**2. Statin intolerance**

Statin intolerance is the inability to tolerate sufficient dose of statin needed to reduce cardiovascular risk due to side effects or intolerance to treatment [11]. The most frequent are muscle symptoms characterised bellow.

#### **2.1. Statin-associated muscle symptoms**

Statin-induced muscle symptoms range from myalgia to mild or severe myopathy and even to rare rhabdomyolysis [12]. The symptoms appear in about 75% in the first 10–12 weeks and in 90% of cases in the first 6 months after treatment initiation or dose up titration [13]. The true frequency muscle related side effects has been widely debated: while an observational study reported as much as about 20% of patients on statins [14], clinical trial data suggests frequencies to be equal or lower than 5% [15], however there was a study reporting that clinical trials did not use a standard definition for statin myalgia [16], which may result in underestimated occurrence of statin-induced muscle symptoms. In any case, given very high usage of statins (the third most frequently prescribed drug), even lower relative frequency numbers would mean substantial absolute number of symptomatic patients.

#### **2.2. Clinical-related risk factors**

The available data shows that the side effects of statin therapy are group-dependent, timedependent and dose-dependent; their frequency is greater at a higher statin dose [17].

Endogenous factors known to increase occurrence of side effects are as follows: another lipid-lowering therapy, alcohol abuse, surgery, heavy exercise. Importantly, interactions with medication may be serious [18]; particularly drug interactions likely contribute the susceptibility to statin related muscle symptoms [19].

Further factors predisposing to statin intolerance are: advanced age (>70 year), female sex, race/ethnicity, family history of muscle disorders, vitamin D deficiency, history of creatine elevation, hepatic and renal impartment, hypothyroidism, low body mass index [20].

#### **2.3. Genetic factors**

Besides the above characterised factors, genetic "make-up" of a given patient is important component in susceptibility to statin intolerance. Indeed, genetic variation represents the major factor responsible for inter-individual differences in patient responsiveness and their inclination towards undesirable side effects of statins.
