Clinical pharmacology of combination therapies for the prevention and treatment of cardiovascular diseases

Hypertension and hypercholesterolemia represent two causal factors of atherosclerotic cardiovascular disease and are modulated by different molecular mediators. These mediators represent the pharmacological targets on which oral therapies have been developed for the control of hypertension and hypercholesterolemia. Pharmacological therapy aimed at modulating cardiovascular risk factors has demonstrated clinical efficacy with the results of several phase 3 clinical trials. In particular, the HMG-CoA reductase inhibitors, including rosuvastatin, and the inhibitor of the cholesterol transporter NPC1L1 ezetimibe are effective drugs in reducing levels of low-density lipoprotein cholesterol. On the other side, antihypertensive drugs include renin-angiotensin-aldosterone system inhibitors, such as angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, calcium channel blockers, beta-blockers and thiazide diuretics. Combination therapy, therefore, represents the most effective and tolerated approach for controlling both risk factors. Based on this evidence, fixed combination therapies have been developed which are useful in simplifying the treatment of patients at high cardiovascular risk. An essential condition for the development of fixed formulations is represented by the complementarity of the pharmacological action of the two or three associated drugs, and similar pharmacokinetic profile allowing the same frequency of administration. Furthermore, the pharmacokinetic profile of the two drugs given in fixed combination must not differ significantly from that observed with the two drugs administered individually. In this review the following fixed combination therapies are examined: rosuvastatin/ezetimibe, ramipril/amlodipine, candesartan/amlodipine, ramipril/amlodipine/hydrochlorothiazide and amlodipine/rosuvastatin, describing their pharmacodynamic and pharmacokinetic characteristics and their bioequivalence with respect to single therapies. This analysis provides essential information for the evaluation of their clinical effectiveness in the control of hypertension and hypercholesterolemia in patients at high cardiovascular risk.