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

Cardiovascular Diabetology

Volumn 17, Issue 1, 2018, Pages

  Rosenstock, Julio ^a   Perkovic, Vlado ^b   Alexander, John H ^c   Cooper, Mark E ^d   Marx, Nikolaus ^e   Pencina, Michael J ^c   Toto, Robert D ^f   Wanner, Christoph ^g   Zinman, Bernard ^h,i   Baanstra, David ^j   Pfarr, Egon ^j   Mattheus, Michaela ^j   Broedl, Uli C ^j   Woerle, Hans Juergen ^k   George, Jyothis T ^j   von Eynatten, Maximilian ^j   McGuire, Darren K ^l  

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

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

^c DUKE CLINICAL RESEARCH INSTITUTE   (United States)

^d MONASH UNIVERSITY   (Australia)

^e UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

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

^g UNIVERSITY HOSPITAL WÜRZBURG   (Germany)

^h MOUNT SINAI HOSPITAL   (Canada)

ⁱ UNIVERSITY OF TORONTO   (Canada)

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

^k UNIVERSITY OF ULM   (Germany)

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

more..

Author keywords

Cardiovascular diseases; Clinical trial, phase IV; Diabetes mellitus, type 2; Diabetic nephropathies; Dipeptidyl peptidase IV inhibitors; Linagliptin; Research design; Treatment outcome

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; ANTITHROMBOCYTIC AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CALCIUM ANTAGONIST; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; HEMOGLOBIN A1C; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN; LINAGLIPTIN; METFORMIN; PLACEBO; SULFONYLUREA; BIOLOGICAL MARKER; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLYCOSYLATED HEMOGLOBIN; HEMOGLOBIN A1C PROTEIN, HUMAN;

ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CARDIORENAL RISK; CHOLESTEROL BLOOD LEVEL; COHORT ANALYSIS; CONTROLLED STUDY; CORONARY ARTERY BYPASS GRAFT; DOUBLE BLIND PROCEDURE; DRUG DESIGN; DRUG EFFICACY; DRUG SAFETY; ESTIMATED GLOMERULAR FILTRATION RATE; FEMALE; GOOD CLINICAL PRACTICE; HAZARD RATIO; HEMOGLOBIN BLOOD LEVEL; HUMAN; HYPERTENSION; INSTITUTIONAL REVIEW; MACROALBUMINURIA; MAJOR CLINICAL STUDY; MALE; MICROALBUMINURIA; NON INSULIN DEPENDENT DIABETES MELLITUS; OUTCOME ASSESSMENT; PERCUTANEOUS CORONARY INTERVENTION; PRACTICE GUIDELINE; RANDOMIZED CONTROLLED TRIAL; RISK ASSESSMENT; THROMBOCYTE AGGREGATION; AGED; BLOOD; CARDIOVASCULAR DISEASE; CAUSE OF DEATH; CHRONIC KIDNEY FAILURE; CLINICAL TRIAL; DIABETIC NEPHROPATHY; DISEASE EXACERBATION; DRUG EFFECT; GLOMERULUS FILTRATION RATE; GLUCOSE BLOOD LEVEL; KIDNEY; METABOLISM; METHODOLOGY; MIDDLE AGED; MORTALITY; MULTICENTER STUDY; PATHOPHYSIOLOGY; RISK FACTOR; TIME FACTOR; TREATMENT OUTCOME;

AGED; BIOMARKERS; BLOOD GLUCOSE; CARDIOVASCULAR DISEASES; CAUSE OF DEATH; DIABETES MELLITUS, TYPE 2; DIABETIC NEPHROPATHIES; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DISEASE PROGRESSION; DOUBLE-BLIND METHOD; FEMALE; GLOMERULAR FILTRATION RATE; GLYCATED HEMOGLOBIN A; HUMANS; KIDNEY; KIDNEY FAILURE, CHRONIC; LINAGLIPTIN; MALE; MIDDLE AGED; RENAL INSUFFICIENCY, CHRONIC; RESEARCH DESIGN; RISK FACTORS; TIME FACTORS; TREATMENT OUTCOME;

EID: 85043768158     PISSN: None     EISSN: 14752840     Source Type: Journal    
DOI: 10.1186/s12933-018-0682-3     Document Type: Article

References (54)

