Invited review
Metabolic management of diabetic patients with ischaemic heart disease

Introduction
Patients with diabetes form a substantial proportion of patients with coronary artery disease (CAD) [1]. In some respects, clinical presentation, management and outcome of CAD patients with diabetes are different from non-diabetic patients. Diabetic patients with CAD have a lower incidence of chest pain and higher incidence of silent ischaemia than non-diabetic. Up to 30% of patients with diabetes and CAD have silent episodes of myocardial ischaemia either during provocative tests (exercise testing, cardiac stress imaging) or during daily life (ambulatory electrocardiographic monitoring) [2, 3]. Although atherosclerotic plaques appear to be morphologically similar in patients with or without diabetes, pathologic studies have demonstrated that coronary arteries in patients with diabetes and CAD show diffuse disease, in contrast to the more localized involvement often seen in the absence of diabetes [4]. From a prognostic point of view, the combination of diabetes and CAD is associated with a higher rate of cardiac events and a poorer prognosis. Evidence for this includes increased risk of recurrent infarction. In the study of Haffner et al. [5], the 7-year risk of myocardial infarction among those with diabetes with and without a prior myocardial infarction at baseline was 45 and 20.2%, respectively. The corresponding values for non-diabetic subjects were 18.8 and 3.5%. Diabetic patients have also increased morbidity and mortality associated with myocardial infarction, as well as a higher risk of developing congestive heart failure. In the FINMONICA project [6], the 1-year mortality rate after a first myocardial infarction among diabetic patients was 44.2% for men and 36.9% for women, compared with 32.6 and 20.2% for non-diabetic men and women, respectively. Several pathophysiological factors contribute to accelerate the atherosclerotic process and predispose to higher rates of CAD in diabetic subjects: microvascular dysfunction [7], decreased fibrinolytic activity [8], elevated spontaneous platelet aggregability [9], atherogenic lipoprotein profile [10], autonomic dysfunction [11] and possible coexisting diabetic cardiomyopathy [12]. Furthermore, the control of vascular tone is altered at an early stage in diabetes with a reduced vasodilatory response to different stimuli that is strongly related to glycaemic control [13]. High glucose levels seem to play a predominant role in pathogenesis of diabetic cardiovascular complications and in particular in the onset of vascular damage. This has been convincingly demonstrated by both the Diabetes Control and Complication Trials (DCCT) [14] and the UK Prospective Diabetes Study (UKPDS) [15]. The relationship between fasting hyperglycaemia and CAD has been addressed in several epidemiologic studies such as the Chicago Heart Association Detection Project [16], Tecumseh Study [17] and Paris Prospective Study [18]. These studies have shown that asymptomatic hyperglycaemia is associated with increased mortality from CAD. In the DECODE study [19], the 2-h post-glucose glucose concentration was more clearly related to cardiovascular mortality than fasting blood glucose. This may be due to microvascular dysfunction related to high values of postprandial glucose and by the higher sensitivity of oral glucose tolerance test in identifying patients with diabetes compared to fasting glucose. Hyperglycaemia induces vascular damage mainly through increased production of free radicals with a reduction in NO availability [7, 20]. Generation of oxygen-derived free radicals is promoted by several mechanisms including autoxidation, nonenzymatic glycation of proteins, increased de novo synthesis of diacylglycerol from glycolytic intermediates and subsequent activation of phosphokinase [21]. Another well known factor involved in atherosclerosis progression and endothelial dysfunction in diabetes is insulin resistance [22]. Hyperinsulinaemia can directly contribute to vascular damage promoting migration of monocytes and smooth muscle cells into the arterial wall [23].
