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Heart failure in patients with diabetes mellitus: Epidemiology, pathophysiology, and management

Heart failure in patients with diabetes mellitus: Epidemiology, pathophysiology, and management
Literature review current through: Jan 2024.
This topic last updated: May 18, 2022.

INTRODUCTION — Heart failure (HF) and diabetes mellitus (DM) are each associated with morbidity and mortality and they often occur together with associated greater risk of adverse outcomes [1]

The epidemiology, pathophysiology, prognosis, and management of HF in patients with diabetes mellitus will be reviewed here. The prevalence of coronary heart disease among patients with DM and the evaluation and general management of HF are discussed separately. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus" and "Heart failure: Clinical manifestations and diagnosis in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

EPIDEMIOLOGY — There is a well-established association between DM and HF that is partly but not entirely linked to coronary heart disease and hypertension.

DM as risk factor for HF — Patients with type 2 or type 1 DM are at increased risk for development of HF.

Type 2 diabetes mellitus — Observational studies of patients with DM (predominantly type 2) have identified an approximately two to fourfold risk of HF compared to individuals without DM [1], and the risk may be even higher in younger individuals (eg, 11-fold in individuals <45 years old [2]). Patients with insulin-resistant states such as obesity and prediabetes are also at increased risk for development of HF [3-5].

The risk of HF associated with DM may be slightly higher in women compared with men [1,6]. A meta-analysis of population-based cohort studies published between 1966 and 2018 included data on type 2 DM from 13 studies of 47 cohorts with 11,925,128 individuals with 249,560 incident HF events [6]. Among the seven included studies presenting data on absolute risks of HF, the risk in women ranged from 1.94 to 20.85 per 1000 person-years and the risk in men ranged from 1.70 to 28.46 per 1000 person-years in these cohorts. The adjusted relative risk (RR) for HF in individuals with type 2 DM compared with controls was 1.95 (95% CI 1.70-2.22) in women and 1.74 (95% CI 1.55-1.95) in men; the pooled adjusted women-to-men ratio of RRs (RRR) was 1.09 (95% CI 1.05-1.13).

While the relative risk of HF in patients with DM compared with patients without DM is higher in younger individuals [2], the frequency of HF is higher in older adults as illustrated by a national sample of Medicare claims from 1994 to 1999 for over 150,000 beneficiaries with DM who were ≥65 years of age [7]. The prevalence of HF was 22.3 percent in 1994, with a subsequent incidence of newly diagnosed HF of 12.6 percent per year.

Factors associated with HF in adult diabetic patients include [2,7-12]:

Duration of DM

Insulin use

Poor glycemic control

Greater body mass index (BMI)

Microalbuminuria

Elevated serum creatinine

Ischemic heart disease

Peripheral artery disease

While studies have shown an association between poor glycemic control and risk of HF, improved glucose control has not been shown to reduce incident HF. A meta-analysis including 27,049 patients with type 2 DM found that more intensive glucose control, compared with less intensive control, did not decrease incident HF or mortality, although major cardiovascular events (primarily myocardial infarction [MI]) were decreased [13]. (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Type 1 diabetes mellitus — HF is more prevalent in individuals with type 1 DM compared with controls, and the relative risk is higher among women. A meta-analysis of population-based cohort studies included two studies with 3,284,123 individuals with type 1 DM and 95,129 incident HF events [6]. Absolute rates of HF in these cohorts were 3.01 and 7.16 per 1000 person-years in women and 3.71 and 7.11 per 1000 person-years in men. The adjusted RRs for HF associated with type 1 diabetes were 5.15 (95% CI 3.43-7.74) in women and 3.47 (95% CI 2.57-4.69) in men. The women-to-men RRR was 1.47 (95% CI 1.14-1.90).

Worse glycemic control and presence of albuminuria are both associated with increased risk of HF [14,15]. As an example, in a study of 20,985 adults with DM, the incidence of HF ranged from 1.42 per 1000 patient-years for HbA1c <6.5 percent to 5.20 per 1000 for ≥10.5 percent [15]. After adjustment for covariates, each 1 percent increase in HbA1c was associated with a 30 percent increased relative risk of HF during follow-up.

In patients with type 1 DM, there is evidence of decreased cardiovascular events (such as nonfatal MI, stroke, cardiovascular death, angina or coronary revascularization) and mortality with intensive insulin therapy (see "Glycemic control and vascular complications in type 1 diabetes mellitus"). However, data are lacking on the effect of intensive glucose control on risk of incident HF.

