Metformin and Heart FailureInnocent until proven guilty

Throughout the world and for manyyears, metformin has been a main-stay of therapy for patients with type

2 diabetes. This highly effective and usu-ally well-tolerated oral agent is, to date,the only one demonstrated to reduce car-diovascular disease (CVD) complicationsin newly diagnosed type 2 diabetic pa-tients (1). It’s precise mechanism of actionremains enigmatic, although it clearly re-sults in a reduction of endogenous glu-cose production, primarily hepaticgluconeogenesis, most likely involvingthe stimulation of AMP-activated proteinkinase activity (2). A peripheral insulin-sensitizing effect in skeletal muscle hasalso been demonstrated by some, but notall, investigators (3). In small studies,metformin appears to exert benefit onvarious other fundamental biological pro-cesses that influence atherogenesis, suchas lipid metabolism, inflammation, andvascular endothelial function (4). An-other insulin sensitizer category, the thia-zolidinediones (TZDs), has also beenproposed to reduce CVD risk, but thatclass carries with it concerns of weightgain and fluid retention. As a result, TZDsremain more popular in combinationtherapy regimens. Perhaps of greatest im-port to clinicians is the recognition thatmetformin is the only oral antidiabeticagent associated with weight loss. Ac-cordingly, metformin remains, in the eyesof many authorities, the optimal initialdrug choice in most type 2 diabetic pa-tients if diet and exercise have not suc-ceeded in adequately reducing bloodglucose levels (5).

Approval of metformin in the U.S.was delayed because of previous experi-ence with phenformin, which was associ-ated with lactic acidosis. Although therisk of such metabolic decompensationwith metformin was known to be signifi-cantly lower than with the earlier bigua-nide, a fair amount of debate occurredduring the approval process (6). TheFood and Drug Administration (FDA)eventually sanctioned metformin’s use,with the stipulation that strong warningsbe included in the package insert regard-ing potential risks (7). Since metformin

accumulates in the setting of renal failure,and since toxic biguanide levels have beenimplicated in lactic acidosis, the drug wasdeemed contraindicated in those witheven modest renal impairment, defined asa serum creatinine concentration �1.4–1.5 mg/dl. Pharmacokinetic data, how-ever, suggest that metformin levelsincrease only when the creatinine clear-ance is reduced to �60 ml/min (8). In-deed, the vast majority of cases ofmetformin-associated lactic acidosis per-tain to patients with acute renal failure,typically in the setting of severe hemody-namic compromise (9). Nonetheless, theFDA deemed it prudent to incorporate amargin of error in the prescribing guide-lines to ensure that the risk of acidosiswould be held to an absolute minimum.Other original contraindications includedthose conditions in which acid-base sta-tus, lactate metabolism, or renal functionmight be compromised, including hyp-oxia, liver dysfunction, alcoholism, andduring radiocontrast studies.

Following the initial U.S. clinical ex-perience with metformin, postmarketingsurveys indicated that reported cases oflactic acidosis frequently involved pa-tients with heart failure (10). Accord-ingly, the package insert was later revisedto include this new contraindicationwhen the condition had progressed to thepoint of requiring medical therapy. Prac-tically, this essentially excluded all heartfailure patients as potential candidates forthis increasingly popular antidiabeticagent. The rationale was reasonable, par-ticularly in light of these emerging re-ports. Patients with heart failure oftenhave coexisting renal dysfunction. Theyare frequently hospitalized with circula-tory embarrassment, a time at which lac-tate levels might be expected to rise.Additionally, these individuals are com-monly treated with potent loop diuretics,which require careful titration to avoidvolume contraction and diminished renalblood flow. Such risks could be increasedin heart failure patients with diabetes,who often have coexisting nephropathy.In the face of this growing list of rigidcontraindications, several studies have

confirmed that a sizable percentage of pa-tients are prescribed metformin inappro-priately (11–14). Interestingly, though,few adverse clinical outcomes have beendemonstrated despite these practices(12,15). Admittedly, such good outcomesmay actually be a vindication of the clin-ical vigilance encouraged by the restric-tive prescribing guidelines.

