Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report

Abstract

Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.

Keywords: Pharmacogenetics; familial hypercholesterolemia (FH); myalgia; precision medicine; statins.

Figure 1

Plasma lipid profile and pharmacotherapy of the FH patient throughout the study period. EZT, ezetimibe; LVT, levothyroxine; RSV, rosuvastatin; SRAE, statin-related adverse events.

Figure 2

Proposed mechanism for patient’s late rosuvastatin response and myalgia. 1. The hepatic uptake of rosuvastatin occurs through SLCO1B1 and SLCO1B3 influx transporters, while atorvastatin and simvastatin are internalized through SLCO1B1. The presence of deleterious variants in these transporters (SLCO1B1*15 and SLCO1B3 c.334T>G and c.699G>A) decreases statin uptake, therefore decreasing their concentration inside the hepatocyte and increasing statin plasma levels. 2. The lack of expression of CYP3A5 due to CYP3A5*3 also decreases atorvastatin and simvastatin metabolization, which contributes to increasing their plasma levels. This enzyme does not participate markedly in rosuvastatin metabolism. 3. The resulting higher blood statin levels increased the patient’s muscular exposure to statins, that are internalized through SLCO2B1 transporter into the skeletal muscle cell. The high concentrations in the skeletal muscle cell possibly caused patient’s myalgia. 4. Rosuvastatin’s bile excretion occurs through ABCB11 efflux protein. ABCB11 c.1331T>C variant results in a reduced activity ABCB11, which decreases rosuvastatin efflux; this increases rosuvastatin intrahepatic levels and blood levels. Although the patient had reduced function influx transporters, we suggest that the small portion of rosuvastatin absorbed in the beginning of the treatment accumulated due to the loss of function of the ABCB11 variant. This, together with rosuvastatin active metabolites generated by the normal function CYP2C9, allowed HMGR inhibition and therefore cholesterol lowering in the last visit.