NON–RESPONSE TO INCLISIRAN THERAPY IN THREE PATIENTS WITH STATIN INTOLERANCE: A CASE SERIES

Abstract Background Inclisiran is the first silencing–RNA therapy used to reduce LDL–C. It is also recommended in patients with statin intolerance. We describe a case series of three no–responder patients to inclisiran. Case Series 64–year–old man with medical history of type II diabetes mellitus, obesity, hypertension, chronic kidney disease (eGFR 38 ml/min/1.73 m^2), dyslipidemia and statin intolerance. In 2022 the coronary angiography showed diffuse atherosclerosis without significant stenosis. His LDL–c was 115 mg/dl. Rosuvatatin 10 mg was prescribed however it was withdrawn due myalgia. Inclisiran and ezetimibe were prescribed, however one, three and four months later his LDL–C was 96 mg/dl, 114 mg/dl, and 115 mg/dl respectively (Fig 1). Due to the lack of effect, lovastatin 20 mg was added after the third dose of inclisiran, reaching LDL–C levels of 100 mg/dl one month after the initiation of lovastatin. Inclisiran was withdraw (as well as statin due to myalgia) and evolocumab 140 mg was administrated three months later the last dose of inclisiran. Ten days after evolocumab, LDL value was 66 mg/dl. 60–year–old man with hypertension, obesity, and dyslipidemia (LDL 152 mg/dl) with a moderate cardiovascular risk (target LDL–C <70 mg/dl). Patient refused statin therapy because he was scared about myalgia. In October 2021 (first Italian patient out of clinical trial) inclisiran was administrated. However, LDL–C did not change one month after the first and the second dose (147 mg/dl and 134 mg/dl respectively, Fig1). Due to the inefficacy, inclisiran was withdraw and the combination rosuvastatin and ezetimibe 10/10 mg was started with a reduction in LDL–cholesterol levels (51 mg/dl) four months later. However, this treatment was withdrawn due to myalgia in favor of bempedoic acid. One month later LDL–C level was 79 mg/dl. 79–year–old woman with history of coronary revascularization. She was statin and ezetimibe–intolerant, so she was treated with alirocumab 150 mg (LDL–C 89 mg/dl). Since the treatment was ineffective to reach the LDL target values, alirocumab was stopped in favor to inclisiran. However, LDL values increased over the time reaching 103 mg/dl one month after the first dose and 120 mg/dl two months later the second dose (Fig1). Conclusion some patients may be no–responder to inclisiran. A polymorphism of the asialoglycoprotein receptors might be a possible reason. Statin intolerance may also affect inclisiran efficacy.