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The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients
European Journal of Internal Medicine 21 (2010) 293–296
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Original article
The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients☆ L.E. Degreef a, F.L. Opdam a, I.M. Teepe-Twiss b, J.W. Jukema c, H.J. Guchelaar b, J.T. Tamsma a,⁎ a b c
Section of Vascular Medicine, Department of Endocrinology & General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Received 8 January 2010 Received in revised form 25 March 2010 Accepted 28 March 2010 Available online 13 May 2010 Keywords: Statin intolerance Low-dose statin Simvastatin LDL-cholesterol Cardiovascular prevention
a b s t r a c t Background/aim: Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. Method: A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia–myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5 mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline. Results: The reached simvastatin dose ranged from 0.825 to 8.75 mg/day with a mean dose of 4 mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% (p b 0.001). Eleven percent of the patients reached LDL-cholesterol target levels (b 2.6 mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin. Conclusion: Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction An elevated low-density lipoprotein cholesterol (LDL-c) level is an established risk factor for cardiovascular disease (CVD). Statin treatment can effectively reduce LDL-c levels. The prevention of cardiovascular (CV) events by lowering LDL-c was studied in many clinical trials. The Cholesterol Treatment Trialists' Collaboration meta-analysis clearly showed the benefit of statin treatment in 90,056 individuals [1]. Recently, a meta-analysis was published extending these findings to women and the elderly [2]. Accordingly, statin therapy has become an important factor in the treatment and prevention of cardiovascular disease [3,4]. Statins are generally well tolerated. However, adverse events associated with their use such as myalgia, myopathy, myositis and
☆ This manuscript is written without any conflict of interest. ⁎ Corresponding author. Section of Vascular Medicine, Department of Endocrinology & General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, PO box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 715262998; fax: +31 715248140. E-mail address: [email protected] (J.T. Tamsma).
elevation of serum liver enzyme levels are well known. Statinassociated adverse events may exceed placebo levels up to 40% [5]. The most common adverse event, myalgia, has been reported by some 2% to 11% of the patients [5–9]. Side effects may result in statin intolerance defined as not being able to tolerate a normal (registered) dose statin treatment. Statin intolerance is now considered an increasingly relevant problem in absolute terms because of the increasing number of treated patients and the stringency of recent LDL-cholesterol targets [6]. Thus, it may be a limiting factor to achieve optimal medical therapy in high risk cardiovascular patients. Individual, partly genetic, factors play a role in statin intolerance [6,10]. Effects and adverse effects of statins are dose-dependent [5,6]. Studies have shown that low-dose rosuvastatin or atorvastatin was tolerated and efficacious in a relevant proportion of statinintolerant patients. For simvastatin this has not been studied. We hypothesized that therapy with very low-dose simvastatin might be tolerated and effective in statin-intolerant patients. Here, we describe the results of our treatment protocol which starts with simvastatin 2.5 mg every other day and is upwardly titrated if possible.
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.03.015
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2. Methods Statin-intolerant patients are referred to the vascular medicine unit of our department since 2006 and treated using a protocol that re-initiates statin therapy using a very low-dose simvastatin given every other day. The dose is up titrated if possible. Statin intolerance is defined as not being able to tolerate registered dose statins due to side effects like myalgia, myopathy, myositis or liver enzyme elevations. In all reported patients the initial side effects disappeared after discontinuation of the medication. A search was performed at the medication records of the department of clinical pharmacy of our institution, which tracks all drug prescriptions at our institution, to identify all 58 prescriptions with a low-dose simvastatin regimen given to 43 patients. Eight patients could not be evaluated due to the following reasons: triglyceride (TG) level exceeding the 4.52 mmol/ l (4 patients), laboratory results not complete (3 patients), one patient never received the low-dose prescription according to the electronic patient file. Thus, we here describe the results of low-dose simvastatin treatment in 35 patients. Retrieval of the data was performed using patient and laboratory files. Patient characteristics include history, anthropometry and blood pressure measurements. A positive family history for CVD was defined as the presence of CVD in a first degree family member before 55 years of age (men) or 60 years of age (women). Fasting laboratory assessments included levels of total cholesterol (TC), TG, HDL-cholesterol (HDL-c). LDL-c was calculated using the Friedewald-formula: LDLc = TC− HDL-c − (0.45 ⁎ TG). Non-HDL was calculated using the following formula: non-HDL = TC − HDL-c. Renal clearance was calculated using the Cockcroft–Gault formula for μmol/l: ((140-age)⁎ body weight (kg) ⁎ constant) / Serum creatinine (μmol/l), where the constant for men is 1.23 and for women 1.04. Cardiovascular risk is expressed as SCORE value for primary prevention in patients [11]. In addition, the Framingham score was calculated if appropriate using the risk assessment tool for as available at http://hp2010.nhlbihin.net/atpiii/ calculator.asp, a website from the National Cholesterol Education Program (NCEP). At baseline the patients had not been on statin treatment for at least three to four weeks due to their statin intolerance. Some patients used other (non-statin) lipid lowering drugs at the time low-dose simvastatin was introduced. As abovementioned, the treatment strategy typically started with simvastatin 2.5 mg every other day with one exception: in one patient 2.5 mg every 3rd day was prescribed resulting in a mean daily dose of 0.825 mg. The treatment strategy is as follows: 8 weeks after initiation of low-dose simvastatin 2.5 mg every other day, the effect and side effects are evaluated. If no side effects occur, and the patient is consenting, the dose is increased to 5 mg every other day. Eight weeks later the next evaluation occurs and the dose is increased to 5 mg every day. If possible the next step is 7.5 mg every day followed by 7.5 mg alternating with 10 mg (resulting in a mean dose of 8.75 mg). During the study, no other changes in lipid lowering medication occurred. Endpoints of the study were tolerability and efficacy. Tolerability was assessed using the percentage patients that remained on lowdose simvastatin therapy. The presence of myalgia, myopathy or myositis as well as liver enzyme elevations was registered. CK and ALT elevations were defined as one and a half time the Upper Limit of Normal (ULN). Other side effects were registered if described in the files, e.g. gastrointestinal complaints including dyspepsia and nausea. On-treatment efficacy was defined as the mean change of serum LDL-c levels compared to baseline. The number of patients that reached LDL-c target (b2.6 mmol/l) was counted in an intention to treat analysis and as percentage on-treatment patients. In a posthoc analysis, the previously observed maximal LDL-c lowering effect of registered dose statin treatment was compared to the LDL-c lowering effect of low-dose simvastatin treatment in that patient. Accordingly, additional information was retrieved from the files and
if necessary, general practioners were contacted, to verify information regarding LDL-c responses on former statin therapy. Thus, data were retrieved on maximal documented previous response to normal dose statin for 77% (27 of 35) of the patients. To describe the characteristics of the subjects included in our study, continuous variables are presented as mean(SD) and categorical variables as frequencies (percentages). The changes of outcome parameters after simvastatin treatment were compared to baseline using paired t-test. The statistical analyses were performed using SPSS version 16.0 (SPPS Inc.). All of the analysis were 2-sided, with a level of significance of α = 0.05. The graphs were made with Graphpad 5.02. 3. Results The characteristics of the patients are shown in Table 1. Mean age of the patients was 56.5 years. Most patients were treated in a primary prevention setting, over 50% of these patients were diagnosed as familial hypercholesterolemia. Sixteen patients had previously used one statin at regular dosage, seventeen patients had used two different statins. Two patients had used three different statins. On treatment SCORE mortality was estimated to be 4.0%/ 10 years. At baseline 5 patients used non-statin lipid lowering medication (ezetimibe) and one patient was treated with fish-oil (self-medication). After dose-titration the mean daily statin dose reached was 4.0 mg/day ranging from 2.5 mg every other day to 8.75 mg/d (alternating 7.5 mg/d and 10 mg/d). Low-dose simvastatin therapy was tolerated in 57% of these statin-intolerant patients. Fourteen patients did not have any adverse events during low-dose simvastatin
Table 1 Main characteristics of the study population on start low-dose simvastatin treatment. Characteristic Age — years Female sex — no. (%) Caucasian — no. (%) Family history of CVD — no. (%) Current smoker — no. (%) Diabetes mellitus — no. (%) Primary prevention — no. (%) Familial hypercholesterolemia Secondary prevention — no. (%) Cardiac — no. (%) Cerebral — no. (%) Peripheral — no. (%) SCORE — % mortality/10 years Framingham — % CV risk/10 years Weight — kg Body mass index — kg/m2 Hypertension — no. (%) Systolic BP — mm Hg Diastolic BP — mm Hg Glucose — mmol/l Serum creatinine — μmol/l Glomerular filtration rate — ml/min TSH — mU/l Number of statins previously used One statin — no. (%) Two statins — no. (%) Three statins — no. (%) Use of lipid lowering drugs — no. (%) Ezetimibe — no. (%) Colesevalam — no. (%) Fibrates — no. (%) Niacin — no. (%) Fish oil — no. (%) Other — no. (%)
56.5(9.9)a 22(62.9) 35(100) 18(51.4) 2(5.7) 5(11.4) 25(71.4) 14(56.0) 10(28.6) 4(11.4) 2(5.7) 4(11.4) 4.0(3.5) 8.5(7.1) 78.3(12.5) 26.7(3.21) 24(68.6) 139.2(16.1) 82.8(8.6) 5.5(0.86) 76.5(14.9) 98.9(24.8) 2.18(1.40)
No. = number; BP = blood pressure. a Data are given as mean(standard deviation) unless stated otherwise.
