Although metformin is first line treatment for patients with diabetes (DM), many patients with moderate chronic kidney disease (CKD) do not receive metformin due to concerns about the risk of lactic acidosis. Within the Veterans Health Administration (VHA) 30-40% of incident DM medications are sulfonylureas, rather than metformin, due in part to underlying CKD. Our group and others have demonstrated that among patients with preserved kidney function, metformin use is associated with better cardiovascular, kidney, and survival outcomes compared with sulfonylureas.1-4 The rapidly increasing number of patients with DM and moderate CKD may also derive cardiovascular and renal benefits from metformin, but do not receive this recommended first line therapy due to the Food and Drug Administration (FDA) warning (contraindication at serum creatinine >1.5 mg/dL for men; >1.4mg/dL for women). Guidelines in the United Kingdom, Canada, and Australia emphasize metformin use based on estimated glomerular filtration rate (eGFR) criteria rather than creatinine. Patients with reduced eGFR may use metformin with frequent monitoring and dose reduction, and an eGFR <30 mL/min is considered an absolute contraindication to metformin. Formal petitions to revise the FDA warning to consider eGFR based prescribing have been filed but additional evidence is needed to inform these policy decisions.6, 7 Randomized trials would be ideal, but the large number of patients needed and existing warning make such studies prohibitive. Methodologically-strong comparative effectiveness observational studies are necessary to determine the relative benefits and risks of metformin versus sulfonylureas use among patients with CKD. This proposal will answer the question: Among patients with Stage 3 CKD, what are the absolute risks of lactic acidosis and cardiovascular and renal events for those initially treated with metformin compared to those treated with a sulfonylurea? We will rebuild an inception diabetes cohort utilizing national Veterans Health Administration (VHA) data (corporate data warehouse-vital signs; pharmacy, medical datasets, Medicare/ Medicaid data and vital status files), national death index and data on echocardiograms. Eligible veterans will have a baseline creatinine >1.5 mg/dL or an eGFR between 30 and 59 ml/min and initially treated with metformin (current N=16,891 through FY2008; anticipated rebuilt cohort N~86,924) or sulfonylurea (current N=41,952; anticipated rebuilt cohort N~149,869). The proposed study follows this inception cohort from monotherapy initiation until an outcome or censoring event (leave VHA, change therapy or death). The comparisons of interest will be: metformin vs. sulfonylurea. Persons included are aged >18 years, utilize VHA from 10/1/2000 through 09/30/2014. In this national cohort of veterans with diabetes and impaired renal function:
Aim 1 will test the hypothesis that the risk of hospitalization for laboratory-confirmed lactic acidosis in patients treated with metformin is similar to the risk in patients treated with sulfonylureas.
Aim 2 will test the hypothesis that fatal or nonfatal cardiovascular events is lower among patients treated with metformin versus sulfonylureas.
Aim 3 will test the hypothesis that heart failure hospitalizations or emergency visits is lower among patients treated with metformin versus sulfonylureas.
Aim 4 will test the hypothesis that CKD progression and all-cause mortality is lower among patients treated with metformin versus sulfonylureas. Propensity score matching will be used to achieve similar groups. We will compare event rates accounting for baseline and time-varying covariates with marginal structural Cox proportional hazards models (MSM) with ?stabilized? inverse probability treatment weights (IPTW). Our team has been extremely productive over the last 3 years and is poised to conduct a rigorous and necessary evaluation of the effectiveness of DM regimens among patients with CKD. Our publication record attests to our ability to use VHA data for accurate measurement of exposures, outcomes and covariates.

Public Health Relevance

Chronic kidney disease (CKD) affects 30% of the approximately 21 million adult Americans with diabetes (DM). Although metformin is first line treatment for patients with DM, many patients with moderate CKD do not receive metformin due to concerns for lactic acidosis, a rare but serious outcome. Our group and others have demonstrated that among patients without CKD, metformin use is associated with cardiovascular, kidney, and survival advantages compared with sulfonylureas. The rapidly increasing number of patients with DM and moderate CKD may also derive cardiovascular and renal benefits from metformin. Evidence on the advantages and risks of metformin versus sulfonylureas in those with moderate CKD is urgently needed but currently lacking. We will conduct a national retrospective cohort study of approximately 40,000 new users of metformin and 75,000 new users of sulfonylureas with Stage 3 CKD to answer these clinical questions. Outcomes will include cardiovascular and renal events and hospitalization for confirmed lactic acidosis and heart failure.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX000570-06
Application #
9378720
Study Section
Epidemiology (EPID)
Project Start
2012-10-01
Project End
2020-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
156385783
City
Nashville
State
TN
Country
United States
Zip Code
37212
Roumie, Christianne L; Greevy, Robert A; Grijalva, Carlos G et al. (2016) Diabetes treatment intensification and associated changes in HbA1c and body mass index: a cohort study. BMC Endocr Disord 16:32
Min, Jea Young; Griffin, Marie R; Hung, Adriana M et al. (2016) Comparative Effectiveness of Insulin versus Combination Sulfonylurea and Insulin: a Cohort Study of Veterans with Type 2 Diabetes. J Gen Intern Med 31:638-46
Hung, Adriana M; Roumie, Christianne L; Greevy, Robert A et al. (2016) Comparative Effectiveness of Second-Line Agents for the Treatment of Diabetes Type 2 in Preventing Kidney Function Decline. Clin J Am Soc Nephrol 11:2177-2185
Roumie, Christianne L; Min, Jea Young; Greevy, Robert A et al. (2016) Risk of hypoglycemia following intensification of metformin treatment with insulin versus sulfonylurea. CMAJ 188:E104-12
Grijalva, Carlos G; Roumie, Christianne L; Murff, Harvey J et al. (2015) The role of matching when adjusting for baseline differences in the outcome variable of comparative effectiveness studies. J Comp Eff Res 4:341-9
Roumie, Christianne L; Greevy, Robert A; Griffin, Marie R (2014) Insulin vs sulfonylureas for second-line diabetes treatment--reply. JAMA 312:1693-4
Roumie, Christianne L; Greevy, Robert A; Griffin, Marie R (2014) Insulin vs sulfonylureas for second-line diabetes treatment. JAMA 312:1694
Roumie, Christianne L; Greevy, Robert A; Grijalva, Carlos G et al. (2014) Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA 311:2288-96
Niesner, Kurt; Murff, Harvey J; Griffin, Marie R et al. (2013) Validation of VA administrative data algorithms for identifying cardiovascular disease hospitalization. Epidemiology 24:334-5
Hung, Adriana M; Roumie, Christianne L; Greevy, Robert A et al. (2013) Kidney function decline in metformin versus sulfonylurea initiators: assessment of time-dependent contribution of weight, blood pressure, and glycemic control. Pharmacoepidemiol Drug Saf 22:623-31