5,557

New-Onset Diabetes in Heart Failure Patients: A Complex Relationship with Clinical Implications

Juana A Flores-Le-Roux, Juan J Chillarón, David Benaiges, Juan Pedro-Botet

Juana A Flores-Le-Roux, Juan J Chillarón, David Benaiges, Juan Pedro-Botet, Endocrinology and Nutrition Department, Hospital del Mar, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

Correspondence to: Juan Pedro-Botet, Endocrinology and Nutrition Department, Hospital del Mar, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Email: 86620@parcdesalutmar.cat
Telephone: +932483711
Fax: +932483313
Received: February 26, 2014
Revised: April 10, 2014
Accepted: April 16, 2014
Published online: May 10, 2014

ABSTRACT

The relationship between heart failure and diabetes mellitus (DM) is bidirectional. DM is a known risk factor for the development of heart failure and is related to a worse outcome. On the other hand, some studies have found that heart failure is also associated with a greater incidence of new-onset diabetes. This relationship has been less evaluated and the underlying mechanisms are not fully understood. We present the evidence linking heart failure with insulin resistance and the development of DM, as well as the possible mechanisms. Furthermore, medications that have been shown to improve clinical outcomes in patients with chronic heart failure may be associated with the development of incident diabetes whereas some hypoglycemic agents raise safety concerns in these patients. Therefore, we will consider pharmacologic interventions that can reverse insulin resistance in this specific population.

Key words: Beta-blockers; Heart failure; Insulin resistance; Insulin sensitizers; Renin-angiotensin-aldosterone system; Type 2 diabetes

© 2014 The Authors. Published by ACT Group Ltd.

Flores-Le-Roux JA, Chillarón JJ, Benaiges D, Pedro-Botet J. New-Onset Diabetes in Heart Failure Patients: A Complex Relationship with Clinical Implications. Journal of Cardiology and Therapy 2014; 1(4): 65-73 Available from: URL: http://www.ghrnet.org/index.php/jct/article/view/671

INTRODUCTION

Heart failure and diabetes mellitus (DM) are chronic diseases that frequently occur in the same patient[1,2]. They have a bidirectional relationship since each condition may impact on the other in terms of causation and outcome (Figure 1). In this regard, DM, characterized by insulin resistance and β-cell dysfunction, is a recognized risk factor for the development of heart failure and this risk increases proportionally as metabolic control worsens[1,3,4]. Heart failure is up to five times more frequent in patients with DM[5,6] and has increased morbidity and mortality[7-10]. Data from the Uppsala study showed that insulin resistance precedes and predicts the development of chronic heart failure, independently of established risk factors for heart failure including diabetes itself[11]. More recently, Vardeny et al[12] provided further support for the incremental risk of heart failure in nondiabetic participants with insulin resistance in the Atherosclerosis Risk in Communities (ARIC) study.

On the other hand, predictors of diabetes in the general population are well established and include anthropometric adiposity parameters, dysglycemia markers and risk scores[13]. However, some studies have stressed the fact that patients with heart failure also have an increased risk of developing DM[14-20]. This causal relationship has been less evaluated and the mechanisms underlying this association are not clearly understood. Interestingly, there has been a shift in the understanding of heart failure in the last decade. In this respect, beyond traditional hemodynamic factors and neurohormonal activation, it is increasingly suggested that chronic heart failure is a much more complex systemic disease involving metabolic derangements that implicate organs such as adipose tissue and skeletal muscle, and the endocrine system, through leptin, adiponectin and insulin-like growth factor. Thus, we considered of interest to review the available evidence linking heart failure with insulin resistance and the development of DM.

EPIDEMIOLOGIC EVIDENCE LINKING HEART FAILURE WITH NEW-ONSET DM

Nearly 25% of all patients participating in major heart failure clinical trials were diagnosed with diabetes at entry compared with only 7% of the general population[21,22]. In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study[15], 43% of patients had either clinically-overt diabetes or preclinical abnormalities of glucose metabolism at the time of enrollment. On the other hand, different studies have reported an increased incidence of DM in patients with heart failure who were normoglycemic at baseline. The first demonstration of the high risk of developing diabetes was by Amato et al[14] in a longitudinal study of elderly patients with heart failure. DM during the 3-year follow-up occurred in 28.8% of patients with heart failure and 18.3% of controls. Heart failure was a risk factor for developing DM regardless of age, sex, body mass index or drug therapy with a 1.4 age-adjusted relative risk. In the Bezafibrate Infarction Prevention (BIP) study[16], the mean baseline glucose concentration was shown to increase during 7.7 years of follow-up in 2,616 non-diabetic patients. DM developed in these patients in a stepwise manner, from 13% in those with a New York Heart Association (NYHA) class I to 20% in patients with NYHA functional class III. A subanalysis of the Studies Of Left Ventricular Dysfunction (SOLVD)[17] found a DM incidence of 5.9% during a mean follow-up of 3 years in the enalapril-treated arm and 22.4% in the placebo group. These results concur with those reported by the Carvedilol or Metoprolol European Trial (COMET)[19], in which DM was diagnosed during follow-up in 10.3% and 12.6% of patients receiving carvedilol or metoprolol, respectively. A recent study evaluating incident diabetes in patients with cardiovascular disease, heart failure, renal disease or depression found heart failure to be the major independent predictor of incident DM, with a 48% increased risk compared with those without heart failure[20]. In non-diabetic patients with chronic heart failure in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program[23], A1C and body mass index were the main factors associated with new-onset diabetes.