HF as risk factor for DM — Not only is there an increased risk of developing HF in patients with DM, there is also a high rate of incident type 2 DM among patients with HF. This risk was illustrated by analysis of data from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial; the incidence of DM was 28 and 21 per 1000 person-years in these studies which is higher than expected for adults of in the general population of similar age (approximately 10 per 1000 person years for adults 45 and older) [1,16,17]. Risk factors for incident DM include longer duration of HF, diuretic therapy, and higher New York Heart Association (NYHA) functional class [1,16,17].

PATHOPHYSIOLOGY — Evidence suggests that DM can cause myocardial dysfunction leading to HF. It has also been postulated that HF contributes to the development of DM.

DM as cause of HF — DM triggers processes that promote atherosclerosis and coronary artery disease (CAD); DM also triggers processes that may cause myocardial disease without major epicardial CAD (known as diabetic cardiomyopathy) [1]. The effect of DM on cardiac function is thought to be mediated by associated conditions including hyperglycemia, and for patients with type 2 DM, insulin resistance and hyperinsulinemia.

Coronary artery disease — In patients with DM, hyperglycemia, insulin resistance and hyperinsulinemia trigger vascular smooth muscle cell proliferation, inflammation, dyslipidemia and endothelial dysfunction leading to accelerated CAD. CAD is the major cause of myocardial ischemia and infarction which results in myocardial dysfunction. The term "ischemic cardiomyopathy" is commonly used to describe significant myocardial dysfunction with left ventricular ejection fraction (LVEF) ≤40 percent caused by CAD (although the technical definition of "cardiomyopathy" excludes dysfunction caused by CAD). (See "Definition and classification of the cardiomyopathies", section on 'Definition and classification'.)

Diabetic cardiomyopathy — Diabetic cardiomyopathy has been defined as ventricular systolic or diastolic dysfunction in a patient with DM without other recognized cause (such as CAD or hypertension) [18-20]. There is limited evidence on the prevalence of diabetic cardiomyopathy.

A study of 2042 residents of Olmsted County aged ≥45 years found a community population prevalence of 1.1 percent [21]. Among individuals with DM, 16.9 percent met criteria for diabetic cardiomyopathy.

In a pooled cohort study that included patients with diabetes, the prevalence of LV dysfunction varied from 67 to 12 percent and depended on the criteria used to define the presence of LV dysfunction [22]. Among asymptomatic patients with evidence of LV dysfunction, the five-year incidence of symptomatic HF was 8 to 13 percent in the least to most restrictive groups.

There is some evidence that diabetic cardiomyopathy is uncommon in patients with type 1 diabetes in the era of intensive insulin therapy [23].

Functional and structural abnormalities — The following cardiac and hemodynamic alterations have been observed in patients with DM [24-27]:

Higher LV mass, wall thickness, and arterial stiffness and reduced systolic function compared with individuals without DM [28]. These abnormalities were independent of BMI and blood pressure.

Prolonged pre-ejection period and a shortened ejection time, both of which correlate with reduced resting LV ejection fraction (LVEF) and diminished systolic function [18]. Diabetic patients also have a lower LVEF in response to exercise, suggesting a reduction in cardiac reserve [29,30].

Diastolic dysfunction [31,32], which may be due in part to increased LV mass [32,33]. For example, an E/e' ratio >15 (a marker of elevated LV diastolic pressure) was observed in 23 percent of 1760 diabetic patients studied in Olmsted County [32]. Greater diastolic dysfunction has been observed in diabetic patients with worse glycemic control and in those who are also hypertensive [34]. In an observational study, HbA1c level correlated with E/e' ratio as well as reduced six-minute walk distance on multivariate analysis [31]. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

Pathologic changes in the myocardium have been described in diabetic patients that may account for observed functional changes [35-37]. These include fibrosis, infiltration of the interstitium with periodic acid-Schiff (PAS)-positive material, and alterations in the myocardial capillary basement membrane, including the formation of microaneurysms.

Etiology — A variety of derangements associated with DM may contribute to ventricular dysfunction [19,38,39]:

Insulin resistance and hyperinsulinemia may cause LV hypertrophy and associated diastolic dysfunction. Diastolic dysfunction is highly prevalent in patients with DM [40].

Advanced glycation end product deposition may increase LV diastolic stiffness and impaired cardiac relaxation directly by cross-linking collagen, or indirectly by enhancing collagen formation or reducing nitric oxide bioavailability [41-43].

Autonomic neuropathy may play a role in the development of LV dysfunction [18]. Sympathetic stimulation increases LV contraction and also increases LV relaxation rates, the latter perhaps by facilitating calcium uptake by the sarcoplasmic reticulum. Autopsy studies in diabetic patients have found depleted myocardial catecholamine stores which could impair both systolic and diastolic function [44]. These changes may be associated with functional impairment in cardiac sympathetic nerve fibers [45].

