Chronic heart failure and type 2 diabetes mellitus: The last battle?

Type 2 diabetes, which will soon effect up to half a billion people worldwide, is a major risk factor for the development of chronic heart failure (CHF). ¹ CHF, secondary to left ventricular (LV) dysfunction, is already a major global healthcare problem. In the United States alone, 5 million individuals suffer from the debilitating symptoms associated with CHF ² and of these at least 25% will also suffer from type 2 diabetes mellitus. ³ CHF not only leads to important symptoms but also associated with a progressive and often irreversible decline in LV function leading to death due to decompensated heart failure. ⁴ CHF is also a strong risk factor for sudden cardiac death (SCD) and its devastating consequences. ⁵ Improved survival after myocardial infarction, an ageing population and the rising prevalence of type 2 diabetes means that CHF is here to stay. Add to this, the cost to healthcare systems of CHF, with direct and indirect costs reaching 30 billion dollars per annum in the United States alone, and we are confronted by a major healthcare challenge.

Over the last 20 years, our understanding of the pathophysiology of CHF has advanced substantially. An initial insult to LV function, such as a myocardial infarction or hypertension, is thought to be followed by compensatory changes in LV size and shape (known as LV remodelling), and activation of a portfolio of neurohumoral systems such as the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS). Neurohumoral activation may initially be beneficial but in the longer term becomes maladaptive, ⁶ leading to cardiac fibrosis and cardiac myocyte death. The progression of CHF often commences with impairment of LV filling known as diastolic heart failure, a scenario accounting for up to 50% of patients with CHF. ⁷ Diastolic heart failure itself has a substantial morbidity and mortality and is a hallmark of chronic type 2 diabetes.

The use of angiotensin-converting enzyme inhibitors, beta-adrenoceptor blockers, aldosterone antagonists and more recently, complex device therapies which address these maladaptions has led to a significant improvement in life expectancy in patients with CHF. ⁸ We have shown a decline in mortality in ambulant outpatients with CHF free of type 2 diabetes from 12.5% to 7.8% in the first year after referral. ⁸ This decline in mortality was substantially due to an improvement in SCD rates.

However, if a patient with CHF also suffers from type 2 diabetes, the outlook is bleak. ³ We have shown that patients with CHF and type 2 diabetes have a risk of all cause mortality double that of similar patients without diabetes. The risk of progressive heart failure death is also double, whereas the risk of SCD is three times greater in patients with CHF suffering from type 2 diabetes. To put this in context, if a patient with CHF suffers from type 2 diabetes, their risk of death at 3 years is approaching 40%. In a further study, we showed that diabetes imparts a risk of hospitalisation due to decompensated heart failure three times that of a patient without diabetes. ⁹ We also examined the characteristics of patients with CHF and type 2 diabetes and demonstrated that diabetes has deleterious effects on renal function, haemoglobin and symptoms as assessed by the New York Heart Association functional class. In addition to compounding the effects of other insults to LV function, it is also thought that diabetes itself leads to CHF with what is described as diabetic cardiomyopathy being an important entity.

So, where does this leave us in our quest to help patients suffering from the lethal combination of CHF and diabetes? Understanding the pathophysiology and progression of the disease is paramount if we are to meet this challenge. It is timely, therefore, the three articles in this issue of the journal begin to examine some of the important components of what we could describe as a new two hit syndromes ‘diabetes and chronic heart failure’.

Amaral and Okonko ¹⁰ present a contemporary view of diabetic cardiomyopathy and the important changes in cardiac metabolism occurring during type 2 diabetes. This area remains a key battlefield in the war against diabetes-related cardiac dysfunction and a potentially fruitful area for preclinical and clinical research. We may have reached the ‘saturation level’ in terms of RAAS/SNS blockade. Some studies have suggested that triple therapy with angiotensin-converting enzyme inhibitors, beta-adrenoceptor blockers and angiotensin receptor blockers may be detrimental to patients with CHF, so alternative approaches targeting cardiac metabolism have the potential to improve the quality and quantity of life.

Walker and Cubbon ¹¹ nicely review the role of diabetes in SCD and potential mechanisms and treatment targets. It is important to recognise that despite imparting a major and heightened risk of SCD in patients with CHF, diabetes is not addressed in most of the major guidelines for its treatment.

Lam ¹² discusses the role of diabetes in diastolic heart failure and reinforces the need to recognise that patients with diabetes are different and the phenotype of early LV dysfunction is changed substantially by the presence of diabetes. While our understanding of heart failure due to LV systolic dysfunction has advanced substantially over the last 2 decades, our understanding of diastolic heart failure has not improved to anywhere near the same scale. Treatment options for patients with CHF and preserved LV systolic function are limited with little evidence on which to base our treatments.

So, what do we do the next time we see a patient with type 2 diabetes and CHF? Contemporary therapies must be prescribed vigorously but we must acknowledge that this is a debilitating and lethal combination, mortality rates are high and unacceptable. Diabetes accelerates multiple aspects of the CHF phenotype increasing the risk of sudden and progressive heart failure death. New therapies are needed as these disorders increase in prevalence on a global scale. Before we try new therapies, we need to better understand the disease. The three articles in this issue of the journal distil some of the contemporary understanding of aspects of the effect of diabetes on CHF and prepare us for what is going to be a long, tough fight against a resilient and tenacious opponent.