European Heart Journal

European Heart Journal Advance Access originally published online on April 18, 2008
European Heart Journal 2008 29(10):1224-1240; doi:10.1093/eurheartj/ehn156

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Diabetes, left ventricular systolic dysfunction, and chronic heart failure

Michael R. MacDonald^1,*, Mark C. Petrie¹, Nathaniel M. Hawkins², John R. Petrie³, Miles Fisher¹, Robert McKelvie⁴, David Aguilar⁵, Henry Krum⁶ and John J.V. McMurray⁷

¹ Glasgow Royal Infirmary, Glasgow, UK
² Aintree Cardiac Centre, Liverpool, UK
³ University of Dundee, Dundee, UK
⁴ McMaster University, Hamilton, Ontario, Canada
⁵ Baylor College of Medicine, Houston, TX, USA
⁶ Monash University/Alfred Hospital, Melbourne, Australia
⁷ Western Infirmary of Glasgow, Glasgow, UK

Received 14 December 2007; revised 3 March 2008; accepted 20 March 2008; online publish-ahead-of-print 18 April 2008.

^* Corresponding author: Email: michaelrossmacdonald{at}yahoo.com

	Abstract

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Chronic heart failure (HF) and diabetes mellitus (DM) commonly coexist. Each condition increases the likelihood of developing the other, and when they occur together in the same patient the risk of morbidity and mortality increases markedly. We discuss the epidemiological overlap and consider the complex patho-physiological pathways linking the two diseases. The treatment of each condition is made more problematic by the presence of the other. We review the evidence-based treatment strategies and discuss the common problems faced by physicians when treating patients with both conditions. This article forms a comprehensive overview of a fascinating intersection between two common diseases.

Key Words: Diabetes • Heart failure

	Introduction

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Chronic heart failure (HF) and diabetes (DM) are both common (and getting more so) and often occur in the same patients. DM is, however, managed by diabetologists and HF by cardiologists, with few physicians specializing in both areas. Yet there are difficulties managing these two conditions when they coexist. For example, many of the drugs used to control hyperglycaemia are relatively ‘contraindicated’ in HF. Here we review the epidemiological overlap, patho-physiological interrelationships, and clinical interactions between these two conditions.

	Methods

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Search strategy
We searched English language publications in Medline from 1966 to January 2008. The search combined terms related to diabetes (‘diabetes,’ ‘insulin resistance,’ ‘dysglycaemia,’ ‘hyperglycaemia,’ ‘glucose tolerance,’) with terms related to HF (‘heart failure,’ ‘ventricular dysfunction,’ ‘systolic dysfunction,’ ‘myocardial failure,’ ‘cardiac failure’) using Boolean operators and database-specific syntax. A hand search of references identified from review articles and meta-analyses was also conducted.

Study selection
Studies that included data on the epidemiology of both diabetes and HF were included.

To address the efficacy of HF treatments in diabetics we examined randomized controlled trials of HF therapies with mortality as an endpoint, only including trials specifying treatment effect in the diabetes subgroup. Similar criteria were used to assess the efficacy of diabetic treatments in patients with HF.

Data collection and outcome measures
Reviewers used standardized data collection forms to extract data from studies for trial design, patients’ characteristics, interventions, and outcomes. The accuracy of extracted data was verified by comparing collection forms. Endpoints were documented according to the definitions used by the authors of each study.

	Epidemiology

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Prevalence of heart failure in diabetics
Population studies
The prevalence of HF in the general population is 1–4% depending on age^1,2 (and around 0.3–0.5% of the general population have both HF and DM^1,3), whereas ~12% of subjects with DM have HF, rising to 22% in those >64 years.^1,4

Clinical trials
Remarkably, large trials in DM either excluded patients with HF (e.g. UKPDS, DIABHYCAR, DCCT) or did not report HF as a co-morbidity (e.g. FIELD, CARDS, PROACTIVE).

Prevalence of diabetes mellitus in patients with heart failure
Population studies
The prevalence of DM in the general population is 4–7%.^1,5 In individuals with left ventricular systolic dysfunction (LVSD) it varies from 6–25% (Table 1) and in subjects with symptomatic HF from 12–30%, and its prevalence is on the increase (Table 2).

View this table: [in this window] [in a new window]   Table 1 The prevalence of DM in populations with and without LVSD

 

View this table: [in this window] [in a new window]   Table 2 The prevalence of DM in general populations with and without HF

 
Hospitalized patients
In patients hospitalized with HF, the prevalence of DM is greater, i.e. up to 40%.^6,7

Ethnic subgroups
Whether or not the prevalence of DM in HF varies according to ethnic group is uncertain.^6,7

Clinial trials
The prevalence of DM ranges from 11–41%, although these patients tend to be highly selected, i.e. younger and have less co-morbidity (and exclusion of certain co-morbidities, e.g. renal dysfunction, may indirectly exclude individuals with DM).^8,9

Incidence of heart failure in diabetics
Population studies
DM is an independent risk factor for the development of HF.^1,10–12 In the Framingham study (between the ages 45–74), the risk of HF was two-fold higher in men and five-fold higher in women with diabetes.¹² This effect was more apparent in the younger subjects, e.g. under 65 years, where the risk of developing HF was four- and eight-fold higher in men and women, respectively, with diabetes. In NHANES and the Cardiovascular Health Study, DM was an independent risk factor for HF with hazard ratios (HR) of 1.85 (1.51–2.28) and 1.74 (1.38–2.19), respectively.^10,11 In Iceland, the age-adjusted odds ratio (OR) for development of HF was 2.8 (2.2–3.6) in diabetics, compared with non-diabetics.¹

