Influence of diabetes mellitus on heart failure risk and outcome

As shown by subgroup analyses of randomized studies, a significant proportion of patients with HF are diabetics (Figure 2). In the SOLVD (Studies of Left Ventricular Dysfunction) clinical trials, 15% of patients were diabetic in the Prevention arm and 26% in the Treatment arm [17]. In the V-HeFT II (Vasodilator Heart Failure Trial II), the proportion of patients with DM was 20% [16]. More recently, Ryden et al reported the results of the ATLAS study in patients with and without DM: of the 3164 patients included in the study, 611 (19%) were taking hypoglycemic agents (oral or insulin) at baseline and were considered as having clinical DM [18]. Information on the prevalence of DM in HF populations can also be obtained from registries; the unselected nature of the patients consecutively included in registries may provide a better estimate of the true rate of DM in patients with HF. The SOLVD Registry was conducted in conjunction with the Prevention and the Treatment trials and enrolled a large cohort of patients with an ejection fraction <45% to determine the baseline characteristics of a population with left ventricular dysfunction. A total of 6076 patients with left ventricular dysfunction were included in the SOLVD Registry; among these, 1425 (23%) were classified as diabetics by the investigators [17]. In the EPICAL study [6], a registry of consecutive patients hospitalized for advanced chronic HF due to left ventricular systolic dysfunction (ejection fraction <30%), 26% of patients had an history of type I or type II DM. Overall, the rate of DM in HF populations is thus close to 20%. This rate is much higher than the 4 to 6% prevalence of DM observed in age-matched control populations [10, 11] (Figure 1).

The first demonstration of an increased risk of HF in patients with DM was reported by Kannel and McGee [11] based on data obtained from 20 years follow-up of the Framingham cohort. The incidence of HF according to sex and diabetic status is shown in Figure 3A; an increased risk of HF was observed in patients with DM. Compared with non-diabetic males and females, the age-adjusted relative risks of HF for diabetic males and females were 2.20 and 5.37, respectively [11]. In a study by Tenenbaum et al in patients with ischemic heart disease, the incidence of HF at 6 to 9-year follow-up was 35.7% in non diabetic patients, 39% in patients with impaired fasting glucose and 45.7% in diabetic patients [21]. 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) [22] (Figure 4A). These results were confirmed in a large population-based sample of 48,858 diabetic patients [23]; after adjustment for age and sex, each 1% increase in HbA1c was associated with a 12% increased risk of hospitalization for HF and/or death. These data demonstrating a strong association between HbA1c levels and HF in diabetic populations should be interpretated with caution; although poor glycemic control may be an independent risk factor for developing HF in diabetic populations, it is also conceivable that these data simply suggest a longer duration of DM, which is difficult to control, and therefore the development of HF may be more closely related to the duration of DM than to glycemic control.

Finally, although our aim was to review studies analyzing the risk of HF as a function of diabetic status, it must also be acknowledged that HF may predict future DM development; this has been demonstrated in an elderly population by Amato et al [24].

DM may be causally related to HF development by at least 3 mechanisms: due to associated comorbidities, by favoring the development of coronary atherosclerosis, or through a specific diabetic cardiomyopathy.

Associated comorbidities or risk factors may partly account for the increased risk of HF in diabetic patients. These cardiovascular risk factors such as dyslipidaemia, hypertension, hypercoagulability, obesity and inflammation are part of the insulin resistance syndrome and are, at least partly, regulated by nuclear peroxisome proliferator-activated receptors (PPARs); activation of PPAR-gamma improve insulin sensitivity and endothelial function, and lower inflammation and blood pressure [25]. In the Framingham cohort, diabetic men and women had higher blood pressures and were more obese than non-diabetics; diabetic women had, in addition, higher LDL-cholesterol values; HDL-cholesterol values were consistently lower in those with DM than in those without DM in both sexes [26]. The same observation has been reported in HF populations: In the SOLVD trials [17, 27], for example, diabetic patients were older and were more likely to have a history of hypertension than non-diabetic patients: in the treatment arm, 54% of diabetics had hypertension versus 38% of non-diabetics (p < 0.001); in the prevention arm, 53% of diabetics had hypertension versus 34% of non-diabetics (p < 0.001). Although this may in part explain the higher incidence of HF in diabetic patients, other mechanisms must also play a role. Indeed, in most of the studies discussed previously, diabetes or poor glycemic control remained significantly associated with HF after adjustment for important baseline clinical variables including age, sex, and hypertension [11, 22, 23].