Energy metabolism of the heart during ischaemia and diabetes
Under aerobic conditions the predominant substrate used by the normal adult human heart is free fatty acids (FFA), accounting for 60-90% of the energy generated [24]. Long-chain fatty acids (LCFA) are the major component of FFA utilisation. Following cellular uptake, LCFA entry into the mitochondria is facilitated by the enzymes carnitine palmitoyl-transferase (CPT) I and II. Beta-oxidation then occurs, which yields acetyl-CoA. Acetyl-CoA enters the tricarboxylic acid cycle and eventually leads to the formation of ATP, which is critical for myocardial contraction and relaxation. Carbohydrate metabolism, on the other hand, contributes only about 10-40% of energy generated by the healthy adult human heart at rest [25]. The glucose taken up by cardiomyocytes is stored as glycogen or converted into pyruvate by glycolysis. Pyruvate is then oxidised within the mitochondria by pyruvate dehydrogenase into acetyl CoA. All metabolic adaptive mechanisms during ischaemia, whether physiological or pharmaceutical, regulate energy metabolism by shifting substrate use towards glucose metabolism. The energetic advantages of incremental glucose utilisation arise from the fact that though fatty acid oxidation yields more ATP than glycolysis in aerobic conditions, this is at the expense of greater oxygen consumption. Fatty acids require approximately 10-15% more oxygen to generate an equivalent amount of ATP compared to glucose [26]. During subtotal ischaemia, the myocardium continues to derive a large proportion of its energy from oxidative metabolism. In moderate-to-severe ischaemia, there is increased utilisation by the myocardium of glucose as a substrate for energy production [27, 28]. Nevertheless, FFA oxidation continues to be the predominant substrate in the ischaemic heart [26, 29]. High levels of FFA uptake and catabolism during the ischaemic period require a higher oxygen expenditure to generate energy than glucose metabolism and may have detrimental effects on the myocardium [30]. High rates of FFA oxidation suppress glucose oxidation through a direct inhibitory action on pyruvate dehydrogenase [31], and increase lactate and proton accumulation in ischaemic cells [32], leading to a reduction in the contractile function of myocardial segments. Accumulation of LCFA intermediates during beta-oxidation has previously been shown to reduce the ventricular arrhythmia threshold [33] and induce diastolic dysfunction [34] during ischaemia. In patients with diabetes and CAD, the metabolic changes occurring as a consequence of the mismatch between blood supply and cardiac metabolic requirements are heightened by the metabolic changes occurring with diabetes. Diabetes causes a switch of the energy metabolism from carbohydrate oxidation to free FFA and ketone oxidation [35]. In diabetes the reduced glucose uptake that is coupled with preferential FFA oxidation occurs as a consequence of inadequate insulin receptor signalling related to either a state of insulin resistance or decreased insulin levels. Increased FFA concentrations and increased skeletal muscle and myocardial FFA uptake and oxidation have detrimental consequences on cardiac function and particularly on the ischaemic heart. The presence of myocardial insulin resistance has been demonstrated in patients with diabetes, suggesting that even early stages of altered glycaemic control may affect myocardial metabolism and predispose to diabetic cardiomyopathy [36-39]. The lack of insulin and the state of insulin resistance may influence cardiac function through several different mechanisms, such as decreased glucose transport and carbohydrate oxidation, increase in FFA use, decrease in sarcolemmal calcium transport, and alterations in myofibrillary regulatory contractile proteins. In the diabetic heart, myocardial glucose uptake, availability and use are blunted when fasting and after insulin stimulation [35, 40]. The increased uptake and use of FFA is maximal during stress and ischaemia and is a major contributor to the increased susceptibility of the diabetic heart to myocardial ischaemia and to a greater decrease in myocardial performance for a given amount of ischaemia compared with the non-diabetic heart [41-44]. Moreover, in the diabetic heart, the preferential increased uptake of FFA during stress or ischaemia causes not only diminished energy production, but also a parallel increase in intermediate metabolic products that are toxic for the cells, especially during ischaemia or increased workload [44]. This can contribute to both the development of contractile dysfunction and to increased sensitivity of the heart to injury during ischaemia [45].