Additional studies have identified DM as an independent risk factor for HF, e.g. among 9951 US diabetics, the incidence of HF was 30.9/1000 person-years compared with 12.4/1000 in matched non-diabetics.¹³ The incidence of HF in a group of elderly American nursing home residents with DM was twice that of those without DM (121 vs. 62 cases/1000-person years).¹⁴ This high incidence rate in the elderly was confirmed by a large US cohort study in 115 803 patients with DM over 64 years old (126 cases of incident HF/1000 person-years).⁴

Clinical trials
The incidence of HF was lower in the younger, selected, patients in trials, e.g. UKPDS, which included patients newly diagnosed DM (mean age of 53), the incidence was 2.3/1000 person-years for those with an HbA1c <6% and 11.9/1000 person-years for those with an HbA1c >10%.¹⁵ In MICRO-HOPE the placebo-group incidence of HF was 13.3% over 4.5 years.¹⁶

Incidence of diabetes mellitus in patients with heart failure
Population studies
In the only non-clinical trial population study, the 3-year incidence of new-onset DM was 28.8% in elderly Italians with HF, compared with 18.3% in matched controls without HF.¹⁷

Clinical trials
In the placebo arm of the CHARM programme, 7.4% of patients with HF developed DM over a median of 3.1 years.¹⁸ In a single-centre substudy of SOLVD treatment, 5.9% of patients developed DM over a mean of 2.9 years.¹⁹ In the Bezafibrate Infarction Prevention Study (BIPS), the incidence of DM in those without HF was 13% (over a mean of 7.7 years), increasing to 15 and 20% in NYHA class II and III HF, respectively (P = 0.05 for trend).²⁰

	Risk of developing heart failure in diabetics

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
A number of independent risk factors for the development of HF have been identified in diabetics, including higher HbA1c^13,15,21,22 and increased body mass index (BMI).^13,23 For every 1% reduction in HbA1c in UKPDS the risk of HF fell by 16%.¹⁵ A 2.5 unit increase in BMI increases the risk of HF by 12%.¹³ Other independent risk factors for HF in diabetics are increasing age,^4,13,22 coronary heart disease (CHD),^4,13,23 use of insulin,¹³ end-stage renal disease,^4,13 nephropathy,⁴ proteinuria and albuminuria,^22–24 retinopathy,^4,25 and duration of DM.¹³ The two most common risk factors for the development of HF are CHD and hypertension, both of which are more prevalent in diabetics.

	Risk of developing diabetes mellitus in patients with heart failure

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Only symptomatic severity has been shown to be a predictor of DM in patients with HF. In a subgroup analysis of 630 patients with HF of ischaemic aetiology in BIPS, NYHA class III was an independent risk factor for DM while NYHA class II was not.²⁰ Similarly, in an Italian longitudinal study of 1339 elderly patients, the association between HF and DM was stronger in patients in NYHA functional classes III/IV than in classes I/II.¹⁷

	Diabetes and mortality in patients with heart failure

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
DM is an independent predictor of mortality in population studies of HF (Table 3) and in HF clinical trials (Table 4).

View this table: [in this window] [in a new window]   Table 3 DM and mortality in HF: non-clinical trial populations

 

View this table: [in this window] [in a new window]   Table 4 DM and mortality in HF: clinical trial populations

 
Interaction with aetiology?
In the SOLVD, BEST, and DIG studies, DM was an independent predictor of mortality in patients with HF (Table 4). In all three trials the increased risk appeared confined to patients with HF of ischaemic aetiology. Though also observed in a French HF clinic population,²⁶ this is not a consistent finding. Both DIAMOND-HF and CHARM reported that DM was an independent predictor of mortality regardless of HF aetiology. Conversely, an American population study found the increased mortality risk of DM was confined to patients with HF of non-ischaemic aetiology.²⁷ This variability is likely explained in part by the under-diagnosis of CHD and the disparate nature of the populations.

Mode of death
Both the SOLVD and BEST trials identified DM as an independent risk factor for death specifically from pump failure, with HR of 1.44 (1.18–1.76, P = 0.0003) and 1.50 (1.15–1.94, P = 0.002), respectively.^28,29

Interaction with gender
A subgroup analysis of the Framingham study suggested that DM predicted mortality in women but not men with HF (Table 3). However, only a small number of patients had both DM and HF and a Scottish³⁰ population study and DIAMOND-HF³¹ did not confirm this interaction.

HbA1c
One observational study of 123 diabetics with advanced HF compared the outcome of patients with an HbA1c 7% against those with HbA1c >7%.³² Patients with HbA1c 7% had an increased 2-year mortality rate (75 vs. 50%). HbA1c was a significant independent predictor of mortality: HR 2.3 (1.0–5.2). Low HbA1c probably reflects cachexia in the sickest patients, rather than increased mortality with improved glycaemic control.

