Diabetes Mellitus and Heart Failure: Epidemiology, Mechanisms, and Pharmacotherapy

Diabetes Mellitus and Heart Failure: Epidemiology, Mechanisms, and Pharmacotherapy

Diabetes Mellitus and Heart Failure: Epidemiology, Mechanisms, and Pharmacotherapy Frederick A. Masoudi, MD, MSPH,a,b,c,* and Silvio E. Inzucchi, MDd ...

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Diabetes Mellitus and Heart Failure: Epidemiology, Mechanisms, and Pharmacotherapy Frederick A. Masoudi, MD, MSPH,a,b,c,* and Silvio E. Inzucchi, MDd Diabetes mellitus and heart failure (HF), both of which are associated with high rates of adverse cardiovascular outcomes, commonly coexist. Given the marked increases in diabetes prevalence in developed countries, the proportion of the population with both conditions is likely to increase substantially. This article reviews the epidemiology of HF and diabetes, the mechanisms whereby diabetes causes HF, and the pharmacotherapy of both HF and diabetes. Specific challenges in treating patients with both HF and diabetes are also addressed. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99[suppl]:113B–132B) Heart failure (HF) affects ⬎5 million persons and is responsible for ⬎250,000 deaths in the United States annually.1 As the most common cause of hospitalization in the elderly population,2 HF also accounts for substantial healthcare costs.1,3 In contrast to many cardiovascular conditions such as myocardial infarction (MI), the prevalence of HF and its impact on the population’s health have been increasing.4,5 Reflecting this trend, HF hospitalization rates in the United States increased by nearly 33% from 1990 –2004, in contrast to a contemporaneous decrease in hospitalization rates for MI of 8%.2,6 Diabetes mellitus and HF commonly coexist. With the increasing prevalence of obesity and diabetes in the United States, it can be expected that the population with diabetes who have HF will also increase.7,8 In this report, we review the epidemiology and proposed mechanisms of HF in patients with diabetes and the recommendations for and challenges surrounding the pharmacotherapy of HF in patients with diabetes and of diabetes in patients with HF.

Epidemiology Several studies have established a strong and independent relation between diabetes and the risk for HF. Early data from the Framingham cohort suggested an association between diabetes and the risk for incident HF independent of differences in coexisting coronary artery disease (CAD) or a Division of Cardiology, Department of Medicine, Denver Health Medical Center, Denver, Colorado, USA; bDivision of Cardiology, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA; cColorado Health Outcomes Program, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, USA; and dSection of Endocrinology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. Reprints are not available. *Address for correspondence: Frederick A Masoudi, MD, MSPH, Division of Cardiology, Department of Medicine, Denver Health Medical Center, MC 0960, 777 Bannock Street, Denver, Colorado 80204. E-mail address: [email protected]

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.11.013

hypertension.9 The population attributable risk—the proportion of HF cases in a population accounted for by diabetes alone—in the Framingham cohort was 12% in women and 6% in men.10 Similarly, in the Cardiovascular Health Study (CHS), diabetes conferred a significantly higher independent risk for incident HF in 5,888 older patients followed for an average of 5.5 years (relative risk [RR], 1.74).11 This risk was similar in patients with and without baseline CAD, and the proportion of incident HF in the population due to diabetes was greater than that due to renal dysfunction, electrocardiographic left ventricular hypertrophy, or left ventricular systolic dysfunction (LVSD). A large survey of patients in a Kaiser Permanente database corroborated the Framingham and CHS results, finding ⬎2 times the baseline prevalence and subsequent incidence of HF in patients with compared with those without diabetes.12 Strikingly, the prevalence of HF in patients with diabetes in this population exceeded 1 in 9. This strong and independent association between diabetes and incident HF has also been demonstrated in clinical trial populations. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subjects aged ⱖ55 years with hypertension and ⱖ1 other cardiovascular risk factor, Davis and colleagues13 found that patients with diabetes had a nearly 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with diabetes was independent from and equivalent in degree to that of CAD and greater than that for electrocardiographic left ventricular hypertrophy. Not surprisingly, because of the strong association between diabetes and HF, the 2 commonly coexist. Despite selection biases that might limit the proportion of patients with multiple comorbidities in clinical trials, randomized controlled trials of HF therapy often include enough subjects with diabetes to allow robust subgroup analyses. However, unselected community-based samples of patients with HF likely provide more accurate estimates of the prevalence of diabetes in the population. www.AJConline.org

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In patients with incident HF in Olmsted County, Minnesota, from 1979 –2000, the prevalence of diabetes was 24%.14 In a nationally representative sample of Medicare beneficiaries hospitalized with principal discharge diagnosis of HF, Havranek and colleagues15 found a prevalence of diabetes exceeding 38%. In addition to a high prevalence in patients with HF, diabetes is also a risk factor for the progression of HF. In a retrospective study of the Studies of Left Ventricular Dysfunction (SOLVD) trial population, Das and colleagues16 found that in patients with asymptomatic ischemic cardiomyopathy, diabetes was a risk factor for the development of HF symptoms (hazard ratio [HR], 1.56), HF hospitalization (RR, 2.16), or the composite of death or symptom development (HR, 1.50). This relation was not observed in patients with nonischemic cardiomyopathies. Finally, several studies, including clinical trials and community-based samples, have identified diabetes as an important predictor of mortality in patients with HF independent of other prognostic factors, including comorbidity and functional status.17–22 These studies collectively represent a wide range of patients, including those hospitalized for HF,17,20,23 ambulatory patients,21 those enrolled in clinical trials,18,19,22 and those with and without LVSD.20,22 Some studies suggest that this association may vary on the basis of patient sex or HF cause. Specifically, some investigators have found that diabetes has greater prognostic importance in women20 or in those with ischemic cardiomyopathies.18,19 The latter association was not confirmed in a recent population-based study from Olmsted County, Minnesota, which found that diabetes was a more important predictor of mortality in patients with HF without clinically manifest CAD.24 Regardless, diabetes should be considered an important independent predictor of mortality in patients with HF. In summary, diabetes and HF commonly coexist. Diabetes is an important risk factor for the development of HF independent of CAD, hypertension, and other potential confounders of the association. Finally, diabetes is associated with the progression of and with a higher rate of adverse outcomes from HF. These observations emphasize the need for the appropriate application of interventions that improve outcomes in this high-risk population.

Mechanisms of Heart Failure in Diabetes The known and proposed mechanisms to explain the higher risk for HF in patients with diabetes are several and include indirect (ie, associated comorbidities) and direct (ie, metabolic) effects of diabetes, many of which are interrelated in a complex manner and can adversely affect both diastolic and systolic myocardial function (Table 1). It is well known that patients with diabetes have higher prevalences of CAD, hypertension, and obesity, all of which increase the risk for developing HF.25–27 Furthermore, in patients with diabetes,

Table 1 Mechanisms of heart failure in patients with diabetes mellitus Higher prevalence of conditions associated with heart failure 1. Coronary artery disease 2. Hypertension 3. Obesity Metabolic abnormalities 1. Hyperglycemia 2. Increased circulating free fatty acids 3. Insulin resistance

these comorbidities may be more severe and may confer a higher risk for HF and adverse sequelae.28 Diabetes is also characterized by metabolic abnormalities that have been implicated as possible mechanisms of HF, including hyperglycemia itself. In a cohort study involving nearly 50,000 patients with diabetes in the Kaiser Permanente Health Plan in California, Iribarren and colleagues29 demonstrated a clear association between glucose control and incident HF, with an 8% increased risk for HF with each 1% increase in hemoglobin A1c (HbA1c). In an investigation of the CHS, Barzilay and colleagues30 found that elevated fasting glucose was a strong predictor of incident HF in patients with diabetes. For each increase in fasting glucose of 60 mg/dL, the risk for HF increased by 41% in those without CAD and by 27% in those with CAD. In an epidemiologic analysis from the United Kingdom Prospective Diabetes Study (UKPDS), the adjusted rate of HF climbed stepwise from 2.3 events/100 person-years in those with HbA1c levels ⬍6% to 11.9 in those whose HbA1c levels were ⬎10% (Figure 1).31 Although potentially a surrogate of the severity of other metabolic abnormalities associated with diabetes, hyperglycemia itself has been implicated as a cause of myocardial dysfunction. Hyperglycemia, and the associated increase in advanced glycosylation end products, can result in the generation of reactive oxygen species,32 which in turn have been implicated in cellular dysfunction and apoptosis.33,34 Corroborating this association, an animal study demonstrated that the increase in myocardial stiffness seen with diabetes was reversed by aminoguanidine, an agent that inhibits the generation of advanced glycosylation end products of collagen, but not by afterload-reducing agents.35 Hyperglycemia is also associated with impaired microvascular endothelial function, which can increase myocardial strain; altered energy dynamics, which may preferentially shift myocardial utilization toward less efficient fatty acid oxidation; and a proinflammatory state.36 Diabetes is also characterized by increased circulating free fatty acid levels, which may also play an important role in the myocardial dysfunction of diabetes. Possibly through the induction of peroxisome proliferator-activated receptor–␣, excess free fatty acids may result in myocardial lipid accumulation.33 The overaccumulation of myocardial lipid may result in lipotoxicity mediated by ceramides or other

