Therapeutic options for statin-intolerant patients

Keywords::

• Colesevelam
• Ezetimibe
• Intermittent dosing
• Intolerance
• Orlistat
• Safety
• Statin
• Vitamin D

Statin intolerance is a common problem in clinical practice. Most frequent statin-specific adverse events include musculoskeletal symptoms (e.g., myalgia or muscle weakness) as well as asymptomatic elevations of the plasma activities of creatine kinase (CK) and liver enzymes [aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)]1–3. Myalgia and elevation of transaminases activities may account for two-thirds of statin-related adverse effects in clinical trials3. Furthermore, central nervous system (e.g., headache or dizziness) and gastrointestinal tract (e.g., nausea or diarrhoea) symptoms are commonly reported by statin-treated patients1–3. Severe adverse events of statins include myositis, rhabdomyolysis, as well as a clinically relevant rise in AST and/or ALT activity1,2. Moderate elevations in serum CK activity during statin treatment are common but often not associated with myalgia or myositis2.

Statin intolerance often results in ‘poor’ adherence (compliance) or drug discontinuation which, in turn, is associated with increased cardiovascular (CV) morbidity and mortality4,5. Of interest, it has been suggested that statin withdrawal may be associated with worse outcomes compared with not taking statins at all4.

Statin-related adverse events seem to be linearly dose-dependent while efficacy in reducing LDL-C increases 5–7% for every doubling in dose1,6. Also, not all statins are equally tolerated by each patient1,6. Therefore, changing to a lower dose of another statin or intermittent use of statins are reasonable strategies for patients who experienced intolerance to statins7. Among statins, atorvastatin and rosuvastatin are preferred for alternate-day use due to their longer half-lives (approximately 14 and 19 h, respectively)8,9. In this issue of the Current Medical Research and Opinion a retrospective study assessing the efficacy and safety of rosuvastatin 5 mg, either daily or intermittently (2–3 times/week or weekly), in patients with dyslipidaemia who exhibited intolerance to >2 statins is presented10.

In this editorial we discuss treatment options for statin-intolerant patients.

Safety

In the study by Meek et al., most patients (75.4%) at baseline exhibited intolerance to simvastatin; 63.3% to atorvastatin, 25.6% to pravastatin, 12.0% to fluvastatin, 1.5% to cerivastatin, and 14.0% to higher doses of rosuvastatin10. This is consistent with other studies showing that simvastatin, especially at high doses, was associated with greater rates of muscular symptoms compared with other statins (except for cerivastatin which was removed from the market)11. However, the findings of the Meek et al. study10 could be misleading since patients were not randomized to equivalent doses of different statins in terms of low-density lipoprotein cholesterol (LDL-C) lowering. Therefore, the exposure of patients to different statins could be variable. In this context, it would be useful to assess the tolerability of different statins in prospective randomized studies, although such a study would be difficult to design. Furthermore, to confirm the association of muscle symptoms with statins, patients should be de-challenged and then re-challenged. This procedure was not performed by Meek et al.10 but it has to be acknowledged that patient acceptance for such a design may be low. During the study period rosuvastatin 5 mg was well-tolerated with 89% of all patients reporting no adverse events at any dosing frequency (daily, 2–3 times/week or weekly)10. Unsurprisingly, the majority of statin-intolerant patients complained of muscle-related toxicity (74% reported myalgia and 8% had myositis)10. In accordance with these findings, previous reports suggested that muscle events may account for up to 95% of statin-associated adverse events12–14. Furthermore, it was shown that 9% of patients experience muscle symptoms immediately after statin initiation15. However, in the statin-experienced population recruited to the Heart Protection Study and receiving 40 mg simvastatin the excess rate of side-effects was only 0.1%16.

After the withdrawal of cerivastatin, an advisory statement of the American Heart Association (AHA), the American College of Cardiology (ACC) and the National Heart, Lung and Blood Institute (NHLBI) identified risk factors for statin-associated myopathy17. These include: advanced age (especially >80 years), small body frame and frailty, hypothyroidism, multisystem disease [e.g., chronic kidney disease (CKD), especially in the clinical setting of diabetes], perioperative periods, drug–drug interactions (especially with gemfibrozil, ciclosporin, amiodarone, verapamil, high-dose diltiazem, antifungal azoles and macrolide antibiotics) and alcohol abuse17. Since diabetes is mentioned among the risk factors for muscle toxicity, it is of interest that statin treatment may increase the risk of diabetes18. However, this evidence mostly comes from post hoc analyses or adverse effect reports of randomized trials; this needs to be evaluated in prospective studies18.