	Heart failure and mortality in diabetics

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Patients with DM that develop HF have a markedly increased mortality. Diabetics in the DIABHYCAR study who developed HF had a 12-fold higher annual mortality than those not developing HF (36.4 vs. 3.2%).²² In a large American cohort study of elderly diabetic patients, those developing HF had a 5-year survival rate of 12.5%, compared with 80% in those not developing HF.⁴

	Diabetes and heart failure: morbidity

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Incidence of first hospitalization due to heart failure in patients with diabetes mellitus
Diabetics are frequently hospitalized for HF. In an American cohort of 48 000 diabetic patients, incidence of hospitalization due to HF was 4.5 vs. 9.2/1000 person-years for those with an HbA1c <7 and >10%, respectively.²¹ A similar incidence was observed in diabetics with albuminuria in DIABHYCAR (10/1000 person-years).²² HF hospitalization incidence is even higher in patients with DM and additional cardiovascular risk factors. Placebo-group patients in LIFE and RENAAL had an incidence of 19 and 54/1000 person-years, respectively.²³

Hospitalization due to heart failure in patients with both diabetes mellitus and heart failure
Numerous studies suggest DM is associated with increased risk of HF hospitalization in patients with established HF. In the BEST trial, DM was an independent predictor of HF hospitalization [relative risk, RR, 1.16 (1.02–1.32, P = 0.027)].²⁸ RESOLVD³³ and MERIT-HF³⁴ confirmed this association.³⁵ In the latter trial, patients with HF and DM had a 1 year rate of hospitalization of 31 compared with 24% for patients without DM [RR 1.28 (1.11–1.49, P =0 .0009)]. Diabetics in the ATLAS trial had more admissions to hospital than non-diabetics.³⁶ Over a median of 3.8 years, diabetics had an average of three hospitalizations (due to any cause) with a mean of 21.4 days in hospital compared with 2.2 hospitalizations with a mean of 17.7 days in hospital for patients without DM.

Importance of glycaemic control
A retrospective case-note review of 100 diabetics admitted with HF, found that the admission blood glucose concentration and the in-hospital glycaemic control strongly correlated with duration of hospitalization.³⁷

	Diabetes and severity of heart failure

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
In a substudy of RESOLVD, diabetics had reduced functional capacity and more severe HF symptoms.³³ Other studies have demonstrated that diabetics with HF have a reduced 6 minute walk time,³⁸ exercise capacity,³⁹ and pulmonary function in comparison to non-diabetics with HF.⁴⁰ A retrospective analysis of SOLVD-Prevention demonstrated that diabetics were more likely to progress to symptomatic HF than non-diabetics,⁴¹ although this enhanced risk seemed to be confined to patients with ischaemic aetiology.

	Heart failure and pre-diabetic abnormalities of insulin and glucose metabolism

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Risk of developing heart failure
Hyperinsulinaemia, impaired glucose tolerance, and insulin resistance are risk factors for developing HF, independent of DM and other established risk factors.⁴²

Prevalence in heart failure
Dysglycaemia, in the absence of DM, is common in HF.^33,43,44 In a substudy of RESOLVD, involving 663 patients with NYHA class II–IV HF, 27% had documented DM.³³ Of the ‘non-diabetics’, 11% met diagnostic criteria for DM, 12% had impaired fasting glucose (IFG) and 34% had elevated plasma insulin concentrations and insulin resistance (Figure 1).

View larger version (12K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Patients without DM in RESOLVD.33 FPG, fasting plasma glucose, PI, plasma insulin

 
Symptoms
The presence of insulin resistance, hyperinsulinaemia, or IFG are associated with lower functional capacity and more severe symptoms.³³ Reduced peak VO2 is an independent predictor of insulin resistance in non-diabetic patients with HF.⁴⁴

Prognosis
Insulin resistance, in the absence of DM, is an independent prognostic indicator in HF.⁴⁵ Similarly, an admission blood glucose of >10 mmol/L is a predictor of mortality, independent of DM, in patients with a first hospitalization for HF.⁴⁶

	Why do patients with heart failure develop insulin resistance?

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Insulin resistance occurs in HF of both ischaemic and non-ischaemic aetiology,^43,44 but why it is so prevalent is not fully understood. Many mechanisms have been suggested, including sympathetic nervous system (SNS) overactivity, sedentary lifestyle, endothelial dysfunction, loss of skeletal muscle mass, and influence of cytokines such as TNF-alpha and leptin on peripheral insulin sensitivity.⁴⁷

Patients with HF have persistent activation of their SNS.⁴⁸ Excessive activation of the SNS may lead to insulin resistance. The complex interactions between the SNS and glucose metabolism are briefly summarized in Figure 2. In healthy subjects, acute SNS activation reduces insulin-induced stimulation of muscle glucose uptake by 25%.⁴⁸ Furthermore, stimulation of β-receptors increases lipolysis resulting in raised plasma free fatty acid (FFA) levels.⁴⁹ FFAs impair insulin-mediated glucose disposal in human skeletal muscle⁵⁰ and can stimulate hepatic gluconeogenesis,⁵¹ further potentiating hyperglycaemia. Catecholamines have also been shown to inhibit pancreatic insulin secretion in humans and stimulate hepatic gluconeogenesis and glycogenolysis, further worsening hyperglycaemia.⁵²

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 The SNS and abnormalities of glucose and insulin. SNS, sympathetic nervous system, FFA, free fatty acid

 

	Why do diabetics develop heart failure?

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Several mechanisms may explain the association between DM and HF:

• Risk factors for HF are common in diabetics (for example hypertension and CHD).
  
