Insulin Resistance and Heart Failure Patrick M. Heck, MA, MRCP, and David P. Dutka, DM, FRCP

Corresponding author David P. Dutka, DM, FRCP Department of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom. E-mail: [email protected] Current Heart Failure Reports 2009, 6:89–94 Current Medicine Group LLC ISSN 1546-9530 Copyright © 2009 by Current Medicine Group LLC

Despite recent therapeutic advances, heart failure remains a leading cause of morbidity and mortality. The prevalence of heart failure continues to rise, and the importance of cardiac energetics underlying myocardial dysfunction is increasingly recognized. The rise in obesity and type 2 diabetes with associated insulin resistance results in abnormal glucose and fatty acid metabolism of the myocardium and the entire body, serving to highlight the fact that deranged metabolism may provide a therapeutic target beyond existing neuroendocrine inhibition. Evidence from clinical studies often confl ict, but it appears that the association between heart failure and insulin resistance is interdependent and complex. Drugs that improve glucose metabolism may harm myocardial performance under stress, and the use of metabolic treatment in patients with heart failure must be targeted on the individual and based on evidence from carefully designed clinical trials.

Introduction In the developed world, the prevalence of insulin resistance (manifest clinically as the metabolic syndrome or type 2 diabetes mellitus) is increasing [1]. As life expectancy continues to rise and more patients survive myocardial infarctions, the number of patients presenting with congestive heart failure (CHF) is also increasing, with up to one fi fth of the population being affected in their lifetime [2]. The association between insulin resistance and heart failure (HF) is not new. The fi rst evidence for a link between insulin resistance, metabolism, and HF was fi rst described in 1881 by a German physician [3]. Thirty years later, a case report from a British physician alluded to the potential benefits of metabolic modulation in HF [4]. More recently, most large clinical trials on HF report rates of diabetes in 25% to 35% of patients studied [5••].

The precise inter-relationship between insulin resistance and HF has been a recent topic of interest because it was previously thought that the higher incidence of myocardial ischemia seen in patients with insulin resistance and type 2 diabetes accounted for the increased prevalence of CHF in these patients. Currently, however, it is believed that the relationship is bidirectional; chronic HF increases insulin resistance [6,7] and insulin resistance predisposes patients to HF.

Evidence for Insulin Resistance Leading to CHF Epidemiology Many recent epidemiologic studies demonstrating a link between insulin resistance and HF have been reviewed comprehensively [8••]. The Framingham Heart Study highlighted diabetes mellitus as an independent risk factor for the development of HF, with a 2.4-fold risk increase in men and a fivefold risk increase in women [9]. The UKPDS study provided additional support for this relationship and reported that for every 1% increase in glycosylated hemoglobin (HbA1c), the risk of developing HF rose by 16% [10]. More specific to insulin resistance, a Swedish 9-year prospective study of nearly 1200 men without prior HF demonstrated that insulin resistance predicted the development of HF; this was independent of other established risk factors, including overt diabetes mellitus [11]. Therefore, there is good epidemiologic evidence for an association between insulin resistance and HF. It may be argued that this association can be accounted for by increased prevalence of hypertension, hyperglycemia with associated free radical generation, microvascular dysfunction, and ischemic heart disease seen in insulin-resistant states; however, the authors have attempted to correct for these factors in their studies. In general, the fact that insulin resistance often precedes the development of HF suggests that the altered metabolic environment results in myocardial dysfunction and HF.

