Diabetes mellitus and heart failure: the new scourge?

Heart failure (HF) is a major and growing public health issue. Similarly, in the western world, prevalence of type 2 diabetes mellitus (DM) is increasing at an alarming rate. It is estimated that approximately 4–5 million Americans have HF, and an additional 400,000 patients are diagnosed with HF each year [1], resulting in HF prevalence of 10 million cases in the USA by the year 2007. In 1991, the total in- and out-patient costs for HF were estimated to be US$38 billion (5.4% of the healthcare budget that year) [2]. As the population ages and the number of patients with HF increases, the burden of HF in terms of economics will increase pari passu. Despite significant advances in management and treatment, the mortality of patients with HF remains high. The Cardiac Insufficiency Bisoprolol Study (CIBIS)II demonstrated that, after a median follow-up of 15 months, the all-cause mortality was 11.8% in the group of patients receiving the β-blocker bisoprolol. In unselected populations, the outcome is even worse: data from the Medicare population demonstrated a 6-year mortality rate in HF patients of 84% in men and 77% in women.

Over recent years, the prevalence of DM, in particular type 2 diabetes, has increased significantly. The prevalence of DM in adults worldwide was estimated to be 4% in 1995, and is projected to rise to 5.4% by the year 2025 [3]. In developed countries, the prevalence of DM is higher in the elderly population (>65 years). DM is a well-recognized and important risk factor for cardiac disease [4]. The most common cardiac manifestation in diabetic patients is coronary artery disease, but DM also appears to be strongly linked to HF. Various studies have shown that approximately 15–25% of patients with HF are diabetics and it has been suggested that DM may play an important role in the pathogenesis, prognosis and response to treatment of HF [5–7]. In addition, advanced HF is related to marked insulin resistance [8]. HF itself can therefore induce the unmasking of latent diabetes in some patients.

Association

The first demonstration of an increased risk of HF in patients with DM was reported by Kannel and McGee, based on data obtained from a 20-year follow-up of the Framingham cohort, where an increased risk of HF was observed in patients with DM. Compared with nondiabetic males and females, the age-adjusted relative risks of HF for diabetic males and females were 2.20 and 5.37, respectively. Other studies have demonstrated that the incidence of HF in diabetic patients is significantly correlated with HbA1c levels. This was primarily shown in the UK Prospective Diabetes Study (UKPDS) [9]. However, there is no consensus as to the exact association of glycemic control vis a vis the duration of diabetes in contributing to the onset and progression of HF. Poor glycemic control as evidenced by high HbA1c has been shown to be a deciding factor in determining the onset of HF. Nonetheless, there are equally convincing arguments in favor of duration of diabetes being the significant predictive factor for the development of HF.

Furthermore, information on the prevalence of DM in HF populations can also be obtained from registries; the unselected nature of the patients consecutively included may provide a better estimate of the true rate of DM in patients with HF than the trial populations. In the Studies of Left Ventricular Dysfunction (SOLVD) registry, a total of 6076 patients with left ventricular dysfunction were included; among these, 1425 (23%) were classified as diabetics by the investigators [2]. In the EPICAL (Epidemiologie de l'Insuffisance Cardiaque Avancee en Lorraine) study, a registry of consecutive patients hospitalized for advanced chronic HF due to left ventricular systolic dysfunction (ejection fraction <30%), 26% of patients had a history of type 1 or 2 DM [10]. Overall, the rate of DM in HF populations is close to 20%; much higher than the 4–6% prevalence of DM observed in age-matched control populations.

Diabetic cardiomyopathy: myth or reality?

