Number 25, 2004
Heart failure in diabetes

Management of chronic heart failure in patients with type 2 diabetes: the importance of an integrated approach

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Vivienne A. Ezzat, Mark T. Kearney
Cardiovascular Division, King's College, London
Correspondence: Vivienne A. Ezzat, Department of Cardiology, GKT School of Medicine, London SE5 9PJ.
Tel: +44 (0)2073463256, fax: +44 (0)2073464771, e-mail: vivienne.ezzat@kcl.ac.uk

Introduction
Chronic heart failure (CHF) is a complex disorder that has a prognosis worse than that of many soft tissue tumors [1]. The most frequent modes of death in patients with CHF are sudden (predominantly arrhythmic) death and a progressive decline in left ventricular function leading to decompensated heart failure [2]. A range of disorders can lead to CHF, the most frequent being ischemic heart disease and hypertension [3]. CHF is characterized by abnormalities of cardiac size [4], electrical activation [5], and renal function [2], increased activity of the sympathetic and renin–angiotensin systems [6], inflammation [7], endothelial dysfunction [8], and oxidative stress [9]. These abnormalities are believed to contribute to the poor prognosis seen in patients with CHF. More recently, it has emerged that CHF is also associated with substantial abnormalities of glucose homeostasis, including cardiac [10] and whole-body insulin resistance [11].
It is now well established that up to 25% of patients with CHF are diabetic [12]. This is not surprising, as type 2 (noninsulin-dependent) diabetes is characterized by accelerated coronary artery disease and hypertension, and is also associated with systemic inflammation [13], increased activity of the sympathetic nervous and renin–angiotensin systems [14], endothelial dysfunction [15], and oxidative stress [16]. The association between diabetes and CHF was reported almost 30 years ago. Data from the Framingham study demonstrated that the increased risk of CHF in patients with diabetes persisted after adjustment for other risk factors, including coronary artery disease, age, and hypertension [17]. Subsequently, it has been demonstrated that not only is CHF more common in patients with diabetes, but morbidity and mortality associated with CHF are worse in diabetic than in nondiabetic patients [18].

Chronic heart failure in diabetes
The management of the diabetic patient with CHF requires an understanding of the pathophysiological mechanisms underlying the association between the two disorders (Table I). The coexistence of myocardial ischemia, hypertension, and a specific diabetic cardiomyopathy has been termed the “cardiotoxic triad” [19]; each process is believed to contribute independently and cumulatively to the biochemical, anatomical, and functional alterations in cardiac cells and tissues that impair overall cardiac function. The factors leading to diabetic cardiomyopathy are unclear, but a number of pathophysiological processes, including those mentioned above, may contribute. The prevention and treatment of CHF in diabetes should be directed towards these abnormal mechanisms and their stimuli, principally by the improvement of glycemic control, aggressive management of coronary artery disease and its risk factors, including hypertension, and neurohumoral blockade.

Table 1. Pathophysiological similarities between diabetes and chronic heart failure.

Contemporary treatments for chronic heart failure in patients with diabetes
The use of angiotensin-converting enzyme inhibitors (ACEIs) and β-adrenoceptor blockers is now clearly established as appropriate for all patients with symptomatic CHF [20], and the same large meta-analysis [20] also demonstrated the benefits of ACEIs and β-blockers in the management of CHF in patients with diabetes. This meta-analysis analyzed data from the 12 largest randomized clinical trials of ACEIs and β-blockers in CHF in order to ensure sufficient statistical power to detect differences in effects of treatment. This included more than 80% of all patients enrolled in any randomized controlled trial of ACEIs or β-blockers that was of at least 12 weeks duration. Both the treatment and prevention arms of the Studies Of Left Ventricular Dysfunction (SOLVD) [12,21] were included in the analysis – that is, symptomatic and asymptomatic patients with an ejection fraction no greater than 0.35. Between them, these trials used five different ACEIs and three different β-blockers. The results demonstrated the benefits of the use of both classes of drug in diabetic patients with CHF. In the case of ACEIs, identical reductions in mortality were achieved in patients with diabetes and those without; in contrast, although the relative risk reduction in patients treated with β-blockers was less in those with diabetes than in those without, because the absolute risk of mortality is greater in diabetic patients, it was estimated that the absolute risk reduction in diabetic patients was at least equal to, if not greater than, that in nondiabetic patients [20].
These results were confirmed in another recent meta-analysis, which also assessed the prognostic benefit of β-blockers in both diabetic and nondiabetic patients [22]. Unless there is a contraindication or inability to tolerate treatment, standard care for all patients with CHF, regardless of its severity or etiology, should include an ACEI and a β-blocker [23]. Combination therapy of ACEIs and β-blockers is now well established as standard practice in the major guidelines [24]. Because of the compelling body of evidence that exists supporting their use, if tolerated, combination therapies should be given to all diabetic patients with CHF. If combination treatment is not tolerated, candesartan is a useful alternative, according to the recent Candesartan in Heart failure – Assessment of Reduction in Mortality and Morbidity (CHARM) study [25].
Adjuvant treatment with the aldosterone antagonist, spironolactone, has also been shown to be prognostically beneficial in patients with severe CHF [26], although the original Randomized Aldactone Evaluation Study (RALES) trial did not report separate data for patients with diabetes. A more recent study, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) evaluated a subgroup of patients with diabetes and found them to have a mortality benefit from aldosterone blockade similar to that of their nondiabetic counterparts [27].