1. 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):2457-71.
2. 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):2581-6.
3. Center for Drug Evaluation and Research. Guidance for industry. Diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD, U.S. Food and Drug Administration; 2008. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed 10 July 2017.
4. Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London. European Medicines Agency; 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed 10 July 2017.
5. Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39(5):738-42.
6. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.
7. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-35.
8. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-42.
9. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.
10. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, Lawson FC, Ping L, Wei X, Lewis EF, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-57.
11. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-22.
12. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-44.
13. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-57.
14. Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, Pratley RE, Haahr PM, Lange M, Brown-Frandsen K, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723-32.
15. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-39.
16. Vaccaro O, Masulli M, Nicolucci A, Bonora E, Del Prato S, Maggioni AP, Rivellese AA, Squatrito S, Giorda CB, Sesti G, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCAIT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017;5(11):887-97.
17. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2016;12(2):73-81.
18. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, Matsushita K, Wen CP. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339-52.
19. Levin A, Tonelli M, Bonventre J, Coresh J, Donner JA, Fogo AB, Fox CS, Gansevoort RT, Heerspink HJL, Jardine M, et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet. 2017;390(10105):1888-917.
20. Baigent C, Herrington WG, Coresh J, Landray MJ, Levin A, Perkovic V, Pfeffer MA, Rossing P, Walsh M, Wanner C, et al. Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2017;92(2):297-305.
21. Afkarian M, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24:302-8.
22. Cahn A, Cernea S, Raz I. An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin Emerg Drugs. 2016;21(4):409-19.
23. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, et al. 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):2067-76.
24. McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB, Bethel MA, Cornel JH, Lopes RD, Halvorsen S, et al. 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):126-35.
25. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010;38(4):667-78.
26. Graefe-Mody U, Friedrich C, Port A, Ring A, Retlich S, Heise T, Halabi A, Woerle HJ. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*). Diabetes Obes Metab. 2011;13(10):939-46.
27. Rosenstock J, Marx N, Neubacher D, Seck T, Patel S, Woerle HJ, Johansen OE. Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2015;14:57.
28. Cooper ME, Perkovic V, McGill JB, Groop PH, Wanner C, Rosenstock J, Hehnke U, Woerle HJ, von Eynatten M. Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes. Am J Kidney Dis. 2015;66(3):441-9.
29. Marx N, McGuire DK, Perkovic V, Woerle HJ, Broedl UC, von Eynatten M, George JT, Rosenstock J. 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):1144-51.
30. Center for Drug Evaluation and Research. Meeting expectations to exclude a CV risk margin of 1.3. In: Application number: 204042Orig1s000 summary review. 2013, p. 20. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000SumR.pdf. Accessed 24 Oct 2017.
31. Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, de Zeeuw D, Cheung AK, Coresh J. 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):821-35.
32. 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):836-7.
33. Mol PG, Maciulaitis R, Vetter T. GFR decline as an end point for clinical trials in CKD: a view from Europe. Am J Kidney Dis. 2014;64(6):838-40.
34. SI Conversion Calculator. American medical association manual of style: a guide for authors and editors. 10th ed. Oxford: Oxford UP. http://www.amamanualofstyle.com/page/si-conversion-calculator. Accessed 22 Jan 2018.
35. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, Gansevoort RT, Kasiske BL, Eckardt KU. The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report. Kidney Int. 2011;80(1):17-28.
36. Jax T, Stirban A, Terjung A, Esmaeili H, Berk A, Thiemann S, Chilton R, von Eynatten M, Marx N. A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes. Cardiovasc Diabetol. 2017;16(1):13.
37. Baltzis D, Dushay JR, Loader J, Wu J, Greenman RL, Roustit M, Veves A. Effect of linagliptin on vascular function: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2016;101(11):4205-13.
38. de Boer SA, Heerspink HJ, Lefrandt JD, Hovinga-de Boer MC, van Roon AM, Juarez Orozco LE, Glaudemans AW, Kamphuisen PW, Slart RH, Mulder DJ. Effect of linagliptin on arterial (18)F-fluorodeoxyglucose positron emission tomography uptake: a randomized controlled trial (RELEASE). J Am Coll Cardiol. 2017;69(8):1097-8.
39. de Boer SA, Heerspink HJL, Juarez Orozco LE, van Roon AM, Kamphuisen PW, Smit AJ, Slart R, Lefrandt JD, Mulder DJ. Effect of linagliptin on pulse wave velocity in early type 2 diabetes: a randomized, double-blind, controlled 26-week trial (RELEASE). Diabetes Obes Metab. 2017;19(8):1147-54.
40. Ou HT, Chang KC, Li CY, Wu JS. Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study. Cardiovasc Diabetol. 2016;15:41.
41. Kim YG, Yoon D, Park S, Han SJ, Kim DJ, Lee KW, Park RW, Kim HJ. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in patients with type 2 diabetes mellitus: a population-based cohort study. Circ Heart Fail. 2017;10(9):e003957.
42. Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA(R)). Diab Vasc Dis Res. 2015;12(3):164-74.
43. Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, Erondu N, Desai M, Shaw W, Vercruysse F, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab. 2017;19(3):387-93.
44. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M, Shaw W, Jiang J, Vercruysse F, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)-a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217-23.
45. Wanner C. EMPA-REG OUTCOME: the nephrologist's point of view. Am J Cardiol. 2017;120(1S):S59-67.
46. Shi S, Koya D, Kanasaki K. Dipeptidyl peptidase-4 and kidney fibrosis in diabetes. Fibrogenesis Tissue Repair. 2016;9:1.
47. 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):3460-8.
48. Cornel JH, Bakris GL, Stevens SR, Alvarsson M, Bax WA, Chuang LM, Engel SS, Lopes RD, McGuire DK, Riefflin A, et al. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care. 2016;39(12):2304-10.
49. Mosenzon O, Leibowitz G, Bhatt DL, Cahn A, Hirshberg B, Wei C, Im K, Rozenberg A, Yanuv I, Stahre C, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care. 2017;40(1):69-76.
50. Groop PH, Cooper ME, Perkovic V, Hocher B, Kanasaki K, Haneda M, Schernthaner G, Sharma K, Stanton RC, Toto R, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes Obes Metab. 2017;19(11):1610-9.
51. Tsuprykov O, Ando R, Reichetzeder C, von Websky K, Antonenko V, Sharkovska Y, Chaykovska L, Rahnenfuhrer J, Hasan AA, Tammen H, et al. The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy. Kidney Int. 2016;89(5):1049-61.
52. Gangadharan Komala M, Gross S, Zaky A, Pollock C, Panchapakesan U. Linagliptin limits high glucose induced conversion of latent to active TGFss through interaction with CIM6PR and limits renal tubulointerstitial fibronectin. PLoS ONE. 2015;10(10):e0141143.
53. Shi S, Srivastava SP, Kanasaki M, He J, Kitada M, Nagai T, Nitta K, Takagi S, Kanasaki K, Koya D. Interactions of DPP-4 and integrin beta1 influences endothelial-to-mesenchymal transition. Kidney Int. 2015;88(3):479-89.
54. Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y, Ishigaki Y, Kitada M, Srivastava SP, Koya D. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes. 2014;63(6):2120-31.