Strilchuk L. Expert Opin Pharmacother. 2020 Feb 8:1-9.

Elevated serum level of low-density lipoprotein cholesterol (LDL-C) is highly correlated with an enhanced risk to arise coronary artery disease and other atherosclerosis-related diseases. Even though statin therapy is an effective lipid-lowering strategy, only about one-fifth of statin users acquired the suggested lipid goals. High-intensity statins showed superior results, although they can also stimulate myopathy and new-onset diabetes. Poor compliance, variability in drug response, inappropriate dose titration, use of low-intensity statins, and poor adoption of current guidelines by health-care providers are other obstacles in reaching the suggested LDL-C goals with statin therapy. The most current guidelines of European Society of Cardiology and European Atherosclerosis Society for the management of dyslipidaemias suggest combination with Ezetimibe for the high-risk patients or with very high LDL-C levels who can’t gain appropriate goals with monotherapy. Thus, Strilchuk L conducted an overview to summarize the main pharmacological features of Rosuvastatin and Ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic impacts, with specific attention to the clinical impact of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as patients influenced by diabetes mellitus and AIDS).

A fully synthetic hydrophilic HMG-CoA reductase inhibitor, Rosuvastatin, is one of the most effective available statins. Rosuvastatin 10–40 mg daily dose decreases LDL-C by 46–55%, as per the STELLAR study. The VOYAGER study showed that Rosuvastatin enhances high-density lipoproteins cholesterol (HDL-C) by 6.1%, while dose abandonedly reducing TG levels from −15% to −31%. Rosuvastatin can be administered once a day, at any time of the day and low rates of severe myopathy, rhabdomyolysis and renal failure are other benefits shown by Rosuvastatin. Ezetimibe reduced the intestinal absorption of both dietary and endogenous cholesterol by 54–67% as it blocks a cholesterol transporter called NPC1L1 protein. It undergoes extensive glucuronidation which is more active than the parent compound, to ezetimibe glucuronide by UGT enzymes. It does not impact the absorption of bile acids, fatty acids, fat-soluble vitamins and triglycerides (TG). Ezetimibe can be administered at any time of the day as a monotherapy or in combination with statins. Ezetimibe also exhibited anti-inflammatory properties with the additional 9 -10% reduction in hs-CRP by ezetimibe/statin combination than statin monotherapy. In the EXPLORER study, substantially more participants could reach the Adult Treatment Panel III (ATP III) LDL-C goal (100 mg/dL) by combo therapy as compared to Rosuvastatin alone (94.0% vs 79.1%, p = 0.001) after 6 weeks of therapy, showed the efficacy and safety of Rosuvastatin (40 mg) in combination with Ezetimibe 10 mg in high-risk hypercholesterolemic patients.

In the I-ROSETTE trial, the percent changes in total cholesterol, TG, non-HDL-C, and apolipoprotein B were also substantially higher in the combination group as compared to the Rosuvastatin users and the Rosuvastatin/Ezetimibe group showed significant reduction in mean LDL-C from the baseline as compared to Rosuvastatin group (57.0% vs. 44.4%, p < 0.05). In the MRS-ROZE, Rosuvastatin/Ezetimibe combination exhibited substantially higher decrease in LDL-C, total cholesterol, TG, non-HDL-C and apolipoprotein B as compared to Rosuvastatin alone, showed lipid lowering efficacy in patients with primary hypercholesterolemia.

Rosuvastatin 20 mg monotherapy and Rosuvastatin/Ezetimibe 5/10 mg combination therapy for 6 weeks showed similar-substantial decrease of LDL-C, non-HDL-C, apolipoprotein B, and apolipoprotein B/apolipoprotein AI ratio in patients with T2DM. Only the combination group showed reduction in the levels of TG and free fatty acids (−6.6% in the Rosuvastatin group and −32.6% in the Rosuvastatin/Ezetimibe group, p = 0.036; 0.0% in the Rosuvastatin group and −25.9% in the Rosuvastatin and Ezetimibe group, resp. p = 0.046). In the HIV-positive patients, who could not reach their lipid goals with maximally tolerated statin monotherapy, showed reduction of mean total cholesterol by 32%, mean LDL-C – by 45%, and mean TG by 49% with the addition of Ezetimibe to the therapy with the high risk of pharmacological interaction of HAART, the Ezetimibe and Rosuvastatin is the safe-preventive therapy of dyslipidaemic HIV+ patients as the use of drugs was not metabolized by CYP3A4 nor interacting with the bowel P-glycoprotein.

Thus, it was concluded that The Rosuvastatin/Ezetimibe combination is an efficacious and efficiently tolerated lipid-lowering therapy. Hence, the Rosuvastatin/Ezetimibe combination is a valuable alternative to statin dose up titration with magnificent safety profile and absence of clinically relevant drug-drug interactions.

AIDS: Acquired Immune Deficiency Syndrome; STELLAR: Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin; VOYAGER: Individual Patient Data Metaanalysis Of Statin Therapy In At Risk Groups: Effects of Rosuvastatin, Atorvastatin and Simvastatin; NPC1L1: Niemann- Pick C1-Like 1; UGT: uridine 5ʹ-diphosphate-glucuronosyltransferase; EXPLORER: Examination of Potential Lipid-modifying Effects Of Rosuvastatin in Combination with Ezetimibe versus Rosuvastatin Alone; I-ROSETTE: Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia; MRS-ROZE: Multicenter Randomized Study of Rosuvastatin and Ezetimibe; HAART: highly active antiretroviral therapy; CYP3A4: Cytochrome P450 3A4