Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure

Conclusions

In our population of newly treated diabetic patients over the age of 30 years, the prevalence of heart failure was 23%, which is almost identical to the 22% reported in a nationally representative sample of Medicare claims in the U.S..^[26] We found that heart failure patients with type 2 diabetes who used metformin (either alone or in combination with a sulfonylurea) had lower all-cause mortality rates than sulfonylurea users, even after adjusting for multiple confounding variables. Importantly, we also found that metformin exposure was not associated with an increase in hospitalizations, supporting the premise that it appears to be safe in this vulnerable population. Moreover, there were no hospitalizations or deaths in any of the cohorts attributed to metabolic acidosis throughout the follow-up period.

Although an observational study such as ours cannot conclusively prove that an agent is efficacious, it can raise hypotheses that may or may not warrant a clinical trial. The first step in deciding whether an observational result mandates a clinical trial is to consider whether the finding is pathophysiologically sound. Is it plausible that metformin use in patients with diabetes and heart failure would reduce mortality? Metformin therapy has been shown to improve hyperinsulinemia in patients with type 2 diabetes.^[33] It is therefore conceivable that, through this action, metformin therapy may be associated with improved outcomes in patients with heart failure and type 2 diabetes.^[16] At the very least, our study suggests that metformin is not associated with an increased risk of adverse outcomes in heart failure patients when compared with sulfonylurea therapy (the most commonly prescribed oral antidiabetic agents, which increase endogenous insulin secretion and may be associated with adverse cardiovascular outcomes).^[16,34,35]

The strengths of our study include the large unselected population-based sample of subjects with heart failure and type 2 diabetes, comprehensiveness and quality of the databases used, the relatively long duration of follow-up, and the ability to control for the effects of comorbidities and drug therapies known to affect outcomes in patients with heart failure. In addition, it has been suggested that observational studies, such as ours, are the preferred method for examining issues related to medication safety in the real world.^[36]

There are also several limitations that need to be considered. First, we did not have access to data on subjects' glycemic control. Several observational studies have indicated that tight glycemic control may be associated with a reduced risk of developing heart failure.^[37,38] Furthermore, tight glycemic control also improves outcomes in patients with diabetes.^[4,5,15,38] Although metformin is equipotent to sulfonylurea therapy in controlling blood glucose levels,^[12] metformin therapy may have been used in subjects who were perceived to have "less severe" diabetes compared with subjects in the sulfonylurea monotherapy group. If this was the case, however, we would have expected to see higher mortality and hospitalization rates in the combination therapy group, since the use of combination therapy would suggest even higher glycemic levels or more severe diabetes.^[33] The significant reduction in morbidity and mortality observed in the combination therapy group compared with the sulfonylurea monotherapy implies that glycemic control is not the sole explanation for our findings.

Second, our results may be attributed to selection bias in that physicians may have withheld metformin in subjects perceived to be at an increased risk of adverse events or death. However, we did adjust for those factors shown to be prognostic in heart failure (age, sex, comorbidities, and proven efficacious medications such as ACE inhibitors, β-blockers, spironolactone, and antiplatelet agents), and we believe that by restricting our analysis to incident cases of heart failure, we minimized the possibility that there were important differences among patients. Moreover, metformin users had a higher number of comorbidities and would have been expected to have a greater, not lesser, risk of mortality. To address this issue further, we also conducted a propensity score analysis; this did not, however, alter the main effects or our study findings.

Third, we do not have any clinical or laboratory information on factors such as functional status, severity of heart failure, left ventricular function, or renal failure. The lack of renal function data is particularly important, since it is an independent predictor of poor outcomes in heart failure.^[2] Although it is possible that people in the metformin group had lower rates of renal failure and because at least 40% of all patients with symptomatic heart failure have reduced renal function,^[39] it is likely that a significant proportion of people in our study who were exposed to metformin would have had renal dysfunction.

Despite a lack of any high-quality evidence, metformin is currently considered contraindicated in patients with heart failure and type 2 diabetes. And yet, we found that vulnerable patients exposed to metformin had lower mortality, less morbidity, and fewer hospitalizations than patients exposed to the much more commonly prescribed sulfonylureas. Conventional wisdom and practice guidelines have created a practice environment where all of the patients in our study who were taking metformin would be considered to be victims of "inappropriate" or "unsafe" prescribing. Whether our findings are sufficiently robust to either liberalize the careful use of metformin in diabetic heart failure patients or simply engender sufficient equipoise to mandate a randomized trial is a question of clinical judgment. Although "patient safety" studies often seem to focus on finding and reducing the use of previously widely prescribed medications that are of unproven benefit or even harmful, our study should serve as a reminder that there is another side to the patient safety coin-some medications that are currently considered contraindicated may have been defined as such on the basis of little or no evidence beyond pathophysiological rationale. Since this rationale alone is considered insufficient evidence for efficacy, it should also be insufficient to declare harm. We believe that the onus in the patient safety literature should shift to acknowledge that both types of patient safety issues can lead to suboptimal prescribing practices.

Diabetes Care. 2005;28(10):2345-2351. © 2005  American Diabetes Association, Inc.

This study is based on unidentifiable data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health.

Cite this: Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure - Medscape - Oct 01, 2005.