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Safety of Metformin in Patients With Diabetes and CKD
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Investigators assessed the cardiovascular and renal safety of metformin in chronic kidney disease (CKD) stages 3 and 4. They performed a post hoc analysis of two clinical trials. The study included patients with eGFR 15–59 mL/min/1.73 m2 who were and were not taking metformin during the trials. A total of 1745 participants using metformin were propensity-matched to those not using metformin. Metformin had neutral effects on major adverse cardiovascular events and all-cause mortality. There was no interaction by CKD stage or with use of exenatide or saxagliptin.
- The study supports the cardiorenal safety of metformin in patients with CKD stages 3 and 4, but it does not show consistent benefit for major adverse cardiovascular events or all-cause mortality in this population.
abstract
This abstract is available on the publisher's site.
Access this abstract nowAIMS
Metformin, the most common first-line therapy for type 2 diabetes, is used frequently in patients with moderate and severe chronic kidney disease (CKD), despite concerns regarding lactic acidosis. We aim to provide evidence on the cardiovascular and renal safety of metformin in CKD3-4.
MATERIALS AND METHODS
This posthoc analysis compared participants with eGFR 15-59 mL/min/1.73m2 in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR)-TIMI 53 trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach. Adjusted Cox proportional hazards models were used to assess risk of major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Metformin effect on eGFR slope was calculated using a mixed model-repeated measures (MMRM) analysis, and the number of lactic acidosis events was tabulated.
RESULTS
No strong trend for lower metformin doses with lower eGFR values was observed in either EXSCEL or SAVOR. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio 0.91, 95%CI 0.76-1.08, p = 0.28) and ACM (0.86, 0.70-1.07, p = 0.18), with no interaction by CKD stage, or with use of exenatide or saxagliptin. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR, but not in other groups.
CONCLUSIONS
This analysis of participants with CKD3-4 from two cardiovascular outcomes trials supports the cardiorenal safety of metformin but does not suggest a consistent benefit on MACE, ACM, or eGFR slope across this population.
Additional Info
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Cardiovascular and Renal Safety of Metformin in Patients With Diabetes and Moderate or Severe Chronic Kidney Disease: Observations From the EXSCEL and SAVOR-TIMI 53 Cardiovascular Outcomes Trials
Diabetes Obes Metab 2021 Jan 04;[EPub Ahead of Print], LE Clegg, Y Jing, RC Penland, DW Boulton, AF Hernandez, RR Holman, J VoraFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Diabetes
Although metformin is the most widely used agent in the treatment of type 2 diabetes mellitus, many providers are hesitant to prescribe it in patients with chronic kidney disease (CKD), given prior recommendations advising against the use of metformin in CKD due to risk for lactic acidosis and a potential negative effect on renal disease progression. It also remains uncertain how metformin affects the risk of major adverse cardiovascular events and all-cause mortality in patients with CKD. In this study, Clegg and colleagues performed a post hoc analysis of participants from the EXSCEL and SAVOR-TIMI 53 cardiovascular outcomes trials to investigate the cardiovascular and renal safety of prevalent use of metformin in stage 3 and 4 CKD. It is important to note that this study was observational, subject to confounding and other forms of bias. The study found 7 cases of lactic acidosis on metformin, 6 occurring at eGFR >60 mL/min/1.73m2. Analysis demonstrated a neutral to slightly positive effect of metformin on eGFR but no cardioprotective benefit. However, this study did not have the statistical precision or methodological strength to rule out the potential for cardiovascular benefit, particularly in selected populations such as overweight individuals.1 Importantly, it provides reassurance that metformin use in stage 3 and 4 CKD is not associated with large increases in the risk of lactic acidosis or accelerated renal function decline.
Reference