The importance of heart failure as acause of morbidity and mortality in dia-betic patients is now apparent. Diabetesmore than doubles the relative risk ofprevalent heart failure (16). In addition,heart failure patients with diabetes are atincreased risk of adverse outcomes com-pared with their nondiabetic peers (17).Despite this increasingly recognized asso-ciation, the underlying link betweendiabetes and heart failure remains incom-pletely understood. Clearly, the multi-tude of CVD risk factors in diabeticpatients, particularly those with type 2 di-abetes, predispose them to coronary ar-tery disease, increasing the likelihood ofmyocardial infarction. Not infrequently,the resulting cardiac injury is disturbinglysilent. However, many patients with co-existing diabetes and heart failure havepreserved systolic function but with im-paired left ventricular relaxation (18).This “diastolic dysfunction” also oftengoes clinically unrecognized. Proposedcontributors include hypertension, dia-betic microcirculatory disease, oxidativestress, and the deleterious influences ofhyperglycemia and insulin resistance oninflammatory mediators, growth factors,vascular endothelial function, and the re-nin-angiotensin system. Ultimately, mal-adaptive ventricular remodeling occurs(19). It is also recognized that heart failuremay itself lead to insulin resistance (20),primarily through sympathetic nervoussystem activation, chronically impairedsystemic blood flow, decreased skeletalmuscle mass, and a consequential seden-tary lifestyle. However, irrespective of thedirectionality of this association, as thepopulation ages, the number of patientswith both diabetes and heart failure is ex-pected to grow substantially. Optimal

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therapeutic strategies are therefore of ut-most importance in this group of patients.

Given the association between diabe-tes and ventricular dysfunction, a linkthat likely involves both atherosclerosisand a number of other mechanisms, thepotential effects of antihyperglycemictherapies on heart failure outcomes is ofsignificant interest. Unfortunately, todate, despite the increased CVD mortalityin diabetes, the benefit of antihyperglyce-mic therapy on overall cardiac end pointshas been, at best, modest. It is unclearwhether this is a manifestation of a morecomplex relationship between hypergly-cemia and CVD than currently recog-nized, our inability to reduce glucoselevels low enough, or a misdirected em-phasis on treatment strategies that do notadequately address insulin resistance.Certainly, epidemiological analyses bothin observational studies (21) and fromclinical trials (22) provide unequivocalevidence that higher glucose levels areassociated with higher CVD risk. Yet, ad-mittedly, we’ve been dramatically moresuccessful thus far in improving clinicalcardiovascular outcomes in our diabeticpatients by focusing on their blood pres-sure and lipid levels. Nonetheless, drugswith insulin-sensitizing properties maybenefit patients with heart failure, giventhe association between insulin resis-tance, type 2 diabetes, and ventriculardysfunction. But herein lies the therapeu-tic conundrum: the classes of antihyper-glycemic drugs that improve insulinsensitivity and have beneficial impact oncardiovascular risk factors, metforminand the TZDs, are both contraindicated inpatients with advanced heart failure.Their treatment is therefore a major chal-lenge, with therapeutic options severelylimited. Because of the reticence of manydiabetic patients to use insulin, it is likelythat many with coexisting heart failure re-main suboptimally treated on sulfonyl-ureas alone. Moreover, insulin itself maycause significant fluid retention and hasbeen recently associated with increasedmortality in this group of patients (23).Therefore, while the prohibition of usingmetformin in those with decompensatedheart failure is logical, preventing its usein patients with compensated, chronicheart failure may be less so.

In light of a series of recent studies,including the one by Eurich et al. (24) inthis issue of Diabetes Care, the case ismounting for a reanalysis of the currentprescribing indications for metformin, atleast for the subset of patients with heart

