The effect of atorvastatin on mevalonate levels in blood plasma in patients with coronary heart disease and muscle side effects

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the mevalonate biosynthesis pathway. By this mechanism, the synthesis of cholesterol is reduced as well as the synthesis of isoprenoid intermediates, which are essential to the isoprenylation of several proteins. Decreased protein isoprenylation has been suggested as a potential pathophysiological mechanism of statin intolerance, but in-vivo studies remain to be conducted.

To assess whether mevalonate levels in blood plasma, in response to atorvastatin treatment, are associated with statin intolerance in patients with coronary heart disease (CHD).

In 2019, 71 CHD patients with self-perceived statin-associated muscle symptoms (SAMS) during atorvastatin therapy were randomized to double-blinded treatment with atorvastatin 40 mg/day and matched placebo in a crossover design. Based on predefined criteria, 20 patients reported more symptoms on atorvastatin than placebo whereas 51 patients showed no difference in muscle symptom intensity. During a 7-months-open-label follow-up period, two research cardiologists attempted to reintroduce statin treatment at the highest tolerable dose. Seven out of 71 patients (10%) were clinically intolerant to statins, i.e. not tolerating ≥3 different statins due to myalgia with no or minor increase in creatine kinase. The remaining 64 patients were statin-tolerant. Mevalonate in blood plasma was measured with LC-MS/MS.

Mean age was 65 (SD 9) years, and 32% were female. There was no significant difference in mevalonate levels in blood plasma between statin intolerant (n=7) and tolerant (n=64) patients (median 39 vs 32 nmol/L, p=0.51). The statin-intolerant patients had a minor reduction in mevalonate on atorvastatin treatment compared to the statin-tolerant (Figure). Absolute differences in mevalonate were median -8.1 nmol/L vs. -24.3 nmol/L (p=0.04), and relative differences were median -9.7% vs -40.9% (p=0.04) for the intolerant vs the tolerant group.

CHD outpatients intolerant to 3 or more statins had a less pronounced reduction in mevalonate levels in blood, during intake of atorvastatin, compared to statin tolerant patients. Statin-induced mevalonate reduction does not seem to be the cause of statin intolerance. Further studies are needed to clarify the role of mevalonate in patients with statin side effects.

Mevalonate differences.