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Figure 1. Heart failure incidence by hemoglobin A1c (HbA1c) in the United Kingdom Prospective Diabetes Study (UKPDS). (Adapted from BMJ.31)

mechanisms, including intracellular protein overexpression.33,37,38 Finally, insulin resistance itself may also contribute to HF.39 The nature of this association is likely bidirectional, however. Patients with insulin resistance, even before the development of diabetes, are frequently hypertensive and obese and exhibit endothelial dysfunction and a proinflammatory state. Each of these factors can contribute to ventricular dysfunction.40 Moreover, hyperinsulinemia, a response to reduced insulin sensitivity, has been associated with sympathetic nervous system activation.41,42 Increased sympathetic activation in turn can contribute to the development of myocardial dysfunction as well as the exacerbation of existing HF. It should also be noted, however, that patients with HF are frequently inactive, have decreased effective circulation to skeletal muscle, and are characterized by sympathetic activation, each of which can worsen insulin sensitivity.43 Thus, the relation between insulin resistance and HF is complex. Likely the result of multiple mechanisms, diabetes results in abnormalities of cardiac structure and function independent of other risk factors for HF. In pathologic specimens, the “diabetic cardiomyopathy” is characterized by myocyte hypertrophy, interstitial fibrosis, and small-vessel disease.44 These changes appear to have important functional consequences. In a study of myocardial function in young patients with diabetes, Zabalgoitia and colleagues45 found echocardiographic evidence of abnormal myocardial relaxation despite good blood pressure control. Investigators from the Strong Heart Study (SHS) found that subjects with diabetes had greater left ventricular mass and wall thickness,46 as well as an increased prevalence of diastolic dysfunction by echocardiography independent of age, blood pressure, left ventricular mass, and systolic function.47 This

evidence of cardiac structural and functional abnormalities, distinct from the effects of hypertension or CAD, provides further evidence that the metabolic abnormalities of diabetes exert a deleterious effect on the heart, providing the substrate for the development of HF.

Medical Therapy of Heart Failure in Patients with Diabetes Several landmark clinical trials over the past 2 decades have established the evidence base for the pharmacotherapy of HF. These trials have allowed the development of robust practice guidelines to help guide clinicians in providing HF care.48,49 The therapies best supported by the clinical evidence are primarily relevant to patients with LVSD and antagonize the neurohormonal systems that are activated in chronic HF and are associated with the progression of HF and adverse clinical outcomes. The guidelines published by the American College of Cardiology (ACC) and the American Heart Association (AHA)48 and the Heart Failure Society of America (HFSA)49 emphasize the importance of neurohormonal blockade as the foundation of HF pharmacotherapy. Although several other adjunctive agents (eg, diuretics, digoxin) are useful in patients with HF, the following discussion focuses on those drugs that act to reduce neurohormonal activation. Angiotensin-converting enzyme inhibitors: Placebocontrolled clinical trials enrolling ⬎7,000 patients with LVSD due to a wide range of causes and with varied symptom severity have demonstrated the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in pro-

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Figure 2. Cumulative mortality for patients with left ventricular systolic dysfunction treated with angiotensin-converting enzyme (ACE) inhibitors or placebo in long-term randomized trials. (Adapted from Lancet.56)

longing life, reducing the risk for hospitalization, and improving health status.48 These benefits have been attributed mechanistically to the reduction in the production of angiotensin II through antagonism of ACE as well as to kininase inhibition, which results in the accumulation of bradykinin. (This latter mechanism, in addition to potential salutary effects, may also account for the cough some patients experience while taking ACE inhibitors.) The benefits of ACE inhibitors in patients with LVSD are substantial.50 –55 In a meta-analysis of 5 clinical trials of patients with LVSD or HF with an average of 35 months of follow-up, therapy with ACE inhibitors was associated with a reduction in the risk for death (absolute RR [ARR], 3.8%; number needed to treat [NNT], 26; RR, 0.80; 95% confidence interval [CI], 0.74 – 0.87) (Figure 2), reinfarction in patients with previous MIs (ARR, 2.1%; NNT, 48; RR, 0.79; 95% CI, 0.70 – 0.89), HF readmission (ARR, 5.2%; NNT, 19; RR, 0.67; 95% CI, 0.61– 0.74), and composite of these events (ARR, 7.2%; NNT, 14; RR, 0.72; 95% CI, 0.67– 0.78).56 Thus, the treatment of 14 patients with LVSD for ⬍3 years with ACE inhibitors would prevent a serious adverse event. The benefits of ACE inhibitors were apparent early in treatment, persisted over as long as 5 years of follow-up, and were independent of age, sex, left ventricular ejection fraction (LVEF), and other baseline pharmacotherapy. Of note, 18% of the patients in these trials had diabetes, but a separate analysis of this subgroup was not performed. Other studies have specifically assessed the comparative benefits of ACE inhibitors in patients with LVSD with and without diabetes. In a meta-analysis of 6 placebo-controlled clinical trials in patients with LVSD, Shekelle and col-

leagues57 found that the reduction in the risk for death conferred by ACE inhibitors was virtually identical in patients with diabetes (RR, 0.84; 95% CI, 0.70 –1.00) and those without diabetes (RR, 0.83; 95% CI, 0.73– 0.92) (Table 2). In a community-based observational study of older patients hospitalized with HF, the prescription of ACE inhibitors at hospital discharge was associated with lower relative risks for death at 1 year in patients with and without diabetes.58 ACE inhibitors should therefore be considered in all patients with diabetes and LVSD, regardless of cause or symptom severity, in the absence of treatment contraindications. Patients who are pregnant or with previous life-threatening adverse reactions, including angioedema or anuric renal failure, should not receive ACE inhibitors, and this class should be used with extreme caution in patients with very low blood pressure, predispositions to hyperkalemia, documented bilateral renal artery stenosis, or renal dysfunction.48 However, it should be noted that with proper monitoring, ACE inhibitors can be used safely in patients with advanced renal failure,59 and there is evidence from observational studies of the benefits of ACE inhibitors in patients with HF and severe renal dysfunction.58 In patients with diabetes specifically, ACE inhibitors should be used cautiously when type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) coexists. Similarly, concurrent therapy with nonsteroidal anti-inflammatory drugs, through effects on efferent glomerular arteriolar tone, may increase the risk for renal insufficiency and hyperkalemia.

