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Is Metformin Therapy Safe For Use In Stage 3 Chronic Kidney Disease?

Apr 9, 2019
Editor: Joy Pape, MSN, FNP-C, CDE, WOCN, CFCN, FAADE

Author: Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy

Metformin may help lower the risk of cardiovascular events and death in patients with moderate to severe renal function.

Nearly half (43%) of the population with type 2 diabetes has chronic kidney disease (CKD). Evidence shows that the incidence of CKD is correlated with advanced age among patients with type 2 diabetes, affecting 61%. The rise in prevalence of CKD will lead to a significant increase in the burden of cardiovascular morbidity and healthcare-related costs. Therefore, it is important to find a more effective treatment to provide better glycemic management in patients with type 2 diabetes and CKD while decreasing the risk mortality.


The effect of many antidiabetic medications has been tested in patients with type 2 diabetes and CKD, but metformin is not one of those. Although the effect of metformin on diabetes-related cardiovascular disease has been established, its use has been prohibited for patients with CKD due to potential adverse effects, particularly increased risk of lactic acidosis. Consequently, the question regarding the safety of metformin in patients with type 2 who have CKD has not been answered.

Metformin has been labeled unsafe for patients with moderate or severe CKD because of  possible lactic acidosis associated with it. This label warning was recently revised to allow metformin use in patients who have stage 3-4 CKD. The revision suggests individualizing metformin dose to decrease the risk of side effects conferring with kidney function and eGFR.

A recently published cohort study analyzed data from a randomized control trial, The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin-alfa) Therapy (TREAT), which was designed to evaluate the use of metformin in patients with diabetes and CKD. This data analysis focused on comparing cardiovascular and kidney disease outcomes amongst  591 individuals with type 2 diabetes and CKD who were on metformin therapy.

The TREAT trial enrolled 4,038 participants with diabetes and CKD. Participants were randomized into two arms. The intervention arm received darbepoetin alfa versus matching placebo for the control arm. Inclusion criteria of TREAT were as follows: An estimated glomerular filtration rate (eGFR) of 20-60 mL/min/1.73 m2, hemoglobin ≤11.0 g/dL, and transferrin saturation ≥15%.

In this cohort study, the pre-selected outcomes included death due to cardiovascular event, ESRD, a kidney disease composite of ESRD or death, and a cardiovascular disease composite, which included hospitalization for heart failure, myocardial infarction, stroke, myocardial ischemia. The outcomes were defined according to the TREAT trial.

Lactic acidosis was not adjudicated and was evaluated based on adverse event reports.

Using chi-squared, t-tests or Kruskal-Wallis tests, investigators compared participants’ baseline characteristics in patients on metformin therapy and patients who were not on metformin therapy. Chi-squared tests were used to assess the difference in event rate among quartiles of HbA1C. Furthermore, researchers used logistic regression to calculate a propensity score, based on all baseline factors, which predict use of metformin at baseline.

The result from this data analysis indicates that a total of 591 patients were on metformin therapy at baseline and the rest of the participants were not on metformin at baseline. It was noted that the majority of patients on metformin were Caucasian females who had diabetes for short period of time. Patients on metformin had better glycemic management at baseline, with average HbA1C of 6.8% in comparison to 7% in patients who were not metformin (P = 0.047). Additionally, data analysis showed that patients on metformin were associated with fewer comorbidities, including heart failure, coronary disease, and peripheral vascular disease (P < 0.01 for each), however, ESRD was marginally higher in patients on metformin versus non-metformin users (4.0% vs 3.6%).

A reduced risk of all-cause mortality (HR, 0.49; 95% CI, 0.36-0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32-0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51-0.88), and the kidney disease composite (HR, 0.77; 95% CI, 0.61-0.98) was independently associated with metformin therapy. Moreover, metformin use was not significantly related to ESRD (HR, 1.01; 95% CI, 0.65 -1.55). Lastly, there were only two incidents of lactic acidosis reported. Investigators concluded that the results from this data analysis show a better safety profile associated with metformin use in patients with CKD compared to prior trails. In addition, the use of metformin may reduce the risk of death and cardiovascular events in patients with stage 3 CKD.

Practice Pearls:

  • The crude frequency rate for death, cardiovascular death, cardiovascular events and the combined endpoint were lower in patients on metformin vs. patients who were not on metformin.
  • Metformin use was not significantly related to ESRD (HR, 1.01; 95% CI, 0.65 -1.55)
  • In patients with stage 3 kidney disease, metformin use may be safe and may  lead to reduction in risk of mortality and cardiovascular events.


Bailey, Robert A et al. “Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: Improving Global Outcomes (KDIGO) staging” BMC research notesvol. 7 415. 2 Jul. 2014, doi:10.1186/1756-0500-7-415

Charytan, David M., et al. “Metformin Use and Cardiovascular Events in Patients with Type 2 Diabetes and Chronic Kidney Disease.” Diabetes, Obesity and Metabolism, John Wiley & Sons, Ltd (10.1111), 4 Mar. 2019, onlinelibrary.wiley.com/doi/full/10.1111/dom.13642.

Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019‐2032.

Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy