(042) Comparative risk of lactic acidosis associated with initiation of metformin among patients with and without renal impairment

Background: Metformin (MET) is first-line therapy for patients with type 2 diabetes. Until 2016, MET was contraindicated in the US for patients with renal impairment due to concerns about MET-induced lactic acidosis (LA), a rare and often fatal condition of lactic acid build-up in the body. In 2016, based on a review of published literature, FDA concluded that MET could be used safely with mild and moderate renal impairment and required changes to labeling to allow use of MET in these patients.

Objectives: To estimate the comparative risk of hospitalization for LA between initiators of MET vs. sulfonylurea (SU), stratified by baseline renal impairment.

Methods: We identified patients with diabetes >65 years enrolled >365 days in US Medicare (2008-2018) newly initiating MET or SU and without history of end stage renal disease or hospitalization for acidosis. Hospitalization for LA was identified using a validated algorithm based on admitting and discharge diagnoses for acidosis (no code for exists LA in ICD-9 or 10). We assessed incidence rates (IR) of LA hospitalizations among MET and SU users stratified by baseline renal impairment (defined by a validated claims-based algorithm). We then performed inverse probability treatment weighted (IPTW) Cox regression using propensity scores estimated using sociodemographic, diagnostic, medication and healthcare utilization variables.

Results: Among 560,963 patients without renal impairment, 476,149 (84.9%) initiated MET. Among 154,573 patients with renal impairment, 107,776 (69.7%) initiated MET. In MET and SU initiators, those with baseline renal impairment were older, had more hypertension, took more diuretics, and were more likely to be male than those without renal impairment. Those initiating MET, regardless of renal impairment status, were younger and had less hypertension, cancer, and healthcare interactions than those initiating SU. There were 94 LA hospitalizations. LA IR without renal impairment was 11.7/100,000 person-years (100kpy) for MET and 15.3/100kpy for SU. LA IR with renal impairment was 29.6/100kpy for MET and 31.3/100kpy for SU. The MET vs SU comparison showed no increase in LA for those with [hazard ratio (HR) 0.68 (0.32-1.45); absolute risk reduction (ARR) -3.56 (-12.80, 5.69)] or without [HR 0.75 (0.22-2.44); ARR -1.75
(-24.01, 20.50)] renal impairment.

Using more specific and more sensitive definitions of LA also resulted in no greater LA risk for MET vs SU, regardless of renal impairment status.

Conclusions: The number of LA events was small for both MET and SU with approximately twice the IRs in patients with vs without renal impairment. Commensurate with the 2016 label changes, MET users had no increased LA risk compared with SU users, regardless of having renal impairment.