Thus, according to the above-mentioned studies, the risk of incident DM in subjects with heart failure is 10 to 48% higher than in the general population adjusted for age.

HEART FAILURE AND INSULIN RESISTANCE

Although epidemiologic studies have established the association between heart failure and the development of DM, the underlying pathophysiologic explanation remains to be clarified. Several lines of clinical research suggest that heart failure is an insulin-resistant state responsible for the increased incidence of DM in these patients. Clinical studies in the early 1990s using the euglycemic hyperinsulinemic clamp demonstrated the existence of fasting hyperglycemia and insulin resistance in patients with heart failure, regardless of the etiology[24,25]. Similarly, in 38 patients with heart failure and ventricular systolic dysfunction, 58% decreased insulin sensitivity and a 131% increase in fasting insulin were found compared with healthy controls, regardless of the etiology of heart failure[26]. In 129 patients with heart failure, Al Zadjali et al[27] observed a 61% prevalence of insulin resistance, a condition that was associated with waist circumference, and triglyceride, high-density lipoprotein (HDL) cholesterol and leptin concentrations. Other studies also revealed a high prevalence of abnormal glucose metabolism in patients with heart failure. A study evaluating carbohydrate metabolism disorders in 94 heart failure patients found a 29% prevalence of known DM, a 15% prevalence of unknown DM, 24% presented oral glucose intolerance and 27% had insulin resistance (as defined by a homeostasis model assessment-insulin resistance above 2); thus, overall 94.6% of heart failure patients presented carbohydrate metabolism disturbances at the time of inclusion in the study[28].

Additionally, several studies reported a direct relationship between the severity of heart failure and insulin resistance, with decreased functional exercise capacity or increased B-type natriuretic peptide levels being associated with greater insulin resistance[25,27]. Swan et al[26] demonstrated that increased heart failure severity, in terms of reduced exercise capacity, correlated with increased insulin resistance, regardless of the etiology of heart failure. These results concur with those of other studies in which insulin resistance increased progressively with worsening of heart failure functional NYHA class[15,19,29]. Berry et al[30], in 454 consecutive patients admitted with acute heart failure, confirmed that abnormal glucose tolerance was a strong predictor of in-hospital mortality.

Taken together, these data indicate that the prevalence of insulin resistance in patients with heart failure is high and correlates with its severity. Furthermore, the prognostic value of insulin resistance is independent of other parameters including left ventricular ejection fraction and peak oxygen consumption, which may imply that insulin resistance could have a pathogenetic role rather than just be a severity marker.

MECHANISM OF INSULIN RESISTANCE IN PATIENTS WITH CHRONIC HEART FAILURE

Heart failure is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood associated with local and systemic metabolic derangements and the development of a progressive catabolic state[31]. Pathologic changes associated with insulin resistance and compensatory hyperinsulinemia are shown in figure 2. The exact mechanisms by which heart failure is accompanied by resistance to the metabolic actions of insulin are unknown, although several possible pathogenetic mechanisms have been involved.

Overactivity of the sympathetic nervous system

This is the most accepted pathway. Elevated norepinephrine levels correlate with the hemodynamic parameters of heart failure, as with insulin sensitivity and glucose tolerance[24,32,33]. Since the peripheral uptake of glucose and insulin in skeletal muscle is mediated by the vascular tone of afferent arterioles, arteriolar vasoconstriction triggered by the stimulation of α-adrenergic receptors causes blood flow to bypass skeletal muscle with a subsequent decrease in glucose utilization[34].

Moreover, the activity of the sympathetic nervous system increases lipolysis in adipose tissue through direct activation of the β-adrenergic cell receptor, thereby increasing circulating free fatty acid concentrations[35]. In patients with heart failure, higher baseline norepinephrine levels correlate with those of free fatty acids, and the decrease in the free fatty acids mediated by insulin is dimmed compared to individuals without heart failure[24]. The increase in free fatty acids inhibits glucose uptake mediated by insulin in skeletal muscle. In addition, free fatty acids raise endogenous glucose production by activating hepatic glycogenolysis[36].

