Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12)

Abstract

Aim: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk.

Methods: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression.

Results: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: -8.59 [95% CI -10.20; -7.00]).

Conclusion: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk.

Trial registration: NCT01959529 (ClinicalTrials.gov).

Keywords: CVOT; Cardiovascular; chronic renal failure; diabetic kidney disease; insulin analogues; type 2 diabetes mellitus.

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.A. has received personal fees related to advisory boards and lectures from Novo Nordisk, Sanofi (South Africa), AstraZeneca, Merck Sharp and Dohme Corp., Lilly South Africa, Boehringer Ingelheim, Merck Biopharma, Servier Laboratories and Novartis South Africa. J.B.B.’s contracted consulting fees (including travel support) are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, vTv Therapeutics and Zafgen; he reports research support – in the form of grants, travel and non-financial support – that is paid to the University of North Carolina by AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, NovaTarg, Novo Nordisk, Sanofi, Theracos, Tolerion and vTv Therapeutics; he is a consultant to Cirius Therapeutics Inc, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics and Stability Health and reports travel support from all companies as well as personal consulting fees from Cirius Therapeutics Inc and CSL Behring; he holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health; and he is supported by grants from the National Institutes of Health (UL1TR002489, R01HL110380, U01DK098246, UC4DK108612, U54DK118612, R01DK119913, R01DK112939, R61HL142680, P30DK124723), JDRFI, PCORI and the American Diabetes Association. D.K.M. has received personal fees from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp and Dohme Corp., Eli Lilly USA, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied Therapeutics, Afimmune and Esperion. T.R.P. has received research support from Novo Nordisk and AstraZeneca (paid directly to the Medical University of Graz); and personal fees as a consultant from Adocia, Arecor, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk and Roche Diabetes Care. T.R.P. is also the Chief Scientific Officer of CBmed (Center for Biomarker Research in Medicine), a public-funded biomarker research company. R.P.B. has received research support to University of Michigan from AstraZeneca; is supported by grants from the National Institutes of Health (NIDDK-1-R01-DK-107956-01, UC4 DK101108); and has received personal fees for consultancy from Novo Nordisk and Bayer. R.E.P. reports grants from Hanmi Pharmaceutical Co.; grants from Janssen; consulting fees from Merck; grants, speaker fees and consulting fees from Novo Nordisk; consulting fees from Pfizer; grants from Poxel SA; grants and consulting fees from Sanofi; consulting fees from Scohia Pharma Inc.; and consulting fees from Sun Pharmaceutical Industries. All fees and honoraria for services were paid directly to AdventHealth (formerly Florida Hospital), a non-profit organisation. B.Z. has received grant support from Boehringer-Ingelheim, AstraZeneca and Novo Nordisk; and consulting fees from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. T.J. is a full-time employee of, and holds stock in, Novo Nordisk A/S. At the time of the study, T.M. and M.B.H. were full-time employees of, and held stock in, Novo Nordisk A/S; T.M. and M.B.H. continue to hold stock in, but are no longer employed by, Novo Nordisk A/S. N.R.P. has received personal fees from Servier, Takeda, Novo Nordisk and AstraZeneca in relation to speakers’ fees and advisory board activities (concerning diabetes mellitus); and research grants for his research group (relating to type 2 diabetes mellitus) from Diabetes UK, National Institute for Health Research Efficacy and Mechanism Evaluation (NIHR EME), Julius Clinical and the British Heart Foundation. Additionally, N.R.P. was a recipient of NIHR Senior Investigator Awards and has been supported by the NIHR Imperial Biomedical Research Centre.

Figures

Figure 1.

eGFR: (a) In the overall trial population, (b) by randomised treatment in patients with type 2 diabetes at high cardiovascular risk. Plot shows mean ± standard error eGFR (by CKD-EPI equation) in the overall trial population (a) and in patients randomised to degludec or glargine U100 (b) in DEVOTE. ETD (degludec/glargine U100) for change in eGFR from baseline to the 24-month visit was analysed using a MMRM within patients using an unstructured covariance matrix among visits at 12 and 24 months of the trial. Interactions between visit and treatment and between visit and baseline eGFR were included as fixed effects. CI: confidence interval; CKD-EPI: chronic kidney disease epidemiology collaboration; eGFR: estimated glomerular filtration rate; ET: end of treatment; ETD: estimated treatment difference; glargine U100: insulin glargine 100 units/mL; MMRM: mixed model for repeated measures.