Treatment of diabetes in patients with CAD
Treatment of diabetes and above all control of glycaemia is a standard recommendation for individuals who have diabetes with CAD. Several studies have shown that intensive glycaemic control is highly effective in preventing and retarding microvascular and, to a lesser degree, macrovascular complications in both type I and type II DM. The DCCT provided definite evidence of a major reduction in chronic microvascular complications among a group of type I diabetic patients with tight glycaemic control and suggested a potential beneficial effect of this strategy on macrovascular disease [14]. Tight glycaemic control reduced major macrovascular events by one-half in diabetics compared with conventionally treated patients [46]. The randomized United Kingdom Prospective Diabetes Study (UKPDS) [15] has reported that, over 10 years of follow-up, intensive glycaemic control by either insulin or sulphonylureas significantly reduced (by 25%) the risk of microvascular complications in NIRDM patients. A similar reduction was observed in diet-treated obese NIRDM patients taking metformin [47]. In addition, a recent retrospective study has reported that optimal glycaemic control in diabetic patients can favourably influence major cardiac events following PTCA [48]. The role of reducing glycaemia has been emphasized in the early stage after myocardial infarction. According to ESC guidelines [49], glucose control by means of insulin should be immediately initiated in diabetic patients admitted for acute MI with significantly elevated blood glucose levels in order to reach normoglycaemia as soon as possible. This goal in the intensive care units has been reached by glucose-insulin-potassium (GIK) infusion. GIK works by stimulating glucose uptake and glycogen synthesis while inhibiting fatty acid release from adipocytes. In the study by Rackley et al. [50], GIK induced an increase in the respiratory quotient, demonstrating a shift in energy substrate metabolism from lipids to carbohydrate. Related factors may also come into play, such as improved sodium and calcium homeostasis. The DIGAMI 1 study [51] recruited 620 diabetic patients with acute MI to be randomly assigned to serve as a control group or to a group receiving intensive insulin treatment initiated by insulin-glucose infusion during the first 24 h post-MI. In the intensively treated group 1-year mortality was reduced by 30%. In a long-term follow-up over an average of 3.4 years, there was an 11% absolute mortality reduction in the intensively treated group. The DIGAMI 2 trial [52] enrolled 1253 diabetic patients with acute MI and compared three management protocols: acute insulin-glucose infusion followed by insulin-based long-term glucose control, insulin-glucose infusion followed by standard glucose control, and routine metabolic management according to local practice. The study did not show any benefit on survival of long-term intensive insulin treatment. Moreover, initiating treatment with an insulin-glucose infusion was not superior to standard management. However, the three glucose management strategies did not result in significantly different long-term glucose control and target glucose levels were not reached in the intensive insulin treated group. A meta-analysis of several studies on GIK therapy in acute MI including 1932 patients suggested a proportional mortality reduction of 28% with 49 lives saved per 1000 patients treated with GIK [53].
Treatment of ischaemia in CAD patients with diabetes
According to the classic pathogenetic view, myocardial ischaemia is caused by an imbalance between myocardial metabolic demands and myocardial blood supply. Such an imbalance may result either from an increase in cardiac work that is not accompanied by a parallel increase in coronary blood flow, or from a primary reduction in coronary blood flow. The conventional management of stable angina focuses on reducing myocardial demand by means of drugs that act on “haemodynamic” parameters. Beta-blockers and calcium channel antagonists reduce cardiac work and myocardial oxygen consumption, reducing heart rate, blood pressure and myocardial contractility. Nitrates lower coronary smooth muscle tone, dilate coronary epicardial vessels and prevent coronary vasospasm. The “haemodynamic” drugs improve symptoms and quality of life in many patients with angina pectoris but they do not have an additive anti-ischaemic effect when given in combination. Also adverse effects are often observed and may limit the usefulness of haemodynamic agents. The most common dose-limiting adverse effects are cold peripheries, weakness and “heavy legs” feeling in patients receiving beta-blockers, fluid retention in those receiving calcium antagonists, and headaches in individuals receiving oral nitrates. To circumvent these effects, suboptimal combination treatment is often used. An alternative strategy is to address the metabolic causes or consequences of ischaemia. The “Metabolic” anti-anginal therapies induce a shift from FFA towards predominantly glucose utilisation by the myocardium to increase ATP generation per unit oxygen consumption. The use of metabolic agents in CAD patients with diabetes represents a logical approach to their treatment, given the mechanism of action of these agents, because patients with diabetes exhibit reduced glucose uptake and utilization, and an increased uptake and utilization of FFAs [35]. Moreover, patients with diabetes are more metabolically vulnerable to ischaemia than non-diabetics.
