; 11: 3. doi: 10.1186/1475-2840-11-3 22234149
13. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013; 36 (11): 3460-3468. doi: 10.2337/dc13-0323 24026560
14. Rosenstock J, Perkovic V, Alexander JH,; CARMELINA Investigators. Rationale, design, and baseline characteristics of the Cardiovascular Safety and Renal Microvascular Outcome Study With Linagliptin (CARMELINA): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018; 17 (1): 39. doi: 10.1186/s12933-018-0682-3 29540217
15. Marx N, McGuire DK, Perkovic V, Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point? Diabetes Care. 2017; 40 (9): 1144-1151. doi: 10.2337/dc17-0068 28830955
16. Center for Drug Evaluation and Research. Meeting expectations to exclude a CV risk margin of 1.3. In: Application Number 204042Orig1s000 Summary Review. Page 20. https://www.accessdata.fda.gov/drugsatfda-docs/nda/2013/204042Orig1s000SumR.pdf. Accessed August 31, 2018.
17. Levey AS, Inker LA, Matsushita K, GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014; 64 (6): 821-835. doi: 10.1053/j.ajkd.2014.07.030 25441437
18. Thompson A, Lawrence J, Stockbridge N. GFR decline as an end point in trials of CKD: a viewpoint from the FDA. Am J Kidney Dis. 2014; 64 (6): 836-837. doi: 10.1053/j.ajkd.2014.09.006 25446026
19. Lo C, Toyama T, Wang Y, Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease. Cochrane Database Syst Rev. 2018; 9: CD011798. 30246878
20. Afkarian M, Zelnick LR, Hall YN, Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA. 2016; 316 (6): 602-610. doi: 10.1001/jama.2016.10924 27532915
21. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014; 312 (24): 2668-2675. doi: 10.1001/jama.2014.15298 25536258
22. Cornel JH, Bakris GL, Stevens SR,; TECOS Study Group. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care. 2016; 39 (12): 2304-2310. doi: 10.2337/dc16-1415 27742728
23. Mosenzon O, Leibowitz G, Bhatt DL, Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care. 2017; 40 (1): 69-76. doi: 10.2337/dc16-0621 27797925
24. Patel A, MacMahon S, Chalmers J,; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358 (24): 2560-2572. doi: 10.1056/NEJMoa0802987 18539916
25. McGuire DK, Alexander JH, Johansen OE, Linagliptin effects on heart failure outcomes in participants with type 2 diabetes at high CV and renal risk in CARMELINA [published online November 11, 2018]. Circulation. doi: 10.1161/CIRCULATIONAHA.118.038352
26. Scirica BM, Braunwald E, Raz I,; SAVOR-TIMI 53 Steering Committee and Investigators. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014; 130 (18): 1579-1588. doi: 10.1161/CIRCULATIONAHA.114.010389 25189213
27. Zannad F, Cannon CP, Cushman WC,; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015; 385 (9982): 2067-2076. doi: 10.1016/S0140-6736(14)62225-X 25765696
28. McGuire DK, Van de Werf F, Armstrong PW,; Trial Evaluating Cardiovascular Outcomes With Sitagliptin Study Group. Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016; 1 (2): 126-135. doi: 10.1001/jamacardio.2016.0103 27437883
29. Turnbull FM, Abraira C, Anderson RJ, Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009; 52 (11): 2288-2298. doi: 10.1007/s00125-009-1470-0 19655124
30. Ruospo M, Saglimbene VM, Palmer SC, Glucose targets for preventing diabetic kidney disease and its progression. Cochrane Database Syst Rev. 2017; 6: CD010137. doi: 10.1002/14651858.CD010137.pub2 28594069
31. Knapen LM, de Jong RG, Driessen JH, Use of incretin agents and risk of acute and chronic pancreatitis: a population-based cohort study. Diabetes Obes Metab. 2017; 19 (3): 401-411. doi: 10.1111/dom.12833 27883260
32. Nauck MA, Jensen TJ, Rosenkilde C, Calanna S, Buse JB; LEADER Publication Committee; LEADER Trial Investigators. Neoplasms reported with liraglutide or placebo in people with type 2 diabetes: results from the LEADER randomized trial. Diabetes Care. 2018; 41 (8): 1663-1671. doi: 10.2337/dc17-1825 29898902
33. Marx N, Rosenstock J, Kahn SE, Design and baseline characteristics of the Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA). Diab Vasc Dis Res. 2015; 12 (3): 164-174. doi: 10.1177/1479164115570301 25780262