The incidence of diabetes mellitus is becoming progressively more frequent. The majority of diabetic patients will develop cardiovascular complications, among which coronary artery disease and diabetic cardiomyopathy are the most frequent and insidious. Apart from a meticulous metabolic control of diabetes, cardiac and vascular complications should be aggressively treated using the usual drugs at present effectively employed for their treatment in the general population. Additionally, the possibility of modifying cardiac substrate metabolism of the diabetic heart appears particularly attractive. Specifically, the possibility of increasing glucose metabolism rate and, accordingly, reducing free fatty acid oxidation, appears to be a very attractive therapeutic approach. Indeed, among traditional pharmacological tools, there is growing evidence that specific metabolically active drugs, the so-called partial free fatty acid inhibitors, of which the most studied is trimetazidine, will play an increasing role in the treatment of diabetic patients with coronary artery disease and cardiomyopathy. The property of these drugs is to facilitate myocardial utilization of glucose instead of free fatty acids which, in the context of ischemic and dysfunctional myocardial cells, appears to be deleterious. Similarly to other compounds that stimulate pyruvate dehydrogenase activity thereby facilitating glucose oxidation and inhibiting free fatty acid oxidation, such as dichloroacetate, trimetazidine has been shown to improve left ventricular function in diabetic patients with heart failure. Prospective studies in large clinical trials would produce more objective and definitive insights into the specific value of these new therapeutic concepts in the treatment of diabetic patients with cardiac diseases.