Mechanisms Insulin has many well-described effects on the myocardium and circulation that change with the onset of insulin resistance [12]. The myocardium has one of the highest energy demands per gram of any human organ. The majority (60%–70%) of adenosine triphosphate (ATP) hydrolysis fuels contractile shortening, and the remaining 30% to 40% is used primarily by the sarcoplasmic reticulum Ca 2+ ATPase and other ion pumps necessary

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to maintain intracellular homeostasis [13]. In the normal adult heart, 60% to 90% of ATP is produced by β-oxidation of free fatty acids (FFAs) because of the high energy yield per gram of substrate metabolized, with 10% to 40% being derived from oxidation of pyruvate, which is produced in equal amounts from glycolysis and lactate oxidation. However, under conditions of stress (eg, those induced by ischemia or HF), the myocardium derives proportionally more ATP from glucose oxidation [14]. This shift in myocardial metabolism is important because the amount of ATP generated per molecule of oxygen consumed is higher for glucose oxidation than when fatty acids are the metabolic substrate. Hence, it offers protection under stressed states when there is often a mismatch between oxygen supply and demand [15]. Glucose oxidation is a more oxygen-efficient process for two reasons. First, in simple stoichiometry, glucose oxidation yields 13% more ATP per oxygen molecule consumed than fatty acid oxidation. Second, FFAs promote the production of mitochondrial uncoupling proteins, which are energetically wasteful, resulting in the production of heat as opposed to ATP [16]. The combination of these mechanisms results in up to 40% more ATP being generated per molecule of oxygen consumed compared with FFA oxidation. These stress-induced adaptations follow a complex series of enzymatic shifts and changes in the relative expression of various transcription factors that have been characterized but are beyond the scope of this article [14]. Insulin exerts a central role in this adaptive mechanism in the stressed or failing heart. Through a variety of different end effectors, insulin directly stimulates glucose uptake [17] and oxidation [18] within the myocardium and directly inhibits FFA oxidation [19]. Insulin also alters substrate availability, primarily by inhibiting lipolysis and reducing the circulating FFA concentration [20]. In subjects with insulin resistance, these adaptive responses of the myocardium to stress are inhibited, with an increase in FFA metabolism being seen in early HF, accompanied by decreased cardiac efficiency and the potential for toxic accumulation of FFA within the myocardium [21]. The direct effects of systemic insulin resistance on myocardial glucose uptake remain contentious [22,23], and the major cause of the reduced myocardial glucose uptake in insulinresistant individuals may be secondary to the increased circulating FFA concentration. The net effect is that insulin resistance prevents the myocardium from increasing its glucose use in response to stress, resulting in ventricular dysfunction and a vicious circle of sympathetic activation that increases FFA concentration and further inhibits glucose oxidation. As HF progresses, there is downregulation in the myocardium of gene expression for the proteins required for FFA oxidation [7]. Combined with insulin resistance that leads to downregulation of genes for glucose oxidation, the myocardium in advanced HF exists in a state of relative energy starvation that promotes further deterioration in contractile performance [24].

Although the detrimental effects of insulin resistance on myocardial function are probably secondary to the effects on myocardial energy metabolism outlined previously, some of the other effects of insulin merit discussion [12]. Of note, insulin has been shown to inhibit cellular apoptosis and stimulate nitric oxide production. It is possible that insulin resistance will impair both these effects and result in increased cell death or endothelial dysfunction, respectively, worsening the predicament of the failing heart. Overall, the net effect of insulin resistance alone is probably not sufficient to cause HF; this is clinically supported by the fact that most individuals with insulin resistance do not develop overt HF. Rather, insulin resistance reduces the heart’s ability to cope with additional insults or stresses (eg, ischemia or hypertension) such that when these are present in the setting of insulin resistance, myocardial performance is impaired. This theory is supported by a study by Raher et al. [25•], in which they induced insulin resistance in mice by feeding them a high-fat diet and then created myocardial pressure overload, similar to that seen in hypertension, by aortic banding in half the mice. They showed that only in the mice with both insulin resistance and pressure overload did left ventricular (LV) dysfunction develop, with an increase in mortality compared with mice without insulin resistance but with pressure overload. Mice with insulin resistance but no pressure overload did not demonstrate any change in cardiac function.

