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Until recently, metformin—the world's most widely prescribed oral antihyperglycemic agent—was contraindicated in patients requiring drug therapy for their heart failure. A Food and Drug Administration (FDA) reassessment in May 2005, however, led to the lifting of the proscription for those with stable and controlled heart failure.
But far too many medical professionals remain unaware that metformin's label has changed.
TYPE 2 AND HEART FAILURE
The management of patients with type 2 diabetes and heart failure has always posed unique challenges, primarily due to the limited pharmacological armamentarium available to these individuals. In addition to metformin, the thiazolidinediones (TZDs), the other insulin sensitizer class, have always been problematic in such patients as well, given their known effect on fluid retention, which may precipitate volume overload in predisposed individuals. Recently, the TZDs actually became contraindicated in those with New York Heart Association class III or IV symptoms.
So, our patients with ventricular dysfunction were limited in terms of glucose-lowering therapies to sulfonylureas (or other secretagogues), the rarely used alpha-glucosidase inhibitors, and insulin itself. Recently, the advent of the incretin modulators (GLP-1 mimetics, DPP-IV inhibitors) has increased the available pharmacological options to them. Notably, however, there is a virtual absence of published safety data with any of these agents in this particularly high-risk group of patients, who continue to experience very high mortality rates.
The population of patients with both diabetes and heart failure is indeed growing.1 Due to advances in cardiology, more of our patients are surviving their myocardial infarctions and are now living with chronic ischemic heart disease. Of course, heart failure in diabetes is not always the result of epicardial coronary disease. Many affected individuals actually have microvascular disease and/or an underlying "diabetic cardiomyopathy"—the origins of which remain controversial. Moreover, many who present with clinical heart failure don't have the more traditional systolic impairment. Instead their hearts demonstrate abnormal ventricular relaxation or the so-called diastolic dysfunction. With our current understanding of cardiac energy dynamics, drugs that enhance insulin sensitivity should, if anything, improve survival, since the heart itself is to some degree insulin-resistant in patients with type 2 diabetes.1 With the TZDs, however—even though basic and animal experiments would suggest a potential benefit to the failing heart—the drugs are very difficult to use in this situation. Clearly, these agents increase the incidence of a diagnosis of heart failure, and they also increase hospitalizations for this condition.
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Thus, the risk-benefit ratio in terms of overall glucose control and possible beneficial effects on the atherosclerotic process must be carefully considered, particularly in at-risk patients. These include older patients with long-standing hypertension and/or prior ischemic events. This equation has become even more complex, with the recent evidence that raised the possibility that rosiglitazone (Avandia, GlaxoSmithKline) may, if anything, increase the risk of myocardial infarction. Although pioglitazone (Actos, Takeda) appears to improve cardiovascular event rates, at least in high-risk patients, it still presents the challenge of fluid overload.2 The recent contraindications for TZDs in advanced heart failure patients make it unlikely that randomized clinical trials will ever be conducted with these agents in this specific group of patients.
With metformin, on the other hand, the concern has never been edema or actual worsening of heart failure but, instead, the risk of lactic acidosis. This feared complication of biguanide therapy was, after all, the reason that metformin's older cousin, phenformin hydrochloride, was removed from the U.S. market in the 1970s. Thankfully, the incidence of lactic acidosis with metformin is actually very low, estimated at one per 30,000 patient-years, and possibly no higher than the background incidence in the general diabetic population.
Nonetheless, the package label for metformin has always included strict recommendations for its safe use in those considered to be at risk for lactic acidosis; patients with renal failure were of particular concern. Soon after the drug's release onto the U.S. market in the mid-1990s, the contraindication for heart failure was added. This proscription stemmed essentially from case reports of heart-failure patients taking metformin who developed lactic acidosis. Whether the heart failure and/or the metformin significantly contributed to the metabolic derangements in these patients, however, is unknown.
Clearly, in those with cardiovascular collapse or cardiogenic shock, lactate production increases and clearance decreases; metformin would be an illogical choice in this setting. Moreover, in patients with less acute but still deteriorating ventricular function, requiring more aggressive diuretic therapy—with its attendant risks of decreasing glomerular filtration rates—metformin would be a poor choice.
But what about the growing group of patients with stable, controlled heart failure? Why couldn't such an effective and otherwise safe agent be used in these individuals?3–5
Over the years, several studies have suggested that the metformin-heart failure contraindication might be too severe. In 2002, researchers randomized 393 metformin-treated patients with active contraindications for the drug's use (including 94 with heart failure) to either continuing or stopping the drug, with the option of using alternative therapies to optimize glycemic control.6 After 4 years of observation, no significant differences were found in overall or cardiovascular mortality between the groups, although patients who were taken off metformin did experience weight gain and deterioration in glucose control. Notably, prospectively measured lactate levels were indistinguishable between the two groups.
