ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD

The Task Force on Diabetes, Pre-Diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and Developed in Collaboration With the European Association for the Study of Diabetes (EASD)

Lars Rydén (ESC Chairperson) (Sweden); Peter J. Grant (EASD Chairperson) (UK); Stefan D. Anker (Germany); Christian Berne (Sweden); Francesco Cosentino (Italy); Nicolas Danchin (France); Christi Deaton (UK); Javier Escaned (Spain); Hans-Peter Hammes (Germany); Heikki Huikuri (Finland); Michel Marre (France); Nikolaus Marx (Germany); Linda Mellbin (Sweden); Jan Ostergren (Sweden); Carlo Patrono (Italy); Petar Seferovic (Serbia); Miguel Sousa Uva (Portugal); Marja-Riita Taskinen (Finland); Michal Tendera (Poland); Jaakko Tuomilehto (Finland); Paul Valensi (France); Jose Luis Zamorano (Spain); Jose Luis Zamorano (Chairperson) (Spain); Stephan Achenbach (Germany); Helmut Baumgartner (Germany); Jeroen J. Bax (Netherlands); Héctor Bueno (Spain); Veronica Dean (France); Christi Deaton (UK); Çetin Erol (Turkey); Robert Fagard (Belgium); Roberto Ferrari (Italy); David Hasdai (Israel); ArnoW. Hoes (Netherlands); Paulus Kirchhof (Germany UK); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Patrizio Lancellotti (Belgium); Ales Linhart (Czech Republic); Petros Nihoyannopoulos (UK); Massimo F. Piepoli (Italy); Piotr Ponikowski (Poland); Per Anton Sirnes (Norway); Juan Luis Tamargo (Spain); Michal Tendera (Poland); Adam Torbicki (Poland); William Wijns (Belgium); Stephan Windecker (Switzerland); Guy De Backer (Review Coordinator) (Belgium); Per Anton Sirnes (CPG Review Coordinator) (Norway); Eduardo Alegria Ezquerra (Spain); Angelo Avogaro (Italy); Lina Badimon (Spain); Elena Baranova (Russia); Helmut Baumgartner (Germany); John Betteridge (UK); Antonio Ceriello (Spain); Robert Fagard (Belgium); Christian Funck-Brentano (France); Dietrich C. Gulba (Germany); David Hasdai (Israel); Arno W. Hoes (Netherlands); John K. Kjekshus (Norway); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Eli Lev (Israel); Christian Mueller (Switzerland); Ludwig Neyses (Luxembourg); Peter M. Nilsson (Sweden); Joep Perk (Sweden); Piotr Ponikowski (Poland); Zeljko Reiner (Croatia); Naveed Sattar (UK); Volker Schächinger (Germany); André Scheen (Belgium);

Disclosures

Eur Heart J. 2013;34(39):3035-3087. 

In This Article

8. Heart Failure and Diabetes

Heart failure and T2DM frequently co-exist, each adversely affecting the natural course of the other. The prevalence of risk factors for heart failure is common in patients with DM, among which CAD and hypertension are the most important. In addition, dysglycaemia may in itself have an unfavourable effect on the myocardium. This has led to recognition of a clinical entity labelled as DM cardiomyopathy, in which compromised diastolic function is an early feature. An analysis of 987 patients with heart failure and preserved LVEF, enrolled in the Digitalis Investigation Group (DIG) ancillary study,[375] revealed that T2DM was associated with significantly increased risk of developing adverse heart failure outcomes. The clinical approach to cardiomyopathy includes echocardiographic assessment of LV diastolic dysfunction, which can worsen during physical exercise.[376] Insulin resistance, which characterizes the heart failure syndrome, regardless of aetiology, seems to be an important factor behind the elevated risk of DM development among heart failure patients. Despite strong evidence linking heart failure and DM, an optimal management of these co-existing conditions is still not fully evidence-based owing to a lack of clinical trials specifically addressing such patient populations.

8.1 Prevalence and Incidence of Heart Failure in Type 2 Diabetes Mellitus, and Type 2 Diabetes Mellitus in Heart Failure

Prevalence and Incidence of Heart Failure in Diabetes Mellitus: The prevalence of heart failure in a general population is 1–4% and 0.3–0.5% of the patients have both heart failure and T2DM. Studies in heart failure populations reveal a prevalence of T2DM from 12–30%, rising with age.[377,378] T2DM is a major independent risk factor for the development of heart failure. In the Framingham study, the relative risk of heart failure in patients with T2DM (age 45–74 years) was doubled for men and six times as high in women.[379] The high incidence of heart failure in patients with T2DM was also confirmed in the National Health and Nutrition Examination Survey, which revealed T2DM as an independent risk factor for heart failure, with an HR of 1.85 (95% CI 1.51–2.28) in T2DM, compared with non-DM.[380] Boonman-de Winter et al.[381] who studied a Dutch group of 581 T2DM patients (aged >60 years) reported that 28% (95% CI 24–31%) had previously unknown heart failure; 5% with reduced LVEF and 23% with preserved LVEF. The prevalence increased rapidly with age, and heart failure with preserved LVEF was more common in women than men. Left ventricular dysfunction was diagnosed in 26% (95% CI 22–29%), and 25% (95% CI 22–29%) had diastolic dysfunction. This underlines the importance of looking for signs and symptoms of compromised myocardial function in patients with T2DM.