The capacity of the vascular bed to meet metabolic demands may be impaired by abnormal epicardial vessel tone and microvascular dysfunction [27,46]. Diabetics have impaired endothelium-dependent relaxation [47], a defect that may be related to inactivation of nitric oxide by advanced glycation end products and by increased generation of free radicals [48]. The abnormal vasodilator response in diabetes extends to the coronary microcirculation [49]. Microcirculatory dysfunction in diabetics may be due in part to downregulation of the expression of vascular endothelial growth factor (VEGF).

Decreased insulin availability or responsiveness can impair energy-independent transport of glucose across the cell membrane. Since ischemic myocardium depends upon anaerobic metabolism of glucose, increased glucose uptake and metabolism are necessary for maintenance of myocardial function [50,51]. Diminished insulin activity limits glucose availability, resulting in a shift toward fatty acid metabolism. These changes increase myocardial oxygen utilization and can reduce the compensatory capacity of noninfarcted myocardium [52].

Other factors that may contribute include myocardial accumulation of lipid and other toxic products of fatty acid metabolism [53-55], impaired calcium handling [19,56,57], upregulation of the renin-angiotensin system [19,58], increased reactive oxygen species [19,59], and mitochondrial defects [19,38].

HF as cause of DM — While clinical and laboratory evidence support the above proposed mechanisms by which diabetes and insulin resistance may cause HF, a reciprocal causal relation has been postulated in which HF promotes insulin resistance [39]. Neurohumoral activation in HF causes increased free fatty acid metabolism, which may cause systemic and myocardial insulin resistance. These metabolic alterations may impair myocardial energetics so that a vicious cycle is produced of HF leading to altered metabolism leading to HF.

PROGNOSIS IN PATIENTS WITH HF AND DM — Among patients with HF, those with DM have worse outcomes as demonstrated by studies of community-based HF cohorts as well as data from randomized trials in patients with HF with reduced ejection fraction (HFrEF; LVEF ≤40 percent) or HF with preserved ejection fraction (HFpEF) [1,60-66]. As examples:

A study from the CHARM program on outcomes in patients with HF found that concurrent DM was associated with greater increased risk of cardiovascular death or HF hospitalization in patients with LVEF >40 percent (adjusted hazard ratio [HR] 2.0, 95% CI 1.70-2.36) than in patients with LVEF ≤40 percent (adjusted HR 1.60, 95% CI 1.44-1.77) [65]. For all-cause mortality, the risk conferred by DM was similar in the two groups (adjusted HR 1.84, 95% CI 1.51–2.26 and adjusted HR 1.55, 95% CI 1.38–1.74).

In the PARADIGM-HF trial enrolling patients with HFrEF, there was increased risk of the primary composite outcome of HF hospitalization or cardiovascular mortality in patients with previously undiagnosed DM (HR 1.39, 95% CI 1.17-1.64) or known DM (HR 1.64, 95% CI 1.43-1.87) compared with patients with hemoglobin A1c (HbA1c) <6.0 percent [63]. Patients with pre-diabetes mellitus were also at higher risk (HR 1.27, 95% CI 1.10-1.47) compared with those with HbA1c <6.0 percent.

Among patients with diabetes, those who develop HF have markedly poorer survival than in those who do not.

In a national sample of Medicare claims, the mortality rates were 32.7 and 3.7 percent per year, respectively (HR 10.6) [7]. This risk was only slightly attenuated by adjustment for age, sex, and race (HR 9.5). The five-year survival rate for diabetics with HF was 12.5 percent.

MANAGEMENT OF HF IN DM — Management of HF in patients with DM is largely the same as treatment of HF in patients without DM. Multidisciplinary team-based care may be helpful although specific data on programs for patients with HF and DM are limited [1].

General management — General management of patients with HF and DM includes lifestyle modification, support of self-care, and palliative care. In addition, management of HFrEF and HFpEF includes exercise training. Data from the HF-ACTION trial showed that patients with HFrEF with concurrent DM had lower baseline functional capacity but significant improvements in peak VO2 and six-minute walk distance [67]. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Cardiac rehabilitation in patients with heart failure".)