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Table 2 Effects of angiotensin-converting enzyme (ACE) inhibitors on mortality in heart failure (HF) and left ventricular systolic dysfunction (LVSD) in patients with and without diabetes mellitus Patients (n) Study 50

CONSENSUS SAVE51 SMILE52

SOLVD-Prevention53 SOLVD-Treatment54 TRACE55 Summary estimate

Population

ACE Inhibitor

LVSD, severe symptoms (NYHA class IV) LVSD, status post AMI, no overt HF symptoms Recent (24-hr) anterior MI LVSD, asymptomatic LVSD, symptomatic LVSD, status post AMI

Captopril

197

Captopril Zofenopril Enalapril Enalapril Trandolapril

No Diabetes

RR (95% CI)

Diabetes

No Diabetes

Diabetes

RRR (95% CI)

56

0.64 (0.46–0.88)

1.06 (0.65–1.74)

1.67 (0.93–3.01)

1,739

492

0.82 (0.68–0.99)

0.89 (0.68–1.16)

1.09 (0.79–1.50)

1,253

303

0.79 (0.54–1.15)

0.44 (0.22–0.87)

0.56 (0.25–1.22)

3,581 1,906 1,512 10,188

647 663 237 2,398

0.97 (0.83–1.15) 0.84 (0.74–0.97) 0.85 (0.74–0.97) 0.85 (0.78–0.92)

0.75 (0.55–1.02) 1.01 (0.85–1.21) 0.73 (0.57–0.94) 0.84 (0.70–1.00)

0.77 (0.54–1.09) 1.21 (0.97–1.50) 0.87 (0.65–1.15) 1.00 (0.80–1.25)

AMI ⫽ acute myocardial infarction; CI ⫽ confidence interval; CONSENSUS ⫽ Cooperative North Scandanavian Enalapril Survival Study; MI ⫽ myocardial infarction; NYHA ⫽ New York Heart Association; RR ⫽ relative risk; RRR ⫽ ratio of RRs (comparing RR in patients with and without diabetes); SAVE ⫽ Survival and Ventricular Enlargement; SMILE ⫽ Survival of Myocardial Infarction Long-Term Evaluation; SOLVD ⫽ Studies of Left Ventricular Dysfunction; TRACE ⫽ Trandolapril Cardiac Evaluation. Adapted from J Am Coll Cardiol.57 Table 3 Effects of ␤-blockers on mortality in heart failure and left ventricular systolic dysfunction in patients with and without diabetes mellitus Patients (n) Study 67

CIBIS-II COPERNICUS65 MERIT-HF66 Summary estimate

␤-Blocker

No Diabetes

Bisoprolol Carvedilol Metoprolol succinate

2,335 1,701 3,006 7,042

RR (95% CI) Diabetes

No Diabetes

Diabetes

RRR (95% CI)

312 586 985

0.66 (0.54–0.81) 0.67 (0.52–0.85) 0.62 (0.48–0.79)

0.81 (0.52–1.27) 1.23 (0.75–2.02) 0.68 (0.47–1.00) 1.02 (0.65–1.61) 0.81 (0.57–1.15) 1.32 (0.86–2.02)

1,883

0.65 (0.57–0.74)

0.77 (0.61–0.96) 1.19 (0.91–1.55)

All studies enrolled patients with symptomatic left ventricular systolic dysfunction. CI ⫽ confidence interval; CIBIS ⫽ Cardiac Insufficiency Bisoprolol Study; COPERNICUS ⫽ Carvedilol Prospective Randomized Cumulative Survival Study; MERIT-HF ⫽ Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure; RR ⫽ relative risk; RRR ⫽ ratio of RRs (comparing RR in patients with and without diabetes). Adapted from J Am Coll Cardiol.57

Angiotensin receptor blockers: Angiotensin receptor blockers provide an alternative to ACE inhibitors to inhibit the renin-angiotensin system. Clinical trials designed to assess their equivalence or superiority compared with ACE inhibitors for HF have generated conflicting results.60 – 62 Some patients do not tolerate ACE inhibitors well because of cough, which is particularly common in women and certain ethnic groups.63 In general, clinical trials suggest that angiotensin receptor blockers are better tolerated than ACE inhibitors,60,62 and a recent trial demonstrated the benefits of angiotensin receptor blockers in patients with HF and ACE inhibitor intolerance.64 Thus, angiotensin receptor blockers are recommended for all patients with HF and LVSD with refractory cough due to ACE inhibitor therapy, including those with diabetes.49 The routine use of angiotensin receptor blockers in addition to ACE inhibitors, although recently shown to be of potential benefit for blood pressure reduction, is not currently recommended for the purposes of treating HF. Angiotensin receptor blockers should also be used with caution in patients with diabetes

with mild hyperkalemia, especially in those with type IV renal tubular acidosis.

␤-Adrenergic receptor blockade: As for ACE inhibitors, the clinical evidence supporting the use of ␤-adrenergic receptor blockade in patients with HF and LVSD is substantial. Clinical trials of ␤-blockade have enrolled ⬎20,000 patients with LVSD already receiving ACE inhibitors and diuretics, including men and women and patients with a wide range of HF causes.48 These studies consistently demonstrate that ␤-blockade significantly reduces the risk of death and hospitalization for HF and also improves symptom status. Although most enrolled patients without severe symptoms, 1 study enrolled patients with severe HF symptoms despite maximal medical therapy (eg, New York Heart Association [NYHA] classes III and IV). The ␤-blocker carvedilol resulted in a 35% reduction in the risk for death and a 24% reduction in the risk for either death or subsequent hospitalization.65 Despite historical concerns that ␤-blockers may be deleterious in patients with diabetes by blunting the adrenergic

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response to hypoglycemia, in most patients, this is not a significant concern. Indeed, clinical trials have demonstrated that patients with diabetes, LVSD, and HF derive important benefits from therapy. In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, comparing the ␤-blocker carvedilol with placebo in patients with LVSD and severe symptomatic HF, the mortality benefit of therapy was significant in the subgroup of patients with diabetes and virtually identical to that of patients without diabetes.65 Trials using other ␤-blockers have also suggested survival benefits in the subgroups with diabetes.66,67 In a formal meta-analysis of these trials, Shekelle and colleagues57 concluded that patients with diabetes, HF, and LVSD derive a significant mortality benefit from ␤-blockers in addition to other pharmacotherapy for HF and that the benefits in patients with diabetes were not statistically different from those without diabetes (Table 3). Because the ␤-blockers used in these randomized trials vary with respect to ␤1-receptor selectivity and other adrenergic receptor antagonism, the superiority of any individual agent has been debated. A comparative trial of carvedilol with immediate-release metoprolol tartrate in patients with HF and LVSD found better survival in patients treated with carvedilol but no difference in the composite of survival and hospitalization.68 Unfortunately, the metoprolol formulation used in this trial was not that established to improve outcomes in the Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), leaving the issue open to debate. Another study of patients with diabetes and hypertension receiving renin-angiotensin blockade assessed the metabolic effects of carvedilol with short-acting metoprolol and found modest but statistically significant increases in HbA1c (0.15%) in metoprololtreated patients, compared with no change in carvediloltreated patients, as well as better insulin sensitivity in the latter group.69 This was not a trial in patients with HF, however, and the clinical impact of these differences in metabolic effects remains unknown. On the basis of these data, all patients with diabetes, LVSD, and stable HF symptoms (even if severe) should be considered for treatment with ␤-blockers in addition to ACE inhibitors in the absence of contraindications. The ␤-blockers should be used with caution in patients with hypotension, bradycardia, histories of known adverse reactions to therapy, or true reactive airways disease. Additionally, they should be used carefully in patients with propensities for hypoglycemia, especially those with preexisting “hypoglycemia unawareness,” which typically affects patients with long-standing disease and recurrent episodes of severely low blood glucose levels (⬍40 mg/dL). Treatment should be confined to those agents proved to improve outcomes in clinical trials in HF (carvedilol, extended-release metoprolol succinate, and bisoprolol). Aldosterone antagonists: Two trials have assessed the effects of adding aldosterone antagonists (spironolactone