Sympathetic nervous system overactivity, as indicated by elevated heart rate, has also been associated with decreased insulin sensitivity and compensatory hyperinsulinemia in populations without heart failure[37,38]. Although sympathetic hyperactivation as a cause of insulin resistance in heart failure has been the most promulgated theory, some studies found no correlation between plasma levels of norepinephrine and insulin resistance[26,27], suggesting that other factors may influence the decline in insulin sensitivity in heart failure patients.

Adiponectin resistance

Adiponectin is a key adipokine which, together with leptin and resistin, contributes to the regulation of energy homeostasis by improving insulin sensitivity. It exerts multiple further actions, such as increasing endothelial function, and has antiapoptotic, anti-inflammatory and antiatherogenic effects (Figure 3). Circulating adiponectin in human plasma may form oligomers and multimers or may exist in monomers. Although the exact role of these isoforms is unclear, it seems that high-molecular-weight adiponectin is of particular importance as it binds to the adiponectin receptor 1 (AdipoR1) that is mainly expressed in skeletal muscle and to the AdipoR2 expressed in the liver to exert insulin-sensitizing and vasoprotective effects[39]. While the adipocyte is well established as the predominant cell type to produce adiponectin, emerging data suggest cardiomyocytes[40-42], skeletal muscle cells[43,44] and other tissues as alternative adiponectin sources[45]. However, it is unclear how much of this non-adipose expression contributes to the circulating adiponectin levels. Van Berendoncks et al[46] found a 5-fold increase in adiponectin expression in skeletal muscle cells of patients with mild to moderate chronic heart failure. In turn, a decreased receptor expression of AdipoR1 and target genes in lipid and glucose metabolism was observed. Thus, increased levels of circulating adiponectin in chronic heart failure could reflect a functional adiponectin resistance. Recent studies using a ventricular assist device suggested that this metabolic scenario could be reversible in patients with advanced heart failure[47,48].

Genetic predisposition

Patients who develop DM may have a genetic susceptibility to failure of the β-cell pancreatic secretory response to chronic hyperglycemia caused by insulin resistance. Thus, heart failure could select predisposed patients to develop DM by a reduction in the insulin sensitivity mediated by chronic activation of the sympathetic nervous system.

The clinical expression of DM usually requires the combination of resistance to peripheral actions of insulin and decreased insulin secretion in response to hyperglycemia[49]. Resistance to insulin action results in decreased glucose uptake in skeletal muscle, decreased inhibition of hepatic glucose production and increased lipolysis and free fatty acid release from adipose tissue. Patients with heart failure may have decreased sensitivity to insulin and glucose intolerance without changes in basal glucose. Over time, however, the metabolic consequences of insulin resistance such as hyperglycemia and increased free fatty acids, in a genetically susceptible population, can result in reduced pancreatic β cell function. This exhaustion of β cells is associated with a decrease in the mass of pancreatic β cells mediated by apoptosis, as demonstrated in autopsy studies of DM patients[50].

INSULIN RESISTANCE AND MYOCARDIUM

Glucose is a specially important substrate for the heart and influences both normal cardiac function and the response to ischemia that promotes glucose uptake and decreases the utilization of free fatty acids by the human heart. On the other hand, patients with chronic heart failure due to coronary artery disease are more likely to have abnormalities in glucose metabolism than patients with heart failure due to idiopathic dilated cardiomyopathy[26].

The development of cardiac insulin resistance may occur independently of systemic insulin resistance; however, systemic insulin resistance significantly contributes to cardiac insulin resistance owing to increased circulating levels of nutrients, oxidative stress and disturbances in the neurohumoral and cytokine balance[51].

Insulin resistance is involved in potentially harmful metabolic dysfunctions that can affect energy supply and blood flow to the myocardium and skeletal muscle[52,53]. Insulin increases glucose utilization and reduces myocardial free fatty acid oxidation by various mechanisms. Obtaining oxygen for glucose oxidation is more efficient than for fatty acid oxidation, and this modification in cardiac metabolism is theoretically beneficial to the heart, mainly during ischemia. This mechanism may have been responsible for the beneficial effects of glucose-insulin and potassium infusions observed in several clinical trials[54,55].

The presence of insulin resistance or DM has been shown to affect glucose metabolism at different levels in the myocardium, from glucose uptake to final oxidation by mitochondria[56-58]. These changes are responsible for reduced resting cardiac efficiency that may predispose to the development of diabetic cardiomyopathy, but also to increased susceptibility to ischemia. It is known that subjects with insulin resistance are at increased risk of heart failure and death compared with insulin-sensitive subjects and that these differences cannot be justified only by other risk factors such as hypertension or vascular disease[59].

