Use of metformin in patients with diabetes and HF
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Heart failure and type 2 diabetes are disease states that frequently coexist. Data from the IMPACT-HF registry demonstrated that more than 45% of patients with HF also have diabetes. Patients with diabetes are also 2.5 times more likely to develop HF than patients without diabetes.
Although appropriate drug therapy is crucial in the management of these complex conditions, choosing drug therapy is complicated by several disease factors and conflicting clinical evidence. Metformin is considered the preferred initial pharmacological agent for diabetes. However, safety concerns surrounding risk for lactic acidosis have limited use of metformin in patients with both diabetes and HF. Emerging evidence suggests that metformin use in HF patients may be not only safe, but also preferable. The evidence is reviewed in this month’s Pharmacology Consult.
Available evidence
There are no randomized controlled trial data available to evaluate metformin use in patients with both HF and diabetes. Therefore, clinical decision making must rely on existing observational studies and case reports.
A meta-analysis and systematic review published in 2013 summarized the available data and sought to provide definitive insight into the appropriate use of metformin in the HF patient population. Data included in this analysis were pooled from nine observational trials. The primary outcome examined was all-cause mortality and a secondary outcome included all-cause hospitalization.
These nine trials included 34,504 patients with HF and diabetes, 6,624 of whom (19%) received metformin therapy. All-cause mortality was observed in 1,497 (23%) metformin-treated patients compared with 10,221 (37%) of 27,880 patients in control groups, which included treatment with any antihyperglycemic agent, but mostly consisted of sulfonylureas. The pooled unadjusted risk estimate for all-cause mortality was 0.69 (95% CI, 0.61-0.79) and the risk reduction was similar in the adjusted data analysis (adjusted risk estimate, 0.8; 95% CI, 0.74-0.87). Three trials evaluated the association between all-cause hospitalization and metformin-based regimens, and showed significant reduction in all-cause hospitalization compared with control groups (35% vs. 64%; pooled adjusted risk estimate, 0.93; 95% CI, 0.89-0.98). In three studies that evaluated the occurrence of lactic acidosis as an endpoint, no difference was observed based on metformin therapy.
Limitations of this meta-analysis include publication bias, as studies with positive findings are more likely to be published and were preferentially selected for this analysis. Also, inability to properly adjust confounding factors when combining these trials could have led to increased heterogeneity of the findings. Nevertheless, recent observational studies suggest metformin is a safe and effective agent for the management of patients with concomitant HF and diabetes.
Available guidelines on use
Several practice guidelines support use of metformin in selected patients with HF and diabetes. The American Diabetes Association 2013 Standards of Medical Care in Diabetes states, “Metformin may be used in patients with stable congestive heart failure (CHF) if renal function is normal, but should be avoided in unstable or hospitalized patients with CHF.” Similarly, the European Society of Cardiology states, “Metformin is not recommended in patients with severe renal or hepatic impairment because of the risk of lactic acidosis, but is widely (and apparently safely) used in other patients with HF.” The Canadian Diabetes Association supports and recommends use of metformin in patients with HF and states, “Current evidence suggests that patients with HF fare at least as well, if not better, with metformin than with other antihyperglycemic agents when limited to those with mild-to-moderate renal dysfunction (estimated glomerular filtration rate >30 mL/min). As such, metformin should be considered as the first-line therapy in HF patients with mild-to-moderate renal dysfunction.” Unfortunately, use of metformin is not addressed in the either the American Heart Association or Heart Failure Society of America practice guidelines.
It is unlikely due to ethical dilemmas and possible denial of benefits to patients that a randomized, placebo-controlled trial in patients with HF and diabetes will be undertaken. Risk for lactic acidosis associated with metformin in this patient population appears to be small and not different from that of other diabetes therapies. Increased diligence must still be exercised in monitoring lactic acid in these patients, with special focus on metformin contraindications such as significant renal dysfunction and acute or chronic metabolic acidosis.
Therefore, in patients with chronic, stable HF and concomitant diabetes, with no other contraindications to use, metformin appears to be a safe and appropriate treatment option.
Disclosure: Smith and Hill report no relevant financial disclosures.