In the study by Meek et al., many of the participants in the 2–3/week and weekly rosuvastatin dosage had mild-to-moderate CKD according to the mean estimated glomerular filtration rate [(eGFR) = 62–64 ml/min/1.73m²]10. In such conditions increased toxicity may be anticipated especially with some statins8. Atorvastatin-associated toxicity is less likely in the clinical setting of CKD due to its limited renal excretion (<2%)8. Rosuvastatin, which was the statin of choice in the Meek et al. study10, also undergoes minimal renal excretion (<10%)8,9. In this context, the AURORA (A Study to Evaluate the Use of Rosuvastatin on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) was a double-blind placebo-controlled trial that included 2776 patients on maintenance hemodialysis. In this study, rosuvastatin 10 mg/day did not reduce the primary endpoint of CV death, non-fatal myocardial infarction or nonfatal stroke after a median of 3.8 years19. Of interest, despite the high incidence of adverse events in the rosuvastatin and placebo group (96.3 and 96.7%, respectively), no significant difference between groups was noted with regard to safety outcomes or specific side-effects likely to be associated with statin therapy (e.g., myositis or rhabdomyolysis)19. In the study by Meek et al., patients on intermittent dosing of rosuvastatin may have had a trend towards more advanced CKD (eGFR 62 ± 12 and 64 ± 6 ml/min/1.73 m² for 2–3 times/week and weekly dosing, respectively, compared with 77 ± 16 ml/min/1.73 m² for daily dosing)10. This potential relationship requires further analysis with larger numbers of statin-intolerant patients.

It has been postulated that the lipophilicity of statins may be related to safety8. Hydrophilic statins, including rosuvastatin, were suggested to have restricted access to vulnerable tissues (e.g., myocytes, liver and renal tissue) by passive diffusion across cell membranes8. The hepatic uptake of these statins is mostly mediated through transporter-mediated system via organic anion transporters (OATPs)8. Genetic variability in OATPs (e.g., SLCO1B1) may account for differences in statin tolerance8,20.

Drug–drug interactions also contribute to statin toxicity2,8. Statins metabolized through the cytochrome (CYP) P450 system are more susceptible to interactions with concomitant medications2,8. Rosuvastatin and pravastatin undergo minimal metabolism via the CYP system8,9. On the other hand, atorvastatin and simvastatin are metabolized mostly by the CYP 3A4 isoenzyme, which is involved in many drug–drug interactions8. Recently, the US Food and Drug Administration (FDA) retracted the 80 mg/day dose of simvastatin due to increased risk of muscle toxicity. Also, the FDA suggested that the simvastatin dose should be restricted if co-administered with several drugs21. For example, simvastatin should not exceed 10 mg/day in patients on amiodarone, verapamil or diltiazem and 20 mg/day in patients taking amlodipine or ranolazine21.

Vitamin D deficiency often coexists with dyslipidaemia and metabolic disorders where statins may be prescribed (e.g., metabolic syndrome)22. Hypo-vitaminosis D was associated with reduced efficacy of statin treatment22. Also, vitamin D depletion has been associated with increased risk for statin-associated muscle dysfunction and/or injury by mechanisms that are not completely understood22,23. Several statins, including atorvastatin and rosuvastatin, may increase vitamin D levels, while others, such as simvastatin and fluvastatin, may not do so14,22,24. In this context, 150 patients who were vitamin D deficient and intolerant to ≥1 statins due to myositis-myalgias were pre-treated with of 25(OH)vitamin D (50,000 IU twice a week) for 3 weeks14. Vitamin D supplementation resulted in a high percentage of patients (i.e., 87%) who tolerated the re-institution of statins after 8.1 months (median) of treatment14. Post-treatment levels of vitamin D were corrected in most (i.e., 78%) of these patients14. Therefore, correcting vitamin D deficiency may improve the tolerability of statins which were previously discontinued due to muscle-related toxicity14.

Efficacy

In the Meek et al. study, daily or intermittent use of rosuvastatin 5 mg was associated with significant decreases in total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels by 29, 16 and 39%, respectively (p < 0.001 for all)10. However, deterioration in the lipid-lowering potency by intermittent dosing of rosuvastatin was the ‘price to pay’. For example, rosuvastatin 5 mg weekly reduced TC by 17%, LDL-C by 23% and had no significant effect on TG10. These changes are enough to provide a benefit in terms of event reduction. For example, in trials with pravastatin similar reductions in LDL-C were associated with significant decrease in vascular events and even in CV mortality both in the primary and secondary prevention setting25,26.

In accordance with these findings previous studies showed that either daily or alternate day low-dose rosuvastatin reduced LDL-C levels. This effect is diminished as dosing frequency decreases. Namely, rosuvastatin 5 mg/day significantly reduced LDL-C levels (by 42%, p < 0.001) after 16 weeks of treatment in 61 patients with hypercholesterolaemia that had previously experienced intolerance to statins12. The decrease in LDL-C levels was lower (34.5%) with every-other-day rosuvastatin administration at a mean dose of 5.6 mg in a retrospective cohort of 51 statin-intolerant patients27. Furthermore, an even lower LDL-C reduction (23%) was reported with a weekly dosing of rosuvastatin 2.5–20 mg after 4 months of treatment in another statin-intolerant population28.