PHARMACOLOGIC INTERVENTION FOR INSULIN RESISTANCE IN HEART FAILURE

The clinical significance of insulin resistance in patients with chronic heart failure lies in potentially reversible metabolic changes, especially at early stages of cardiac dysfunction. Thus, since heart failure is an insulin-resistant state, insulin resistance may be considered a therapeutic target in these patients.

Lifestyle interventions are essential tools in the management of insulin resistance. Physical activity was shown to improve insulin resistance in patients with impaired glucose tolerance in the Diabetes Prevention Project (DPP) study[60]. Exercise training has proved to enhance muscle glucose uptake and reduce insulin resistance in patients with idiopathic cardiomyopathies[61]. Diet and drug-induced weight loss studies have also been reported to improve functional status in patients with chronic heart failure[62].

Controversial data exist regarding pharmacologic interventions in heart failure: some antidiabetic medications raise safety concerns in these patients, while heart failure medication that has been shown to improve clinical outcomes may be associated with the development of new-onset diabetes. We will review the latest evidence in pharmacologic interventions that can reverse insulin resistance in this specific population.

ACEIs and ARBs

The use of ACEIs and ARBs has been reported to significantly reduce the incidence of new-onset diabetes in large heart failure trials[17,18]. In the SOLVD program, enalapril significantly reduced the incidence of diabetes in patients with left ventricular dysfunction, mainly in those with impaired fasting plasma glucose[17]. Furthermore, enalapril was the greatest predictor for a lower risk of developing diabetes in the multivariate analysis. In the CHARM-Preserved study in patients with chronic heart failure and preserved ejection fraction, treatment with candesartan was associated with a 40% reduction in the development of newly-diagnosed diabetes, and in other subgroups of the CHARM study the decline was 22%[18]. Overall, the results of this subanalysis suggest that renin-angiotensin system blockade with ACEIs or ARBs prevents the development of DM in patients with chronic heart failure. However, in a clinical trial designed to evaluate the effect of telmisartan and candesartan on insulin sensitivity in patients with heart failure, no significant changes in insulin sensitivity were observed after 5 months of treatment[28]. In the Diabetes Reduction Assessment with Ramipril or Rosiglitazone Medication (DREAM) study, ramipril treatment did not significantly lower the incidence of new-onset diabetes in patients with impaired fasting glucose[63]. However, in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study[64], valsartan modestly reduced the incidence of DM. These differences in the reduction of incident diabetes and insulin resistance could be due to aldosterone escape that could affect their efficacy[65-67]. The meta-analysis of Andraws et al[68] proved that renin-angiotensin system drug inhibition may prevent the onset of DM. Specifically, in ACEI trials, the reduction in the risk of developing DM was 28%, and 27% in the ARB trials.

Beta-blockers

Beta-blockers have a different effect on lipid and glucose metabolism according to their receptor specificity. Several studies have reported that first-generation beta-blockers increased the risk of diabetes after 10 years of treatment[69]. The ARIC Study showed that propranolol and timolol raised the diabetes risk by 28%[70]. In contrast, second-generation beta-blockers such as atenolol and metoprolol, among others, have been associated with 13% and 20% reductions in insulin sensitivity, respectively[34,71]. Finally, third generation beta-blockers, such as dilevalol, carvedilol and celiprolol which combine properties of nonselective beta-blockers with other effects such as vasodilatation and protection against oxidation, usually increase insulin sensitivity and improve the lipid profile. In a study of 72 non-diabetic patients, insulin sensitivity dropped by 14% after 12 weeks of treatment with metoprolol compared with an increase of 9% in those who continued treatment with carvedilol[72]. In the COMET study[19], carvedilol was associated with a reduced incidence of new-onset DM in patients with chronic heart failure compared with metoprolol. Furthermore, non-selective beta-blockers such as nebivolol and carvedilol that do not worsen insulin sensitivity appear to exert beneficial effects on heart failure[73]. Nebivolol also inhibits the angiotensin II-induced activation of NADPH oxidase and reactive oxygen species, thereby providing a rationale for its exerting beneficial effects on insulin sensitivity[74].

Thiazolidinediones

Thiazolinidediones are peroxisome proliferator-activated (PPAR-γ) receptor agonists that modulate the transcription of insulin-sensitive genes involved in the control of glucose and lipid metabolism in adipose tissue, muscle and liver. It is recognized that they improve insulin sensitivity and reduce free fatty acids; however, as a result of their effects on renal sodium reabsorption and vascular permeability, they cause fluid retention, edema and weight gain, thereby raising the risk of heart failure[75].