Evidence for CHF Causing Insulin Resistance Epidemiology Several studies have assessed the development of diabetes mellitus in the setting of HF. An Italian study reported the 3-year incidence of new-onset diabetes mellitus as 28.8% in subjects with HF compared with an incidence of 18.3% in age-matched control subjects [26]. The BIPS study reported similar findings with an incidence of new-onset diabetes of 13% over 7.7 years in subjects without HF compared with up to 20% incidence in those with New York Heart Association (NYHA) class III HF [27]. The underlying cause of HF does not appear to affect the development of insulin resistance itself as it has been reported in both ischemic and nonischemic cardiomyopathy [6].

Mechanisms The evidence for insulin resistance causing HF is perhaps more extensive than evidence for HF increasing insulin resistance. The mechanisms underlying the development or worsening of insulin resistance in the setting of HF are not well understood, but are probably multifactorial. Postulated mechanisms include abnormal sympathetic activation, loss of skeletal muscle mass, endothelial dysfunction, an enforced sedentary lifestyle because of reduced cardiac output, and a potential effect of increased circulating cytokines, such as tumor necrosis factor-α on peripheral insulin sensitivity [28]. If HF is left untreated, this may result in a vicious cycle of ventricular dysfunction and insulin resistance, with each aggravating the other.

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Figure 1. The relationship between chronic heart failure and insulin resistance. FFA—free fatty acid; NO—nitric oxide.

Perhaps the best understood mechanism in which HF causes insulin resistance is the maladaptive neurohormonal activation seen in HF. The chronic reduction in cardiac output results in an increased activation of the sympathetic nervous system and the closely linked renin-angiotensin-aldosterone system. The increase in catecholamines impairs the efficiency of the heart independent of substrate metabolism [29], but it also increases the circulating FFA concentration by stimulating adipocyte lipolysis [30]. This increase in circulating FFA concentration further augments sympathetic activity [31], adversely affects insulin signaling, and reduces glucose utilization by human skeletal muscle [32]. Further evidence implicating the central role of the elevated FFA concentration in the development of insulin resistance comes from a study in humans, demonstrating that an acute decrease in FFA concentration reduces insulin resistance [33]. The detrimental metabolic effects of increased sympathetic activity extend further to include inhibition of pancreatic insulin secretion and stimulation of hepatic gluconeogenesis and glycogenolysis, both of which worsen hyperglycemia [34]. Thus, the relationship between insulin resistance, myocardial dysfunction, and HF is complex and incompletely understood. The proposed interdependent mechanisms discussed are presented in Figure 1.

Treatments for Insulin Resistance in HF Possible treatments for insulin resistance are not limited to pharmacologic agents. Standard lifestyle recommendations, including exercise and weight loss, are associated with improvements in insulin sensitivity [35]. A recent study by Leichman et al. [36] reported improvements in insulin resistance and diastolic ventricular dysfunction in obese patients following successful bariatric surgery.

Conventional CHF therapy Conventional pharmacologic therapy for HF improves insulin sensitivity. Neurohormonal modification with

angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been shown recently in a meta-analysis by Andraws and Brown [37] to reduce the risk of developing diabetes mellitus by more than 25%. Experimental work in mice suggests that at least some of this benefit is because of protection of the pancreatic β-cells. The effect of β-blockers on insulin resistance is more complex, as different agents have variable effects. The majority of β-blockers increase insulin resistance, although carvedilol, a combined α- and β-blocker, favorably influences myocardial metabolism by reducing FFA uptake [38]. A recent study reported that these beneficial effects of carvedilol were not seen with bisoprolol, but the study investigated a relatively small number of patients, and further studies are required [39].