The increased risk of atherosclerosis in diabetic patients may also contribute significantly to the increased risk of HF. Coronary artery disease is the underlying cause of HF in approximately two thirds of patients with left ventricular systolic dysfunction [28]. DM is associated with a markedly increased risk of coronary artery disease. In the Framingham study, the incidence of coronary artery disease was increased in diabetic subjects (Figure 3B). In UKPDS, the risk of myocardial infarction increased as a function of HbA1c levels [22] (Figure 4B). In the study by Haffner et al [29], the seven-year incidence rate of myocardial infarction in diabetic subjects without prior myocardial infarction at baseline was 20.2% versus only 3.5% in non-diabetic subjects without prior myocardial infarction at baseline (Figure 5). This increased risk of atherosclerosis in diabetic subjects has been attributed to diverse mechanisms such as endothelial dysfunction [30] or altered hemostatic factors (higher levels of fibrinogen [31], plasminogen activator-inhibitor-1 [32, 33] or VonWillebrand factor [34]), or altered platelet function [35‐38]). Molecular mechanisms linking hyperglycemia and atherosclerosis have been recently reviewed by Aronson et al [39].

There are also data to suggest that DM may predispose to HF development through the existence of a specific diabetic cardiomyopathy [40]. The exact mechanism(s) by which DM may induce HF independent of epicardial coronary artery disease is (are) unknown but several hypotheses have been advanced; these include microangiopathy, metabolic factors, and fibrosis. Intramyocardial microangiopathy has also been observed in diabetic hearts [41‐43]; combined with functional abnormalities related to endothelial dysfunction, diabetic microangiopathy may explain the reduced coronary blood flow reserve observed in diabetic patients [30, 44, 45]. Metabolic factors may also play a role in the development of myocardial dysfunction; hyperglycemia, impaired myocardial glucose uptake, and increased turnover of free fatty acids may all contribute to DM-related myocardial dysfunction (for review see [46‐48]. Finally, experimental and clinical data also point to a potential role for myocardial fibrosis in diabetic cardiomyopathy; intramyocardial accumulation of collagen is a well-demonstrated consequence of DM [49, 50]; moreover, the deposition of advanced glycation end products (AGEs) may result in increased left ventricular stiffness and consequently to diastolic dysfunction [51‐53]. In summary, various mechanisms may induce a specific diabetic cardiomyopathy. Whether this diabetic cardiomyopathy alone may cause HF is however unknown; another possibility is that these myocardial alterations related to DM may predispose to the development of HF in response to other insults such as coronary artery disease or hypertension (Figure 6). After an acute myocardial infarction, decreased compensatory responses of non-infarcted area have been described in diabetic patients [54‐56]. Similarly, a synergistic effect may exist between DM and hypertension for the development of myocardial fibrosis [57].

Risk stratification is an important step in the management of patients with HF; high risk patients may indeed benefit from more aggressive therapeutic strategies. Parameters such as New York Heart Association (NHYA) class, maximal VO2, left and right ventricular ejection fraction have been identified as powerful predictors of clinical outcome in HF patients [58‐62].

The first suggestion that DM may be a predictor of poor clinical outcome in HF patients came in a report from Shindler et al [17]. A subgroup analysis of the SOLVD trials (combining the Prevention and the Treatment trials), showed that both all cause mortality and cardiovascular mortality at a mean follow-up of 3 years were significantly higher in diabetic patients than in non-diabetic patients (Figure 7). Multivariate analysis was used to assess the significance of DM as an independent predictor of outcome. After adjusting for important baseline variables such as age, sex, NYHA classification, or left ventricular ejection fraction, DM remained a significant predictor of clinical outcome in both the Prevention and the Treatment trials. More recently, Dries et al reanalyzed the SOLVD database to determine whether DM would have a different impact on clinical outcome in ischemic versus non-ischemic HF [27]. After adjustment for baseline variables, they found that DM was associated with an increased risk for all-cause mortality in patients with ischemic HF (RR 1.37, 95% CI 1.21 to 1.55), but not in patients with non-ischemic HF (RR 0.98, 95% CI 0.76 to 1.32) (Figure 8). Moreover, they suggested that the increased mortality in patients with ischemic HF compared with non-ischemic HF (reviewed in [63]) may be limited to the diabetic subgroup. If these findings are confirmed in independent studies, at least two explanations may account for the negative interaction between DM and the ischemic etiology of heart failure. Firstly, diabetic HF patients may have a higher risk of coronary plaque rupture and thrombosis [29, 64]; recurrent myocardial infarction is a major cause of death in patients with ischemic HF [65]; in addition, non fatal myocardial infarction may further deteriorate left ventricular function in patients with ischemic HF. Furthermore, the presence of various components of a specific diabetic cardiomyopathy such as impaired myocardial glucose uptake may be especially deleterious in patients with ischemic HF [66‐69].