The European Society of Cardiology (ESC) 2012 guidelines for the diagnosis and management of heart failure included thiazolidinediones on the list of treatments not recommended[76]. Similarly, in accordance with American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 guidelines, thiazolidinediones adversely affect the clinical status of patients with current or previous symptoms of heart failure with reduced ejection fraction and should be avoided or withdrawn whenever possible[77].

Metformin

It is known that the use of metformin prevents progression to new-onset DM in patients with prediabetes[60]. Until recently, metformin was contraindicated in heart failure patients; however, heart failure patients on metformin have better outcome than those treated otherwise[78-81]. A systematic review of observational studies involving 34,000 patients with DM and heart failure on metformin indicated that this medication is at least as safe as other glucose-lowering treatments in patients with DM and heart failure, and even in those with reduced left ventricular ejection fraction or concomitant chronic kidney disease[82]. In a randomized controlled trial in 62 heart failure patients with insulin resistance to receive metformin or placebo for a period of 4 months, Wong et al[83] analyzed the effect on exercise capacity. Although no enhancement of exercise capacity measured by peak oxygen uptake was observed, metformin treatment significantly improved insulin resistance with a favorable safety profile. Recently, metformin was shown to prevent the development of chronic heart failure in a hypertensive insulin-resistant rat model[84]. Thus, in view of this evidence, metformin use appears to be safe and may be beneficial in chronic heart failure patients. Nevertheless, prospective randomized studies are required to ascertain the benefits of metformin treatment in patients with heart failure.

Incretin-based therapies

Incretin-based therapy such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors, in addition to the benefits of tight glycemic control, has independent cardioprotective effects that might also provide a novel treatment strategy for patients with insulin resistance and heart failure[85]. A recent meta-analysis confirmed the cardiovascular safety of GLP-1 receptor agonists, at least in the short term and in low-risk individuals[86]. Two main findings of the potential benefits of GLP-1 agonists in heart failure stem from the meta-analysis of Munaf et al[87]. Firstly, preclinical studies on different animal models showed favorable functional effects of GLP-1 in failing hearts, with significant improvements in left ventricular systolic and diastolic function. Secondly, the four clinical studies included in this meta-analysis also showed enhanced left ventricular contractile function in patients with chronic heart failure, but without improvement in B-type natriuretic peptide levels. The small sample sizes and non-randomized nature of these studies are the main limitations.

Regarding DPP-4 inhibitors, two meta-analyses confirmed their cardiovascular safety, at least in the short and medium term[88,89]. Of the four large prospective randomized trials with cardiovascular outcomes, two are ongoing[90,91] and two have been completed. Among the latter, the rates of major adverse cardiovascular events with alogliptin treatment in DM patients who had suffered an acute coronary syndrome were not increased compared with placebo[92]. Further analysis of the EXAMINE trial showed that new-onset heart failure and hospitalizations for heart failure were not increased with alogliptin compared with placebo[93]. Contradictory data were reported in the Saxagliptin Assessment of Vascular Outcomes Recorded (SAVOR) study[94]; despite not affecting cardiovascular event rates, saxagliptin was associated with a 27% increase in the risk of hospitalization for heart failure. Therefore, we do not currently have enough evidence to support the use of incretin-based therapies to improve insulin sensitivity in patients with chronic heart failure.

CONCLUSIONS

The relationship between heart failure and DM is bidirectional. Although DM is a recognized risk factor for the development of heart failure, the association between heart failure and DM development has been less explored and the underlying pathophysiologic explanation remains to be clarified. Chronic heart failure is an insulin resistance state and the degree of insulin resistance is associated with disease severity and prognosis. Among the pathophysiologic mechanisms that may explain the association between heart failure and insulin resistance, the most accepted are sympathetic overactivity, increased circulating free fatty acid concentration and adiponectin resistance. Pharmacologic and non-pharmacologic strategies to improve insulin sensitivity must be considered in the clinical management of patients with heart failure although further studies are required to assess their efficacy and safety (Table 1).

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

REFERENCES

1 Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001; 103: 2668-2673

2 Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence and risk factors. Diabetes Care 2001; 24: 1614-1619

3 UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703-713

4 Horwich TB, Fonarow GC. Glucose, obesity, metabolic syndrome, and diabetes relevance to incidence of heart failure. J Am Coll Cardiol 2010; 55: 283-293

5 Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 1974; 23:105-111

6 Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974; 34: 29-34

7 Bauters C, Lamblin N, McFadden E, Van Belle E, Millaire A, de Groote P. Influence of diabetes mellitus on heart failure risk and outcome. Cardiovasc Diabetol 2003; 2: 1

8 de Groote P, Lamblin N, Mouquet F, Plichon D, McFadden E, Van Belle E, Bauters C. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J 2004; 25: 656-662

9 Ahmed A, Aban IB, Vaccarino V, Lloyd-Jones DM, Goff DC, Zhao J, Love TE, Ritchie C, Ovalle F, Gambassi G, Dell’Italia LJ. A propensity matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age. Heart 2007; 93: 1584-1590.