• DM may have a direct effect on the myocardium.
  
• DM may activate neurohormonal systems.
  

Rarely DM and HF are caused by a multi-system disorder (e.g. hemochromatosis).

A complete review of the molecular processes occurring in the heart, kidneys and vasculature of patients with DM is outwith the scope of this article and has been reviewed in detail elsewhere.⁵³ We have, however, illustrated some of the more important processes in Figure 3 and reviewed them online (see Supplementary material online).

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3 Proposed mechanisms of cardiac dysfunction in diabetics. CPT-1, carnitine palmitoyltransferase-1, SERCA 2a, sarcoplasmic endoplasmic-reticulumCa2+-ATPase2a

 

	Reducing the risk of diabetes mellitus in patients with heart failure

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Lifestyle changes
Trials showing that weight reduction and increased exercise reduced the risk of progression to DM excluded patients with HF.⁵⁴

Inhibition of the RAAS
A single-centre retrospective, analysis from SOLVD treatment, showed that enalapril reduced the incidence of DM, compared with placebo: HR 0.22 (0.10–0.46, P < 0.0001).¹⁹ Candesartan reduced the incidence of DM in patients with HF enrolled in CHARM.¹⁸ Of the 5436 patients without DM at randomization, 202 (7.4%) in the placebo group developed DM compared with 163 (6.0%) in the candesartan group: HR 0.78 (0.64–0.96, P = 0.02).

Beta-blockers
In the COMET study, carvedilol was associated with a reduced incidence of new-onset DM in patients with HF when compared with metoprolol: 10.4 vs. 12.6%, HR 0.78 (0.61–0.99).⁵⁵

	Reducing the risk of heart failure in diabetics

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Glycaemic control
Diabetics with higher HbA1c concentrations are at increased risk of HF.²¹ It is not known whether improving glycaemic control reduces the incidence of HF. Intensive glycaemic control did not reduce the incidence of HF, significantly, in UKPDS.⁵⁶ DCCT did not report HF event rates.⁵⁷

Blood pressure control
In UKPDS, 1148 hypertensive diabetics without HF were randomized to tight or less tight BP-control.⁵⁸ Those assigned to tight BP-control had a decreased risk of developing HF [HR 0.44 (0.2–0.94, P = 0.0043)].

ACE Inhibitors
In the 3577 diabetics in MICRO-HOPE ramipril lowered the risk of developing HF by 20% (4–34, P = 0.019).¹⁶ In the 1502 diabetics in PERSUADE (EUROPA substudy), there was a 46% relative-risk reduction in first HF hospitalization, although this was not statistically significant.⁵⁹

Angiotensin receptor blockers
In RENAAL, 1513 diabetics with nephropathy were randomized to losartan 50–100 mg or placebo.⁶⁰ There was a 32% reduction in the risk of first HF hospitalization with losartan (P = 0.005). In IDNT, 1715 diabetics with nephropathy were randomized to irbesartan, amlodipine, or placebo. Irbesartan reduced the incidence of HF, compared with placebo: HR 0.72 (0.52–1.00, P = 0.048). In diabetics in LIFE, losartan reduced the risk of first hospitalization for HF when compared with atenolol: HR 0.59 (0.38–0.92, P = 0.019).⁶¹

Statins
Patients with stable CHD (1501 with DM) were randomized to atorvastatin 80/10 mg in TNT.⁶² The higher dose significantly reduced first hospitalization for HF in diabetics and non-diabetics. In diabetics in ASCOT-LLA there was a non-significant trend towards reduction in HF with atorvastatin 10 mg.⁶³ CARDS and ASPEN examined statin therapy in diabetics, they did not report HF as an endpoint.^64,65

	Screening for heart failure in diabetics

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
The presence of risk factors, particularly CHD, advancing age, hypertension, proteinuria,²² and retinopathy,²⁵ should alert the physician to the possibility of HF. A history of relevant symptoms should be sought. The use of b-type natriuretic peptide (BNP) as a screening tool to identify diabetics with asymptomatic LVSD has shown promise.⁶⁶ Further investigation of screening strategies using electrocardiography, BNP and echocardiography is warranted.

	Treatment of diabetes mellitus in patients with heart failure: Non-pharmacological measures

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Strategies to improve glycaemic control through weight loss or increased physical activity have not been studied in patients with both DM and HF.

	Treatment of diabetes mellitus in patients with heart failure: Pharmacological measures

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Sulfonylureas
Sulfonylureas are frequently used in diabetics with HF. Of 1833 Canadians with DM and a new diagnosis of HF, 42% were treated with monotherapy and 47% were treated with a combination of sulfonylurea and metformin.⁶⁷ Sulfonylureas stimulate endogenous insulin production, which is not a particularly rational approach in the insulin resistant states of DM and HF. These agents, however, are probably used preferentially because of concerns about other oral hypoglycaemics in HF.

Sulfonylureas and the incidence of heart failure in diabetics
In UKPDS 33, sulfonylurea use was not associated with the development of HF.⁵⁶ Patients commenced on insulin in a retrospective American cohort study had a higher incidence of HF hospitalization than those commenced on sulfonylureas: HR 1.56 (1.00–2.45), P = 0.05.⁶⁸

Sulfonylureas and mortality
An American retrospective cohort study of over 16 000 diabetics with HF found no relationship between sulfonylurea use and mortality: HR 0.99 (0.91–1.08).⁶⁹ In a non-randomized cohort study, diabetics with a new diagnosis of HF had a superior 1-year mortality on metformin than those treated with sulfonylureas: adjusted HR 0.66 (0.44–0.97).⁶⁷

To establish whether sulphonlyurea-based strategies result in improved outcomes, when compared with metformin or insulin-based strategies, a prospective study is needed.

