Strategies to overcome statin intolerance

Abstract

This editorial discusses several options to overcome statin intolerance in clinical practice. For example, switching to a different statin, changing statin dosing, using lipid-lowering drugs other than statins (e.g., ezetimibe, bile acid sequestrants and fibrates, alone or in combination), or combining statins with other lipid-lowering drugs. The authors focus on the potential mechanisms involved in statin-related myopathy. New lipid-lowering drugs currently in development (e.g., cholesterol ester transfer protein inhibitors [anacetrapib] and proprotein convertase subtilisin/kexin 9 inhibitors) inhibitors may help in the management of statin intolerance while achieving low-density lipoprotein cholesterol targets as set out by the guidelines.

Keywords:

• combination therapy
• ezetimibe
• low-density lipoprotein cholesterol targets
• myopathy
• statin intolerance

1. Statin intolerance

Statins are the cornerstone of lipid-lowering therapy with beneficial effects for both primary and secondary cardiovascular (CV) disease prevention [1]. They improve survival and reduce the risk of major CV events in those with or without established CV disease [2].

Although statins are generally well tolerated, some patients have side effects, mainly muscle- and liver-related [3-5]. In addition, some other less common side effects may lead to statin discontinuation (e.g., nephrotoxicity, peripheral neuropathy, memory loss, sleep disturbances and erectile dysfunction) [3].

In a study carried out in the United States the median time to discontinuation of statins in 161,540 patients was 27.5 months [6]. A high discontinuation rate of statins (28.9% by the end of first year) was reported in the same population [6]. At 18 months and by the end of the second year, 39.6 and 46.5% of the patients, respectively, discontinued statins [6].

Management of high-risk patients, intolerant to statins, is important so as to achieve low-density lipoprotein cholesterol (LDL-C) targets as set out by guidelines [2,7]. Reaching guideline targets (e.g., LDL-C < 70 mg/dl [1.8 mmol/l] in high-risk patients) reduces CV events but is difficult to achieve in clinical practice [2,7].

2. Strategies to manage statin intolerance

2.1 Switching to a different statin

Patients intolerant to a statin may tolerate another one possibly because of pharmacogenomic, pharmacokinetic or pharmacodynamic differences [7]. Experience from several general practices suggests that 92% of patients can tolerate a second statin [3] and 72.5% could successfully tolerate a third statin after discontinuing their initial statin(s) due to various adverse events [8]. The Conversion to Atorvastatin in Patients Intolerant or Refractory to Simvastatin Therapy (CAPISH) study showed that atorvastatin improved LDL-C and creatine kinase levels, and was well tolerated in patients who previously were on simvastatin [9]. In another study, rosuvastatin 5 – 10 mg/day was well tolerated, effective, and had a good safety profile in 61 patients intolerant to other statins [10].

2.2 Changing statin dosing

Statins with a longer half-life such as atorvastatin and rosuvastatin enables less frequent administration in patients intolerant to a statin [7]. It has been reported that once or twice weekly or alternate day treatment with atorvastatin or rosuvastatin was generally well tolerated and improved the lipid profile [11-15]. However, these studies were of short duration, included small numbers of patients and did not document CV events [11-15]. As expected, daily dosing of atorvastatin [16] or rosuvastatin [17] was superior in lowering LDL-C to alternate-day dosing.

2.3 Using lipid-lowering drugs other than statins

2.3.1 Ezetimibe

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed that adding ezetimibe to simvastatin significantly reduced CV events compared with simvastatin monotherapy (34.7 vs 32.7%, p = 0.016) in 18,144 patients with acute coronary syndromes [18]. It follows that ezetimibe should now be considered as an evidence-based drug, at least when added to simvastatin. There is no evidence that ezetimibe monotherapy reduces vascular events.

Ezetimibe appears to be well tolerated in patients intolerant to statins [14,19] or who are not at goal of LDL-C targets despite taking a statin [20]. Ezetimibe monotherapy lowers LDL-C levels by ∼ 19%, triglycerides by 8% and increases high-density lipoprotein cholesterol (HDL-C) by 3% [21]. Thrice-weekly ezetimibe is another option [22]. Overall, it is difficult to reach LDL-C targets with ezetimibe monotherapy.

2.3.2 Bile acid sequestrants

The available bile acid sequestrants (BAS) include colestyramine, colestipol and colesevelam [23]. They lower LDL-C levels by 10 – 20% [23]. In addition, colesevelam improves glycaemic control in diabetic patients [24]. Although BAS have been shown to reduce CV events, they are poorly tolerated and can decrease the absorption of other co-administered drugs [23].

2.3.3 Fibrates

The effect of fenofibrate on LDL-C is variable, ranging from a small decrease in hypercholesterolaemic patients to no change, or even a slight increase, in individuals with combined dyslipidaemia or hypertriglyceridaemia [25]. Fibrates reduce triglyceride levels by 30 – 50% and raise HDL-C levels by 2 – 20% [25]. In The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study fenofibrate significantly reduced all CV disease events by 11% (p = 0.035, secondary end point) whereas it did not affect coronary artery disease death or nonfatal myocardial infarction rates (−11%, p = 0.16, primary end point) [26]. Fibrates are generally well tolerated but their discontinuation rate seems to be higher than that of statins [6]. The most common adverse events observed are muscle and liver toxicity [27]. Other side effects concern the gastrointestinal system, the skin and serum creatinine elevation [27]. Essentially fibrate monotherapy should be reserved for patients with low HDL-C levels and/or hypertriglyceridaemia [25-27].