10 Frigola-Capell E, Comin-Colet J, Davins-Miralles J, Gich-Saladich IJ, Wensing M, Verdú-Rotellar JM. Survival in Mediterranean ambulatory patients with chronic heart failure. A population-based study. Rev Esp Cardiol 2013;66:539-544.

11. Ingelsson E, Sundström J, Arnlöv J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA 2005; 294: 334-341

12 Vardeny O, Gupta DK, Claggett B, Burke S, Shah A, Loehr L, Rasmussen-Torvik L, Selvin E5, Chang PP, Aguilar D, Solomon SD. Insulin resistance and incident heart failure: the ARIC Study (Atherosclerosis Risk in Communities). JACC Heart Fail 2013; 1: 531-546

13 Buijsse B, Simmons RK, Griffin SJ, Schulze MB. Risk assessment tools for identifying individuals at risk of developing type 2 diabetes. Epidemiol Rev 2011; 33: 46-62

14 Amato L, Paolisso G, Cacciatore F, Ferrara N, Ferrara P, Canonico S, Varricchio M, Rengo F. Congestive heart failure predicts the development of non-insulin-dependent diabetes mellitus in the elderly. The Osservatorio Geriatrico Regione Campania Group. Diabetes Metab 1997; 23: 213-218

15 Suskin N, McKelvie RS, Burns RJ, Latini R, Pericak D, Probstfield J, Rouleau JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 2000 ;21: 1368-1375

16 Tenenbaum A, Motro M, Fisman EZ, Leor J, Freimark D, Boyko V, Mandelzweig L, Adler Y, Sherer Y, Behar S. Functional class in patients with heart failure is associated with the development of diabetes. Am J Med 2003; 114: 271-275

17 Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362: 777-781

18 Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif JC. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003; 107: 1291-1296

19 Torp-Pedersen C, Metra M, Charlesworth A, Spark P, Lukas MA, Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Remme WJ, Scherhag A; COMET investigators. Effects of metoprolol and carvedilol on pre-existing and new onset diabetes in patients with chronic heart failure: data from the Carvedilol or Metoprolol European Trial (COMET). Heart 2007; 93: 968-973

20 Nichols GA, Moler EJ. Cardiovascular disease, heart failure, chronic kidney disease and depression independently increase the risk of incident diabetes. Diabetologia 2011; 54: 523-526

21 Kostis JB, Sanders M. The association of heart failure with insulin resistance and the development of type 2 diabetes. Am J Hypertens 2005; 18: 731-737

22 MacDonald MR, Petrie MC, Hawkins NM, Petrie JR, Fisher M, McKelvie R, Aguilar D, Krum H, McMurray JJ. Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J 2008; 29: 1224-1240

23 Preiss D, Zetterstrand S, McMurray JJ, Ostergren J, Michelson EL, Granger CB, Yusuf S, Swedberg K, Pfeffer MA, Gerstein HC, Sattar N; Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Investigators. 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 2009; 32: 915-920

24 Paolisso G, De Riu S, Marrazzo G, Verza M, Varricchio M, D’Onofrio F. Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure. Metabolism 1991; 40: 972-977

25 Paolisso G, Gambardella A, Galzerano D, D’Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D’Onofrio F. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 1994; 43: 174-179

26 Swan JW, Anker SD, Walton C, Godsland IF, Clark AL, Leyva F, Stevenson JC, Coats AJ. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J Am Coll Cardiol 1997; 30: 527-532

27 ALZadjali MA, Godfrey V, Khan F, Choy AM, Doney AS, Wong AK, Petrie JR, Struthers AD, Lang CC. Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. J Am Coll Cardiol 2009;53:747-753.

28. Clodi M, Resi M, Stelzeneder D, Pacini G, Tura A, Mörti D, Struck J, Morgenthaler NG, Bergmann A, Riedl M, Anderwald-Stadler M, Luger A, Pacher R, Hülsmann M. Interactions of glucose metabolism and chronic heart failure. Exp Clin Endocrinol Diabetes 2009; 117: 99-106

29 Doehner W, Rauchhaus M, Ponikowski P, Godsland IF, von Haehling S, Okonko DO, Leyva F, Proudler AJ, Coats AJ, Anker SD. Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure. J Am Coll Cardiol 2005; 46: 1019-1026

30 Berry C, Brett M, Stevenson K, McMurray JJ, Norrie J. Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure. Heart 2008; 94: 296-304