Metformin
Is metformin ‘contraindicated’ in patients with heart failure?
The guidelines of the ADA state that metformin is contraindicated in patients with HF. Metformin has a FDA ‘black-box’ warning, stating that it is contraindicated in patients with HF requiring pharmacological management. Despite being ‘contraindicated’, metformin is commonly used. Of 1833 Canadian diabetics with newly diagnosed HF, 11% received metformin alone and 47% received combination therapy with a sulfonylurea and metformin.⁶⁷ Of 16 417 Americans with DM hospitalized with HF, 13% were discharged on metformin.⁶⁹ As metformin is commonly used in diabetics with HF, and the alternatives for treating diabetics with HF are limited, the risks and benefits of metformin in this population need to be elucidated.

Metformin and lactic acidosis
In the 1970s, a drug from the same class (biguanides), phenformin, was withdrawn after 306 cases of lactic acidosis were reported.⁷⁰ Metformin differs from phenformin in many ways, e.g. it does not require hepatic metabolism and is excreted unchanged by the kidney. In the first year of post-marketing surveillance in the USA, metformin was associated with a total of 47 cases of lactic acidosis, 18 in patients with HF.⁷¹ However, neither of the two retrospective cohort studies examining metform use in diabetics with HF reported high rates of lactic acidosis.^67,69 The Canadian study (n = 1833) did not report any cases,⁶⁷ and the American study (n = 16 417) reported a hospitalization rate with metabolic acidosis of 2.3% in those treated with metformin and 2.6% in those not treated with metformin (P = 0.40).⁶⁹ The risk of lactic acidosis associated with metformin in diabetics with HF does not seem high.

Outcomes in diabetics with heart failure on metformin
The two retrospective, non-randomized cohort studies of diabetics with HF suggest that outcomes may be better in patients treated with metformin compared with other anti-diabetic therapies. In Canadian patients with a new diagnosis of HF, metformin monotherapy was associated with a reduced 1-year mortality when compared with sulfonylurea treatment: HR 0.66 (0.44–0.97).⁶⁷ One-year mortality was also lower in patients taking metformin and sulfonylurea combination therapy than in patients taking sulfonylurea monotherapy: HR 0.54 (0.42–0.70). In Americans admitted to hospital with HF, metformin use was associated with a lower 1-year mortality when compared to treatment with insulin or sulfonylurea (24.7 vs. 36%, P < 0.0001).⁶⁹ All-cause re-admission and HF hospitalization were also less common in patients treated with metformin than in those not treated with an insulin-sensitizing drug. We must stress that these two studies were not prospective, randomized, or designed to address the safety or efficacy of metformin in this population.

Should metformin be contraindicated in heart failure?
An argument can be made that metformin should not be universally ‘contraindicated’ in HF. The incidence of lactic acidosis does not appear to be high. Before definitive conclusions can be drawn, prospective randomized studies both in stable HF and in acute decompensated HF are necessary to determine beneficial or adverse effects.

	Thiazolidinediones

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
TZDs are peroxisome proliferator-activated (PPAR-) receptor agonists.

Should thiazolidinediones be used in patients with heart failure?
A consensus statement published by the ADA/AHA states that TZDs can be used cautiously in patients with NYHA class I/II HF, but should not be used in patients with NYHA class III/IV HF.⁷² The FDA states that TZDs are not recommended for use in patients with NYHA class III/IV HF and they have introduced a ‘black-box’ warning regarding the increased risk of HF. A full review of TZD use in HF is out of the scope of this article and has been reviewed in detail elsewhere.⁷³ Here we review the more important issues.

Thiazolidinediones and fluid retention
TZDs cause fluid retention (with an associated decrease in haemoglobin and hematocrit), oedema and weight gain (averaging 1–3 kg) and some studies have reported an increased incidence of HF.^74–76 The mechanisms whereby TZDs cause fluid retention are not clear. Several mechanisms have been suggested, e.g. the promotion of sodium retention and plasma volume expansion through a PPAR-gamma dependent pathway in the collecting ducts; increased endothelial permeability and increased intestinal ion transport.⁷³ When TZDs are combined with insulin, the rate of oedema increases markedly. In a placebo-controlled study of rosiglitazone and insulin the oedema rates were: placebo 4.7%, rosiglitazone 4 mg 13.1%, and rosiglitazone 8 mg 16.2%.⁷⁷ A similar pattern is seen with pioglitazone.⁷⁸

Thiazolidinediones and cardiac structure and function
Do TZDs simply precipitate HF through fluid retention, or do they have detrimental effects on cardiac structure and function as well? In patients without HF, a 52-week study comparing glyburide with rosiglitazone demonstrated that neither drug caused a reduction in left ventricular ejection fraction.⁷⁹ In a 52-week placebo controlled trial in 224 patients with NYHA I/II HF, rosiglitazone was not shown to adversely affect cardiac function.⁸⁰

Incidence of heart failure in clinical trials of thiazolidinediones
Several large randomized controlled trials have reported an increased incidence of HF in patients treated with TZDs.^74–76 A recent meta-analysis examined the combined outcomes of 20 191 patients treated with pioglitazone or rosiglitazone in seven randomized controlled trials.⁸¹ In comparison to controls, patients treated with TZDs had an increased risk of HF with a RR of 1.72 (1.21–2.42). However, this was not associated with an increased risk of cardiovascular death: RR 0.93 (0.67–1.29).