CHANGING VIEWS
In 2005, a research team demonstrated that metformin was not only safe but also potentially effective in a large group of diabetic Medicare patients discharged from U.S. hospitals with a principal diagnosis of heart failure. In this retrospective study, patients prescribed metformin actually experienced 13% less mortality over 1 year, as compared with those treated with either sulfonylureas or insulin (p<0.01), after adjustment for a wide variety of baseline clinical characteristics.7 Later that year, Canadian collaborators reported outcomes data from a large health insurance database from Saskatchewan.8 In this investigation, after adjustments, patients with type 2 diabetes and incident heart failure who took metformin experienced 30% less mortality than those treated with sulfonylureas or insulin (p<0.01). Finally, a recent systematic review from this same group concluded that metformin was the only antihyperglycemic drug not found to be associated with some harm in heart failure patients.4
That metformin might improve outcomes in heart failure should come as no surprise. It is, after all, also the only antihyperglycemic agent shown to reduce cardiovascular outcomes in primary prevention (U.K. Prospective Diabetes Study).9 In addition to the expected reductions in glycated hemoglobin (A1C), metformin therapy has been associated with an improvement in insulin sensitivity, plasma lipids, inflammatory markers, and endothelial function—each of which may improve or at least stabilize cardiac ventricular function over time.
As previously noted, in May 2005 these emerging reports persuaded the FDA to inform metformin manufacturers that an update in the prescribing guidelines regarding the heart failure contraindication was advisable.10 Over the ensuing months, the labels for a variety of generic formulations were accordingly changed. In November 2006, the final package insert, that of the original branded product, Glucophage (Bristol-Myers Squibb), was changed.11
I was surprised to learn of this label change—almost 1 year after it had been implemented. Interestingly, in subsequent discussions with colleagues around the country, I found that few diabetologists, including several well-known authorities, some editors of diabetes journals, and even a few first authors of landmark metformin papers, were aware that any metformin label change had actually taken place.
This essential absence of publicity for what is an important change in the prescribing guidelines for an important drug is likely the result of metformin's loss of patent protection. Accordingly, we were not inundated with direct-mail advertising or updates from our friendly sales representatives. (Contrast this with the overkill updates we recently received concerning the TZDs' label changes!)
This incident raises significant questions concerning how clinicians receive pertinent information about indications and contraindications of drugs, particularly those no longer being aggressively marketed. The FDA and the medical community need to develop a reliable and robust system for the expeditious and unbiased dissemination of such information.
We should remember that several contraindications for metformin remain. First, the drug is still contraindicated in patients with renal disease, although the well-known serum creatinine cut points (1.5 mg/dl in men, 1.4 mg/dl in women) may also be a bit too rigid. With the widespread availability of estimated glomerular filtration rate, the prescribing guidelines probably should be rewritten to instead refer to this more useful estimate of renal function. Metformin also remains contraindicated in patients with either acute or chronic metabolic acidosis.
Heart failure still appears in the metformin label under the "Warnings" and "Precautions" sections. Clearly, the drug still should not be used in patients being treated for heart failure in the hospital, in anyone with acute or unstable symptoms, or when there is any concern about worsening renal function. However, the good news for patients with stable, compensated heart failure (without other contraindications) is that metformin now can be considered an effective—and safe—alternative means to achieve lower glucose levels.
The FDA used the best available evidence to push for this change, and this
recently much-maligned governmental body should be congratulated. Our patients
with type 2 diabetes and heart failure will benefit significantly for years to
come. 
Footnotes
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References
2. Fonarow GC: Approach to the management of diabetic patients with heart failure: Role of thiazolidinediones. Am Heart J 148: 551–558, 2004.[Medline]
3. Jones GC, Macklin JP, Alexander WD: Contraindications to the use of
metformin: Evidence suggests that it is time to amend the list.
BMJ 326:4–5, 2003.
4. Misbin RI: The phantom of lactic acidosis due to metformin in
patients with diabetes. Diabetes Care 27: 1791–1793, 2004.
5. Inzucchi SE: Metformin and heart failure: Innocent until proven
guilty. Diabetes Care 28:2585–2587, 2005.
6. Rachmani R, Slavachevski I, Levi Z, et al.: Metformin in patients with type 2 diabetes mellitus: Reconsideration of traditional contraindications. Eur J Intern Med 13: 428–433, 2002.[Medline]
7. Masoudi FA, Inzucchi SE, Wang Y, et al.: Thiazolidinediones,
metformin, and outcomes in older patients with diabetes and heart failure: An
observational study. Circulation 111: 583–590, 2005.
8. Eurich DT, Majumdar SR, McAlister FA, et al.: Improved clinical
outcomes associated with metformin in patients with diabetes and heart
failure. Diabetes Care 28:2345–2351, 2005.
9. UKPDS Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998.[Medline]
10. Misbin RI: Evaluating the safety of diabetes drugs: Perspective of
a Food and Drug Administration insider. Diabetes Care 28: 2573–2576, 2005.
11. Bristol-Myers Squibb Company: Glucophage prescribing information. Available online at http://www.bms.com/cgi-bin/anybinpl?sql=select%20PPI%20from%20TB_PRODUCT_PPI%20where%20PPI_SEQ=86&key=PPI. Accessed October 16, 2007.
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