Comparative Effectiveness of Second-Line Agents for the Treatment of Diabetes Type 2 in Preventing Kidney Function Decline.
Diabetes 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.



We 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.



There 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).



Among 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.
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Veterans Health Administration Tennessee Valley Healthcare System Clinical Science Research and Development, Nashville, Tennessee; and.|Departments of Medicine.
Adriana M
AM
Hung
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Veterans Health Administration Tennessee Valley Healthcare System Clinical Science Research and Development, Nashville, Tennessee; and.|Departments of Medicine.
Christianne L
CL
Roumie
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Biostatistics, and.
Robert A
RA
Greevy
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.
Carlos G
CG
Grijalva
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Biostatistics, and.
Xulei
X
Liu
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Departments of Medicine.
Harvey J
HJ
Murff
Veterans Health Administration Tennessee Valley Healthcare System Clinical Science Research and Development, Nashville, Tennessee; and.|Departments of Medicine.
T Alp
TA
Ikizler
Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.|Departments of Medicine.|Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.
Marie R
MR
Griffin
D000368:Aged; D057186:Comparative Effectiveness Research; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D015994:Incidence; D007328:Insulin / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000453:epidemiology* / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D012189:Retrospective Studies; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D013714:Tennessee / Q000453:epidemiology
D003404:Creatinine; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D013453:Sulfonylurea Compounds; C517652:hemoglobin A1c protein, human
Confidence Intervals; Diabetes Mellitus, Type 2; Glucose; Kidney Failure, Chronic; Metformin; Propensity Score; Retrospective Studies; Sulfonylurea Compounds; Veterans; comparative effectiveness; creatinine; diabetes management; diabetes mellitus; diabetic nephropathy; humans; insulin; kidney; treatment intensification