Alternative therapeutic options should be considered in statin-intolerant patients29. For example, the addition of ezetimibe to intermittent statin administration could be a useful strategy to attain LDL-C goals. In this context, the safety and efficacy of ezetimibe 10 mg/day either alone or in combination with atorvastatin 10 mg twice a week was assessed in 56 high-risk hypercholesterolaemic patients intolerant to daily statin use30. Ezetimibe monotherapy was well-tolerated (two withdrawals) and produced a significant though modest decrease in LDL-C levels (20%, p < 0.05)30. The addition of atorvastatin 10 mg twice/week to ezetimibe monotherapy was associated with a greater decrease in LDL-C levels (37%, p < 0.001) and a larger proportion of patients (84%) attained LDL-C goals30. Combination treatment was well-tolerated (three withdrawals)30. These findings are in accordance with most studies showing that ezetimibe, alone or in combination with statins, was not associated with increased rates of myopathy or rhabdomyolysis31.

A meta-analysis of randomized controlled trials, which involved 5039 patients, assessed the efficacy and safety of adding ezetimibe 10 mg/day to ongoing statin treatment32. A weighed mean difference of 23.6% (p < 0.0001) for LDL-C reduction favouring ezetimibe/statin over placebo/statin treatment, was noted32. Furthermore, the addition of ezetimibe to statin therapy was associated with advantageous changes in HDL-C (1.7% increase, p < 0.0001) and TG levels (10.7% decrease, p < 0.0001) compared with placebo/statin treatment32. In this meta-analysis, elevations of plasma CK and/or AST/ALT were not different between groups32. In another meta-analysis of 13 studies (5080 hypercholesterolaemic patients) adding ezetimibe 10 mg/day to a statin was more effective in decreasing LDL-C levels and attaining LDL-C goals compared with doubling the statin dose33. The weighed mean difference for LDL-C reduction was 15.3% in favour of combination treatment33.

It was suggested that ezetimibe lacks the pleiotropic effects of statins and that this may affect its efficacy in terms of reducing vascular events34. However, there is evidence showing that ezetimibe also has pleiotropic properties35,36. In the end the most important issue is reducing vascular events. In this context, the Study of Heart And Renal Protection (SHARP) included 9270 patients with CKD (3023 on dialysis and 6247 pre-dialysis patients) randomized to either simvastatin 20 mg/day and ezetimibe 10 mg/day combination or placebo37. After 4.9 years (median) the simvastatin and ezetimibe combination significantly reduced major atherosclerotic vascular events by 17% (p = 0.0021) compared with placebo37.

Combining lipid-lowering drugs acting at the level of the gastrointestinal tract could help statin-intolerant patients38. A retrospective study showed that the combination of colesevelam (1.875 g twice daily) with ezetimibe significantly reduced LDL-C levels by 42% in 16 patients with diabetes or metabolic syndrome and a history of statin intolerance, after 3 months of treatment39. Colesevelam is better-tolerated than older bile acid sequestrants40. However, colesevelam should be used with caution in patients with hypertriglyceridaemia40.

Orlistat monotherapy or in combination with other hypolipidaemic drugs could be a useful option for the management of statin-intolerant obese patients. In 30 non-diabetic statin-intolerant obese and overweight patients with dyslipidaemia ezetimibe 10 mg/day and orlistat 120 mg 3 times daily significantly decreased LDL-C levels by 28.4% (p < 0.01) after 3 months41. In 89 obese and overweight patients orlistat monotherapy 120 mg 3 times daily significantly reduced LDL-C levels (by 18%, p < 0.01) after 3 months42. This decrease was more prominent with the combination of orlistat with micronized fenofibrate 200 mg/day (p < 0.001)42. However, the use of orlistat may be associated with clinically relevant adverse effects (e.g., oily stools, diarrhoea, abdominal pain and faecal spotting)43.

Conclusions

Re-starting with a low dose of another statin could be an effective option in statin-intolerant patients. Concomitant medications should also be taken into consideration. Correction of vitamin D deficiency may be helpful. Less frequent statin dosing in patients susceptible to muscle toxicity may reduce the risk of intolerance although intermittent dosing of statins may adversely affect the LDL-C lowering potential. In this context, hypolipidaemic drugs acting at the level of the gastrointestinal tract (ezetimibe, colesevelam, orlistat) may reduce LDL-C levels even in the absence of statin treatment. Whether these strategies are also effective in reducing CV risk in statin-intolerant patients should be assessed in randomized trials.

Transparency

Declaration of funding

The author declares no funding for this manuscript.

Declaration of financial/other relationships

D.M. is the recipient of sponsorship funding to attend meetings on behalf of Merck and Sharpe & Dohme, is a consultant for Merck and Sharpe & Dohme, and is a member of the speakers’ bureaux for Merck, Sharpe & Dohme and Genzyme.

Acknowledgements

The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.