Results from a retrospective cohort comparing metformin vs. sulfonylurea to assess the safety of metformin with impaired kidney function.
A recent study investigated metformin vs. sulfonylureas in patients with reduced kidney function and diabetes regarding major adverse cardiovascular events (MACE). In the past, safety concerns over metformin use in kidney disease have limited its use. There have been several large studies supporting metformin as the initial treatment in diabetes treatment. Approximately 20% of patients with diabetes also have impaired kidney function, and the kidneys eliminate metformin. Because a reduction in eGFR could lead metformin to accumulate and increase the potential for lactic acidosis, the FDA has recommended against the use of metformin in patients with a certain degree of kidney impairment. Due to metformin’s high efficacy and ability to decrease the incidence of macrovascular complications, it is important to study whether patients with reduced kidney function could continue to use metformin.
This study tested the hypothesis that, among patients with diabetes who develop reduced kidney function, continued metformin use is associated with a lower risk of fatal or nonfatal major adverse cardiovascular events than sulfonylureas. The study design was a retrospective cohort of Veterans Health Administration Patients; they utilized pharmacy data and laboratory results, as well as dates and causes of death. The study population included veterans aged at least 18 years old; they then identified patients with new-onset diabetes and followed along with those patients longitudinally to select patients who experienced a decline in kidney function. Reduced kidney function was defined as an eGFR of less than 60/ml/min/1.73m2 or serum creatinine level of 1.5mg/dL for men or 1.4mg/dL for women. Cohort entry was between January 2002 and December 2015. The study investigated the persistent use of metformin or sulfonylurea (glyburide, glipizide, and glimepiride) after reaching the previously defined kidney threshold. Followup began the date the kidney threshold was reached and continues through either: non-persistence to antidiabetic therapy, no longer under CHA contact, non-cardiovascular death, or the study end. The composite outcome was the major adverse cardiovascular events (hospitalization for MI, ischemic or hemorrhagic stroke, transient ischemic attack, or date of cardiovascular death). The secondary outcome was the same as the primary, except it excluded TIA as part of the composite analysis. Study covariate included age, sex, race, fiscal year, number of months from initial antidiabetic medication to kidney threshold, and Veterans Integrated Service Networks of care. The statistical analysis compares the cause-specific hazard of MACE between the medication groups utilizing the cox proportional hazards model to estimate the hazard ratios. Statistical significance was set at 0.05.
The study identified 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment, met the reduced kidney function threshold ad satisfied cohort entry criteria. Patients were 98% male and 81.8% white. The study found that a larger proportion of metformin users reached the kidney threshold in later study years. Among the metformin patients with reduced kidney function, there were 1048 composite events; the sulfonylurea patients had 1394 events yielding 23.0 (95% CI, 21.7-24.4) vs. 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively. Results were consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87 [95% CI, 0.80-0.95]) and cardiovascular deaths (aHR, 0.70 [95% CI, 0.63-0.78]). The secondary outcome yielded consistent results. Subgroup analysis stratified by a history of cardiovascular disease, age, race, eGFR, and kidney threshold, and if the patient entered via reaching the defined elevated creatinine or reduced eGFR threshold was also consistent with the main analysis.
The results of this study suggest that among patients with diabetes who develop reduced kidney function, persistent use of metformin compared with sulfonylurea was associated with a decreased hazard of MACE. Newer guidelines state that metformin can be used in patients with mild kidney function impairment and they recommend using eGFR rather than creatinine. This study did yield important results; however, it is limited. The patients were mainly male, cohort entry and start of follow up was defined by eGFR or elevated serum creatinine, and it is possible that some of these thresholds could have been made by acute kidney injury; data came from the CHA facilities and may not be all-inclusive for all patients, and the study did not include any dose analysis.
- A reduction in eGFR could lead metformin to accumulate and increase the potential for lactic acidosis; the FDA has recommended against the use of metformin in patients with a certain degree of kidney impairment.
- In patients with diabetes who develop reduced kidney function, persistent use of metformin compared with sulfonylurea was associated with a decreased hazard of MACE.
- Newer guidelines state that metformin can be used in patients with mild kidney function impairment, and they recommend using eGFR rather than creatinine.
CG, Elasy T, Griffin MR. Association of Treatment With Metformin vs. Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function. JAMA. 2019 Sep 19:1-11. doi: 10.1001/jama.2019.13206.]
Alessa Grieff, PharmD candidate, University of South Florida College of Pharmacy