31 Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation 2007; 116: 434-448

32 Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982; 49: 1659-1666

33 Marangou AG, Alford FP, Ward G, Liskaser F, Aitken PM, Weber KM, Boston RC, Best JD. Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis. Metabolism 1988; 37: 885-891

34 Pollare T, Lithell H, Selinus I, Berne C. Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ 1989; 198: 1152-1157

35 Ng TB. Adrenergic control of lipolysis in adipocytes of several mammalian species. Comp Biochem Physiol C 1985; 82: 463-466

36 Boden G. Free fatty acids, insulin resistance and type 2 diabetes mellitus. Proc Assoc Am Phys 1999; 111: 241-248

37 Festa A, D’Agostino R, Hales CN, Mykkanen L, Haffner SM. Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects. Diabetes Care 2000; 23: 624-628

38 Carnethon MR, Golden SH, Liao D. Autonomic nervous system dysfunction and diabetes. Cardiol Rev 2003; 20: 36-40

39 Ye R, Scherer PE. Adiponectin, driver or passenger on the road to insulin sensitivity? Mol Metab 2013; 2: 133-141

40 Pineiro R, Iglesias MJ, Gallego R, Raghay K, Eiras S, Rubio J, Diéguez C, Gualillo O, González-Juanatey JR, Lago F. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett 2005; 579: 5163-5169

41 Ding G, Qin Q, He N, Francis-David SC, Hou J, Liu J, Ricks E, Yang Q. Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor γ. J Mol Cell Cardiol 2007; 43: 73-84

42 Wang Y, Lau WB, Gao E, Tao L, Yuan Y, Li R. Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia–reperfusion injury. Am J Physiol Endocrinol Metab 2010; 298: E663-670

43 Delaigle AM, Jonas J-C, Bauche IB, Cornu O, Brichard SM. Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies. Endocrinology 2004; 145: 5589-5597

44 Liu Y, Sweeney G. Adiponectin action in skeletal muscle. Best Pract Res Clin Endocrinol Metab 2014; 28 :33-41

45 Dadson K, Liu Y, Sweeney G. Adiponectin action: a combination of endocrine and autocrine/paracrine effects. Front Endocrinol (Lausanne) 2011; 2: 62

46 Van Berendoncks AM, Garnier A, Beckers P, Hoymans VY, Possemiers N, Fortin D, Fortin D, Martinet W, Van Hoof V, Vrints CJ, Ventura-Clapier R, Conraads VM. Functional adiponectin resistance at the level of the skeletal muscle in mild to moderate chronic heart failure. Circ Heart Fail 2010; 3: 185-194

47 Chokshi A, Drosatos K, Cheema FH, Ji R, Khawaja T, Yu S, Kato T, Khan R, Takayama H, Knöll R, Milting H, Chung CS, Jorde U, Naka Y, Mancini DM, Goldberg IJ, Schulze PC. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 2012; 125: 2844-2853

48 Khan RS, Kato TS, Chokshi A, Chew M, Yu S, Wu C, Singh P, Cheema FH, Takayama H, Harris C, Reyes-Soffer G, Knöll R, Milting H, Naka Y, Mancini D, Schulze PC. Adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure: correction after ventricular assist device implantation. Circ Heart Fail 2012; 5: 340-348

49 Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennett PH. A two-step model for development of non-insulin dependent diabetes. Am J Med 1991; 90: 229-235

50 Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus. Expl Biol Med (Maywood) 2003; 228: 1213-1217

51 Aroor AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin 2012; 8: 609-617

52 Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607

53 Feldman RD, Bierbrier GS. Insulin-mediated vasodilatation: impairment with increased blood pressure and body mass. Lancet 1993; 342: 707-709

54 Cottin Y, Lhuillier I, Gilson L, Zeller M, Bonnet C, Toulouse C, Louis P, Rochette L, Girard C, Wolf JE. Glucose insulin potassium infusion improves systolic function in patients with chronic ischemic cardiomyopathy. Eur J Heart Fail 2002; 4: 181-184

55 Khoury VK, Haluska B, Prins J, Marwick TH. Effects of glucose-insulin-potassium infusion on chronic ischaemic left ventricular dysfunction. Heart 2003; 89: 61-65

56 Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984;69:1079-1087.