and eplerenone) to standard therapy in patients with HF. The Randomized Aldactone Evaluation Study (RALES) enrolled patients with LVSD and severe symptomatic HF despite therapy with ACE inhibitors, diuretics, and digoxin, who were randomized to spironolactone 25 mg/day or placebo. Spironolactone therapy resulted in a significant reduction in mortality (ARR, 11%; NNT, 9; RR, 0.70; 95% CI, 0.60 – 0.82) as well as a lower risk for hospitalization and a reduction in symptoms.70 Neither the proportion of patients with diabetes nor a subgroup analysis of patients with diabetes was reported. Furthermore, only about 10% of patients in RALES were treated with ␤-blockers, leaving the trial unable to address the incremental benefit of aldosterone blockade in patients receiving ACE inhibitors and ␤-blockers. The Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) compared the selective aldosterone inhibitor eplerenone with placebo in patients with LVSD and symptoms of HF after acute MI. Subjects with diabetes (32% of the population) were enrolled with LVSD alone regardless of symptoms.71 Treatment with eplerenone resulted in a significant reduction in all-cause mortality (ARR, 2.3%; NNT, 43; RR, 0.85; 95% CI, 0.75– 0.96) as well as the risk for cardiovascular death and hospitalization or sudden cardiac death. Subgroup analysis showed similar benefits in strata of patients according to diabetes status. As a result of these studies, guidelines recommend consideration of an aldosterone antagonist in patients with LVSD and advanced symptoms (NYHA class III or IV) despite baseline therapy with ACE inhibitors and ␤-blockers in the absence of contraindications and provided that adequate follow-up of renal function and serum potassium is feasible. The last point is particularly important in patients with diabetes, who have a relatively high prevalence of renal insufficiency, some of whom may also have type IV renal tubular acidosis, which increases the risk for hyperkalemia, particularly in the context of baseline ACE inhibitor therapy. Aldosterone antagonists should not be given to patients with estimated creatinine clearance ⬍30 mL/min per 1.72 m2 or potassium levels ⬎5.0 mmol/L or in conjunction with other potassium-sparing diuretics, and careful monitoring for hyperkalemia is recommended for patients receiving treatment. Unfortunately, studies of current practice patterns suggest that the prescription of aldosterone antagonists does not conform to these precautions,72 which may result in adverse consequences.73 HF with preserved left ventricular systolic function: It is now well known that substantial proportions of populations with HF have preserved left ventricular systolic function, which is more common in older subjects and in women.74,75 Unfortunately, with rare exceptions,76 the preponderance of clinical trials of pharmacotherapy for HF have focused entirely on patients with LVSD. Thus, evidence-based treatment recommendations for these patients, whose health outcomes may be as poor as those of patients

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with LVSD,77 remain elusive, and recommendations for therapy are relatively generic. Excellent blood pressure control and the judicious use of diuretics to control symptoms of congestion and fluid overload are recommended.48 Summary—HF therapy in patients with diabetes: Because diabetes is associated with worse outcomes in patients with HF, the institution of evidence-based drug therapy to reduce mortality and morbidity is an imperative. Patients with HF and LVSD should, whenever possible, be treated with drugs that address the neurohormonal activation characteristic of HF. Thus, absent contraindications for therapy, patients with diabetes and LVSD should receive ACE inhibitors and ␤-blockers. Patients with persistent severe HF symptoms despite these therapies should also be considered for treatment with aldosterone antagonists, with careful monitoring for hyperkalemia. Those who do not tolerate ACE inhibitors because of cough or allergy should be treated with angiotensin receptor blockers. In general, drug doses should be titrated upward to those shown to provide benefits in clinical trials (Table 4).

Medical Therapy of Diabetes in Patients with Heart Failure The landscape of pharmacologic management of hyperglycemia in patients with type 2 diabetes has changed remarkably over the past decade. Previously, therapeutic options were confined to injectable insulin and the sulfonylureabased insulin secretagogues. Today, physicians can choose from a wide array of agents, each with a unique mechanism of action and metabolic benefits and each with a distinct set of adverse effects.78 The management of patients with type 2 diabetes who have ventricular dysfunction presents a particular challenge, because 2 of the most popular classes of antihyperglycemic drugs, the biguanides (ie, metformin) and the thiazolidinediones (TZDs) (eg, rosiglitazone, pioglitazone), are currently contraindicated in patients with advanced HF. In the next section, we review rational antihyperglycemic therapy in this growing patient population. Pathogenesis of hyperglycemia in type 2 diabetes: One of the major goals in treating patients with type 2 diabetes is to reduce plasma glucose concentrations as close to the normal range as possible, while avoiding hypoglycemia. This has unequivocally been shown to reduce the incidence of microvascular complications, such as nephropathy and retinopathy.79 There are also strong indicators that metabolic control additionally improves macrovascular outcomes.80 HbA1c (normal range 4%– 6%) is the standard measurement to assess the quality of glucose control. In most patients, the HbA1c goal is ⬍6.5%–7.0%.81 The attainment of this goal is frequently elusive and often requires therapy with several antihyperglycemic agents. Understanding which drugs to use and when is advantaged by a thor-

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Table 4 Inhibitors of the renin-angiotensin system and ␤-blockers commonly used for the treatment of patients with heart failure and left ventricular systolic dysfunction Drug ACE inhibitors Captopril Enalapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Trandolapril Angiotensin receptor blockers Candesartan Losartan Valsartan Aldosterone antagonists Spironolactone Eplerenone ␤-blockers Bisoprolol Carvedilol

Metoprolol succinate extended release (metoprolol CR/XL)

Initial Daily Dose

Maximum Dose

6.25 mg 3 times 2.5 mg twice 5–10 mg once 2.5–5 mg once 2 mg once 5 mg twice 1.25–2.5 mg once 1 mg once

50 mg 3 times 10–20 mg twice 40 mg once 20–40 mg once 8–16 mg once 20 mg twice 10 mg once 4 mg once

4–8 mg once 25–50 mg once 20–40 mg twice

32 mg once 50–100 mg once 160 mg twice

12.5–25 mg once 25 mg once

25 mg once or twice 50 mg once

1.25 mg once 3.125 mg twice

10 mg once 25 mg twice 50 mg twice for patients ⬎85 kg 200 mg once

12.5–25 mg once

ACE ⫽ angiotensin-converting enzyme. Adapted from J Am Coll Cardiol.48

ough understanding of the pathogenesis of hyperglycemia in this disease. Broadly speaking, hyperglycemia in type 2 diabetes is the end result of the combined effects of resistance to the action of insulin and relative insulin deficiency.82 The former is characterized by decreased insulin-mediated glucose uptake by peripheral tissues, especially skeletal muscle, and augmented endogenous glucose production, predominantly in the liver. In adipocytes, insulin resistance is characterized by enhanced lipolytic activity, which increases circulating free fatty acid concentrations. Insulin resistance by itself, however, does not result in elevated glucose concentrations, because of acute and chronic compensation by the endocrine pancreas. Acutely, the pancreatic ␤-cell, within the islets of Langerhans, increases its insulin output, sometimes dramatically so, to provide a sufficient insulin concentration to allow glucose to enter cells.83 Chronically, increased insulin demands result in islet hypertrophy. In some patients who may be genetically predisposed, islet dysfunction develops, first manifested by a functional impairment of insulin secretion and, subsequently, by an actual decrement in islet mass. Hyperglycemia is therefore the net result of an imbalance between the ability of peripheral tissues to respond to insulin signaling and the actual insulin secretory capacity of the pancreas. The interplay among the pancreas, muscle, and liver is

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Figure 3. The complex interplay of the various pathophysiologic defects contributing to hyperglycemia in type 2 diabetes mellitus.

