Mevalonate in blood and muscle: Response to atorvastatin treatment and the relationship to statin intolerance in patients with coronary heart disease

Abstract

Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference -38%, range -77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range -47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho -0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference -8.1 (-22 to 3.5) nmol/L versus -25 (-93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential.

FIGURE 1

Study flow chart. CHD, coronary heart disease; SAMS, statin‐associated muscle symptoms (self‐perceived). *Not tolerating ≥3 statins due to muscle symptoms, no or minor increase in creatine kinase. **Included 3 of the 6 categorized as statin intolerant during the clinical follow‐up after MUSE RCT and one in addition that was categorized during the biopsy study and later follow‐up. ***Included the 6 categorized as intolerant during the clinical follow‐up after MUSE RCT and one in addition that was categorized during the biopsy study and later follow‐up. ^§On statin (n = 26) and off statin (n = 22) (4 patients had only one biopsy).

FIGURE 2

Mevalonate and low‐density lipoprotein cholesterol (LDL‐C) in blood plasma. Seven‐weeks randomized blinded treatment periods; atorvastatin 40 mg/day and placebo, 1‐week washout without statin prior to each period. One dot equals one participant, and the horizontal lines are group medians, n = 70. p‐Values are derived by the Wilcoxon signed‐rank test.

FIGURE 3

Mevalonate in skeletal muscle tissue. Seven‐weeks open treatment with atorvastatin 40 mg/day and then 8 weeks off statin. One dot equals one participant, and the horizontal lines are group medians. On statin; n = 26, off statin; n = 22. p‐Values are derived by the Wilcoxon signed‐rank test.

FIGURE 4

Mevalonate and low‐density lipoprotein cholesterol (LDL‐C) as biomarkers for differentiating statin tolerance and intolerance. The biomarkers are expressed as absolute differences between measurements on atorvastatin 40 mg/day vs. off statin. Statin tolerant; n = 63, statin intolerant; n = 7 (not tolerating ≥3 statins).