16(45.7) 17(48.6) 2(5.7) 6(21.4) 5(14.3) 0(0.0) 0(0.0) 0(0.0) 1(2.9) 0(0.0)
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treatment. Six patients suffered from myalgia, but not severe enough to stop treatment. In the patients tolerating low-dose statin, one (3%) patient developed a CK elevation and one (3%) other patient developed an ALT elevation. The elevations were mild (b3 times ULN). Of the 15 patients that could not tolerate low-dose simvastatin, 12 patients complained of myalgia, two patients had gastrointestinal complaints and one patient never used the low-dose statin fearing the adverse events. Four patients stopped their medication almost immediately after initiation of low-dose therapy. Lipid values are given in Table 2. The primary efficacy measure, mean(SD) change in LDL-c, significantly decreased with 25.9(12.1)% during treatment (Fig. 1). The mean(SD) percentage change for LDL-c was 29.3(12.0)% in patients tolerating low-dose simvastatin. Four patients (11%) reached target LDL-c level on low-dose simvastatin in an intention to treat analysis, for the on-treatment patients this was 13%. One of these patients showed a strong LDL-c reduction (N50%), after adding low-dose simvastatin to ezetimibe. Of the patients that tolerated low-dose simvastatin 20% reached LDL-c targets. In addition, three more patients were within 0.2 mmol/l of LDL-c target. To explore the dose–effect relation, a post-hoc analysis was performed relating previous responses to normal dose statin to the response on low-dose simvastatin. Normal dose-response data were retrieved for 27 patients. Twenty one patients previously used simvastatin [10 mg (7 patients), 20 mg (13 patients) and 40 mg (1 patient)]. Three patients used rosuvastatin [5 mg (1 patient) and 10 mg (2 patients)], and 3 patients used atorvastatin [10 mg (1 patient) and 20 mg (2 patients)]. Of these 27 patients, 3 patients did stop low-dose statin treatment early after prescription. The response of the remaining 24 patients on low-dose simvastatin could be compared to the reaction on normal dose statin treatment. The average low dose used in these patients was 4.3 mg daily (range: 1.25 mg daily to 8.75 mg daily). The mean change on normal dose statin was −37.7(11.4)% compared to −26.8(11.7)% for low dose (Fig. 2). In seventeen patients, the response to low-dose statin was less (N10% worse) than their previous response to a regular dose statin. A comparable (ranging within 10% worse or better response) or even better response (N10% better) was observed in respectively 3 and 4 patients. 4. Discussion In this study we describe that low-dose simvastatin is tolerated in 57% of previously statin-intolerant patients with significant efficacy. On this low statin dose, the mean decrease of LDL-c levels was 25.9%. A LDL-c target level of b2.6 mmol/l was reached in 10% of the patients in an intention to treat analysis, and in 20% of the patients that tolerated low-dose simvastatin. Given the relation between statin induced LDL-c lowering and reductions of CV events as reviewed in several meta-analyses [2,12,13] we expect the now observed reduction of LDL-c on low-dose simvastatin treatment to be a relevant preventive measure. Statin intolerance is an increasingly important issue in primary and secondary prevention of cardiovascular disease. Several studies have now described the effects of ‘lower than usual dose’ statin treatments including studies applying increased dose intervals [14–19]. Non-daily dose studies used atorvastatin [14,15] and rosuvastatin [16–19],
295
Fig. 1. Changes of mean(SD) percentages of LDL-c − 25.9(12.1)%, TC − 18.3(8.6)%, TG − 3.7(34.1)%, HDL-c 2.0(18.2)% and non-HDL − 23.6(11.3)% on low-dose simvastatin treatment.