enormously complex and involves many other signals in addition to insulin. For example, the adipocytes, previously ignored in the pathophysiologic framework of type 2 diabetes, now appear to play a critical role in the dysfunction at all 3 organ sites.84 A deranged ratio in the production of a variety of other systemic factors (“adipocytokines”) by fat cells appears to be deleterious to both insulin action and insulin supply. Substantial information has emerged over the past decade underscoring the critical influence of these factors on insulin sensitivity, hepatic glucose production, and the integrity of ␤-cell function. An overview of the pathophysiology of type 2 diabetes is diagrammed in Figure 3. An exhaustive description of our current understanding of the cellular and metabolic events that culminate in this disease is beyond the scope of this review. Suffice it to say, however, that multiple defects are involved, and each is targeted by ⱖ1 specific antihyperglycemic agent (Table 5). Two other fundamental concepts concerning the pathogenesis of type 2 diabetes involve the association between insulin resistance and cardiovascular disease and the progressive nature of the ␤-cell dysfunction. Insulin resistance, widely agreed to be the earliest pathophysiologic lesion detected in those at risk for type 2 diabetes, is associated with a variety of other clinical features that place patients at increased risk for MI and stroke. These include obesity, hypertension, dyslipidemia, hypercoagulability, and abnormal endothelial function. The term “metabolic syndrome”

has been used to refer to patients with this constellation of clinical findings and has been an area of intensive investigation over the past decade.85 In the setting of insulin resistance, once ␤-cell dysfunction becomes manifest, it appears to be an inexorable process. It is responsible for the transition of patients from prediabetic states (ie, impaired fasting glucose and impaired glucose tolerance) to frank diabetes.86 Moreover, progressive insulin deficiency characterizes the typical deterioration in glycemic control over time and the need for more aggressive treatment strategies, including combination pharmacologic therapy and, frequently, insulin itself. Hyperglycemia and HF: As discussed earlier, there is a strong relation between hyperglycemia and incident HF. Given the adverse systemic effects of hyperglycemia, the known benefits of tight glucose control are apt to apply to patients with ventricular dysfunction, especially those with underlying ischemic heart disease. Few data explore the association between glucose control and HF, especially with regard to clinical outcomes once the diagnosis of HF has been established. In a single study, Eshaghian et al87 reported an unexpected inverse relation between HbA1c and mortality in a small (n ⫽ 123) group of patients with diabetes and advanced HF (mean LVEF, 0.25) followed at a single center. In this study, patients whose HbA1c levels were ⱕ7% experienced 35% 2-year all-cause mortality, compared with 20% in those with HbA1c levels ⬎7%

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Table 5 Antihyperglycemic drugs and their mechanisms of action Agent

Mechanism of Antihyperglycemic Action

Sulfonylureas Glyburide Glipizide Glimepiride Meglitinides Repaglinide Nateglinide Biguanides Metformin ␣-Glucosidase inhibitors Acarbose Miglitol Thiazolidinediones Rosiglitazone Pioglitazone

Binds to sulfonylurea receptor on ␤-cells, stimulating insulin release; long duration of action

Incretin modulators GLP-1 analogues/mimetics Exenatide

Dipeptidyl peptidase-IV inhibitors Sitagliptin Vildagliptin Insulins Glargine, detemir NPH, lente Regular Lispro, aspart, glulisine Premixed

Binds to sulfonylurea receptor on ␤-cells, stimulating insulin release; short duration of action Decreases hepatic glucose production Retards gut carbohydrate absorption

Activates the nuclear receptor PPAR-␥, increasing peripheral insulin sensitivity; may also reduce hepatic glucose production Activates GLP-1 receptors, increasing glucose-dependent insulin secretion, decreasing glucagon secretion, and delaying gastric emptying Inhibits degradation of endogenous GLP-1 (and GIP), thereby enhancing these incretins’ effects Increases insulin supply

GIP ⫽ glucose-dependent insulinotropic peptide; GLP-1 ⫽ glucagon-like peptide–1; NPH ⫽ neutral protamine Hagedorn; PPAR ⫽ peroxisome proliferator-activated receptor.

(p ⬍0.01), a difference that persisted after multivariate adjustment (HR, 2.3; 95% CI, 1.0 –5.2). The explanation for these findings remains unclear but could potentially involve the type of therapy used in the respective groups of patients (see later), the negative effects of hypoglycemia, or even the diuretic effects of hyperglycemia. Although more data are clearly needed from larger studies to confirm or refute these findings, this study underscores the importance of fully understanding the effect of various antihyperglycemic therapies in the HF population. Indeed, drug choice in patients with diabetes with HF is challenging, predominantly because of the contraindications involving the 2 insulin-sensitizing drugs, metformin, and the TZDs. Antihyperglycemic therapy overview: The sulfonylureas (glyburide, glipizide, and glimepiride), previously the mainstays of type 2 diabetes therapy, augment endogenous insulin secretion.88 These agents have been associated with ␤-cell failure and increased cardiovascular risk, although this has not been convincingly borne out in most prospective clinical trials. However, because of the risk for hypoglycemia and weight gain, as well as the availability of other

pharmacologic classes, this drug class has recently become less popular. The meglitinides (eg, repaglinide, nateglinide) are rapidacting insulin secretagogues that are taken before meals and have an activity profile that is ostensibly more physiologic than sulfonylureas.89 Postprandial glucose levels are better controlled, although at the expense of reduced maintenance of fasting glucose. These agents are still associated with hypoglycemia and weight gain, but to a lesser degree than the sulfonylureas. Whether the intermittent (compared with sustained) stimulation of pancreatic insulin secretion has any benefit on the long-term function of the ␤-cells is not clear. Incretin modulators are a newer category of medication that express some activity as insulin secretagogues.90 This broad class is currently represented by the injectable glucagon-like peptide (GLP)–1 analogues and mimetics (eg, exenatide) and the oral dipeptidyl peptidase IV (DPP-IV) inhibitors (eg, sitagliptin, vildagliptin). In addition to glucose-dependent insulin secretion, these drugs also reduce pancreatic glucagon secretion and delay gastric emptying. Exenatide may also have a central effect to promote satiety.

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The ␣-glucosidase inhibitors block carbohydrate absorption in the proximal small bowel, thereby reducing postprandial glucose excursions.91 In epidemiologic studies, there is a tighter association between postprandial glucose and cardiovascular risk than with fasting glucose. These agents are generally less efficacious at lowering glucose than other available drug classes. In addition, their use is associated with frequent gastrointestinal side effects, including abdominal cramping, flatulence, and diarrhea, which can be mitigated but not entirely avoided by slow drug titration. Metformin, a biguanide, reduces hyperglycemia predominantly by decreasing hepatic glucose production and is therefore often referred to as an “insulin sensitizer.”92 Because of the association between biguanides and lactic acidosis, metformin has many contraindications that must be considered. Therapy leads to modest weight loss but is also associated with nausea and diarrhea, especially at the initiation of treatment. Metformin addresses several features of the metabolic syndrome and is believed to offer a cardiovascular advantage, primarily on the basis of the UKPDS, in which overweight, metformin-treated patients experienced a reduction in cardiovascular end points.93 The TZDs comprise another class of insulin-sensitizing medications. This class improves glucose uptake in peripheral tissues, predominantly skeletal muscle and adipocytes,94 and may also decrease hepatic glucose production. TZDs likely exert most of their action through adipocytes, where they appear to improve dysregulated adipocytokine production. The TZDs have been associated with several cardiovascular benefits, because they improve many of the features of insulin resistance and the metabolic syndrome.95 The insulin resistance observed in type 2 diabetes is relative. Therefore, insulin, if provided at sufficient doses, will always lower blood glucose levels. Accordingly, insulin remains a mainstay of treatment, although it is traditionally used later on in the disease course, after oral agents fail, because the only method of administration was, until recently, subcutaneous injection.96 In addition to the associated discomfort and relative complexity of insulin therapy, weight gain and hypoglycemia are significant concerns. Insulin is typically added to or substituted for oral agents once the latter are no longer effective in maintaining glucose concentrations. If insulin therapy is used, multiple formulations are available. These include “basal” insulins (eg, glargine, detemir), which are dosed once or twice per day and provide the body with low-level, peakless insulin exposure, and “prandial” insulins (eg, regular, lispro, aspart, glulisine), which are shorter acting, are dosed before meals, and blunt postprandial hyperglycemia. Intermediate-acting insulins (eg, neutral protamine Hagedorn insulin) and convenient mixtures (eg, 70/30, 50/50) are also available. Recently, inhaled insulin was approved for use by the US Food and Drug Administration (FDA). The availability of this delivery route may provide a new opportunity for patients previously resistant to the notion of insulin therapy. Obvi-