Thiazolidinediones use in diabetics with heart failure: Cohort studies
An American retrospective cohort study of over 16 000 diabetics with HF demonstrated a lower risk of death in those treated with TZDs than in those not treated with an insulin-sensitizer: HR 0.87 (0.80–0.94).⁶⁹ However, this was tempered with a significantly higher risk of all-cause hospital re-admission and HF re-admission (68% compared with 65%, P = 0.02) in the TZD-treated group. Another retrospective cohort study of 7147 diabetics with HF at a Veteran Affairs medical centre, did not show an increased rate of death or HF hospitalization with TZDs.⁸²

A retrospective case-note review of 111 consecutive out-patients with HF treated with TZDs included 50 patients in NYHA class III.⁸³ Only 17.1% developed fluid retention however, few required hospital treatment and oedema was usually quick to reverse with drug withdrawal and an increase in diuretics.

Thiazolidinediones use in diabetics with heart failure: Clinical trials
Most studies with TZDs have excluded patients with NYHA class III/IV HF. Only one prospective study has examined the use of TZDs in patients with NYHA I/II HF.⁸⁰ This 52-week study randomized 224 patients to rosiglitazone or placebo. Rosiglitazone did not adversely affect cardiac function but did increase frequency of oedema.

Theoretical benefits of thiazolidinediones
To date, there is only evidence that pioglitazone, but not rosiglitazone, may reduce macrovascular events in patients with diabetes.⁷³ TZDs may also have some effects on the cardiovascular system, that are theoretically beneficial in patients with HF, e.g. improved endothelial function, BP reduction and vasodilatation.⁷³ These effects, however, have not been demonstrated in patients with HF.

Should thiazolidinediones be avoided in diabetics with heart failure?
TZDs are an effective therapy to control blood glucose in patients with DM. It is now recognized that they do increase the risk of HF. However, it is not clear whether this increased risk of HF leads to an increase in death. It is appropriate that they are not recommended in patients with NYHA class III/IV HF. More data are needed to determine practice in patients with milder HF.

Insulin
Insulin use independently predicts both development of HF and mortality in diabetics.^28,68,84,85 It is likely a marker for diabetes of longer duration with perhaps more extensive macrovascular disease.

Insulin and the incidence of heart failure in diabetics
Insulin use is an independent risk factor for the development of HF in diabetics.¹³ An American retrospective cohort study of 23 440 diabetics without HF examined the effect of initiation of any single new therapy for DM on HF hospitalization.⁶⁸ Those commenced on insulin had a higher incidence of HF hospitalization than those commenced on sulfonylureas: HR 1.56 (1.00–2.45, P = 0.05). UKPDS 33 did not show an increase in HF with insulin treatment.⁵⁶

Insulin and mortality in heart failure
The evidence regarding the effect of insulin on mortality in HF is conflicting. Diabetics treated with insulin in CHARM had a greater risk of death than those not treated with insulin.⁸⁴ Treatment with insulin was a significant independent predictor of cardiovascular mortality in the BEST trial [HR 1.30 (1.03–1.65)].²⁸

In a retrospective analysis, 132 of 554 consecutive patients referred to an advanced HF centre had DM.⁸⁵ One-year survival was 89.7% in patients without DM, 85.8% in diabetics not on insulin and 62.1% in diabetics on insulin (n = 43). Treatment with insulin was an independent predictor of mortality: HR 4.30 (1.69–10.94).

In contrast, an American retrospective cohort study of over 16 000 diabetics with HF did not identify any association between insulin and mortality: HR 0.96 (0.88–1.05).⁶⁹ Likewise, in UKPDS-33 insulin use did not predict mortality.⁵⁶

Prospective, randomized trails are needed to determine the best treatment strategy for diabetics with HF.

	Treatment of heart failure in diabetics: Pharmacological therapies

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Diuretics
Diuretics are necessary for the treatment of the symptoms of fluid overload in HF. There are no data to indicate their effects differ between diabetics and non-diabetics. However, clinicians managing diabetics with HF should be aware that thiazides can promote hyperglycaemia.

Digoxin, nitrates, and hydralazine
No DM subgroup analysis is available from DIG or V-HeFT.^9,86,87 In A-HeFT, baseline diabetes did not modify the benefit of hydralazine and isosorbide dinitrate.⁸⁸

ACE inhibitors
There is a large meta-analysis of the effect of ACE inhibitors in patients with (n = 2398) and without (n = 10 188) DM, it included four HF trials and three post-MI left ventricular dysfunction trials.⁸⁹ The RR of death in ACE inhibitor-treated, compared with placebo-treated, patients was 0.85 (0.78–0.92) in non-diabetics and 0.84 (0.70–1.00) in diabetics. The possible importance of ACE-inhibitor dose was raised by a retrospective analysis of the ATLAS trial (19% with DM), which compared high and low-dose lisinopril in patients with HF. The RR reduction in mortality in the high vs. low-dose lisinopril group was 14% in diabetics and 6% in those without DM.³⁶ The interaction P-value, however, was not significant (P = 0.502).

