Statins are the foundation of lipid lowering pharmacotherapy for prevention and management of atherosclerotic cardiovascular disease (ASCVD). Evidence from outcomes studies shows a consistent linear relationship between the extent of low-density lipoprotein cholesterol (LDL-C) lowering with a statin and the relative reduction in risk of ASCVD events.1 Moreover, the low cost of statins means that treatment is also cost effective even in patients at lower risk (including those with a 7.5% 10-year calculated cardiovascular disease risk).2
For the clinician, the ongoing issue is LDL-C goal attainment, especially in patients at high ASCVD risk. For example, the CEPHEUS study in more than 35,000 patients (mean age 60 years) enrolled in 29 countries across Asia, Western Europe, Eastern Europe, the Middle East, and Africa, showed that only 50% of patients at high cardiovascular risk and 20% of those at very high risk attained guideline-recommended LDL-C target levels.3 Additionally, EUROASPIRE, a pan-European survey of care of coronary patients, showed that while there has been improvement in uptake of statins, less than one in 5 patients attained an LDL-C goal of <1.8 mmol/L.4
What are the reasons for poor LDL-C control?
Clinician inertia and less than optimal use of high-dose, high-intensity statin therapy are key factors responsible for lack of LDL-C goal attainment factor, as shown by evidence from EUROASPIRE.4 However, other contributors merit consideration.
First, there may be prescribing issues, with patient factors negatively influencing clinical decision making, as well as treatment adherence. The media may have played some part in this; in a recent report from Denmark, negative statin-related news stories may be a factor contributing to less than optimal adherence and early statin discontinuation.5 For some patients, the risk of symptoms (real or perceived) may negate any potential gain from treatment.
Second, there may be tolerability issues that impact treatment adherence. A key focus of attention is the potential for statin-associated muscle symptoms (SAMS). The reported prevalence varies, but is likely to be in the region of about 10%, based on observational and prescription data.6,7 Management of SAMS has been the focus of a recent European Atherosclerosis Society Consensus Panel statement, which provides information on diagnosis, assessment and management of SAMS.8 Debate concerning the aetiology of SAMS continues;9 indeed, it is relevant that in recent trials assessing PCSK9 inhibitors, up to 50% of patients thought to be ‘statin intolerant’ were in fact able to tolerate a statin, albeit at a lower dose or intermittent dosing schedules, suggesting that SAMS may not be due to the statin.9 While the aetiology is still indeterminate, a recent report suggests that an elevated creatine kinase may help in identification of true SAMS.10
Ezetimibe is the first choice alternative therapy for patients with verified SAMS unable to tolerate a statin,8 although the extent of LDL-C reduction is usually inadequate, especially in patients at high ASCVD risk. PCSK9 inhibition may merit consideration in very high risk patients,11,12 although the clinical need for this treatment also needs to be balanced against the cost of treatment.
Another issue to consider is the patient’s responsiveness to statin treatment, bearing in mind that a genetic component may account for substantial inter-individual variability in the response. Recent evidence from a meta-analysis of genome-wide association studies in more than 40,000 subjects showed that two loci of the genome, SORT1/CELSR2/PSRC1 and SLCO1B1, involved in intracellular statin transport, as well as APOE and LPA,, are responsible for about 5% of the variation in an individual’s response to statin treatment.13 Other genetic loci may be implicated; recent research suggests that genetic variation in PCSK9 may also modify statin responsiveness.14
Evidence from the JUPITER study highlights the wide variability in statin responsiveness.15 In this secondary analysis, while the median LDL-C lowering response was 50%, more than half showed a response less than this; 43% had an LDL-C reduction <50% and 11% showed no reduction or even an increase in LDL-C with rosuvastatin 20 mg. The magnitude of the response was an important determinant of the clinical benefit accrued from statin treatment, as the incidence of first cardiovascular events was about two-fold higher in patients who did not respond to a statin, compared with those showing at least 50% reduction in LDL-C. Evidence from a real-world setting substantiates the magnitude of statin non-responsiveness, with 60% of high risk patients showing less than 30% reduction in LDL-C levels with statin therapy.16
The patient’s responsiveness to a statin becomes increasingly relevant when considering its impact on progression of ASCVD. This was clearly shown in an intravascular ultrasound study in patients with angiographic coronary artery disease.17 Patients who were non-responders to statin (i.e. <15% reduction in LDL-C levels with a recommended statin dose), had significantly greater progression of atherosclerosis, as assessed by percent atheroma volume, than statin responders. This association remained even after adjustment for baseline characteristics and plaque burden. While the prevalence of statin non-response is indeterminate, in this study, 20% of patients were shown to be hypo-responders to a statin and therefore at greater risk of progressive ASCVD.
