Metformin Therapy in Patients with Type 2 Diabetes and Mild to Moderate CKD

Worldwide, there are an estimated 380 million people affected by type 2 diabetes mellitus; approximately 20% of those patients have an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Due to low cost, favorable adverse event profile, and a possible beneficial effect on cardiovascular risk, metformin hydrochloride is the recommended first-line medication for treatment of type 2 diabetes. Because of concern of drug accumulation and lactic acidosis, metformin is often avoided in patients with chronic kidney disease (CKD).

Some guidelines suggest that metformin may be an option in patients with mild to moderate CKD. Recently, the US FDA amended the metformin label from contraindicated at serum creatine level >1.5 mg/dL in men and >1.4 mg/dL in women to contraindicated at eGFR <30 mL/min/1.73 m2; initiation of metformin is not recommended at eGFR <45 mL/min/1.73 m2. Metformin is cautiously recommended in other guidelines at eGFR 30 to 60 mL/min/1.73 m2, including the recommendation that metformin be reviewed at eGFR 30 to 45 mL/min/1.73 m2 along with consideration of dose adjustment.

Results of previous studies of the safety of metformin in patients with eGFR <60 mL/min/1.73 m2 are inconclusive. Benjamin Lazarus, MBBS, MPH, and colleagues recently conducted a study designed to examine the relationship between metformin therapy and acidosis across the spectrum of eGFR in a large, integrated electronic medical record cohort (Geisinger Health System), accounting for time-dependent eGFR stage, and for potential confounding from variables, including concomitant insulin use. They then sought to replicate the findings in a separate nationwide cohort derived from 350 private health systems.

In both cohorts, the researchers compared risk of acidosis during metformin use with the risk during alternative management of diabetes mellitus to test the hypothesis that acidosis would be more common among metformin users within categories of eGFR. Results were reported in JAMA Internal Medicine [2018;178(7):903-910].

The Geisinger cohort included 75,413 patients with diabetes, with time-dependent assessment of eGFR stage from January 2004 until January 2007. The primary outcome of interest was hospitalization with acidosis, using International Classification of Diseases, Ninth Revision, Clinical Modification code 276.2.

Mean age in the Geisinger cohort was 60.4 years, 51% were female, and mean body mass index was 34.1. At the time of enrollment, 14,662 patients had an eGFR <60 mL/min/1.73 m2 and 1765 had an eGFR <30 mL/min/1.73 m2. Median duration of follow-up was 5.7 years and the median number of creatinine measurements per year was 2.1; the number of measurements increased with lower eGFR.

At study enrollment, 45% of patients were taking metformin (n=34,095); 13,781 of the remaining patients were subsequently prescribed metformin during follow-up. Median duration of metformin use was 2.8 years.

There were 2335 hospitalizations with acidosis over 470,114 person-years of follow-up: 737 events occurred over 188,578 person-years of metformin use and 1598 occurred over 281,536 person-years of no metformin use. Only 29 of these events had an acidosis code in the primary position.

Overall, the adjusted hazard ratio (HR) of acidosis during metformin use compared with nonuse was 0.98 (95% confidence interval [CI], 0.89-1.08). At lower eGFR, the risk of acidosis was higher (P=.01 for interaction). The risk associated with metformin use was not statistically significant at eGFR >90 mL/min/1.73 m2 (adjusted HR, 0.88; 95% CI, 0.73-1.05); eGFR 60 to 89 mL/min/1.73 m2 (adjusted HR, 0.87; 95% CI, 0.75-1.02), eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16; 95% CI, 0.95-1.41), and eGFR 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.09; 95% CI, 0.83-1.44). At eGFR <30 mL/min/1.73 m2, there was an increased risk of acidosis associated with metformin use (adjusted HR, 2.07; 95% CI, 1.33-3.22). Following adjustment for other time-dependent medication use, the results were similar.

In the MarketScan database (replication cohort), there were 67,578 new metformin users and 14,439 new sulfonylurea users from 2010 to 2015. Compared with the sulfonylurea users, the metformin users were slightly younger and more likely to be female. Median follow-up was 12.0 months in the metformin group and 11.5 months in the sulfonylurea group.

The number of acidosis events in the metformin group was 238; in the sulfonylurea group the number was 94. The incidence rate of acidosis in the metformin group was 2.7 events per 1000 person-years; in the sulfonylurea group, the incidence rate was 5.0 events per 1000 person-years.

In both groups, lower eGFR was a risk factor for acidosis. Overall, the risk associated with metformin use was slightly lower than with sulfonylurea (adjusted HR, 0.75; 95% CI, 0.58-0.97) and was not increased in patients with eGFR 45 to 59 mL/min/1.73 m2 and eGFR 30 to 44 mL/min/1.72 m2 (adjusted HR, 0.83; 95% CI, 0.42-1.62 and 0.86; 95% CI, 0.37-2.01, respectively). There was a higher but not statistically significant risk in patients with eGFR <30 mL/min/1.73 m2 (adjusted HR, 1.83; 95% CI, 0.57-5.88).

There were some limitations to the study, including the possibility of residual confounding due to the observational design, the use of a diagnostic code that was not specific for lactic acidosis, the inability to differentiate whether a change in eGFR stage occurred due to progression of CKD or an acute kidney injury, and the possibility of limited generalizability of the results due to the majority of Geisinger Health System population being white.

In conclusion, the researchers said, “Metformin use was not associated with incident acidosis in patients with eGFR 30 to 60 mL/min/1.73 m2 in two large and diverse cohorts, but there was increased risk at eGFR <30 mL/min/1.73 m2. Our results support cautious use of metformin in patients with type 2 diabetes mellitus and eGFR of at least 30 mL/min/1.73 m2.”

Takeaway Points

  1. Data regarding the safety of metformin in patients with type 2 diabetes mellitus and mild to moderate chronic kidney disease (CKD) are inconclusive.
  2. Researchers conducted a study in two large cohorts of patients with type 2 diabetes and mild to moderate CKD designed to examine the relationship between metformin therapy and the incidence of acidosis in that patient population.
  3. Results of the study support “cautious” use of metformin in patients with type 2 diabetes and estimated glomerular filtration rate of at least 30 mL/min/1.73 m2.