Pharmacologic therapy

For HFrEF — Pharmacologic therapy for HFrEF in adults with DM is generally the same as for adults with HFrEF; the efficacy of the medical regimen is similar in these two groups. Data supporting this approach for HFrEF are available for angiotensin system blockers (angiotensin converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or angiotensin receptor-neprilysin inhibitor [ARNI]), beta blockers, mineralocorticoid receptor antagonists [MRAs], and sodium-glucose co-transporter 2 (SGLT2) inhibitors [1]. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

Angiotensin system blockers and sacubitril-valsartan – Angiotensin system blockers have favorable effects on the development of DM and glycemic control in patients with HFrEF [1] and have similar efficacy in patients with and without DM:

In a meta-analysis of ACE inhibitor trials in HFrEF that included 2398 patients with diabetes and 10,188 patients without diabetes, the survival benefit with ACE inhibitor therapy was similar for those with diabetes as for those without (relative risk [RR] 0.84 and 0.85, respectively) [68].

In ARB trials in patients with HF (some but not all limited to HFrEF), similar benefits on composite outcomes were observed in patients with and without DM [1]. As an example, in the CHARM program which enrolled patients with HFrEF and HF with LVEF >40 percent, the beneficial effect of candesartan on cardiovascular morbidity and mortality was similar in patients with and without DM [65].

In PARADIGM-HF, the benefit of the ARNI sacubitril-valsartan compared with enalapril in patients with HFrEF was consistent across the range of HbA1c [63].

Beta blockers – Beta blockers were found to have generally similar mortality benefits in patients with HFrEF with and without DM (eg, RR of mortality from HF 0.77, 95% CI 0.61-0.96 in diabetics and RR 0.65, 95% CI 0.57-0.74 in nondiabetics [68]) in meta-analyses [1]. However, one meta-analysis found a greater benefit in individuals without DM (RR of mortality 0.84, 95% CI 0.73-0.96 in diabetics and RR 0.72, 95% CI 0.65-0.79 in nondiabetics) [69]. Each of the three beta blockers with established efficacy in reduce mortality in patients with HFrEF (carvedilol, metoprolol succinate, and bisoprolol), also reduce mortality in the subgroup of patients with DM and HFrEF with generally similar degrees of risk reduction [1].

Carvedilol may have favorable effects on glycemic control not identified with bisoprolol or metoprolol tartrate [1,70-74]. Therefore, carvedilol may be preferred in patients with HFrEF with poorly controlled DM.

Mineralocorticoid receptor antagonists – In the EMPHASIS-HF trial in patients with HFrEF, the beneficial effect of eplerenone compared with placebo was similar in patients with DM (hazard ratio [HR] 0.54, 95% CI 0.42-0.70) and without DM (HR 0.72, 95% CI 0.58-0.88) [75].

For patients who are candidates for MRA therapy, spironolactone may have less effect on blood glucose levels than eplerenone, though the differences may not be clinically significant. A systematic review of 18 randomized trials found that spironolactone slightly increased hemoglobin A1c by an average of 0.16 percent (95% CI 0.02-0.30) [76]. In a small randomized trial in patients with HFrEF, the hemoglobin A1c was significantly increased in patients treated with spironolactone 25 mg daily (from 5.61 percent to 5.8 percent) but not in those treated with eplerenone 50 mg daily [77].

Sodium-glucose co-transporter 2 inhibitors – The SGLT2 inhibitor dapagliflozin had similarly beneficial effects on the primary composite outcome (hospitalization for HF, an urgent visit resulting in intravenous therapy for HF, or death from cardiovascular causes) in patients with type 2 DM (HR 0.75, 95% CI 0.63-0.90) and without type 2 DM (HR 0.73, 95% CI 0.60-0.88) in the DAPA-HF trial [78]. In addition, the effect of empagliflozin on the combined endpoint of cardiovascular death or HF hospitalization was similar in patients with type 2 DM (HR 0.72, 95% CI 0.60-0.87) and without type 2 DM (HR 0.78, 95% CI 0.64-0.97) [79].

Use of SGLT2 inhibitors in patients with HFrEF (with or without type 2 DM) is discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Sodium-glucose co-transporter 2 inhibitors'.)

In patients with HF and diabetes, additional agents for the treatment of HF may be indicated. Subgroup analyses of large trials that evaluated the efficacy of digoxin [80], ivabradine [81], and vericiguat [82] found similar efficacy between patients with and without diabetes. A complete discussion of these agents can be found elsewhere. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

For HFpEF — Pharmacologic therapy of HFpEF in adults with DM is the same as that for other adults and includes appropriate use of diuretics, an SGLT2 inhibitor, MRA, and sacubitril-valsartan. The approach to use of these agents in patients with HFpEF with and without DM is discussed elsewhere. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Pharmacotherapy'.)

