Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function

Abstract

IMPORTANCE Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown. OBJECTIVE To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m 2 or creatinine Ն1.4 mg/dL for women or Ն1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016). EXPOSURES New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function. MAIN OUTCOMES AND MEASURES MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death. RESULTS There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m 2 [IQR, 51.6-58.2] and hemoglobin A 1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use. CONCLUSIONS AND RELEVANCE Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.

Hospitalization for Lactic Acidosis Among Patients With Reduced Kidney Function Treated With Metformin or Sulfonylureas

“…On the basis of our estimates, this risk difference of 0.03% over 5 years translates into one additional lactic acidosis hospitalization per 3,300 patients treated with metformin for 5 years. Our prior work estimated that a single year of metformin versus sulfonylurea treatment in this same cohort of patients with diabetes and reduced kidney function was associated with prevention of 167 major adverse cardiovascular events (19). Taken together, in patients with type 2 diabetes and kidney disease, the association of lactic acidosis hospitalization with metformin is small and MACR, microalbumin-to-creatinine ratio.…”

Incidence of cancer after asthma development: 2 independent population-based cohort studies

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The right place for metformin today

“…Com-pared with sulfonylureas and other hypoglycaemic agents, metformin has been associated with a statistically significant lower risk of all-cause mortality in people with T2DM and various stages of CKD, in both a Swedish population-based [31] longitudinal study (n = 51,675) and a large cohort study [32] of veterans with diabetes and CKD (n = 175,296). In a very recent retrospective cohort study of the US Veterans Health Administration [33], there were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (eGFR < 60 mL/min/1.73 m2 or creatinine ! 1.4 mg/dL for women or !…”