Most of the data on HF in diabetics summarized above have been obtained from post-hoc analysis of randomized studies or registries and as such should be interpreted with caution. In the SOLVD trial for example, the diagnosis of DM was solely based on self-reporting by the patient or on documentation in the patient's medical records and data on the duration of DM, severity of DM, and medications used to treat DM were not available. Similarly, in SOLVD, the definition of the etiology of HF (i.e., ischemic versus non ischemic) was based on the judgement of the investigators at the participating sites after reviewing all available information and did not routinely include cardiac catheterization or non-invasive testing.

New studies in HF populations with careful and prospective characterization of diabetic patients are needed; these studies may be designed either as ancillary studies of prospective randomized trials or as part of prospective registries on HF. The variables recorded should provide information on DM type and duration, and antidiabetic management (diet alone, oral hypoglycemic drugs, insulin). The presence/absence of signs of end-organ damage (retinopathy, neuropathy, nephropathy) would be a useful indicator of DM severity and duration and should also be recorded. Important biological variables related to the presence of DM or its complications (glycemia, HbA1c, serum creatinine, albuminuria, etc.) 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 versus non ischemic).

Such studies would provide information on the characteristics of the diabetic cohort in HF populations and on the relationship between CAD and HF in diabetics. In addition, when coupled with clinical follow-up, these studies would allow propective confirmation of the hypothesis that DM has a deleterious impact on prognosis in HF patients and could determine whether biological markers such as HbA1c may serve as prognostic indicators in HF patients.

Post-hoc analyses of large randomized studies have shown that the beneficial effect of conventional HF treatment is maintained in the subgroup of diabetic patients. This has been conclusively demonstrated for the two classes of drugs, regarded as cornerstone treatments, namely ACE inhibitors and beta-blockers. In the SOLVD prevention and Treatment trials [70, 71], patients were randomized to either placebo or the ACE inhibitor enalapril; the efficacy was similar in diabetic and non-diabetic patients (Figure 7). There was no interaction between diabetic status and drug assignement with respect to the study endpoints [17]. In the ATLAS trial [4], patients were randomized to high or low doses lisinopril. The relative risk reduction in mortality for high-dose vs low-dose lisinopril was 14% for patients with diabetes mellitus and 6% for those without [18]; high-dose lisinopril was as effective in reducing hospitalizations for heart failure in diabetics as in non-diabetics (21% vs 24%) [18]. In ACE inhibitor-intolerant HF patients, the available literature supports the use of angiotensin II blockers [72]. In the CIBIS II trial, patients were randomized to placebo or the beta-blocker bisoprolol [3]; the efficacy was similar in diabetic and non-diabetic patients with respect to all mortality/morbidity endpoints [73]. For example, the relative risk (bisoprolol vs placebo) for mortality was 0.81 (95% CI 0.51–1.28) in diabetics and 0.66 (95% CI 0.54–0.81) in non-diabetics; the heterogeneity test for interaction was not statistically significant. Although these results were obtained from post-hoc analyses and as such have limitations from a methodological standpoint, the well-demonstrated benefits of ACE inhibitors and beta-blockers appears to be maintained in the diabetic subgroups. In addition, a similar relative risk reduction when applied to a high risk population such as diabetic HF patients will automatically translate into a major benefit in term of reduction in the absolute number of events.

In addition to ACE inhibitors and beta-blockers, patients with ischemic HF also benefit from secondary prevention with agents demonstrated to reduce atherosclerosis progression and to diminish the rate of acute coronary events. The use of antiplatelet agents was associated with an improvement in survival in patients with symptomatic or asymptomatic left ventricular dysfunction in the SOLVD study [74]. Statin therapy has been associated with an improved outcome in patients with coronary artery disease and left ventricular dysfunction [75]; moreover, in the 4S study, administration of simvastatin reduced the occurrence of HF [76]. Although no data are available concerning diabetic patients with ischemic HF, the demonstrated benefit of antiplatelet and statin therapy in diabetic patients with coronary artery disease [77‐79] clearly supports a strategy of aggressive secondary prevention in diabetic patients with ischemic HF.

Besides medical treatment for HF and the optimal use of secondary prevention strategies in cases with an ischemic origin, there are still important unanswered questions that will require further studies. For many diabetic patients with ischemic HF, the decision to revascularize and the choice of the revascularization technique are key issues. Moreover, the impact of DM treatment on HF outcome also needs to be considered.