Device therapy — Standard indications for implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) apply to patients with DM and HF. Studies have found similar improvements in outcomes from ICD (for primary prevention of sudden cardiac arrest) and/or CRT therapy in patients with and without DM [1]. One exception is the SCD-HeFT trial in patients with HFrEF with LVEF ≤35 percent; the reduction in death with ICD in patients with DM (HR 0.95, 97.5% CI 0.68-1.33) was nominally less but overlapped that in patients without DM (HR 0.67, 97.5% CI 0.50-0.90). Presence of DM is a risk factor for worse survival in patients receiving ICDs for secondary prevention of sudden cardiac arrest [83] but data are lacking on the impact of DM on the efficacy of ICD therapy for secondary prevention. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

Advanced therapies — Heart transplantation is an option for selected patients with DM and advanced HF. DM in common among patients undergoing heart transplantation (eg, 18 percent in one series) [84]. DM with evidence of significant end-organ damage (eg, neuropathy or nephropathy, but not nonproliferative retinopathy) or persistent poor glycemic control (glycosylated hemoglobin [HbA1c] >7.5 percent or 58 mmol/mol) despite optimal effort is a relative contraindication to heart transplantation [85]. However, carefully selected patients with DM without significant renal dysfunction can undergo successful cardiac transplantation with similar morbidity and mortality as patients without DM. For selected patients with DM and renal dysfunction, combined heart and kidney transplantation is an option. (See "Heart transplantation in adults: Indications and contraindications".)

DM with severe end-organ damage is a relative contraindication to durable mechanical circulatory support. Among patients with advanced HF and DM who undergo LVAD placement, glycemic control often improves [1]. (See "Management of long-term mechanical circulatory support devices" and "Treatment of advanced heart failure with a durable mechanical circulatory support device".)

MANAGEMENT OF DM IN HF — The initial management of blood glucose as well as the general medical care in adults with type 2 or type 1 diabetes mellitus and HF is similar to that for other adults. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Initial pharmacologic therapy' and "Management of blood glucose in adults with type 1 diabetes mellitus" and "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

For patients with type 2 diabetes and HF, who do not tolerate or have suboptimal glycemic control with initial therapy, the choice of alternative or additional glucose-lowering medication is guided by patient comorbidities, and in particular, the presence of clinical cardiovascular disease, including HF. Diabetes medications with demonstrated cardiovascular benefit are reviewed separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Initial pharmacologic therapy' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

The use of a sodium-glucose co-transporter 2 (SGLT2) inhibitor to treat patients with HF is discussed separately. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Preferred therapies for symptomatic patients'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

Epidemiology – There is a well-established association between diabetes mellitus (DM) and heart failure (HF) that is partly but not entirely linked to coronary heart disease and hypertension. Patients with type 1 or type 2 DM are at increased risk for development of HF. However, a causal relationship between improved glucose control and reduced HF has not been established. (See 'Epidemiology' above.)

Pathophysiology – Evidence suggests that DM can cause myocardial dysfunction leading to HF. DM triggers processes that promote atherosclerosis and coronary artery disease (CAD); DM also triggers processes that may cause myocardial disease without major epicardial CAD (known as diabetic cardiomyopathy) [1]. The effect of DM on cardiac function is thought to be mediated by associated conditions including hyperglycemia, and for patients with type 2 DM, insulin resistance and hyperinsulinemia. (See 'DM as cause of HF' above.)

Prognosis in patients with HF and DM – Among patients with HF, those with DM have worse outcomes as demonstrated by studies of community-based HF cohorts as well as data from randomized trials in patients with HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤40 percent) or HF with preserved ejection fraction (HFpEF). (See 'Prognosis in patients with HF and DM' above.)

Management of HF in patients with DM – Management of HF in patients with DM is largely the same as treatment of HF generally in patients without DM. Multidisciplinary team-based care may be helpful although specific data on programs for patients with HF and DM are limited. (See 'Management of HF in DM' above.)

General management – General management includes lifestyle modification, support of self-care, and exercise training. (See 'General management' above.)

Therapy for HFrEF – Pharmacologic therapy for HFrEF in adults with DM is generally the same as for adults with HFrEF given evidence of similar efficacy of for nearly all agents in patients with or without DM. (See 'For HFrEF' above and "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

Therapy for HFpEF – Pharmacologic therapy for HFpEF in adults with DM is the same as for other adults with HFpEF. (See 'For HFpEF' above and "Treatment and prognosis of heart failure with preserved ejection fraction".)

Device therapy – Standard indications for implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) apply to patients who have HF and DM. (See 'Device therapy' above.)

Advanced therapies – Heart transplantation and durable mechanical circulatory support are options for selected patients with advanced HF and DM without significant end-organ damage. (See 'Advanced therapies' above.)

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Topic 3458 Version 27.0

References

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