Nonconventional HF therapy Pharmacologic treatments that may improve insulin sensitivity and cardiac metabolism fall primarily into two groups—drugs conventionally used to treat diabetes and specific metabolic-modulating drugs. Agents for diabetes Because the underlying problem is resistance to insulin, treatment with additional insulin may overcome this to an extent. Indeed, a study that gave glucose-insulin-potassium to patients with chronic ischemic cardiomyopathy demonstrated that it improved LV function [40]. However, observational data have suggested that insulin use is an independent risk factor in the development of HF, although this may reflect the fact that insulin therapy is normally reserved as a treatment for more advanced diabetes mellitus. Also, insulin use is associated with weight gain, worsening insulin resistance, and other complications, making its use unappealing. These caveats also apply to the use of insulin secretagogues, such as sulfonylureas. Metformin is one of the oldest insulin-sensitizing drugs in use. An observational study of 12,272 patients in Canada reported that metformin but not sulfonylureas

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reduced all-cause mortality in patients with diabetes and HF [41]. Similar results have been shown in a population study in Scotland. Unfortunately, metformin use in HF is formally contraindicated because of a perceived increased risk of lactic acidosis, although the evidence for this is somewhat lacking. A recent meta-analysis by Eurich et al. [42••] assessed the use of drugs to treat diabetes mellitus in subjects with HF and concluded that only metformin was not associated with any harm and offered a reduced mortality risk. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists (rosiglitazone and pioglitazone) are agents that theoretically are ideally suited to reduce insulin sensitivity. They modulate the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in adipose hepatic and muscular tissue. These drugs improve insulin sensitivity in hepatic and peripheral tissue, reduce plasma insulin concentrations and HbA1c, improve lipid profiles, and are associated with anti-inflammatory and antiatherosclerotic properties [43]. However, these agents also cause fluid accumulation and edema because of activation of amiloride-sensitive sodium channels in the collecting ducts, not through worsening myocardial function [44,45]. Further data and more consistent definitions of HF are needed to fully assess the safety of the PPAR-γ agonists in diabetes and HF. Concerns have been raised regarding the cardiovascular side effects of rosiglitazone in a metaanalysis of 42 studies and an ongoing study (RECORD) reported interim safety data in mid-2007 [1], which showed no increase in mortality but an increase in HF. The incretin glucagon-like peptide (GLP-1) is an endogenous hormone that is released postprandially and promotes insulin secretion and improves insulin sensitivity. GLP-1 infusions have been shown to improve LV function in dogs and humans with HF [46]. The peptide has not been shown to reduce insulin resistance in HF and so the mechanism in which ventricular function is improved may be due to a more direct effect on myocardial metabolism. GLP-1 is impractical for clinical use because of its rapid degradation by dipeptidyl peptidase IV (DDP-IV), but oral inhibitors of DDP-IV for the treatment of diabetes (sitagliptin, vildagliptin) are in clinical use. An alternative is exenatide, a partial agonist of the GLP-1 receptor, which is not broken down by DDP-IV; however, no published data are available regarding the use of any of these agents in patients with type 2 diabetes and HF. A recent review highlights some of the potential therapeutic benefits of these novel agents [47]. Metabolic modulators Because insulin resistance and HF often coexist and have a detrimental circular interaction, conventional lifestyle and pharmacologic management of HF reduces insulin resistance as a result of the decline in neurohormonal activation, which is one of the mechanisms underlying and increasing insulin resistance. Improving insulin sensitivity is a challenging problem, although many agents are under investigation.

