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Number 25, 2004 |
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Abstract
The increased incidence of cardiovascular disease in patients with diabetes exposes them to a greater risk of mortality. Ischemic heart disease, which is often found in patients with diabetes, is a metabolic disease that relies on changes in cardiac metabolism. Because of this, manipulation of the energy metabolism of the diabetic heart has been investigated with the aim of relieving symptoms and improving exercise capacity and left ventricular contractile work. Trimetazidine (Vastarel MR), the first twice-daily 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor, is a well known metabolically active agent that is widely used for the treatment of stable angina. This review highlights recent publications that demonstrate the anti-ischemic and cardioprotective value of trimetazidine in patients with diabetes and coronary heart disease. ▪ Heart Metab. 2004;25:23–25. Keywords: Diabetes, ischemic heart disease, trimetazidine, cardiac metabolism |
Introduction
It is now well established that patients with diabetes present with a greater incidence and severity of cardiovascular events such as angina, myocardial infarction, and heart failure than do those without diabetes. For example, the risk of an event is as high in patients with diabetes as in those without diabetes who have suffered a previous myocardial infarction (Figure 1) [1]. This increased risk can be explained by the existence of a diabetic cardiomyopathy that is associated with the following signs: reduction in diastolic relaxation and left ventricular end-diastolic diameter; prolongation of maximal filling velocity and isovolumetric filling time. The left ventricular diastolic dysfunction is likely to appear at an early stage. The severity of this diabetic cardiomyopathy is strongly related to changes in energy metabolism of the myocytes. It has been demonstrated that ischemic damage is exacerbated by the excessive use of fatty acids by the diabetic heart. These observations have led to consideration of pharmacological manipulation of the cardiac metabolism as a promising approach to counteracting the deleterious consequences of myocardial ischemia, particularly in patients with diabetes who have coronary heart disease.
Figure 1. Cardiovascular mortality in diabetic and nondiabetic individuals with coronary artery disease. IHD, ischemic heart disease; MI, myocardial infarction.
Trimetazidine (Vastarel MR): a unique metabolic mechanism of action
The rationale of optimizing myocardial energy production through a reduction in fatty acid oxidation to relieve symptoms and improve contractile work is now well demonstrated [2]. Trimetazidine (Vastarel MR) opens up a new class of metabolic anti-ischemic agents known as 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitors. When the diabetic heart is under ischemic conditions, trimetazidine shifts cardiac metabolism away from fatty acids to glucose oxidation, secondary to selective inhibition of the 3-KAT [3] (Figure 2). This metabolic anti-ischemic agent effectively reduces the incidence of angina attacks and improves exercise performance in various subsets of patients with coronary heart disease [4], and these benefits are unrelated to changes in hemodynamic variables such as heart rate or blood pressure [5]. As both diabetes and coronary artery disease can be considered as metabolic diseases, the clinical benefits of trimetazidine are most likely to be operative in patients with diabetes who have ischemic cardiomyopathy.
Figure 2. Trimetazidine (Vastarel MR), the first twice-daily 3-ketoacyl coenzyme A (CoA) thiolase (3 KAT) inhibitor, optimizes cardiac metabolism. β-ox, β-oxidation; PDH, pyruvate dehydrogenase.
Trimetazidine (Vastarel MR): evidence-based efficacy in patients with diabetes and coronary heart disease
Several publications have demonstrated the value of trimetazidine in patients with diabetes and coronary heart disease. In a pilot study, Fragasso et al [6] showed that short-term (2 weeks) and long-term (6 months) treatment with trimetazidine was able to produce a significant increase in the left ventricular ejection fraction (P <0.001) of patients with diabetes and ischemic cardiomyopathy (Figure 3). Plasma concentrations of endothelin-1 were also significantly reduced, reflecting an improvement in endothelial function, along with glycated hemoglobin concentrations. Another double-blind, parallel-group, placebo-controlled study also produced evidence of the beneficial effect of trimetazidine on left ventricular function in patients with diabetes who had coronary artery disease [7].
Figure 3. Improvement in left ventricular contractile function in response to short- and long-term treatment with trimetazidine (Vastarel MR) in patients with diabetes and dilated ischemic cardiomyopathy.
In patients with coronary artery disease and type 2 (non-insulin-dependent) diabetes, 6 months of treatment with trimetazidine in addition to standard therapy was associated with significant improvement in left ventricular ejection fraction and wall motion score index in comparison with placebo. These studies confirmed previous findings that established the cardioprotective effect of trimetazidine in patients with chronically dysfunctioning myocardium [8]. Finally, in another study, in 50 patients with diabetes and stable angina whose condition remained uncontrolled with conventional treatment (long-acting nitrates, β-blockers, or calcium antagonists), 4 weeks of treatment with trimetazidine resulted in improved exercise capacity and exercise duration, and a significant reduction in the mean number of angina attacks per week (Figure 4), independently of any change in hemodynamic parameters [9]. This study of daily practice also demonstrated the excellent tolerance profile of trimetazidine in these at-risk patients, in whom no specific adverse event was reported and biological variables remain unchanged.
Figure 4. Effective relief of symptoms with trimetazidine (Vastarel MR) in patients with diabetes and stable angina (substudy of Trimetazidine in Poland I).
Conclusion
Modulation of cardiac energy metabolism has proved to be an attractive option for the treatment of ischemic heart disease in patients with diabetes, as reflected by the significant improvements obtained in exercise capacity, symptom relief, and left ventricular function. In these fragile populations, at high risk of cardiovascular events, twice-daily trimetazidine should be considered seriously as a treatment of choice to provide efficient protection of the diabetic heart against the deleterious consequences of chronic myocardial ischemia. ▪
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