Perhexiline
Perhexiline is the oldest anti-ischaemic drug with metabolic effects. It was frequently prescribed as an anti-anginal agent in the 1970s. Early randomised controlled trials in patients with coronary artery disease demonstrated that perhexiline markedly relieved symptoms of angina, improved exercise tolerance and increased the workload needed to induce ischaemia when used as monotherapy [54]. More recently, randomised controlled trials have demonstrated that perhexiline exerts marked, incremental anti-anginal effects in patients receiving beta-blockers or even “triple” prophylactic anti-anginal therapy [55]. Perhexiline is not negatively inotropic and does not alter systemic vascular resistance to a significant degree at plasma levels that are within therapeutic range. It acts through the inhibition of palmitoyl camitine transferase [56]. Despite its potential benefits, perhexiline use declined dramatically in the early 1980s following reports of hepatotoxicity [57] and peripheral neuropathy [58]. These effects were later demonstrated to occur most commonly in patients who are “slow hydroxylators”, bearers of a genetic variant of the cytochrome P-450 enzyme family [59].
Trimetazidine
Trimetazidine (TMZ) was developed and registered as anti-anginal in the late 1980s. Since then TMZ has been marketed in Europe, Asia and Latin America as a safe cellular anti-ischaemic drug devoid of haemodynamic effects. The mechanism of action of TMZ has been experimentally well established and is related to the inhibition of the enzyme long-chain 3-ketoacyl coenzyme A thiolase (LC 3-KAT), which is a crucial enzyme in the beta-oxidation pathway. TMZ is also effective in protecting cells from oxygen free radical-induced damage. This antioxidant effect of TMZ was first documented by Maridonneau-Parini and Harpey [60], who demonstrated in human red blood cells that TMZ significantly reduced the loss of intracellular K+ and the membrane content of peroxidated lipids, as measured by MDA concentrations, induced by oxygen free radicals. Additional studies confirmed these initial results in various animal models. Guarnieri and Muscari [61] showed that TMZ decreased lipid peroxidation in monocrotaline-induced hypertrophy of the rat heart. Abadie et al. [62] studied isolated rat hearts subjected to electrolysis as a source of oxygen free radicals. An abrupt reduction in heart function was observed at the end of electrolysis. The addition of TMZ to the perfusate significantly counteracted the deleterious effects of electrolysis on haemodynamic performance, so that coronary flow, heart rate and isovolumetric left ventricular pressure were significantly improved. Several authors have investigated the effects of TMZ on glucose utilization in rats and dogs undergoing prolonged ischaemia [63]. They demonstrated a shift of cellular metabolism to preferential glucose utilization by the oxidative pathway, resulting from decreasing fatty acid oxidation in ischaemia, and suggested that this goal could be achieved either by inhibiting beta-oxidation or by blocking CPT. In the study of Kantor et al. [64] TMZ reduced the rate of FFA oxidation, with a concomitant 210% increase in glucose oxidation rates during low-flow ischaemia. Their data also suggested that the likely route by which this was achieved was through the inhibition of the enzyme LC 3-KAT, which is a crucial enzyme in the beta-oxidation pathway. Other authors, however, did not demonstrate any significant inhibitory effects of TMZ on LC 3-KAT or inhibition of other enzymes of beta-oxidation at doses exceeding those which have previously been found to be clinically effective for angina. Several clinical trials have demonstrated the potential benefits of TMZ in ischaemic heart disease. TRIMPOL II, a large, randomised, controlled trial, enrolled 426 patients with stable angina who were randomised to either TMZ 20 mg three times a day or placebo in addition to metoprolol [55]. This study demonstrated an improvement in time to ST segment depression on exercise tolerance, total exercise workload, mean nitrate consumption and angina frequency in patients randomised to receive TMZ. In stable effort angina, TMZ improves exercise tolerance and elevates ischaemic threshold as much as beta-blockers or calcium antagonists [66, 67]. When given in combination with beta-blockers, TMZ has a greater anti-ischaemic effect than nitrates and calcium antagonists [68]. Six months of therapy with a modified-release (MR) formulation of TMZ dosed twice daily has been evaluated in patients with stable angina pectoris [69]. Patients in this multinational, randomized, double-blind, placebo-controlled study received atenolol 50 mg per day and MR TMZ 35 mg or placebo for 6 months. Primary efficacy was based on change in time to 1-mm ST-segment depression. Time to 1-mm