because of the relatively long plasma half-lives, which render them potentially suitable for non-daily dosing regimens to lower LDL-c levels while possibly reducing adverse events [5]. The potential of every other day treatments was shown for atorvastatin in 35 patients with hyperlipidemia. In a double-blind, placebo-controlled trial, treatment with 10 mg of atorvastatin every other day resulted in LDL-c reductions of 27% [14]. This regimen has not been studied in statin-intolerant patients [6]. Non-daily dosing of rosuvastatin was reported in 40 patients with statin-intolerance. Rosuvastatin 5 mg or 10 mg twice weekly alone or added to other lipid lowering medication decreased LDL-c by 26%. Eight patients discontinued twice weekly rosuvastatin treatment because of muscle-related symptoms [16]. We chose to combine an increased dose interval with a strong reduction in dose, using simvastatin. The potential of simvastatin to decrease LDL-c at lower than usual applied doses was already shown in a publication of Mol et al.: doses of 1.25, 2.5 and 5 mg daily resulted in LDL-c reductions of respectively 8%, 17.7% and 26.5% in patients with familial hypercholesterolemia [20]. The LDL-c lowering effect of statins is dose-dependent, which also holds for statin induced side effects. Some patients may be more sensitive to statin effects than others. Considering that patients presenting with statin side effects are very sensitive to statin treatment, we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. Our results are compatible with this hypothesis and now suggest that different statin-intolerant phenotypes may exist. Psychological components may be present in some patients. The patients not tolerating 2.5 mg simvastatin every other day may also include the most sensitive subgroup potentially with a small individual therapeutic window. Another group seems to tolerate low-dose simvastatin with a significant response on LDL-c levels, without side effects. Low-dose effectiveness at least suggests a leftward shift of the dose effect curve, the width of the therapeutic window remains to be established in these patients. Intriguingly, phenotypic differences have not yet been related to different pathophysiological mechanisms. Mechanisms of statin intolerance are now being discovered. Recently, evidence was provided that variance in the SLCO1B1 gene
Table 2 Efficacy of the low-dose statin treatment.
Before treatment — mmol/l After treatment — mmol/l Absolute change — mmol/l Change — percentages Data are given as mean (standard deviation). a p b 0.001.
LDL-c
TC
TG
HDL-c
Non-HDL
5.27(1.33) 3.85(1.20) − 1.42(0.68) − 25.9(12.1)a
7.76(1.39) 6.32(1.22) − 1.44(0.74) − 18.3(8.6)a
2.03(0.87) 1.96(1.07) − 0.07(6.13) − 3.7(34.1)
1.57(0.34) 1.59(0.40) 0.02(0.26) 2.0(18.2)
6.19(1.39) 4.73(1.25) − 1.46(0.73) − 23.6(11.3)a
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• Up titration of a very low dose is a feasible procedure in almost all patients • Variability exists among response of statin-intolerant patients to the here described approach suggesting different phenotypic expressions. • If statin induced LDL-cholesterol lowering is the mechanism relating statin treatment to beneficial cardiovascular outcome, low-dose treatment may prove beneficial given the observed significant 25.9% LDL-cholesterol lowering.
References
Fig. 2. Percentage change of LDL-c levels in individual patients. The maximal observed response on normal dose statin in a patient is shown on the left side, the response to low-dose simvastatin treatment in the same patients is shown on the right side (see text for further explication). Black symbol: patients that did not tolerate low-dose statin and stopped its use. Open symbol: patients tolerating low-dose simvastatin and on treatment.