ously, in patients with type 1 diabetes, who are completely insulin-dependent for glucose control and the avoidance of ketoacidosis, insulin is the only therapy. Typically, treatment regimens are more complex, with more frequent dosing (3– 4 injections/day or continuous subcutaneous infusion via a computerized insulin pump) in patients with type 1 disease. Those with type 2 diabetes, who continue to produce some endogenous insulin even in late stages of the disease, can often be maintained on 1–2 injections/day. Amylin analogues (eg, pramlintide) are a recent addition to the diabetes pharmacopeia. This class mimics the effect of another ␤-cell product, amylin, which attenuates pancreatic glucagon secretion, delays gastric emptying, and may also decrease appetite through central mechanisms.97 Amylin therefore serves to blunt postprandial glucose excursions. The injectable pramlintide is helpful in selected patients with type 1 and type 2 diabetes who are already on comprehensive insulin replacement regimens but not achieving adequate control, particularly overweight patients. Antihyperglycemic therapy in patients with HF: The insulin secretagogues are frequently used in patients with HF. There is, however, a theoretical risk in those patients whose impaired ventricular function is associated with CAD because of potential effects of these drugs on ischemic preconditioning.98 The sulfonylureas and the meglitinides exert their action by blocking adenosine triphosphate (ATP)–sensitive potassium channels on pancreatic ␤-cells. Under ischemic conditions, similar channels on cardiac myocytes are opened, with energy requirements thereby reduced, seemingly in a self-protective fashion. Theoretically, the closure of cardiac potassium channels by a drug might interfere with this ischemic preconditioning, conceivably exacerbating myocardial injury, as some have demonstrated in animal models. It has been proposed that this effect may explain the increased cardiovascular mortality with sulfonylureas in an older prospective trial99 and in some more recent retrospective studies.100,101 However, it is important to point out that in the UKPDS, the largest prospective, randomized clinical trial involving antihyperglycemic therapy in type 2 diabetes, no increased cardiac mortality with sulfonylureas was found.79 This may reflect the significantly reduced affinity of these agents for cardiac as opposed to pancreatic ATP-sensitive potassium channels, particularly for glipizide and glimepiride.102 Binding of the newer meglitinides is also negligible.103 Accordingly, the actual clinical importance of ischemic preconditioning visà-vis secretagogue therapy has never been demonstrated clinically. Moreover, sulfonylureas have been proposed to have some antiarrhythmic properties. Aronson et al104 showed reduced ventricular ectopy in patients with diabetes admitted with decompensated HF who were treated with sulfonylureas. There are no data yet available with the incretin modulators (GLP-1 analogues and mimetics and the DPP-IV

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inhibitors) or with amylin analogues in patients with HF. There is no intrinsic reason, however, why these drugs could not be used in this setting. It is noteworthy, however, that GLP-1 receptors are found in the heart, and preliminary investigations in animal models of atherosclerotic heart disease and cardiomyopathy are intriguing.105,106 Several groups have reported improvement in left ventricular performance, particularly in the postischemic setting. ␣-Glucosidase inhibitors (eg, acarbose) are nonsystemic agents with an excellent safety profile. These drugs are specifically effective in reducing postprandial glucose, which has been associated with greater cardiovascular risk than fasting glucose. In the Study to Prevent Non–InsulinDependent Diabetes Mellitus (STOP-NIDDM), a dramatic reduction of 91% (p ⫽ 0.02) in MI was observed in patients with impaired glucose tolerance randomized to acarbose versus placebo.107 Adequate studies in patients with diabetes have not yet been conducted. Nonetheless, in patients with HF requiring modest efficacy to achieve glucose targets, especially in those with ischemic heart disease, these agents may be an ideal choice. By default, many patients with diabetes and HF are treated with insulin. In modest doses, insulin may have salutary effects on cardiac function, irrespective of its effects on glucose itself. Insulin has been demonstrated to have potent anti-inflammatory108 and coronary vasodilatory109 properties. It may also serve as a positive cardiac inotrope, in part through effects on cardiac myocyte glucose and lipid metabolism.110 In the acute setting of MI, intensive insulin therapy has been shown to improve short-term and long-term outcomes.111 It should be noted, however, that insulin, particularly at high doses, is associated with increased renal sodium retention and could potentially worsen fluid balance in those with severe ventricular impairment.112 Indeed, some retrospective studies have suggested an increased incidence of HF in insulin-treated patients with type 2 diabetes and, once HF is manifest, markedly increased mortality. For example, Nichols et al113 recently reported a higher incidence of HF in patients with type 2 diabetes in the Kaiser Permanente Northwest Diabetes Registry who were treated with insulin versus oral therapies after adjustment for a variety of clinical factors, including cause of ventricular dysfunction, diabetes duration, and glycemic control (HR, 2.3 vs sulfonylureas and 2.7 vs metformin; both p ⬍0.0001). In another study by Smooke et al,114 554 consecutive patients with advanced systolic HF at a single center were stratified into 3 groups on the basis of the presence or absence of diabetes and insulin use. Of 132 patients (approximately 1 in 4) with diabetes, 43 were being treated with and 89 without insulin. The groups were similar in baseline demographics and LVEFs. Survival at 1 year was 89.7% for patients without diabetes, 85.8% for patients with diabetes who were not treated with insulin, and 62.1% for patients with diabetes who were treated with insulin (p ⬍0.00001). After multivariate adjustment, insulin-treated diabetes was found to be an independent predictor of mor-

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Table 6 Cardiovascular benefits of metformin 2 2 2 2 1 1 2 2 2 2

Weight Hyperinsulinemia Triglycerides, 2 LDL cholesterol Free fatty acids Vascular reactivity and endothelial function AMP kinase Plasminogen activator inhibitor–1, 2 platelet aggregation Oxidative stress Atherosclerosis in animal models Macrovascular event rates (UKPDS)

AMP ⫽ adenosine monophosphate; LDL ⫽ low-density lipoprotein; UKPDS ⫽ United Kingdom Prospective Diabetes Study; 1 ⫽ increased; 2 ⫽ decreased. Adapted from Drugs.92 Table 7 Metformin contraindications Absolutely contraindicated in conditions that predispose to tissue anoxia, increase circulating lactate levels, lower pH, or decrease metformin clearance: ● Renal dysfunction (serum creatinine ⱖ1.5 mg/dL in men, ⱖ1.4 mg/dL in women) ● Radiocontrast studies ● Age ⬎80 yr (unless glomerular filtration rate is normal) ● Liver disease ● Alcoholism ● Hemodynamic impairment ● Dehydration ● Hypoxia ● Metabolic acidosis ● Heart failure requiring pharmacologic therapy

tality (HR, 4.3; 95% CI, 1.7–11.0), whereas non–insulintreated diabetes was not (HR, 1.0; 95% CI, 0.3–2.9). However, because insulin is usually reserved for patients with type 2 diabetes who have “failed” oral agents, this form of therapy usually identifies a group of patients with more advanced disease who are in worse metabolic control. Therefore, instead of indicating a cause-and-effect relation, observational data may simply indicate that patients with diabetes who require insulin are a high-risk group. Further study in this area is required, especially in light of the current contraindications for insulin sensitizers, the use of which could delay or prevent the need for insulin in some, if not many, of these patients. Special consideration—metformin and HF: Metformin has several purported cardiovascular benefits (Table 6).92 This medication may therefore be particularly suited for use in patients with HF and type 2 diabetes, especially those with pronounced features of the metabolic syndrome. However, the biguanides have also been associated with lactic acidosis in at-risk patients, especially those with renal insufficiency, in whom metformin clearance is reduced.115 The overall rate of lactic acidosis with metformin has been estimated at 1/30,000 patient-years of use, significantly lower than an earlier biguanide, phenformin, and probably not dissimilar from the background rate in the diabetic

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Figure 4. Adjusted heart failure outcomes in patients with type 2 diabetes mellitus receiving metformin versus other therapies from the Saskatchewan Health Study (SHS). Hosp. ⫽ hospitalization. (Adapted from Diabetes Care.120)