Several clinical correlates are independent risk factors for the development of heart failure in T2DM, including high HbA1c, increased body mass index, advancing age, associated CAD, retinopathy, nephropathy and insulin use. Also, in recent studies, end-stage renal disease, nephropathy, proteinuria and albuminuria, retinopathy and duration of T2DM were associated with heart failure and its progression.[382]

Prevalence and Incidence of Diabetes Mellitus in Heart Failure: the prevalence of DM in a general population is 6– 8% but, as reviewed by McDonald et al., it is higher in people with symptomatic heart failure (12–30%) increasing towards 40% among hospitalized patients.[1,383] However, the heart failure populations are older than the general population. It should be noted that the prevalence of DM patients is lower in heart failure trials, indicating a selection bias towards younger and/or less sick DM patients. Information on the incidence of DM in heart failure populations is sparse but, in an elderly Italian population, new-onset DM occurred in 29% during three years of follow-up, compared with 18% in controls without heart failure.[384] When people with two or more visits in the Reykjavik study (n = 7060) were followed over 30 years, DM and heart failure did not predict each other independently, although fasting glucose and BMI were significant risk factors, both for glucose disturbances and heart failure.[385]

Diabetes Cardiomyopathy: Long-standing hyperglycaemia may—even in the absence of other risk factors such as CAD, valvular disease or hypertension—affect the myocardial tissue, increasing the risk of dysfunction. A reduction of LV compliance—an early sign of DM cardiomyopathy—may indeed already be detectable early in the course of DM.[386] The frequent co-existence of hypertension and DM makes the contribution of the glucometabolic state to the diastolic dysfunction difficult to isolate. The pathogenic mechanisms involve accumulation of advanced glycation products, collagen formation and interstitial fibrosis, leading to impaired calcium homeostasis and impaired myocardial insulin signalling (See Section 4 for further details and references). These perturbations increase myocardial stiffness and reduce myocardial compliance.[387,388] According to the recommendations of the ESC, LV diastolic dysfunction is identified by quantitative estimation of LV diastolic properties, using conventional Doppler parameters of the transmitral inflow of blood and tissue Doppler imaging of the mitral annulus. Deteriorating diastolic dysfunction is associated with a progressive increase in LV filling pressure which, in turn, has an impact on the transmitral flow pattern.[389] It has been claimed—but not verified in longitudinal studies—that myocardial dysfunction may progress in a time-dependent fashion after the onset of diastolic dysfunction, leading to systolic dysfunction and the classical features of heart failure. Due to the frequent co-existence of DM, hypertension and CAD, it has been debated whether the myocardial dysfunction is primarily triggered by the glucometabolic disorder itself, rather than by the synergistic action of these factors. From a clinical perspective, prevention of the development of LV systolic dysfunction and subsequent heart failure is currently focussed on pharmacological treatment of the co-morbidities. It may also explain why meticulous blood pressure-lowering seems to be particularly effective in people with DM.

8.2 Diabetes Mellitus and Heart Failure: Morbidity and Mortality

Heart failure was a major cause of hospitalization in patients with T2DM in the Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events and Ramipril (DIABHYCAR) trial, investigating hospitalizations in T2DM patients with albuminuria.[382] Conversely T2DM increased the risk of hospitalization in patients with heart failure in the BEta blocker STroke trial (BEST) trial[390] (RR 1.16; 95% CI 1.02–1.32; P = 0.027). In Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),[391] patients with heart failure and T2DM had one-year hospitalization of 31%, compared with 24% for those free from DM.