substantially alters the risk of simvastatin-induced myopathy. SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which mediates the hepatic uptake of most statins and statin acids [21]. Other proposed mechanisms for statin-related myopathy include decreased cholesterol content of skeletal myocyte membranes inducing membrane instability, depletion of isoprenoids or coenzyme Q10, and induction of mitochondrial dysfunction [5,21]. A limitation of our study is that we performed an observational study and not a blinded randomized controlled trial. This may have influenced outcome. Patients were aware of their treatment as were their doctors, both trying to “treat” statin intolerance in a real life patient care setting. Thus, tolerability and efficacy may have been overestimated. However, the mean efficacy for LDL-c decrease of 25.9(12.1)% for a mean daily dose of 4 mg as we observed is reminiscent to the 26.5% for 5 mg as described by Mol et al. [20] suggesting the observed mean pharmacological response was within an expected range. The second limitation of the study is the external validity, in other words, the applicability of our approach to other settings of patient care. However, the real life approach chosen suggests this protocol carries the potential for similar results in other patients at other outpatient wards. Another limitation is the definition of statin intolerance. We chose to accept the diagnosis as given by a referring physician. Mostly patients did not tolerate statins due to myopathy or myalgia without signs of myositis. Our approach was to take this documented clinical history as starting point for a treatment protocol aiming at introduction of simvastatin starting with an extremely low dose. For future studies, unification of the classification of statin intolerance is very important. Currently, the definition of statin myopathy varies between different organisations: The American College of Cardiology (ACC), American Heart Association (AHA), National Heart, Long and Blood Institute (NHLBI), U.S. Food and Drug Administration (FDA) and National Lipid Association (NLA) have each proposed definitions for statin-associated muscle adverse effects [6]. In summary, low-dose simvastatin starting with 2.5 mg every other day and titrated upward if possible is tolerated in more than 50% of statin-intolerant patients with good lipid lowering efficacy. This approach should be considered in patients referred for statin intolerance, and may be used in combination with other lipid lowering medication. 5. Learning points • More than half of statin-intolerant patients can be treated with lowdose simvastatin in the current study with significant efficacy.
[1] Corsini A, Windler E, Farnier M. Colesevelam hydrochloride: usefulness of a specifically engineered bile acid sequestrant for lowering LDL-cholesterol. Eur J Cardiovasc Prev Rehabil 2009;16(1):1–9. [2] Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 2009;338:b2376. [3] Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, et al. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2007;14(Suppl 2):S1–S113. [4] Ward S, Lloyd JM, Pandor A, Holmes M, Ara R, Ryan A, et al. A systematic review and economic evaluation of statins for the prevention of coronary events. Health Technol Assess 2007;11(14):1–160, iii-iv. [5] Silva M, Matthews ML, Jarvis C, Nolan NM, Belliveau P, Malloy M, et al. Metaanalysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 2007;29(2):253–60. [6] Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150(12):858–68. [7] Pasternak RC, Smith Jr SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/ AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002 Aug 7;40(3):567–72. [8] Arora R, Liebo M, Maldonado F. Statin-induced myopathy: the two faces of Janus. J Cardiovasc Pharmacol Ther 2006 Jun;11(2):105–12. [9] Baer AN, Wortmann RL. Myotoxicity associated with lipid-lowering drugs. Curr Opin Rheumatol 2007;19(1):67–73. [10] Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr Opin Lipidol 2007;18(4):401–8. [11] Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De BG, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24(11):987–1003. [12] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. [13] Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423. [14] Matalka MS, Ravnan MC, Deedwania PC. Is alternate daily dose of atorvastatin effective in treating patients with hyperlipidemia? The Alternate Day Versus Daily Dosing of Atorvastatin Study (ADDAS). Am Heart J 2002;144(4):674–7. [15] Ferrer-Garcia JC, Perez-Silvestre J, Martinez-Mir I, Herrera-Ballester A. Alternateday dosing of atorvastatin: effects in treating type 2 diabetic patients with dyslipidaemia. Acta Diabetol 2006;43(3):75–8. [16] Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol 2008;101(12): 1747–8. [17] Ruisinger JF, Backes JM, Gibson CA, Moriarty PM. Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. Am J Cardiol 2009;103(3): 393–4. [18] Backes JM, Moriarty PM, Ruisinger JF, Gibson CA. Effects of once weekly rosuvastatin among patients with a prior statin intolerance. Am J Cardiol 2007;100(3):554–5. [19] Mackie BD, Satija S, Nell C, Miller III J, Sperling LS. Monday, Wednesday, and Friday dosing of rosuvastatin in patients previously intolerant to statin therapy. Am J Cardiol 2007;99(2):291. [20] Mol MJ, Erkelens DW, Leuven JA, Schouten JA, Stalenhoef AF. Effects of synvinolin (MK-733) on plasma lipids in familial hypercholesterolaemia. Lancet 1986;2 (8513):936–9. [21] Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, et al. SLCO1B1 variants and statin-induced myopathy — a genowide study. N Engl J Med 2008;359(8): 789–99.