In the light of ongoing outcomes trials with PCSK9 inhibitors, statin responsiveness may have particular relevance. Given the linear relationship between LDL-C lowering and relative risk for cardiovascular events, the potential benefit from PCSK9 inhibitor treatment may be greater in individuals showing a low response to high-intensity statin treatment than in those with more than 50% reduction in LDL-C.15 Thus, identifying the extent of statin responsiveness may be relevant in evaluating the clinical benefit from LDL-C lowering with a PCSK9 inhibitor on top of lipid lowering treatment.
Statins: effective but not a panacea
Statins are the basis for preventive cardiology. It should be recognised, however, that statins are not a panacea: other treatments are often required to attain LDL-C goal. Indeed, in patients at high and very high cardiovascular risk, current and novel therapeutic options are generally considered for use ‘on top of’ statins. Finally, the importance of lifestyle interventions targeting diet, smoking and physical inactivity across the spectrum of cardiovascular risk should not be neglected.
- Laufs U, Descamps OS, Catapano AL, Packard CJ. Understanding IMPROVE-IT and the cardinal role of LDL-C lowering in CVD prevention. Eur Heart J 2014;35:1996-2000.
- National Institute for Health and Clinical Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease (July 2014). https://www.nice.org.uk/guidance/indevelopment/GID-CGWAVER123
- Chiang CE, Ferrières J, Gotcheva NN et al. Suboptimal control of lipid levels: Results from 29 countries participating in the Centralized Pan-Regional Surveys on the Undertreatment of Hypercholesterolaemia (CEPHEUS). J Atheroscler Thromb 2015 Dec 2. [Epub ahead of print]
- Reiner Ž, De Backer G, Fras Z, Kotseva K, Tokgözoglu L, Wood D, De Bacquer D, EUROASPIRE Investigators. Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries – Findings from the EUROASPIRE IV survey. Atherosclerosis 2016;246:243–50.
- Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J 2016;37:908-16.
- Bruckert E, Hayem G, Dejager S et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14.
- Laufs U, Scharnagl H, Halle M, Windler E, Endres M, März W. Treatment options for statin-associated muscle symptoms. Dtsch Arztebl Int 2015;112:748-55.
- Stroes ES, Thompson PD, Corsini A et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012-22.
- Newman CB, Tobert JA. Statin intolerance: reconciling clinical trials and clinical experience. JAMA 2015;313:1011-2.
- Taylor BA, Panza G, Thompson PD. Increased creatine kinase with statin treatment may identify statin-associated muscle symptoms. Int J Cardiol 2016;209:12-3.
- Stroes E, Colquhoun D, Sullivan D et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.
- Moriarty PM, Thompson PD, Cannon CP et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol 2015;9:758-69.
- Postmus I, Trompet S, Deshmukh HA et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nature Comm 2014;5: 5068.
- Feng Q, Wei WQ, Chung CP et al. The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy. Pharmacogenomics J 2016. doi: 10.1038/tpj.2016.3. [Epub ahead of print]
- Ridker PM, Mora S, Rose L; JUPITER Trial Study Group. Per cent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J 2016 Feb 24. pii: ehw046. [Epub ahead of print].
- Vupputuri S, Joski PJ, Kilpatrick R et al. LDL cholesterol response and statin adherence among high-risk patients initiating treatment. Am J Manag Care 2016;22:e106-15.
- Kataoka Y, St. John J, Wolski K et al. Atheroma progression in hyporesponders to statin therapy. Arterioscler Thromb Vasc Biol 2015;35:990-5.
The EAS Consensus Panel statement on statin-associated muscle symptoms can be read here http://eurheartj.oxfordjournals.org/content/early/2015/02/18/eurheartj.ehv043