57 Lillioja S, Young AA, Culter CL, Ivy JL, Abbott WG, Zawadzki JK, Yki-Järvinen H, Christin L, Secomb TW, Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest 1987; 80: 415-424

58 Hambrech R, Fiehn E, Yu J, Niebauer J, Weighi C, Hillbrich L, Adams V, Riede U, Schuler G. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol 1997; 29: 1067-1073

59 Banerjee S, Peterson LR. Myocardial metabolism and cardiac performance in obesity and insulin resistance. Curr Cardiol Rep 2007; 9: 143-149

60 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403

61 Kemppainen J, Tsuchida H, Stolen K, Karlsson H, Björnholm M, Heinonen OJ, Nuutila P, Krook A, Knuuti J, Zierath JR. Insulin signalling and resistance in patients with chronic heart failure. J Physiol 2003; 550: 305-315

62 Beck-da-Silva L, Higginson L, Fraser M, Williams K, Haddad H. Effect of orlistat in obese patients with heart failure: a pilot study. Congest Heart Fail 2005; 11: 118-123

63 Potter BJ, LeLorier J. Effect of ramipril on the incidence of diabetes. N Engl J Med 2007; 356: 522-523

64 NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362: 1477-1490

65 Lastra G, Dhuper S, Johnson MS, Sowers JR. Salt, aldosterone, and insulin resistance: impact on the cardiovascular system. Nat Rev Cardiol 2010; 7: 577-584

66 Tamargo J, López-Sendón J. Novel therapeutic targets for the treatment of heart failure. Nat Rev Drug Discov 2011; 10: 536-555

67 Messaoudi S, Azibani F, Delcayre C, Jaisser F. Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012; 350: 266-272

68 Andraws R, Brown DL. Effect of inhibition of the renin-angiotensin system on development of type 2 diabetes mellitus (meta-analysis of randomized trials). Am J Cardiol 2007; 99: 1006-1012

69 Samuelsson O, Hedner T, Berglund G, Persson B, Andersson OK, Wilhelmsen L. Diabetes mellitus in treated hypertension: incidence predictive factors and the impact of non-selective β-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden. J Hum Hypertens 1994; 8: 257-263

70 Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000; 342: 905-912

71 Pollare T, Lithell H, Morlin C, Prantare H, Hvarfner A, Ljunghall S. Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. J Hypertens 1989; 7: 551-559

72 Jacob S, Rett K, Wicklmayr M, Agrawal B, Augustin HJ, Dietze GJ. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens 1996; 14: 489-494

73 Ladage D, Schwinger RH, Brixius K. Cardio-selective beta-blocker: pharmacological evidence and their influence on exercise capacity. Cardiovasc Ther 2013; 31: 76-83

74 Manrique C, Lastra G, Habibi J, Pulakat L, Schneider R, Durante W, Tilmon R, Rehmer J, Hayden MR, Ferrario CM, Whaley-Connell A, Sowers JR. Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat. Metabolism 2011; 60: 1757-1766

75 Erdmann E, Wilcox RG. Weighing up the cardiovascular benefits of thiazolidinedione therapy: the impact of increased risk of heart failure. Eur Heart J 2008; 29: 12-20

76 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787-1847

77 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147-239

78 Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005; 28: 2345-2351

79 Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin and outcomes in older patients with diabetes and heart failure. Circulation 2005; 111: 583-590

80 Evans JM, Doney AS, AlZadjali MA, Ogston SA, Petrie JR, Morris AD, Struthers AD, Wong AK, Lang CC. Effect of metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am J Cardiol 2010; 106: 1006-1010

81 Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail 2011; 4: 53-58

82 Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, Vanderloo SE, McAlister FA. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013; 6: 395-402

83 Wong AKF, Symon R, AlZadjali MA, Ang DSC, Ogston S, Choy A, Petrie JR, Struthers AD, Lang CC. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail 2012; 14: 1303-1310

84 Cittadini A, Napoli R, Monti MG, Rea D, Longobardi S, Netti PA, Walser M, Samà M, Aimaretti G, Isgaard J, Saccà L. Metformin prevents development of chronic heart failure in the SHHF rat model. Diabetes 2012; 61: 944-953

85 Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev 2012; 33: 187-215

86 Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014; 16: 38-47

87 Munaf M, Pellicori P, Allgar V, Wong K. A meta-analysis of the therapeutic effects of glucagon-like peptide-1 agonist in heart failure. Int J Pept 2012; 2012: 249827

88 Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK, Lavie CJ, Bell DS, O’Keefe JH. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol 2012; 110: 826-833

89 Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 112-120

90 Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, Califf RM, Holman RR. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013; 166: 983-989

91 Rosenstock J, Marx N, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Bluhmki E, Patel S, Johansen OE, Woerle HJ. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 2013; 10: 289-301

92 White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-1335

93 Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-1326

94 White WB, Zannad F. Saxagliptin, alogliptin, and cardiovascular outcomes (reply). N Engl J Med 2014; 370: 484

Peer reviewer: Min Zhou, MD, Department of Internal Medicine, Aultman Hospital & Canton Medical Education Foundation, Northeast Ohio Medical University, Canton, Ohio 44710, United States; Tin Kyaw, Vascular Biology and Atherosclerosis, Baker IDI heart and diabetes institute, 75 Commercial Road Melbourne, VIC, 3004, Australia.

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.