Prevention of chronic heart failure in diabetes
Successful treatment of established CHF is a pressing concern, but the advantages of preventative strategies are also clear. The prevention of CHF in diabetes relies on the aggressive management of coronary artery disease and its risk factors, particularly hypertension. Several trials have demonstrated that the drugs used for the treatment of these conditions, especially ACEIs, not only attenuate these disease processes and the microvascular complications of diabetes, but also decrease the incidence of CHF in previously asymptomatic individuals [22,28].
In addition, there are now many studies that promote the tight control of diabetes itself as means of directly affecting the progression of CHF. The results of the UK Prospective Diabetes Study (UKPDS) 35 suggested that the incidence of CHF was associated with poor glycemic control [29]. Further studies have confirmed that increased glycated hemoglobin is an independent predictor of CHF risk, with no apparent threshold value and no differences observed in relation to CHF pathogenesis or hypertension status [30,31]. Although it is possible that poor glycemic control may reflect inadequately focused physician care or poor compliance with treatment (extending to blood pressure and lipid-decreasing treatments), in view of the emergence of the phenomenon of diabetic cardiomyopathy it now seems likely that prolonged periods of hyperglycemia inflict direct myocardial damage that may be avoided by more strenuous glycemic control [31].

Treatment and prevention of diabetes in chronic heart failure
Diabetes mellitus is a multisystem disorder. Aggressive management of this condition through lifestyle modifications and pharmaceutical intervention is essential to prevent its consequences, regardless of duration of illness or comorbidities. The prevention of microvascular and other complications through tight glycemic control is well established; prevention of the development of diabetes itself may also be possible. Trials assessing the effects of ACEIs [32,33], angiotensin II receptors blockers [34], and some β-blockers [35] have all shown a decreased incidence of diabetes in patients with CHF, in keeping with the concept of diabetes as a cardiovascular disease. The thiazolidinediones are another group of drugs with antidiabetic and insulin-sensitizing properties, which may also have beneficial cardiovascular effects [36]; however, their use has been hampered by associated liver toxicity, weight gain, and a significantly increased risk of edema [37,38]. In view of the fact that clinical trials assessing the safety and efficacy of thiazolidinediones have excluded patients with moderate to severe limitation of physical activity from CHF, the American Heart and Diabetes Associations have issued a consensus statement asserting that, for the time being at least, their use is contraindicated in individuals with New York Heart Association (NYHA) class III or IV symptoms [38]. Thiazolidinediones may, however, be initiated in patients with diabetes who are known to have a depressed ejection fraction (eg, less than 0.40) but do not have symptoms or signs of CHF, and with caution in patients with NYHA class I or II symptoms. These patients should be monitored closely for weight gain and edema and if, after investigation into other possible causes, the thiazolidinedione is believed to have precipitated these effects, it should be discontinued [38].

Conclusion
The presence of diabetes makes the treatment of CHF even more complex, and a focused, individualized treatment package is therefore important. The tenets of practice remain the same: evidence-based treatments for CHF include ACEIs, β-blockers, and aldosterone antagonists; tight glycemic control is essential to minimize the risks of diabetic complications; aggressive management of hypertension and coronary artery disease is paramount to alleviate the potential burden of CHF to both the individual and the wider community. Evidence for the use of angiotensin II receptor blockers as an alternative to ACEIs is gathering, and another promising avenue appears to be the development of drugs aimed at increasing insulin sensitivity. Health care professionals are under an obligation on an individual level to personalize patient care in order to ensure optimal compliance and benefit, and on a national and international level to implement strategies allowing adequate care and access to all. ▪

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REFERENCES

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