Figure 5. Adjusted mortality curves for patients hospitalized with heart failure and diabetes mellitus receiving prescriptions for metformin at hospital discharge and those not treated with insulin-sensitizing drugs. (Adapted from Circulation.122)

population.116 Metformin is also now contraindicated in HF requiring pharmacologic therapy. This stems from concerns that such patients are predisposed to decompensation from progressive pump dysfunction, overdiuresis, and other conditions that may alter renal blood flow. Indeed, after metformin’s original release onto the United States market in 1995, the FDA received several postmarketing reports of lactic acidosis associated with metformin therapy, many of which occurred in the setting of HF.117 In several clinical surveys since in the inpatient and outpatient arenas, ⱖ20%– 30% of metformin-treated patients have active contraindi-

cations for its use (Table 7), most frequently renal dysfunction.118,119 In none of these reports, however, have cases of lactic acidosis been identified, raising the question as to whether the current proscription against metformin in patients with HF is truly justified. A recent study from Saskatchewan, Canada, found decreased mortality in patients with diabetes treated with metformin who developed HF compared with those managed with non–metformin-based therapy (primarily sulfonylureas and/or insulin) (Figure 4).120 The investigators’ conclusion that metformin may provide benefit to patients with HF was

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further supported by the finding of reduced mortality in those patients using combination therapy with both sulfonylureas and metformin, traditionally a group with longer disease duration and, potentially, a greater burden of vascular complications. We have recently reported patterns of antihyperglycemic drugs and outcomes in elderly Medicare beneficiaries with diabetes discharged from United States hospitals from 1998 to 2001 with primary diagnoses of HF.121,122 In the 1,851 patients discharged on metformin, 1-year all-cause mortality and HF readmissions were reduced by 13% (HR, 0.87; 95% CI, 0.78 – 0.97) and 8% (HR, 0.92; 95% CI, 0.86 – 0.99), respectively, compared with those not discharged on insulin sensitizers after adjustment for patient, physician, and hospital characteristics (Figure 5). Moreover, in the small subgroup of patients (n ⫽ 261) discharged on metformin and a TZD, mortality was 24% lower (HR, 0.76; 95% CI, 0.58 –1.00). Notably, there was no excess of admissions for metabolic acidosis in patients treated with metformin. On the basis of these studies, several authorities have proposed that the current contraindication for metformin therapy in HF should be reconsidered.123,124 Unfortunately, no prospective trials are available that have formally assessed the effects of metformin in this group of patients. If metformin is ever used in this setting, however, careful assessment of volume status and renal function should be ensured. Special consideration—TZDs and HF: The TZDs present a separate group of considerations and concerns. These drugs also appear to have several potential cardiovascular benefits, including a reduction in atherosclerosis (Table 8).95,125 Pertinent to any discussion of their potential use in HF, improvement in endothelial function, a vasodilatory effect with modest reductions in blood pressure, and lowering of systemic markers of inflammation have each been associated with TZD therapy in animal and human studies.126 –128 Some preclinical investigations also suggest a benefit on cardiac remodeling after ischemic injury.129,130 Conceptually, using an insulin sensitizer may also improve the energy dynamics within the heart, with reduction in insulin resistance decreasing free fatty acid availability as well as their oxidation within the myocardium.131,132 There is therefore the theoretical potential for this class of insulinsensitizing drug to help patients with ventricular failure. Supporting clinical outcomes data are, thus far, quite few. In the only randomized cardiovascular outcomes trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), 5,238 high-risk patients with type 2 diabetes and preexisting macrovascular disease were randomized to pioglitazone versus placebo in addition to their baseline antihyperglycemic therapy.133 Over an average follow-up of 3 years, the primary end point, a broad cardiovascular composite, proved negative (HR, 0.90; 95% CI, 0.80 –1.02). However, a secondary end point of mortality,

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Table 8 Cardiovascular benefits of thiazolidinediones 2 Insulin resistance, 2 hyperinsulinemia 2 Triglycerides, 1 HDL cholesterol, 2 LDL particle size and oxidation rates 2 Free fatty acids 2 Blood pressure 1 Vascular reactivity and endothelial function Improved ventricular remodelling Improved cardiac metabolism (1 glucose oxidation, 2 fatty acid oxidation) 2 Plasminogen activator inhibitor–1, 2 platelet aggregation 2 Vascular smooth muscle cell proliferation 2 Neointimal proliferation after vascular injury 2 Expression of adhesion molecules, metalloproteinases 2 C-reactive protein, other inflammatory mediators 2 Oxidative stress 2 Atherosclerosis in animal models 2 Carotid atherosclerosis (by IMT), 1 aortic pulsewave velocity 2 Macrovascular events (PROactive study) HDL ⫽ high-density lipoprotein; IMT ⫽ intimal-medial thickness; LDL ⫽ low-density lipoprotein; PROactive ⫽ Pioglitazone Clinical Trial in Macrovascular Events; 1 ⫽ increased; 2 ⫽ decreased. Adapted from Ann Intern Med.95

MI, and stroke was significantly reduced by 16% (HR, 0.84; 95% CI, 0.72– 0.98) in those patients receiving pioglitazone (absolute reduction, 2.1% [14.4% to 12.3%]). Despite these generally favorable findings, there remains significant concern about the use of this drug class in patients with HF, because TZDs have been universally associated with fluid retention. In the original clinical trials of TZDs, edema rates in active-therapy patients ranged from 4%–16%, with the higher rates in patients concurrently treated with insulin.134,135 HF, however, occurred in ⱕ1% of patients. In clinical practice, edema likely occurs in ⱖ10%– 20% of patients, especially in those taking insulin. The pathophysiologic explanation for this is not fully known but appears to involve altered renal sodium handling. The precise culprit may be an amiloride-sensitive endothelial sodium channel in the collecting duct, which is activated by TZDs.136 Other proposed mechanisms include an increase in vascular permeability, mediated possibly through increased levels of vascular endothelial growth factor, as well as vasodilation from a calcium channel– blocking effect that could activate the renin-angiotensin system.137 There are no human data to suggest an actual deleterious effect of TZDs on ventricular function. In a study of 154 patients with type 2 diabetes and normal baseline cardiac status, troglitazone, was compared with glyburide, and serial cardiac function was assessed by echocardiography.138 There were small but statistically significant increases in cardiac index and stroke volume, with decreases in systemic vascular resistance in the troglitazone group. In a second study involving a small group (n ⫽ 8) of patients with type 2 diabetes and HF, Ogino et al139 performed serial echocardiography over 4 hours after a single dose of troglitazone. A significant de-

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Figure 6. Adjusted mortality curves for patients hospitalized with heart failure and diabetes mellitus receiving prescriptions for thiazolidinediones (TZDs) at hospital discharge and those not treated with insulin-sensitizing drugs. (Adapted from Circulation.122)

crease in mean left ventricular end-systolic dimension and an increase in percentage fractional shortening and in the E/A ratio (the ratio of early to late ventricular filling) was found, suggesting an acute positive inotropic effect from the TZD. During postmarketing surveillance, however, case reports of patients with de novo HF after initiating therapy with TZDs have emerged,140,141 prompting retrospective database queries, which have yielded conflicting results.122,142–144 In 1 such study involving ⬎33,000 patients treated with oral antidiabetic agents, TZD use was predictive of a health insurance claim for HF diagnosis (HR, 1.7; p ⬍0.001), with an adjusted incidence of HF at 40 months of 8.2% in TZD-treated patients and 5.3% for non–TZDtreated patients.142 Hartung et al143 confirmed these findings using a claims database involving Oregon Medicaid patients with diabetes hospitalized for HF (n ⫽ 288). The investigators reported an adjusted odds ratio for exposure to a TZD of 1.37 (95% CI, 0.98 –1.92), compared with a control group of patients admitted for non-HF diagnosis. More recent studies have not corroborated these initial findings. Karter et al144 evaluated the Kaiser Permanente Northern California Diabetes Registry, involving ⬎23,000 patients with type 2 diabetes who initiated any diabetes drug over a 2-year period. With a mean follow-up period of 10 months, after adjusting for baseline demographic and clinical factors, there was no significant increase in the incidence of HF hospitalization in those initiating pioglitazone therapy (HR, 1.28; 95% CI, 0.85–1.92). However, there was a significantly higher rate in those initiating insulin (HR, 1.56; 95%

