Type 2 diabetes (T2D) is a common cause of end-stage kidney disease and is associated with CV complications.Dipeptidyl peptidase-4 inhibitors (DPP-4i) have been studied in several dedicated CV outcome trials, but the number of participants with chronic kidney disease (CKD) has been limited; hence there is a dearth of clinical outcomes data in this population.
CARMELINA® (NCT01897532) randomized people with T2D and either i) UACR >30 mg/g with concomitant CV disease, or ii) eGFR 200 mg/g, to receive the DPP-4i linagliptin (5 mg) or placebo once daily in a double-blind fashion. The primary CV endpoint was 3P-MACE, with a key secondary kidney endpoint adjudicated ESKD, renal death, or sustained ≥40% decrease in eGFR from baseline. Glycemic effects and hypoglycemia were also analyzed. Subgroups were assessed by baseline kidney function (eGFR ≥/<45).
6979 participants (mean age 65.9 years, HbA1c 8.0%, eGFR 54.6 ml/min/1.73m2, 43% eGFR 30 mg/g) from 605 centers across 27 countries were followed-up for median 2.2 yrs. Linagliptin reduced HbA1c (overall mean (95% CI) difference linagliptin vs placebo -0.36% (-0.42, -0.29) based on least square means), regardless of eGFR (eGFR < 45: -0.35% (-0.45, -0.25); eGFR ≥ 45: -0.36% (-0.45, -0.28)), with fewer patients initiating or intensifying insulin in the linagliptin group (HR 0.75 (0.65, 0.81), also regardless of eGFR (eGFR < 45: HR 0.69 (0.59, 0.81); eGFR ≥ 45: HR 0.76 (0.65, 0.88)). Risk for 3P-MACE (HR 1.02 (0.89, 1.17), hospitalization for heart failure (hHF) (HR 0.90 (0.74, 1.08), the secondary kidney endpoint (HR 1.04 (0.89, 1.22)), were also similar between randomized groups. All outcomes occurred at higher incidence rates in those with reduced eGFR, however, results were consistent across eGFR subgroups (p heterogeneity >0.1). Incidence rates of any hypoglycaemia (100 participant-yrs) was not different across treatment groups (linagliptin: 19.9, placebo 20.2), including in those with eGFR < 45 (linagliptin: 28.4, placebo: 28.5) or eGFR ≥ 45 (linagliptin 14.5, placebo 14.9).
The use of linagliptin over a median 2.2 years compared with placebo resulted in a noninferior risk of a composite CV outcome with no effect on the secondary kidney outcome or hHF. HbA1c was significantly reduced with linagliptin regardless of eGFR, without increasing risk for hypoglycaemia.
In a large, international CV outcome trial in participants with T2D and concomitant CV and/or kidney disease, linagliptin did not affect CV/hHF/kidney risk. Significant reductions in HbA1c and insulin need was observed regardless of eGFR.
Robert Toto– Professor and associate dean, UT Southwestern’s Department of Internal Medicine, Texas
Vlado Perkovic– Professor, The George Institute for Global Health, UNSW Sydney, Sydney, Australia
Odd Erik Johansen– Global Clinical Program Lead, Boehringer Ingelheim, Norway
Mark Cooper– Professor, Diabetes department at the Central Clinical School at Monash University., Australia
Julio Rosenstock– Director, Dallas Diabetes Research Center at Medical City, Dallas, TX, USA., Dallas, Texas
Steven Kahn– Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA., Seattle, Washington
Nikolaus Marx– Professor of Medicine / Cardiology; Head of the Department of Internal Medicine I, RWTH Aachen University
John H Alexander– Professor of Medicine / Cardiology, Duke Clinical Research Institute
Jyothis George– Global late stage clinical development head, Boehringer Ingelheim, Ingelheim, Germany
Bernard Zinman– Senior Scientist, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada, Division of Endocrinology, University of Toronto, Toronto, Canada., Toronto, Ohio
Professor and associate dean
UT Southwestern’s Department of Internal Medicine, Texas
Prof Toto is the Mary M. Conroy Professor of Kidney Disease in UT Southwestern’s Department of Internal Medicine. He specializes in kidney disease treatment and research. Dr. Toto also is the Associate Dean of Clinical and Translational Research in the Graduate School of Biomedical Sciences; the Director of the Center for Translational Medicine; and the Medical Director of UT Southwestern’s Multi-Specialty Clinic.
The George Institute for Global Health, UNSW Sydney
Vlado Perkovic is Executive Director of The George Institute, Australia, Professor of Medicine at UNSW Sydney, and a Staff Specialist in Nephrology at the Royal North Shore Hospital.
Global Clinical Program Lead
Boehringer Ingelheim, Norway
Dr Johansen is a clinician scientist and trialist with background in diabetology and vascular medicine. He has authored > 100 papers and lead several CV outcome trials from his employer to completion.
Diabetes department at the Central Clinical School at Monash University., Australia
Professor Mark Cooper AO is Head of the recently formed (1 January 2017) Diabetes Department in the Central Clinical School at Monash University. He was formerly Chief Scientific Officer, Baker IDI Heart and Diabetes Institute, and maintains an active clinical practice at The Alfred as a senior endocrinologist.
Dallas Diabetes Research Center at Medical City, Dallas, TX, USA.
Dr. Julio Rosenstock is Director of the Dallas Diabetes Research Center at Medical City Dallas, and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center, Dallas.
Professor of Medicine
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
Reaearch interests are pathophysiology, prevention and treatment of type 2 diabetes.
Professor of Medicine / Cardiology; Head of the Department of Internal Medicine I
RWTH Aachen University
Nikolaus Marx, born in 1968, is Professor of Medicine / Cardiology and Head of the Department of Internal Medicine I, University Hospital Aachen, Germany. He received his medical training at the Universities of Mainz, Genf (Switzerland) and Düsseldorf, obtaining his MD in 1994. His thesis on growth regulation in human renal cancer cell lines was completed at the laboratory of Professor Gerharz at the Institute of Pathology, University of Mainz. After a post-doctoral fellowship with Dr. Peter Libby and Dr. Jorge Plutzky at Brigham and Women's Hospital, Harvard Medical School, Nikolaus Marx later became a board-certified internist, then cardiologist, before specialising in intensive care medicine in internal medicine at the University of Ulm. He was appointed Professor of Medicine / Cardiology and Head of the Department of Internal Medicine I at the University of Aachen in 2009.
Professor Marx is a member of several organisations within the field of cardiology and diabetes, including the European Society of Cardiology, American Heart Association (AHA), German Diabetes Association and the European Association for the Study of Diabetes. In addition to reviewing submitted manuscript to numerous journals, including Circulation, Diabetologia, Diabetes, Diabetes Care, the Journal of Immunology and The Lancet, he is currently Associate Editor for Diabetes and Vascular Disease Research. Professor Marx was awarded the Servier Young Investigators Award in 1999 at the First European Meeting on Vascular Biology and Medicine more recently was winner of the Poster Award Competition in Epidemiological Science at AHA 2002, the 2004 Morgagni Young Investigator Award as well as the Rising Star Award 2005 of the European Association for the Study of Diabetes (EASD). Professor Marx has served as President of the German Atherosclerosis Society (DGAF) from 2012 to 2015.
Professor of Medicine / Cardiology
Duke Clinical Research Institute
Professor of Medicine / Cardiology. Clinical trials.
Global late stage clinical development head
Associated therapeutic area head and heads up the global late stage clinical development in metabolism, Bohringer Ingelheim