Trimetazidine is a partial fatty acid oxidase inhibitor (PFAOI) that is thought to work by inhibiting long-chain 3-ketoacyl coenzyme A thiolase, the fi nal enzyme in the β-oxidation of FFAs. Although it primarily serves as an agent to treat angina (and is not approved for use in the United Kingdom or the United States, although available in areas of Europe), there have been several studies of its use in HF, with generally favorable results in terms of NYHA functional class and objective echocardiographic measures of LV function. In a recent randomized study of 55 patients with ischemic and nonischemic myocardial dysfunction who were followed for more than 1 year, trimetazidine improved both LV ejection fraction and exercise capacity regardless of HF cause [48]. In 2008, Tuunanen et al. [24] reported a study in which trimetazidine was given in a randomized single-blinded fashion to 19 subjects with idiopathic dilated cardiomyopathy and positron emission tomography tracers were used to assess myocardial metabolism. After 3 months of trimetazidine, LV ejection fraction improved (30.9%–34.8%; P = 0.027) with a modest reduction in myocardial β-oxidation and improved insulin sensitivity. However, the same group also reported in 2006 that acute dramatic reductions in myocardial FFA metabolism in subjects with idiopathic dilated cardiomyopathy actually worsens cardiac performance [24]. In this study, they used acipimox (an inhibitor of lipolysis) and achieved an 80% reduction in myocardial FFA oxidation, as opposed to approximately 10% reduction in the trimetazidine study. This suggests that in the failing heart, in which FFA oxidation is already downregulated and insulin resistance reduces glucose use, creating an energy-starved state, further marked reductions in FFA availability without increased glucose use may be excessive, and gentler modulation with a PFAOI may be appropriate. Ranolazine is an agent that is similar in structure to trimetazidine and has been shown to increase glucose oxidation and reduce FFA oxidation in experimental studies [49]. It was approved as a treatment for chronic angina by the Food and Drug Administration in early 2006. Although it was initially felt to be a PFAOI, more recent data have suggested that it acts through inhibition of the late sodium current, reducing the sodium-dependent calcium overload and lessening the abnormalities of ventricular repolarization and contractility that are associated with HF [50]. Two experimental studies on the use of ranolazine in HF have been reported recently, with one showing beneficial effects on diastolic dysfunction in the failing human myocyte [51] and the other showing reduced systolic dysfunction when ranolazine is added to enalapril or metoprolol in dogs with HF [52]. Although the use of ranolazine in HF appears to be promising, it seems likely that the mechanism of action is not by metabolic modulation, as previously thought. Perhexiline is a PFAOI that was fi rst used as an antianginal in the 1970s, but its use declined following reports of hepato- and neurotoxicity. Because assays have been

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developed that facilitate monitoring of the plasma concentration of the drug, it is regaining popularity for refractory angina in Australia and New Zealand, with restricted use in parts of Europe. Perhexiline is thought to work by inhibition of carnitine palmitoyl transferase-I, the ratelimiting step in FFA β-oxidation. A recent double-blind placebo-controlled study of perhexiline in 56 subjects with CHF over 2 months reported substantial improvements in LV ejection fraction, Vo2 maximum, and functional class, with no significant toxicity [53]. Although the results for these agents are promising, the total number of subjects enrolled in randomized, doubleblinded trials remains quite small, and more research is needed to define the use of metabolic modulation as a treatment for HF. A number of other agents exhibit PFAOI activity, including oxfenicine and etomoxir. Oxfenicine has been used to treat angina, but there are no reports of its use in patients with HF. Etomoxir is another PFAOI thought to work by partial inhibition of carnitine palmitoyl transferase-I, with promising results in a small study of subjects with HF [54]. Unfortunately, the subsequent randomized, double-blind, placebo-controlled study was terminated prematurely in 2007 because of increased hepatic enzymes in the active group, effectively terminating the use of etomoxir clinically [55].

Conclusions Although neurohormonal antagonists have lead to a considerable reduction in morbidity and mortality from chronic HF, many patients remain limited, and the associated metabolic abnormalities may provide another target to reduce the high death rate from this disabling syndrome. As the detrimental cycle of HF and insulin resistance promotes abnormal myocardial metabolism and contractile dysfunction, treatment to suppress FFA oxidation offers an attractive alternative to enable ATP generation in the setting of constrained oxygen delivery. Although current data are not sufficiently robust to support the targeted use of metabolic therapy to reduce insulin resistance, agents that improve myocardial substrate use offer the promise of improving LV function and performance with resultant improvement in quality of life and reduced morbidity and mortality. Carefully designed controlled clinical trials are required to enable such targeted therapy to be developed and applied.

Clinical Trial Acronyms BIPS—Bezafibrate Infarct Prevention Study; RECORD— Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes; UKPDS—UK Prospective Diabetes Study.

Disclosure No conflicts of interest relevant to this article were reported.

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