Stopping Versus Continuing Metformin in Patients With Advanced CKD: A Nationwide Scottish Target Trial Emulation Study

Abstract

Rationale & objective: Despite a lack of supporting evidence, current guidance recommends against the use of metformin in people with advanced kidney impairment. This observational study compared the outcomes of patients with type 2 diabetes who continued versus stopped metformin after developing stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR]<30mL/min/1.73m²).

Study design: Nationwide observational cohort study.

Setting & participants: All adults with type 2 diabetes and incident stage 4 CKD in Scotland who were treated with metformin between January 2010 and April 2019.

Exposure: Stopping versus continuing metformin within 6 months following incident stage 4 CKD.

Outcome: Primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE).

Analytical approach: Target trial emulation with clone-censor-weight design and marginal structural models fit for sensitivity analyses.

Results: In a population of 371,742 Scottish residents with a diagnosis of type 2 diabetes before April 30, 2019, 4,278 were identified as prevalent metformin users with incident CKD stage 4. Within 6 months of developing CKD stage IV, 1,713 (40.1%) individuals discontinued metformin. Compared with continuing metformin, stopping metformin was associated with a lower 3-year survival (63.7% [95% CI, 60.9-66.6] vs 70.5% [95% CI, 68.0-73.0]; HR, 1.26 [95% CI, 1.10-1.44]), and the incidence of MACE was similar between both strategies (HR, 1.05 [95% CI, 0.88-1.26]). Marginal structural models confirmed the higher risk of all-cause mortality and similar risk of MACE in patients who stopped versus continued metformin (all-cause mortality: HR, 1.34 [95% CI, 1.08-1.67]; MACE: HR, 1.04 [95% CI, 0.81-1.33]).

Limitations: Residual confounding.

Conclusions: The continued use of metformin may be appropriate when eGFR falls below 30mL/min/1.73m². Randomized controlled trials are needed to confirm these findings.

Plain-language summary: Current guidance recommends against the use of metformin in people with advanced kidney impairment despite a lack of evidence. It is therefore currently unclear how the decision to stop versus continue metformin in patients who reach stage 4 CKD impacts their risk of mortality and cardiovascular events. This study showed that stopping metformin after reaching stage 4 CKD was associated with reduced survival that did not appear to be mediated by an increase in adverse cardiovascular outcomes. These findings may support the continued use of metformin in patients with advanced kidney impairment, but further research is needed to confirm these observations.

Keywords: Chronic kidney disease; diabetes; epidemiology; metformin; target trial emulation.

Graphical abstract

Figure 1

Study flow chart. Abbreviations: CKD, chronic kidney disease; T2D, type 2 diabetes.

Figure 2

Weighted cumulative incidence curves for mortality, by treatment strategy.