• Adriana M Hung, Christianne L Roumie, Robert A Greevy, Carlos G Grijalva, Xulei Liu, Harvey J Murff, T Alp Ikizler, and Marie R Griffin.
• Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee; Adriana.hung@vanderbilt.edu.
• Clin J Am Soc Nephrol. 2016 Dec 7; 11 (12): 2177-2185.

Background And ObjectivesDiabetes is the leading cause of ESRD. Glucose control improves kidney outcomes. Most patients eventually require treatment intensification with second-line medications; however, the differential effects of those therapies on kidney function are unknown.Design, Setting, Participants & MeasurementsWe studied a retrospective cohort of veterans on metformin monotherapy from 2001 to 2008 who added either insulin or sulfonylurea and were followed through September of 2011. We used propensity score matching 1:4 for those who intensified with insulin versus sulfonylurea, respectively. The primary composite outcome was persistent decline in eGFR≥35% from baseline (GFR event) or a diagnosis of ESRD. The secondary outcome was a GFR event, ESRD, or death. Outcome risks were compared using marginal structural models to account for time-varying covariates. The primary analysis required persistence with the intensified regimen. An effect modification of baseline eGFR and the intervention on both outcomes was evaluated.ResultsThere were 1989 patients on metformin and insulin and 7956 patients on metformin and sulfonylurea. Median patient age was 60 years old (interquartile range, 54-67), median hemoglobin A1c was 8.1% (interquartile range, 7.1%-9.9%), and median creatinine was 1.0 mg/dl (interquartile range, 0.9-1.1). The rate of GFR event or ESRD (primary outcome) was 31 versus 26 per 1000 person-years for those who added insulin versus sulfonylureas, respectively (adjusted hazard ratio, 1.27; 95% confidence interval, 0.99 to 1.63). The rate of GFR event, ESRD, or death was 64 versus 49 per 1000 person-years, respectively (adjusted hazard ratio, 1.33; 95% confidence interval, 1.11 to 1.59). Tests for a therapy by baseline eGFR interaction for both the primary and secondary outcomes were not significant (P=0.39 and P=0.12, respectively).ConclusionsAmong patients who intensified metformin monotherapy, the addition of insulin compared with a sulfonylurea was not associated with a higher rate of kidney outcomes but was associated with a higher rate of the composite outcome that included death. These risks were not modified by baseline eGFR.Copyright © 2016 by the American Society of Nephrology.

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