failure. These same investigators recentlyreported decreased total mortality fromSaskatchewan, Canada, in patients withtype 2 diabetes managed with metforminover those treated with sulfonylureas(25). In that retrospective analysis, a haz-ard ratio for mortality of 0.63 was re-ported, a finding consistent across alltreatment groups, with varying baselinecharacteristics. Masoudi et al. (26) re-cently demonstrated that, in a group ofMedicare recipients discharged from U.S.hospitals with a principal diagnosis ofheart failure, the prescription of an insu-lin-sensitizing agent, either metformin ora TZD, was associated with a 13% lowerrisk of death at 1 year. Metformin-treatedpatients were also hospitalized less fre-quently, whereas TZD-treated patientshad a borderline increase in all-cause re-admission, primarily due to a modest in-crease in heart failure readmissions. In thecurrent study, the Saskatchewan Health-care database was again analyzed, with afocus on the relationship between antihy-perglycemic therapy and heart failure. Inthis group of �12,000 new users of anti-hyperglycemic drugs, �1,800 developedheart failure during the observation pe-riod. Patients treated with metforminwere compared with those treated withsulfonylureas and those on combinationtherapy. (The study period [1991–1996]did not allow for analysis of the then-unavailable TZDs.) After multivariableadjustment, fewer deaths occurred in themetformin (hazard ratio 0.70 [95% CI0.54 – 0.91]) and combination therapy(0.61 [0.52–0.72]) groups than in thesulfonylurea group. The similar reduc-tions in the combination therapy group,which typically includes patients withmore advanced disease, support the con-tention that the association of improvedoutcomes with metformin is real and notsimply due to any treatment-related selec-tion bias. A reduction in the compositeend point of death or hospitalization wasalso observed, although without an effecton first hospitalization itself.

If a benefit from metformin therapy inheart failure does exist, then are thereplausible pathophysiological explana-tions? Since both the link between diabe-tes and heart failure and the actualmechanism of action of metformin re-main incompletely understood, this re-mains a difficult question to fully answer.Generally, many of the characteristicscommon to diabetes and heart failure,such as insulin resistance, endothelialdysfunction, inflammation, and oxidative

stress, are improved by metformin. At amore fundamental level, the contractingheart appears to elaborate most of its en-ergy from the metabolism of nonesterifiedfatty acids, an adaptation that may be fur-ther heightened in the insulin-resistantdiabetic heart due to an increased avail-ability of this substrate (27). Notably, inconditions of cardiac ischemia or in-creased ventricular wall stress, the avail-ability of the more metabolically efficientglucose as an energy source becomes in-creasingly important. Accordingly, drugsthat enhance insulin-mediated glucoseuptake by the myocardium may improvethe function of the failing ventricle. In ad-dition, stimulation of AMP-activated pro-tein kinase in the heart may augmentcardiac energy dynamics (28), as mightmetformin’s modest effect to lower circu-lating nonesterified fatty acid levels.

It is certainly difficult to derive anyfirm conclusions from retrospective anal-yses, particularly when their methods in-volve predominately administrativedatabases or even chart reviews. Unrecog-nized confounding variables may sub-stantially influence the results of suchinvestigations, and therefore prospectivestudies are sorely needed to confirm theprovocative findings of observationalstudies. However, until such data becomeavailable, the FDA, in conjunction withthe diabetes and cardiology communities,should at least begin to readdress the cur-rent package labeling that constrains theuse of metformin in stable heart failurepatients, as has been suggested by others(29,30). For instance, in those withtreated, compensated ventricular dys-function, and normal renal function, thecautious use of metformin may be advis-able as part of a comprehensive glucose-lowering program. The evidence is clearlyaccumulating that this agent may actuallybenefit type 2 diabetic patients with thiscomorbidity. Some might propose thatdrug labeling should be altered onlybased on the results of randomized clini-cal trials and not influenced by observa-tional datasets. Yet it should be recalledthat it was, to a large extent, precisely thisinferior level of evidence that led to theinitial contraindication of metformin inheart failure patients in the first place. Fornow, to optimize glycemic control in thisgrowing group of patients with type 2 di-abetes and heart failure, rational guide-lines must be developed, using the bestavailable evidence. Based on this, at leastin heart failure patients, one might say

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2586 DIABETES CARE, VOLUME 28, NUMBER 10, OCTOBER 2005

that metformin should be considered “in-nocent until proven guilty.”

SILVIO E. INZUCCHI, MD

From the Section of Endocrinology, Yale UniversitySchool of Medicine, New Haven, Connecticut.

Address correspondence to Silvio E. Inzucchi,MD, LLCI-101/Section of Endocrinology, Yale Uni-versity School of Medicine, New Haven, CT 06520-8020. E-mail: silvio.inzucchi@yale.edu.

S.E.I. has served on an advisory panel for andreceived honoraria from Takeda.

© 2005 by the American Diabetes Association.

Acknowledgments— The author thanks Drs.Fred A. Masoudi and Clifford J. Bailey for theirhelpful comments during the preparation ofthis manuscript.

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