2.3.4 Nicotinic acid

Although nicotinic acid improves LDL-C, HDL-C and triglyceride levels, it is no longer on the market in many countries due to its side effects, particularly flushing and worsening glycaemic control in diabetic patients as well as negative findings in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High TGs: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials [28]. However, it is possible that these negative findings should not be generalized to patients with elevated LDL-C.

2.3.5 Plant sterols and nutraceuticals

Phytosterols and phytostanols lower LDL-C levels; they also beneficially affected triglyceride and HDL-C levels in some studies [29]. In addition, they may exert beneficial effects on other atherosclerotic risk factors, inflammation and oxidative stress [29].

Red yeast rice has been tried in intolerant to statin patients with beneficial effects on LDL-C lowering but there are some warnings regarding its efficacy and safety [30].

2.4 Combination of non-statin lipid-lowering drugs

Combined therapies including ezetimibe [31], BAS or fibrates may be useful for patients intolerant to statins or unable to reach their LDL-C targets [32]. The combinations of fenofibrate with ezetimibe or with colesevelam can be useful in patients with mixed hyperlipidaemia [32]. Moreover, the combination of ezetimibe with colesevelam appears to be an efficacious and well-tolerated alternative for patients with hypercholesterolaemia [31]. In patients with serious hypertriglyceridaemia, fenofibrate plus n-3 fatty acids is another approach for a further reduction in triglyceride levels [32].

2.5 Combination of statins with other lipid-lowering drugs

Patients who develop statin side effects may tolerate lower doses of the same agents [7]. Therefore, a second lipid-lowering agent such as ezetimibe [14,20,33], BAS [34] or fenofibrate [35] could be added in order to achieve lower LDL-C targets. For example, ezetimibe daily was added in atorvastatin 10 mg twice weekly during a 6-month period in 56 high-risk patients intolerant to daily statin monotherapy [14]. There was a 37% fall in LDL-C levels; 90% of the patients tolerated this regime [14].

2.6 Coenzyme Q10 to reduce statin-related myopathy

Coenzyme Q10 (CoQ10) is an essential co-factor for ATP production and exerts antioxidant activities [36]. CoQ10 supplementation reduced muscle pain in statin-treated patients, in some but not all studies; a meta-analysis of randomized controlled trials does not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy [36].

2.7 LDL-C apheresis

This process can be used either as monotherapy or in combination with other lipid-lowering drugs. LDL-C apheresis may also allow a lower dose of statin to be used. LDL-C apheresis is mainly used to treat patients with familial hypercholesterolaemia [37].

3. Expert opinion

Although statin treatment is essential for CV event prevention, statin intolerance remains a problem in clinical practice [38]. The discontinuation of these drugs may be associated with an increase in morbidity and mortality [38]. Therefore, achieving aggressive LDL-C targets that are recommended by guidelines is important in high-risk patients [7]. Another option could be the combination of ezetimibe daily with once or twice weekly or alternate day low doses of a statin. Ezetimibe is currently the only add-on lipid-lowering drug that has been shown to further reduce vascular risk in patients taking a statin [18].

It is worth mentioning that some factors increase the risk of statin myopathy: for example old age, hypothyroidism, impaired renal function, ethnicity, co-administration with other drugs (e.g., ciclosporin, macrolide antibiotics, antifungal agents, diltiazem, verapamil and amiodarone) or vitamin D deficiency [7]. These factors should be considered when prescribing a statin. Treating some of these conditions may improve statin intolerance. It has been suggested that vitamin D replacement in deficient patients may decrease the risk of developing statin-related myalgia [39]. In addition, genetic associations with statin myopathy have been identified [40]. This includes genes that affect statin metabolism and transport [40]. Patients with inherited muscular disorders may also be more susceptible to statin-related myopathy [40]. The clinical application of these genetic tests is still limited. However, in the future, genetic screening may prove useful for diagnostic purposes and even possibly to guide the selection of optimal treatment options.

There is a need for additional LDL-C reduction in high-risk patients intolerant to statins. New agents (e.g., cholesterol ester transfer protein inhibitors [anacetrapib] and proprotein convertase subtilisin/kexin 9 inhibitors) inhibitors are in development and ongoing randomized controlled trials will clarify their role in clinical practice [41]. These novel agents may prove to be a promising option for the treatment of high-risk patients intolerant to statins or not at goal for LDL-C levels while taking a statin [41]. However, the cost of these drugs could be a serious limitation.

Declaration of interest

This editorial was written independently. No company or institution supported it financially. DP Mikhailidis has given talks, attended conferences and participated in studies sponsored by Merck, Sharp & Dohme, and Genzyme. AP Agouridis is supported by a grant from the Hellenic Atherosclerosis Society. DR Nair has given talks, attended meetings and conferences, participated in clinical trials sponsored by Pfizer, MSD, Sanofi, Amgen and Abbott.