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Original article
The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients☆ L.E. Degreef a, F.L. Opdam a, I.M. Teepe-Twiss b, J.W. Jukema c, H.J. Guchelaar b, J.T. Tamsma a,⁎ a b c
Section of Vascular Medicine, Department of Endocrinology & General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Received 8 January 2010 Received in revised form 25 March 2010 Accepted 28 March 2010 Available online 13 May 2010 Keywords: Statin intolerance Low-dose statin Simvastatin LDL-cholesterol Cardiovascular prevention
a b s t r a c t Background/aim: Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. Method: A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia–myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5 mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline. Results: The reached simvastatin dose ranged from 0.825 to 8.75 mg/day with a mean dose of 4 mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% (p b 0.001). Eleven percent of the patients reached LDL-cholesterol target levels (b 2.6 mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin. Conclusion: Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction An elevated low-density lipoprotein cholesterol (LDL-c) level is an established risk factor for cardiovascular disease (CVD). Statin treatment can effectively reduce LDL-c levels. The prevention of cardiovascular (CV) events by lowering LDL-c was studied in many clinical trials. The Cholesterol Treatment Trialists' Collaboration meta-analysis clearly showed the benefit of statin treatment in 90,056 individuals [1]. Recently, a meta-analysis was published extending these findings to women and the elderly [2]. Accordingly, statin therapy has become an important factor in the treatment and prevention of cardiovascular disease [3,4]. Statins are generally well tolerated. However, adverse events associated with their use such as myalgia, myopathy, myositis and
☆ This manuscript is written without any conflict of interest. ⁎ Corresponding author. Section of Vascular Medicine, Department of Endocrinology & General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, PO box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 715262998; fax: +31 715248140. E-mail address: [email protected] (J.T. Tamsma).
elevation of serum liver enzyme levels are well known. Statinassociated adverse events may exceed placebo levels up to 40% [5]. The most common adverse event, myalgia, has been reported by some 2% to 11% of the patients [5–9]. Side effects may result in statin intolerance defined as not being able to tolerate a normal (registered) dose statin treatment. Statin intolerance is now considered an increasingly relevant problem in absolute terms because of the increasing number of treated patients and the stringency of recent LDL-cholesterol targets [6]. Thus, it may be a limiting factor to achieve optimal medical therapy in high risk cardiovascular patients. Individual, partly genetic, factors play a role in statin intolerance [6,10]. Effects and adverse effects of statins are dose-dependent [5,6]. Studies have shown that low-dose rosuvastatin or atorvastatin was tolerated and efficacious in a relevant proportion of statinintolerant patients. For simvastatin this has not been studied. We hypothesized that therapy with very low-dose simvastatin might be tolerated and effective in statin-intolerant patients. Here, we describe the results of our treatment protocol which starts with simvastatin 2.5 mg every other day and is upwardly titrated if possible.
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.03.015
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2. Methods Statin-intolerant patients are referred to the vascular medicine unit of our department since 2006 and treated using a protocol that re-initiates statin therapy using a very low-dose simvastatin given every other day. The dose is up titrated if possible. Statin intolerance is defined as not being able to tolerate registered dose statins due to side effects like myalgia, myopathy, myositis or liver enzyme elevations. In all reported patients the initial side effects disappeared after discontinuation of the medication. A search was performed at the medication records of the department of clinical pharmacy of our institution, which tracks all drug prescriptions at our institution, to identify all 58 prescriptions with a low-dose simvastatin regimen given to 43 patients. Eight patients could not be evaluated due to the following reasons: triglyceride (TG) level exceeding the 4.52 mmol/ l (4 patients), laboratory results not complete (3 patients), one patient never received the low-dose prescription according to the electronic patient file. Thus, we here describe the results of low-dose simvastatin treatment in 35 patients. Retrieval of the data was performed using patient and laboratory files. Patient characteristics include history, anthropometry and blood pressure measurements. A positive family history for CVD was defined as the presence of CVD in a first degree family member before 55 years of age (men) or 60 years of age (women). Fasting laboratory assessments included levels of total cholesterol (TC), TG, HDL-cholesterol (HDL-c). LDL-c was calculated using the Friedewald-formula: LDLc = TC− HDL-c − (0.45 ⁎ TG). Non-HDL was calculated using the following formula: non-HDL = TC − HDL-c. Renal clearance was calculated using the Cockcroft–Gault formula for μmol/l: ((140-age)⁎ body weight (kg) ⁎ constant) / Serum creatinine (μmol/l), where the constant for men is 1.23 and for women 1.04. Cardiovascular risk is expressed as SCORE value for primary prevention in patients [11]. In addition, the Framingham score was calculated if appropriate using the risk assessment tool for as available at http://hp2010.nhlbihin.net/atpiii/ calculator.asp, a website from the National Cholesterol Education Program (NCEP). At baseline the patients had not been on statin treatment for at least three to four weeks due to their statin intolerance. Some patients used other (non-statin) lipid lowering drugs at the time low-dose simvastatin was introduced. As abovementioned, the treatment strategy typically started with simvastatin 2.5 mg every other day with one exception: in one patient 2.5 mg every 3rd day was prescribed resulting in a mean daily dose of 0.825 mg. The treatment strategy is as follows: 8 weeks after initiation of low-dose simvastatin 2.5 mg every other day, the effect and side effects are evaluated. If no side effects occur, and the patient is consenting, the dose is increased to 5 mg every other day. Eight weeks later the next evaluation occurs and the dose is increased to 5 mg every day. If possible the next step is 7.5 mg every day followed by 7.5 mg alternating with 10 mg (resulting in a mean dose of 8.75 mg). During the study, no other changes in lipid lowering medication occurred. Endpoints of the study were tolerability and efficacy. Tolerability was assessed using the percentage patients that remained on lowdose simvastatin therapy. The presence of myalgia, myopathy or myositis as well as liver enzyme elevations was registered. CK and ALT elevations were defined as one and a half time the Upper Limit of Normal (ULN). Other side effects were registered if described in the files, e.g. gastrointestinal complaints including dyspepsia and nausea. On-treatment efficacy was defined as the mean change of serum LDL-c levels compared to baseline. The number of patients that reached LDL-c target (b2.6 mmol/l) was counted in an intention to treat analysis and as percentage on-treatment patients. In a posthoc analysis, the previously observed maximal LDL-c lowering effect of registered dose statin treatment was compared to the LDL-c lowering effect of low-dose simvastatin treatment in that patient. Accordingly, additional information was retrieved from the files and
if necessary, general practioners were contacted, to verify information regarding LDL-c responses on former statin therapy. Thus, data were retrieved on maximal documented previous response to normal dose statin for 77% (27 of 35) of the patients. To describe the characteristics of the subjects included in our study, continuous variables are presented as mean(SD) and categorical variables as frequencies (percentages). The changes of outcome parameters after simvastatin treatment were compared to baseline using paired t-test. The statistical analyses were performed using SPSS version 16.0 (SPPS Inc.). All of the analysis were 2-sided, with a level of significance of α = 0.05. The graphs were made with Graphpad 5.02. 3. Results The characteristics of the patients are shown in Table 1. Mean age of the patients was 56.5 years. Most patients were treated in a primary prevention setting, over 50% of these patients were diagnosed as familial hypercholesterolemia. Sixteen patients had previously used one statin at regular dosage, seventeen patients had used two different statins. Two patients had used three different statins. On treatment SCORE mortality was estimated to be 4.0%/ 10 years. At baseline 5 patients used non-statin lipid lowering medication (ezetimibe) and one patient was treated with fish-oil (self-medication). After dose-titration the mean daily statin dose reached was 4.0 mg/day ranging from 2.5 mg every other day to 8.75 mg/d (alternating 7.5 mg/d and 10 mg/d). Low-dose simvastatin therapy was tolerated in 57% of these statin-intolerant patients. Fourteen patients did not have any adverse events during low-dose simvastatin
Table 1 Main characteristics of the study population on start low-dose simvastatin treatment. Characteristic Age — years Female sex — no. (%) Caucasian — no. (%) Family history of CVD — no. (%) Current smoker — no. (%) Diabetes mellitus — no. (%) Primary prevention — no. (%) Familial hypercholesterolemia Secondary prevention — no. (%) Cardiac — no. (%) Cerebral — no. (%) Peripheral — no. (%) SCORE — % mortality/10 years Framingham — % CV risk/10 years Weight — kg Body mass index — kg/m2 Hypertension — no. (%) Systolic BP — mm Hg Diastolic BP — mm Hg Glucose — mmol/l Serum creatinine — μmol/l Glomerular filtration rate — ml/min TSH — mU/l Number of statins previously used One statin — no. (%) Two statins — no. (%) Three statins — no. (%) Use of lipid lowering drugs — no. (%) Ezetimibe — no. (%) Colesevalam — no. (%) Fibrates — no. (%) Niacin — no. (%) Fish oil — no. (%) Other — no. (%)
56.5(9.9)a 22(62.9) 35(100) 18(51.4) 2(5.7) 5(11.4) 25(71.4) 14(56.0) 10(28.6) 4(11.4) 2(5.7) 4(11.4) 4.0(3.5) 8.5(7.1) 78.3(12.5) 26.7(3.21) 24(68.6) 139.2(16.1) 82.8(8.6) 5.5(0.86) 76.5(14.9) 98.9(24.8) 2.18(1.40)
No. = number; BP = blood pressure. a Data are given as mean(standard deviation) unless stated otherwise.