ST-segment depression was increased significantly with TMZ compared with placebo. Rates of adverse events were similar and no differences in corrected QT intervals were observed between treatment groups. A meta-analysis of 12 double-blind, randomized, controlled clinical trials of TMZ in the treatment of stable angina was published in 2003 [70]. This analysis of studies conducted from 1986 to 2001 included patients who were treated with TMZ for at least 2 weeks and included controls with placebo or conventional anti-anginal therapy. Trimetazidine was associated with significant reductions in the number of weekly angina attacks, improved time to 1-mm segment depression, and total work at peak exercise. Tolerability of TMZ was mentioned in only 8 of these 12 studies, and was not thoroughly evaluated in most of these trials, mainly because of the excellent tolerability of this drug. Overall, this metaanalysis showed that TMZ was an effective anti-anginal agent when used alone or in combination with traditional haemodynamic agents. Our group has recently shown that in patients with diabetes and chronic stable angina, the addition of TMZ to standard medical therapy reduces the number of episodes of ST-segment depression, the episodes of silent ischaemia, and the total ischaemic burden [71]. In addition to the anti-ischaemic effect, partial inhibition of FFA oxidation may represent an alternative approach to the treatment of patients with diabetes and heart failure. Trimetazidine seems to facilitates the recovery of hibernating myocardium. We and others have recently demonstrated that the adjunct of TMZ to standard therapy improves left ventricular systolic and diastolic function of chronically dysfunctional myocardium in patients with type 2 diabetes, CAD and reduced LV function [72, 73].
Ranolazine
Another potential drug in the metabolic management of chronic angina is ranolazine, which reduces the late sodium current, decreasing sodium entry into ischaemic myocardial cells. This drug was initially suggested to block beta-oxidation, while more recently there has been a shift in the proposed mechanism of action for this drug. As a consequence, ranolazine is now proposed to reduce calcium uptake indirectly via the sodium/calcium exchanger and to preserve ionic homeostasis and reverse ischaemia-induced contractile dysfunction [74]. The anti-ischaemic effect of ranolazine is very mild compared to other metabolic agents. Since January 2006, extended-release ranolazine has been approved in the US for use as an add-on therapy in patients with chronic angina. The drug is not approved in Europe. The MARISA study [75], the first trial of monotherapy with SR ranolazine in patients with chronic angina, assessed the efficacy and tolerability of 3 doses (500, 1000 and 1500 mg) of ranolazine compared with placebo in treadmill exercise performance. All strengths of ranolazine were associated with significant albeit small improvement in total exercise duration, time to angina, and time to 1-mm ST segment depression at both trough and peak time points compared with placebo. Adverse events on ranolazine appeared to be dose related and included dizziness, nausea, asthenia, constipation and prolongation of the QT interval. The efficacy and tolerability of SR ranolazine in combination with beta-blockers or calcium channel blockers have been investigated in a double-blind, 3-group, parallel trial, the Combination Assessment of Ranolazine In Stable Angina (CARISA) study [76]. Compared with placebo, both doses of SR ranolazine demonstrated an increase in treadmill exercise duration at both trough and peak, an effect that was sustained throughout 12 weeks of therapy. Both the MARISA and CARISA clinical trials suggest that ranolazine may have some anti-anginal effect. However, its long-term safety, particularly in relation to QT prolongation, remains to be established. In the more recent ERICA trial [77] that enrolled 565 patients with angina while in treatment with amlodipine, ranolazine reduced frequency of angina compared with placebo. Until now there are no studies with ranolazine that evaluate the benefit in the subgroup of patients with diabetes. Preliminary safety concerns observed in clinical trials include dose-related QT prolongation and clinically significant drug interactions. In conclusions patients with diabetes have impaired myocardial handling of glucose with reduced energy production that is reversed, at least in part, by drugs that improve glucose sensitivity and interfere with beta-oxidation. Up until now the only sound clinical data with metabolic agents in patients with coronary artery disease and diabetes have been obtained with trimetazidine, which should therefore be considered the metabolic drug of choice for these patients.
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