Influence of diabetes mellitus on heart failure risk and outcome
© Bauters et al; licensee BioMed Central Ltd. 2003
Received: 6 December 2002
Accepted: 8 January 2003
Published: 8 January 2003
Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure.
The studies linking diabetes mellitus (DM) with heart failure (HF)
The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy.
Treatment of heart failure in diabetic patients
The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients.
Heart failure (HF) is a major and growing public health issue. It is estimated that approximately 4 to 5 million Americans have HF, and that an additional 400,000 patients are diagnosed with HF each year . HF prevalence is expected to reach 10 million cases in the U.S. by the year 2007 .
In spite of significant advances in management and treatment, the mortality of patients with HF remains high. In the CIBIS II (Cardiac Insufficiency Bisoprolol Study II) trial, after a median follow-up of 15 months, the all cause mortality was 11.8% in the group of patients receiving the beta-blocker bisoprolol . In the ATLAS (Assessment of Treatment with Lisinopril And Survival) trial, after a median follow-up of 46 months, the all cause mortality was 42% in the group of patients randomized to high dose of the angiotensin converting enzyme (ACE) inhibitor lisinopril . 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 . In the EPICAL (Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine) observational study, the all cause one-year mortality was 35.4% .
HF is also a major cause of morbidity; chronic HF results in almost 1 million hospitalizations each year in the U.S. . This has a major impact on health care expenditure. In 1991, the total inpatient and outpatient costs for HF were estimated to be $38 billion (5.4% of the health care budget that year) . As the population ages and the number of patients with HF increases, the economic burden of HF will inevitably increase .
While the most common cardiac manifestation in diabetic patients is coronary artery disease, DM also appears to be strongly linked to HF. Approximately 15 to 25% of patients with HF are diabetics [6, 16–18] and it has been suggested that DM may play an important role in the pathogenesis, prognosis, and response to treatment of HF . In addition, advanced HF is related to marked insulin resistance . The aim of this paper will be to summarize and discuss the available literature linking DM with HF, and to address the issue of the optimal treatment for diabetic patients with HF.
The studies linking DM with HF
The epidemiological evidence linking DM with HF
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 .
The mechanisms of HF in diabetic patients
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 . 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 . 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].
Determining diabetic status: an additional prognostic indicator in heart failure patients?
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 links between DM and HF: the need for new studies
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.
Treatment of HF in diabetic 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 . In the ATLAS trial , 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 ; high-dose lisinopril was as effective in reducing hospitalizations for heart failure in diabetics as in non-diabetics (21% vs 24%) . In ACE inhibitor-intolerant HF patients, the available literature supports the use of angiotensin II blockers . In the CIBIS II trial, patients were randomized to placebo or the beta-blocker bisoprolol ; the efficacy was similar in diabetic and non-diabetic patients with respect to all mortality/morbidity endpoints . 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 . Statin therapy has been associated with an improved outcome in patients with coronary artery disease and left ventricular dysfunction ; moreover, in the 4S study, administration of simvastatin reduced the occurrence of HF . 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.
The need for new strategies/studies
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.
Future studies will have to clarify the role of revascularization in diabetic patients with ischemic HF. It will be important to determine if revascularization in diabetics carries any advantage over medical therapy, a question that is currently under evaluation in the BARI 2D study (although not specifically in HF patients). If it is shown that revascularization improves prognosis, it would be appropriate to aggressively exclude an ischemic origin in diabetic HF patients.
The impact of DM treatment in HF patients should also be considered. At the present time, it has not been determined whether improved metabolic control might favorably influence the outcome of diabetic HF patients and large clinical studies are urgently needed to provide an answer to this important question. The need for such studies is underlined by preliminary data suggesting that strict metabolic control may reverse to some extent the consequence of diabetic cardiomyopathy . Such studies would also determine whether the preferred treatment for DM should be an insulin-sensitizing regimen or an insulin-providing regimen. Lifestyle interventions  (including dietary changes, increased physical activity and weigth loss) could also be specifically tested in diabetic HF patients. Finally, taking into account the possible interaction between HF etiology and the impact of metabolic control, prespecified subgroup analysis (non ischemic HF vs ischemic HF) would appear mandatory.
In summary, HF in diabetic patients is an important health problem. Approximately 20 to 25% of HF patients are diabetics. The review of the available literature suggests that the diabetic subgroup of HF patients deserves special consideration: at the present time, the natural history of HF in diabetic patients appears different with a higher mortality especially in the case of ischemic HF; moreover, although conventional HF treatments appear to be uniformly beneficial, in the case of ischemic HF the choice of the revascularization technique may differ according to diabetic status. Thus, an early and precise characterization of diabetic status should be encouraged not only in future clinical trials but also in everyday management of HF patients.
The present review underscores the need for new studies to help unravel the interplay between diabetes, atherosclerosis, and heart failure and to determine the specific role of currently available and novel therapies in the diabetic population.
Finally, a better understanding of the mechanisms leading to HF in diabetic patients may also help to design preventive strategies. At the present time, the well-documented beneficial effects of primary prevention of CAD in diabetics supports the preventive use of drugs such as statins  and ACE inhibitors ; other aspects such as for example careful blood pressure control  may also have a tremendous impact on the prevention of HF in this high risk population.
Angiotensin converting enzyme
Advanced Glycation End products
Assessment of Treatment with Lisinopril and Survival trial
Bypass Angioplasty Revascularization Investigation
Coronary Artery Bypass Grafting
- CIBIS II:
Cardiac Insufficiency Bisoprolol Study II
Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine
New York Heart Association
Percutaneous Transluminal Coronary Angioplasty
Studies of Left Ventricular Dysfunction
UK Prospective Diabetes Study
- V-HeFT II:
Vasodilator Heart Failure Trial II
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