ABC | Volume 112, Nº4, April 2019

Review Article Ferrari et al PCSK9 Inhibitors in Clinical Practice Arq Bras Cardiol. 2019; 112(4):453-460 Figure 1 – Mechanisms of PCSK9 involvement in LDL metabolism. Table 1 – Indications for PCSK9i use in Brazil, according to the Brazilian Guideline on Dyslipidemia. 24 Patients at high risk of a CV event On treatment with statins at the highest tolerated dose Statin or statin + ezetimibe therapy Statin-intolerant or has not met recommended LDL or non-HDL goals ↓ Evolocumab (Repatha™)  Alirocumab (Praluent®) 140 mg by subcutaneous injection every 2 weeks or 420 mg once a month Both doses reduce LDL by approximately 60%. 25 75 mg or 150 mg by subcutaneous injection every 2 weeks The 75-mg and 150-mg doses are associated with average LDL reductions of 45% and 60%, respectively. 25 PCSK9i is recommended only if the LDL concentration is persistently above 4.0 mmol/L (approximately 154 mg/dL). If the patient is considered to be at very high CV risk, PCSK9i therapy is recommended only if the LDL concentration is persistently above 3.5 mmol/L (approximately 135 mg/dL). 23 In contrast, the updated Brazilian Guidelines for Dyslipidemias and Prevention of Atherosclerosis 24 adopted a much less conservative addendum. In those patients at high risk for CV disease, the therapeutic goal of LDL should be below 70 mg/dL, while in those considered at very high risk CV, the goal is to reach LDL levels below 50 mg/dL. Accordingly, the 2017 consensus of the American College of Cardiology states that, for patients at higher risk (such as those with acute coronary syndrome or with multivessel CAD), a target LDL level of < 50 mg/dL can be considered. 25 The American Association of Clinical Endocrinologists /American College of Endocrinology statement recommends a target LDL level < 55 mg/dL for: a) patients with progressive atherosclerotic CV disease; b) patients with atherosclerotic CV disease in association with diabetes and/or stage 3 or 4 chronic kidney disease; c) patients with heterozygous familial hypercholesterolemia (HF); and d) those with premature atherosclerotic CV disease. In turn, the European Society of Cardiology / European Atherosclerosis Society  Task  Force recommends PCSK9i therapy when LDL is ≥ 140 mg/dL and the patient is already on combined statin and ezetimibe therapy; or when LDL is ≥ 100 mg/dL in cases of rapid progression of atherosclerotic CV disease. 26 In these individuals, PCSK9i therapy is recommended with a target LDL level < 70 mg/DL. 27 Patients with and without diabetes mellitus Preclinical and clinical epidemiological studies have revealed an association of PCSK9 levels with insulin resistance and the risk of developing type 2 diabetes mellitus (DM2). 28,29 Although genetic study findings have been contradictory, there seems to be a positive association between levels of PCSK9 and the incidence of DM2. 28 The Dallas Heart Study found that PCSK9 levels were significantly higher in patients with DM2. 29 Regular use of statins and fibrates may increase 455