TY - JOUR
T1 - Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction
T2 - the randomized MARLINA-T2D trial
AU - Groop, Per Henrik
AU - Cooper, Mark E.
AU - Perkovic, Vlado
AU - Hocher, Berthold
AU - Kanasaki, Keizo
AU - Haneda, Masakazu
AU - Schernthaner, Guntram
AU - Sharma, Kumar
AU - Stanton, Robert C.
AU - Toto, Robert
AU - Cescutti, Jessica
AU - Gordat, Maud
AU - Meinicke, Thomas
AU - Koitka-Weber, Audrey
AU - Thiemann, Sandra
AU - von Eynatten, Maximilian
N1 - Funding Information:
The authors thank the participants and staff involved in this study. Data from this study have been presented previously at the American Diabetes Association 76th Scientific Sessions, New Orleans, Louisiana, June 10 to 14, 2016. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Giles Brooke, PhD, CMPP, of Envision Scientific Solutions during the preparation of this manuscript. P-H. G. has been a member of advisory panels for AbbVie, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme Corp., Novartis, Sanofi and AstraZeneca; has received research support from Eli Lilly and Roche; and has been a member of Speaker's Bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genzyme, Merck Sharp & Dohme Corp., Novartis, Novo Nordisk and Sanofi. M. E. C., B. H., G. S. and K. S. have received fees for advisory services to Boehringer Ingelheim. V. P. consults for AbbVie, Astellas, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline and Janssen; has received lecture fees or grant support from Baxter, Boehringer Ingelheim, Merck and Pfizer; and his institution has held clinical trial contracts with AbbVie, Roche, Janssen, Servier and Novartis. K. K. has received lecture fees from Boehringer Ingelheim, Eli Lilly and Sanofi. Boehringer Ingelheim, Mitsubishi Tanabe Pharma and Ono Pharmaceutical contributed to establishing the Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University. K. K. is under contract for consultancy with Boehringer Ingelheim. M. H. reports consulting fees, lecture fees, moderator fees, supervising fees, payment for manuscript writing, research support or grants from Sanofi, Tanabe Mitsubishi, Takeda, Eli Lilly, Boehringer Ingelheim, Novo Nordisk, Novartis, MSD, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas, Kowa, Asahi Kasei Pharma, Ajinomoto Pharma, Otsuka, Ono, Kaken, Kissei, GlaxoSmithKline, Sanwa Kagaku Kenkyusho, Shionogi, Johnson & Johnson, Sumitomo Dainippon, Chugai, Teijin Pharma, Terumo, Torii, Bayer Yakuhin, Pfizer, Bristol-Myers Squibb, Mochida, Roche Diagnostics, AstraZeneca, Taisho Toyama and Taisho. R. C. S. has served on the Global Renal Advisory Board for Boehringer Ingelheim. R. T. is a consultant to AbbVie, Amgen, Boehringer Ingelheim, Stealth Peptides, Bristol-Myers Squibb, Celgene, ZS Pharma and Relypsa and receives grant support from Ardelyx and the NIH. J. C., M. G., T. M., A. K-W., S. T. and M. vE. are employees of Boehringer Ingelheim. P-H. G., M. E. C., V. P., B. H., K. K., M. H., G. S., K. S., R. C. S. and R. T. participated in design of the study, collection and interpretation of data, and drafting and revision of the manuscript. J. C. participated in design of the study, performed the statistical analysis, and participated in interpretation of data and drafting and revision of the manuscript. M. G., T. M., A. K-W., S. T. and M. vE. participated in design of the study, interpretation of data, and drafting and revision of the manuscript. All authors have approved the final version of the manuscript. P-H. G. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
PY - 2017/11
Y1 - 2017/11
N2 - Aims: The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48–86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 30–3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [CI], −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was −6.0% (95% CI, −15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.
AB - Aims: The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48–86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 30–3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [CI], −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was −6.0% (95% CI, −15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.
KW - DPP-IV inhibitor
KW - antidiabetic drug
KW - clinical trial
KW - diabetic nephropathy
KW - glycaemic control
KW - linagliptin
UR - http://www.scopus.com/inward/record.url?scp=85026454641&partnerID=8YFLogxK
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U2 - 10.1111/dom.13041
DO - 10.1111/dom.13041
M3 - Article
C2 - 28636754
AN - SCOPUS:85026454641
SN - 1462-8902
VL - 19
SP - 1610
EP - 1619
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 11
ER -