In the DIABHYCAR study, the combination of heart failure and T2DM resulted in a 12-fold higher annual mortality than among patients with T2DM but without heart failure (36 vs. 3%).[382] BEST and Studies Of Left Ventricular Dysfunction (SOLVD) reported T2DM as an independent predictor of mortality, mostly in ischaemic heart failure.[390,392] Also, the Danish Investigations and Arrhythmia ON Dofetilide (DIAMOND) and Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials reported DM as an independent predictor of mortality, irrespective of aetiology.[393,394]

8.3 Pharmacological Management of Heart Failure in Type 2 Diabetes Mellitus

Three neurohormonal antagonists—an ACE-I or ARB, a beta-blocker and a mineralocorticoid receptor antagonist (MRA)—comprise the important pharmacological agents for the treatment of all patients with systolic heart failure, including those with DM. They are usually combined with a diuretic for relieving congestion and may also be supplemented by ivabradine.[389]

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers: ACE-I is indicated in T2DM and heart failure, since it improves symptoms and reduces mortality. The SOLVD trial, using enalapril, showed a significant mortality reduction in DM with heart failure.[392] Mortality risk reduction in the high-dose vs. low-dose lisinopril groups was 14% in DM and 6% in non-DM in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial.[395] In a meta-analysis, the risk ratio for death was the same in the ACE-I treated group as in the placebo-treated group in T2DM (n = 2398) and non-T2DM (n = 10 188).[396]

Subgroup analyses of clinical trials indicate that the beneficial effects of ARBs are equivalent to those of ACE-I.[397–400] An ARB can therefore be used as an alternative in ACE-I-intolerant patients. ACE-I and ARBs should not be combined in patients with an LVEF <40%, who are symptomatic despite optimal treatment with an ACE-I in combination with a beta-blocker. According to the 2012 ESC heart failure Guidelines, such patients should be prescribed an MRA (see below), which causes a larger morbidity and mortality reduction than that following addition of an ARB.[389]

When ACE-I and ARBs are used in patients with DM, surveillance of kidney function and potassium is mandatory, since nephropathy is a frequent occurrence.

Beta-blockers: In addition to an ACE-I (or, if not tolerated, an ARB) a beta-blocker should be given to all patients with an LVEF ≤40%. As an example, a subgroup analysis of the MERIT-HF trial shows that beta-blockers reduce mortality and hospital admission and improve symptoms without significant differences between T2DM and non-DM.[391] Further, two meta-analyses of major heart failure trials indicate that the RR of mortality in patients with DM receiving a beta-blocker was significantly improved (0.84 vs. 0.72).[396,401] Beta-blockers also reduce hospitalizations for heart failure in both DM and non-DM.[390,391,402,403] Despite this, people with T2DM are less likely to be discharged from hospital on a beta-blocker (OR 0.72; 95% CI 0.55–0.94) than non-DM with heart failure.[404] The following beta-blockers are recommended in heart failure and T2DM: metoprolol succinate in the slow release form (MERIT-HF), bisoprolol [Cardiac Insufficiency Bisoprolol Study (CIBIS II)] and carvedilol [Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) and Carvedilol Or Metoprolol European Trial (COMET)].[402,403,405,406]

Unwanted Effects of Beta-blockers in Patients With DM and Heart Failure:

a) Hypoglycaemia. Evidence indicates that beta-blockers in DM alter counter-regulatory responses to hypoglycaemia with decreased tremor and palpitations but increased sweating.[407] Prolonged hypoglycaemia has been described with non-cardio-selective beta-blockade (propranolol), but not with beta-1-selective agents or with carvedilol.[408,409] Elderly DM patients on insulin (n = 13 559), without heart failure, experienced an increased risk of serious hypoglycaemia with non-selective beta-blockade (RR 2.16; 95% CI 1.15–4.02) but not with beta-1-selective drugs (RR 0.86; 95% CI 0.36–1.33).[410]

b) Negative metabolic effects. In hypertensive patients without heart failure, different beta-blockers may have varying effects on glycaemic indices, decreasing insulin sensitivity and increasing the risk of T2DM.[410] The marked clinical benefits of beta-blockers in patients with DM and heart failure outweigh the risks of hypoglycaemia and dyslipidaemia or decreased insulin sensitivity.

Mineralocorticoid Receptor Antagonists: To reduce the risk of hospitalization and premature death, a low-dose MRA is indicated in all patients with persisting symptoms [New York Heart Association (NYHA) Class II–IV] and an LVEF ≤35%, despite treatment with an ACE-I (or, if not tolerated, an ARB) and a beta-blocker.[411] The mortality benefit of spironolactone[412] and eplerenone[413] did not differ between patients with and without T2DM and heart failure. Surveillance of kidney function and potassium is mandatory, considering the increased risk of nephropathy in patients with DM.

Diuretics: The effect of diuretics on mortality and morbidity has not been investigated, but these drugs are useful for the relief of dyspnoea and oedema in heart failure with fluid overload, irrespective of the EF. Loop diuretics are recommended, rather than thiazides, which have been shown to promote hyperglycaemia.