CI, 1.00 –2.45) and a lower incidence in those starting metformin (HR, 0.70; 95% CI, 0.49 – 0.99). In our own analysis of Medicare beneficiaries discharged from United States hospitals with diagnoses of HF, similar to the findings in metformin-treated patients mentioned previously, 1-year adjusted mortality was reduced by 13% (HR, 0.87; 95% CI, 0.80 – 0.94) in those prescribed TZDs (n ⫽ 2,226) (Figure 6).122 However, in contrast to the metformin-treated group, there was a trend toward an increase in all-cause hospitalization with TZDs (HR, 1.04; 95% CI, 0.99 –1.10), driven mainly by an increase in HF hospitalization (HR, 1.06; 95% CI, 1.00 –1.12). Similarly, in our follow-up study involving Medicare patients discharged from a United States hospital with primary diagnoses of acute MI, a trend toward increased all-cause hospitalization was also seen in TZD-treated patients (n ⫽ 819; HR, 1.09; 95% CI, 1.00 –1.20), driven primarily by a significant increase in HF readmissions (HR, 1.17; 95% CI, 1.05–1.30).145 Despite this, TZD-treated patients in this study experienced 8% less 1-year mortality, although the results were not statisticly significant (HR, 0.92; 95% CI, 0.80 –1.05). Although provocative, such observational studies may be limited by confounding factors inherent in retrospective analyses, which can be only partly overcome by adjustments for other patient characteristics. For instance, TZDs have traditionally been used as add-on therapy and are therefore typically prescribed to patients in more advanced stages of diabetes who may already be at greater risk for HF. Also, because the diagnosis of HF in each of these investigations

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Figure 7. Fluid status in patients with heart failure with type 2 diabetes mellitus treated with thiazolidinediones (TZDs) versus other therapies. The study included patients with chronic systolic dysfunction, approximately 50% of whom were categorized in New York Heart Association class III or IV. JVD ⫽ jugular venous distension. (Adapted from J Am Coll Cardiol.146)

Figure 8. Proposed pharmacologic antihyperglycemic therapy algorithm in patients with type 2 diabetes mellitus and advanced heart failure, in whom metformin and thiazolidinediones are contraindicated. Not all combinations are currently approved by the US Food and Drug Administration (FDA). *Insulin can be added to or substituted for the above regimens. DPP-IVi ⫽ dipeptidyl peptidase IV inhibitor; ␣-GI ⫽ ␣-glucosidase inhibitor.

was not adjudicated, it is conceivable that some patients merely experienced the anticipated fluid retention associated with TZD therapy, without actual ventricular dysfunction. Data from Tang et al146 are noteworthy in this light. In this group’s retrospective analysis involving patients with type 2 diabetes from a HF clinic, TZD-treated patients did indeed develop more peripheral edema but, if anything, less pulmonary edema than those prescribed other antihyperglycemic strategies (Figure 7). These data suggest that fluid retention from TZDs, even in patients with significant ven-

Table 9 American Heart Association and American Diabetes Association consensus recommendations: thiazolidinediones (TZDs), fluid retention, and heart failure New York Heart Association class I or II symptoms ● TZDs are not contraindicated ● Start with low dose; increase dose very gradually to optimize glycemic control; observe for excessive weight gain, edema, or other signs of heart failure New York Heart Association class III or IV symptoms ● TZDs not recommended

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tricular dysfunction, occurs mainly in peripheral, dependent sites, which would not necessarily be associated with adverse HF outcomes. In PROactive,133 the generally beneficial cardiovascular effects of pioglitazone were partially offset by more HF events. In this prospective randomized trial, HF, a nonadjudicated outcome, was diagnosed more frequently in patients receiving active therapy than in those receiving placebo (281 [10.89%] vs 198 [7.5%]). Hospitalization for HF was also more common in pioglitazone-treated patients (149 [5.7%] vs 108 [4.1%]), although HF mortality was similar between groups (25 [1.0%] vs 22 [0.8%]). In the midst of this controversy, a consensus statement from the American Diabetes Association (ADA) and the AHA emerged in 2004, outlining the risks of TZD therapy in patients with HF and offering rational advice to clinicians.147 The key recommendations from this group are outlined in Table 9. Despite the concerns raised by some of these studies, it is clear that the effects of TZDs in HF are complex. There is no convincing proof, however, of any direct deleterious effect on cardiac ventricular function. In fact, benefit to the failing ventricle has been proposed and is supported by some observational studies. Nonetheless, because of increases in extracellular fluid volume, patients with preexisting ventricular dysfunction may clearly decompensate on exposure to TZDs. As a result, and in concert with the AHA/ADA’s position statement, neither of the 2 currently available TZDs is recommended in patients with NYHA class III or IV HF and should be used very cautiously even in patients with lesser degrees of ventricular dysfunction. Current prescribing information for rosiglitazone makes reference to increased cardiovascular events in a 52-week company-sponsored trial involving patients with type 2 diabetes, NYHA class I or II HF, and LVEFs ⱕ0.45. Current prescribing information for pioglitazone refers to a company-sponsored 24-week trial in patients with type 2 diabetes, NYHA class II or III HF, and LVEFs ⬍0.40. Over the course of the study, 9.9% of patients receiving pioglitazone compared with 4.7% of those receiving glyburide required overnight hospitalization for HF. As in the case with metformin, rigorously designed, randomized clinical trials of TZDs in this patient population appear warranted. Aggressive and standardized approaches to managing the expected edema should also be incorporated in any such investigations. A rational therapeutic approach: It is difficult to outline an evidence-based antihyperglycemic treatment strategy in patients with type 2 diabetes and HF, because there have been no randomized trials that have adequately explored the risks and benefits of available therapies in this group. Until more information is available, patients with diabetes with HF should be managed as aggressively as other patients, with the important caveat that certain medication types are contraindicated for many patients. In most,

treatment should begin with lifestyle changes, including diet, exercise as tolerated, and the optimization of body weight. This may obviously be a significant challenge in this group of patients, whose activity tolerance is often markedly impaired. When pharmacotherapy is required, insulin secretagogues, DPP-IV inhibitors, or ␣-glucosidase inhibitors are reasonable initial therapies (Figure 8). Exenatide can also be used, although this agent is currently approved only as add-on therapy to patients already being treated with sulfonylureas and/or metformin. The failure of initial monotherapy should be addressed with combinations of drugs that complement each other’s mechanism of action. In patients with mild HF, the primary use of metformin or TZDs could be considered, especially in those with clinical features of insulin resistance and metabolic syndrome, but only if close follow-up of the patients is ensured. Although preliminary observational data suggests a potential benefit from insulin-sensitizing drugs, especially metformin, these medications should still probably be avoided in patients with advanced symptoms. If prescribed, they should be used cautiously, with very careful ongoing assessment of patients’ clinical status. Ultimately, insulin therapy will be required in many patients, although there are emerging concerns about its own safety in those with HF. 1. American Heart Association, Heart and Stroke Statistics—2004 Update. Dallas, Texas: American Heart Association, 2003. 2. DeFrances CJ, Podgornik MN. 2004 National Hospital Discharge Survey. Advance Data From Vital and Health Statistics. Report No. 359. Hyattsville, MD: National Center for Health Statistics, 2006. 3. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994;13:S107–S112. 4. Masoudi FA, Havranek EP, Krumholz HM. The burden of chronic congestive heart failure in older persons: magnitude and implications for policy and research. Heart Fail Rev 2002;7:9 –16. 5. Braunwald E. Shattuck lecture— cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360 –1369. 6. Graves EJ. National Hospital Discharge Survey: Annual Summary 1990. Hyattsville, MD: National Center for Health Statistics, 1992. 7. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195–1200. 8. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76 –79. 9. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974;34: 29 –34. 10. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA 1996;275: 1557–1562. 11. Gottdiener JS, Arnold AM, Aurigemma GP, Polak JF, Tracy RP, Kitzman DW, Gardin JM, Rutledge JE, Boineau RC. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628 –1637. 12. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care 2001;24:1614 –1619. 13. Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, Goff D, Leenen F, Mohiuddin S, Papademetriou V, et al. Role of

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