β-blockers
Diabetics are less likely than non-diabetics with HF to be discharged from hospital on a beta-blocker: OR 0.72 (0.55–0.94).⁹⁰ This may reflect inappropriate concerns about β-blocker use in diabetics.

β-blockers reduce mortality in diabetics with heart failure
Between 12–26% of patients in the major β-blocker trials in HF were diabetic.^91,92 Diabetics obtained similar treatment benefits to non-diabetics. In a meta-analysis of the landmark trials in HF,⁹³ the RR of mortality for diabetics receiving a beta-blocker (compared with placebo) was 0.84 (0.73–0.96, P = 0.011) compared with 0.72 (0.65–0.79, P < 0.001) in non-diabetics. A second meta-analysis of CIBIS-II, COPERNICUS, and MERIT-HF confirmed the benefit of β-blockers in diabetics with HF.⁸⁹

β-blockers reduce morbidity in diabetics with heart failure
Beta-blockers reduce hospitalizations for HF similarly in diabetics and non-diabetics.^28,34,94,95 In MERIT-HF, the risk of hospitalization was reduced by metoprolol CR/XL in diabetics by 37% (53–15%, P = 0.0026) compared with 35% (48–19%, P = 0.0002) in non-diabetics. In BEST, treatment with bucindolol reduced total hospitalizations [HR 0.85 (0.73–0.99, P = 0.039)] and HF hospitalizations [HR 0.72 (0.60–0.88, P = 0.001)] in diabetics.²⁸ In patients without DM there was a reduction in HF hospitalizations [HR 0.81 (0.69–0.95, P = 0.0078)], but not total hospitalizations [HR 0.95 (0.84–1.08, P = 0.4270)].

Concerns of using β-blockers in patients with diabetes mellitus
There have been concerns about adverse effects of β-blockers in diabetics, including increased risk of hypoglycaemia, dyslipidaemia, and decreased insulin sensitivity. What is the evidence for these?

Hypoglycaemia
The biological response to hypoglycaemia involves SNS activation, leading to the symptoms of tremor, palpitations, tachycardia, and sweating while stimulating hepatic gluconeogenesis and glycogenolysis, restoring glucose levels. Do β-blockers decrease these symptoms and blunt the compensatory increase in plasma glucose?

Frequency of hypoglycaemic episodes
One large retrospective cohort study examined the use of β-blockers in 13 559 elderly diabetics without HF.⁹⁶ Patients on insulin experienced an increased risk of serious hypoglycaemia with non-selective β-blockers: RR 2.16 (1.15–4.02), but not cardioselective β-blockers: RR 0.86 (0.36–1.33). No such effect was seen for those on sulfonylureas. Two smaller case–control studies did not identify a relationship between β-blockers and hypoglycaemia.^97,98 The proportion of patients with HF in these studies was not stated. UKPDS 39 compared the efficacy of atenolol to captopril in 758 hypertensive diabetics.⁹⁹ There was no difference in the rate of hypoglycaemia between the group groups.

Hypoglycaemic awareness
Small studies in patients without HF suggest the response to hypoglycaemia might change with use of β-blockers. Tremor and palpitations decrease, but sweating increases.¹⁰⁰ In healthy volunteers, hypoglycaemic awareness was not affected by treatment with either cardioselective or non-cardioselective β-blockers.¹⁰¹

Recovery from hypoglycaemia
Hepatic glucose production is controlled in part by β₂-receptor stimulation. Prolonged hypoglycaemia has been described with use of a non-cardioselective β-blocker (propanolol), but not with β₁ selective β-blockers or carvedilol, a non-selective β-blocker.^100,102 However, in one small study in type 1 diabetics, both non-cardioselective and cardioselective β-blockers led to prolongation of hypoglycaemia.¹⁰³ These were small studies in patients without HF.

There is no evidence specifically addressing the frequency or severity of hypoglycaemic episodes in diabetics with HF.

Dyslipidaemia
β-blockers in hypertensive patients can cause dyslipidaemia.¹⁰⁴ This has not been studied in patients with HF.

Insulin sensitivity
In hypertensive patients without HF, some non-vasodilating β-blockers decrease insulin sensitivity and can increase the risk of developing DM.¹⁰⁴

The marked clinical benefits of β-blockers in diabetics with HF outweigh the risks of hypoglycaemia and dyslipidaemia or decreased insulin sensitivity. Education on prevention, recognition, and management of hypoglycaemic episodes is already established in the management of diabetics.

Which beta-blocker should be used in patients with diabetes mellitus and heart failure?
Carvedilol has some properties that are of theoretical benefit in diabetics with HF. Through its -adrenoceptor, vasodilator action, carvedilol may increase skeletal muscle blood flow, improve glucose uptake, leading to a reduction in insulin resistance.¹⁰⁵ There is some support for this hypothesis from a small trial in diabetic patients with hypertension,¹⁰⁶ but no evidence supports the use of one β-blocker over another in diabetics with HF.