There are also data, somewhat controversially, suggesting that DM may predispose to HF development through the existence of a specific diabetic cardiomyopathy [11]. The mechanisms by which DM may induce HF independent of demonstrable coronary artery disease are unknown. Microangiopathy, metabolic factors, and fibrosis and intramyocardial microangiopathy have also been observed in patients with diabetes. Endothelial dysfunction, combined with diabetic microangiopathy, may contribute to the reduced coronary blood flow reserve observed in diabetic patients. Hyperglycemia, impaired myocardial glucose uptake and increased turnover of free fatty acids (FFAs) may all contribute to DM-related myocardial dysfunction. The deposition of advanced glycation end products (AGEs) may result in increased left ventricular stiffness and, consequently, diastolic dysfunction [12]. In summary, various mechanisms may induce a specific diabetic cardiomyopathy. Whether this diabetic cardiomyopathy alone may cause HF is unknown, but it is likely that a combination of these structural changes at the myocardial level, along with further insults such as hypertension and coronary artery disease, contribute to the development of HF.

Diabetes induced by heart failure?

HF is clearly an insulin-resistant state, possibly due to an association with higher plasma FFA concentrations [13]. It has been demonstrated that overdrive of the sympathetic nervous system in chronic heart failure (CHF), which acts to increase cardiac output by enhancing heart rhythm, stimulates lipolysis by adipose cells, producing a secondary increase in fasting plasma FFA concentrations. This suggests that CHF might be associated with a greater prevalence and incidence of noninsulin-dependent diabetes (NIDDM) [14]. Aging is also a pathophysiologic condition associated with insulin resistance and with a greater prevalence and incidence of CHF and NIDDM. As HF and DM are both highly prevalent in the aging population, it should be noted with increasing interest that these two entities play deterministic roles in the progression of one other.

Although several reports have shown that diabetes is a risk factor for the development of CHF, no large study has investigated the predictive role of CHF on the development of NIDDM. In a study undertaken recently, it was found that nearly a third of the HF population had DM, and up to 20% had undiagnosed DM. The relationship between CHF and NIDDM might be mediated by plasma FFA concentrations in CHF patients. It is widely known that plasma norepinephrine concentrations in these patients are increased and may influence the prognosis of CHF [15]. It has also been demonstrated that a moderate elevation of plasma norepinephrine concentrations significantly increases lipolysis and FFA concentrations. Thus, CHF may interfere with glucose metabolism.

From a clinical point of view, the association between CHF and NIDDM appears to be an important finding. Long-term insulin resistance and NIDDM are associated with hyperinsulinemia, which may contribute to the genesis of coronary heart disease (CHD) [16,17]. In CHF patients, CHD frequently occurs, contributing to a worsening of cardiac output. Moreover, insulin resistance is also associated with increased sodium reabsorption, which, in turn, might be responsible for a further volume overload [18]. This latter condition is usually corrected by diuretic therapy, which, on the other hand, might deteriorate glucose handling. Thus, a vicious circle could be easily created.

New studies needed

Needless to say, new studies in HF populations with careful and prospective characterization of diabetic patients are needed. They may be designed as ancillary studies of prospective randomized trials, or as part of prospective registries on HF. The multiple variables should provide information on DM type and duration, and different antidiabetic management such as insulin, oral antidiabetic treatment and/or diet alone. The signs of end-organ damage (retinopathy, neuropathy and nephropathy) would be a useful indicator of DM severity and duration. Important biologic variables related to the presence of DM or its complications (e.g., glycemia, HbA1c, serum creatinine and albuminuria) should also be prospectively determined. Finally, in view of the potential interactions between DM and CAD on HF risk and outcome, special attention should be given to prospective characterization of HF etiology (i.e., ischemic vs. nonischemic). Future studies should provide insight into temporal relationships between HF and DM, demonstrating the interesting interplay between the two entities. Larger studies are needed to determine how HF leads to the onset and progression of DM. Such studies would provide information on the characteristics of the diabetic cohort in HF populations, and the relationship between CAD and HF in diabetics. In addition, when coupled with clinical follow-up, the studies would allow prospective confirmation of the hypothesis that DM has a deleterious impact on prognosis in HF patients and could determine whether biologic markers such as HbA1c may serve as prognostic indicators in HF patients.