Ivabradine: In a large, randomized, double-blind, placebo-controlled trial involving 6558 patients with heart failure in sinus rhythm and heart rate ≥70 bpm (3241 on ivabradine; 30% with T2DM), ivabradine demonstrated a significant reduction in composite endpoints of cardiovascular death and hospital admission for worsening heart failure. The beneficial difference was similar in a pre-specified subgroup analysis of patients with and without DM.[414]

8.4 Non-pharmacological Therapies for Heart Failure in Diabetes Mellitus

Cardiac Resynchronization Therapy and Implantable Cardioverter Defibrillators: Cardiac resynchronization therapy is a guideline-recommended heart failure treatment, proved to reduce mortality in patients in NYHA function class III – IV, an LVEF ≤35% despite optimal pharmacological treatment, in sinus rhythm and with a prolonged QRS duration (≥120–130 ms).[415] Despite a lack of subgroup analyses, there is no reason to believe that the effect of resynchronization therapy should be any different in patients with or without DM. Also, there is no additional benefit from implantable cardioverter defibrillators in a subgroup of patients with T2DM and heart failure, compared with patients free from this disease.[416]

Cardiac transplantation is an accepted treatment for end-stage heart failure. The presence of DM is not a contra-indication, but the stringent selection criteria have to be acknowledged. The higher likelihood of cerebrovascular disease, decreased renal function and increased risk of infection has to be considered and may contra-indicate heart transplantation more often in patients with- than in those without DM.[417] DM was an independent risk factor for decreased 10-year survival in a large registry study of patients (n = 22 385) transplanted between 1987 and 1999.[418]

8.5 Glucose-lowering Treatment in Patients With Heart Failure

The impact of various glucose-lowering drugs on T2DM patients with heart failure was systematically reviewed by Gitt et al.[419] They noted that the only drugs addressed in RCTs were thiazolidinediones, while evidence on other compounds is largely based on subgroup analyses of larger intervention studies in systolic heart failure, observational studies or on registries.

The use of metformin , the recommended first-hand glucose lowering treatment, has previously been contra-indicated in patients with heart failure because of concerns regarding lactic acidosis. This drug has, however, been reported to be associated with lower mortality rates, lower rates of all-cause hospital admission and fewer adverse events,[420,421] and an accumulation of lactic acidosis was not verified in a study by Masoudi et al., who reported that 2.3% of metformin users had metabolic acidosis, in comparison with 2.6% in those not treated with metformin.[422] In a nested case-control study including patients with newly diagnosed heart failure and DM, who were either exposed to glucose-lowering drugs or not, the use of metformin [adjusted OR 0.65 (0.48–0.87)] or metformin with or without other agents [OR 0.72 (0.59–0.90)] was associated with lower mortality, while other oral glucose-lowering agents or insulin were neutral in this respect.[423]

Recommendations on sulphonylureas and heart failure are based on observational data. No relationship was seen between sulphonylurea and heart failure mortality in UKPDS,[152] but in a large number of patients (n = 12 272) in the Saskatchewan Health database, mortality (52 vs. 33%) and hospitalizations (85 vs. 77%) were higher among patients treated with sulphonylureas than with metformin during an average of 2.5 years of follow-up.[424] A similar difference, to the disadvantage of sulphonylureas, was not confirmed in a study on Medicare beneficiaries, concluding that there was no association with such treatment (HR = 0.99; 95% CI 0.91–1.08) or insulin (HR = 0.96; 95% CI 0.88–1.05) and mortality.[422]

The PPARγ-activating thiazolidinediones induce sodium retention and plasma volume expansion. The resulting fluid retention may provoke or worsen heart failure and cause increased numbers of hospitalizations.[175,425,426] In the review by Gitt et al.,[419] it was stated that thiazolidinediones should not be used because of an increased event rate in patients with T2DM and established heart failure and a large increase in incident heart failure. Accordingly, this class of glucose-lowering drugs is discouraged when treating T2DM patients with heart failure.

There is a lack of information on the impact of GLP-1 analogues or DPP-4 inhibitors in patients with heart failure, although experimental and early clinical observations indicate favourable effects on myocardial performance.[427]

Regarding the use of insulin , a retrospective cohort study of 16 417 patients with DM and a primary diagnosis of heart failure did not reveal any association between the use of insulin and mortality (HR 0.96; 95% CI 0.88–1.05), in comparison with several other classes of glucose-lowering drugs.[422] In the ORIGIN trial, people at high CVD risk plus IFG, IGT or T2DM received insulin glargine or standard care, which mainly included metformin and sulphonylurea treatment. During the 6.2-year-long follow-up period there was no difference in hospitalizations for heart failure.[168]

8.6 Gaps in Knowledge

  • The impact of glucose-lowering drugs including metformin, GLP-1 analogues and DPP-IV inhibitors on the prevention of heart failure is unknown.

8.7 Recommendations for Management of Heart Failure in Diabetes

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....