Angiotensin receptor blockers
In the two low-ejection fraction CHARM trials, the benefit of candesartan was similar in those with and without DM (P-value for interaction was 0.12).¹⁰⁷ Of the patients taking candesartan, 35.7% experienced cardiovascular death or HF hospitalization compared with 41.3% in the placebo group: HR 0.82 (0.74–0.90, P < 0.001). The Val-HeFT trial demonstrated a significant reduction in morbidity and mortality in patients with HF treated with valsartan.¹⁰⁸ A similar effect was seen in diabetics and non-diabetics.

Aldosterone antagonists
The mortality benefit of spironolactone (compared with placebo) was similar in diabetics [HR 0.70 (0.52–0.94), P = 0.019] and non-diabetics [HR 0.70 (0.60–0.82, P < 0.001] with severe HF.¹⁰⁹

	Treatment of heart failure in diabetics: Non-pharmacological therapies

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Cardiac resynchronization therapy
In both the CARE-HF and COMPANION studies, CRT reduced mortality to a similar extent in patients with and without DM.^110,111

Implantable cardioverter defibrillators
In SCD-HEFT, 30% of patients had DM. The ICD:Placebo HR was 0.95 (97.5% CI: 0.68–1.33) in diabetics (n = 524) and 0.67 (97.5% CI: 0.50–0.90) in non-diabetics, although no diabetes-treatment interaction was reported.¹¹² No diabetes-treatment interaction was noted in CABG-PATCH or MADIT-2 either.^113,114

Cardiac transplantation
Current guidelines state DM with end-organ damage is a relative contraindication to cardiac transplantation.¹¹⁵ Concerns are based on increased risk of infection after transplantation and accelerated coronary and peripheral arterial disease. Use of prednisolone-based immunosuppression is also problematic as it worsens glycaemic control. A number of studies have demonstrated reduced survival in patients with DM post-transplantation.^116,117 However, with modern immunosuppresion regimens allowing more rapid tapering of steroid doses, and steroid-free immunosupression, cardiac transplantation in diabetics should be carefully considered.

	Who should manage patients with diabetes mellitus and heart failure?

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Patients with both DM and HF should be managed by health professionals with an interest in both DM and HF. Local discussions should focus on the management of issues raised by the concurrence of DM and HF. Doctors and nurse specialists with an interest in DM and HF should be aware of the issues that complicate the management of these patients and systems of care put in place to achieve optimal management. Chronic disease management programmes have shown some promise in optimizing the treatment of both DM and HF.¹¹⁸

	Conclusion

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
DM and HF coexist commonly. They have overlapping patho-physiological processes that have yet to be fully elucidated. Screening strategies are needed to identify DM patients at high risk of HF and those with asymptomatic LVSD. Efforts should be directed towards establishing patients with DM and HF on optimal medical therapy for HF. Strategies for managing DM in patients with HF should be prospectively compared. Those caring for patients with both HF and DM should be aware of the issues that arise when these conditions occur together.

	Supplementary material

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 
Supplementary material is available at European Heart Journal online.

Conflict of interest: Drs MC and JR Petrie, Fisher and McMurray have received research grants, honoraria for lectures and/or consulting fees from a number of companies manufacturing and selling pharmaceuticals related to this article.

	References

Top Abstract Introduction Methods Epidemiology Risk of developing heart... Risk of developing diabetes... Diabetes and mortality in... Heart failure and mortality... Diabetes and heart failure:... Diabetes and severity of... Heart failure and pre-diabetic... Why do patients with... Why do diabetics develop... Reducing the risk of... Reducing the risk of... Screening for heart failure... Treatment of diabetes mellitus... Treatment of diabetes mellitus... Thiazolidinediones Treatment of heart failure... Treatment of heart failure... Who should manage patients... Conclusion Supplementary material References

 

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				D. Preiss, S. Zetterstrand, J. J.V. McMurray, J. Ostergren, E. L. Michelson, C. B. Granger, S. Yusuf, K. Swedberg, M. A. Pfeffer, H. C. Gerstein, et al. Predictors of Development of Diabetes in Patients With Chronic Heart Failure in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Program Diabetes Care, May 1, 2009; 32(5): 915 - 920. [Abstract] [Full Text] [PDF]

				J. McMurray, M. Petrie, K. Swedberg, M. Komajda, S. Anker, and R. Gardner CHAPTER 23 Heart Failure ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]

				M. R. MacDonald, P. S. Jhund, M. C. Petrie, J. D. Lewsey, N. M. Hawkins, S. Bhagra, N. Munoz, F. Varyani, A. Redpath, J. Chalmers, et al. Discordant Short- and Long-Term Outcomes Associated With Diabetes in Patients With Heart Failure: Importance of Age and Sex: A Population Study of 5.1 Million People in Scotland Circ Heart Fail, November 1, 2008; 1(4): 234 - 241. [Abstract] [Full Text] [PDF]

				Authors/Task Force Members, K. Dickstein, A. Cohen-Solal, G. Filippatos, J. J.V. McMurray, P. Ponikowski, P. A. Poole-Wilson, A. Stromberg, D. J. van Veldhuisen, D. Atar, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) Eur. Heart J., October 1, 2008; 29(19): 2388 - 2442. [Full Text] [PDF]

				K. Dickstein, A. Cohen-Solal, G. Filippatos, J. J.V. McMurray, P. Ponikowski, P. A. Poole-Wilson, A. Stromberg, D. J. van Veldhuisen, D. Atar, A. W. Hoes, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) Eur J Heart Fail, October 1, 2008; 10(10): 933 - 989. [Full Text] [PDF]

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