16(45.7) 17(48.6) 2(5.7) 6(21.4) 5(14.3) 0(0.0) 0(0.0) 0(0.0) 1(2.9) 0(0.0)
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treatment. Six patients suffered from myalgia, but not severe enough to stop treatment. In the patients tolerating low-dose statin, one (3%) patient developed a CK elevation and one (3%) other patient developed an ALT elevation. The elevations were mild (b3 times ULN). Of the 15 patients that could not tolerate low-dose simvastatin, 12 patients complained of myalgia, two patients had gastrointestinal complaints and one patient never used the low-dose statin fearing the adverse events. Four patients stopped their medication almost immediately after initiation of low-dose therapy. Lipid values are given in Table 2. The primary efficacy measure, mean(SD) change in LDL-c, significantly decreased with 25.9(12.1)% during treatment (Fig. 1). The mean(SD) percentage change for LDL-c was 29.3(12.0)% in patients tolerating low-dose simvastatin. Four patients (11%) reached target LDL-c level on low-dose simvastatin in an intention to treat analysis, for the on-treatment patients this was 13%. One of these patients showed a strong LDL-c reduction (N50%), after adding low-dose simvastatin to ezetimibe. Of the patients that tolerated low-dose simvastatin 20% reached LDL-c targets. In addition, three more patients were within 0.2 mmol/l of LDL-c target. To explore the dose–effect relation, a post-hoc analysis was performed relating previous responses to normal dose statin to the response on low-dose simvastatin. Normal dose-response data were retrieved for 27 patients. Twenty one patients previously used simvastatin [10 mg (7 patients), 20 mg (13 patients) and 40 mg (1 patient)]. Three patients used rosuvastatin [5 mg (1 patient) and 10 mg (2 patients)], and 3 patients used atorvastatin [10 mg (1 patient) and 20 mg (2 patients)]. Of these 27 patients, 3 patients did stop low-dose statin treatment early after prescription. The response of the remaining 24 patients on low-dose simvastatin could be compared to the reaction on normal dose statin treatment. The average low dose used in these patients was 4.3 mg daily (range: 1.25 mg daily to 8.75 mg daily). The mean change on normal dose statin was −37.7(11.4)% compared to −26.8(11.7)% for low dose (Fig. 2). In seventeen patients, the response to low-dose statin was less (N10% worse) than their previous response to a regular dose statin. A comparable (ranging within 10% worse or better response) or even better response (N10% better) was observed in respectively 3 and 4 patients. 4. Discussion In this study we describe that low-dose simvastatin is tolerated in 57% of previously statin-intolerant patients with significant efficacy. On this low statin dose, the mean decrease of LDL-c levels was 25.9%. A LDL-c target level of b2.6 mmol/l was reached in 10% of the patients in an intention to treat analysis, and in 20% of the patients that tolerated low-dose simvastatin. Given the relation between statin induced LDL-c lowering and reductions of CV events as reviewed in several meta-analyses [2,12,13] we expect the now observed reduction of LDL-c on low-dose simvastatin treatment to be a relevant preventive measure. Statin intolerance is an increasingly important issue in primary and secondary prevention of cardiovascular disease. Several studies have now described the effects of ‘lower than usual dose’ statin treatments including studies applying increased dose intervals [14–19]. Non-daily dose studies used atorvastatin [14,15] and rosuvastatin [16–19],
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Fig. 1. Changes of mean(SD) percentages of LDL-c − 25.9(12.1)%, TC − 18.3(8.6)%, TG − 3.7(34.1)%, HDL-c 2.0(18.2)% and non-HDL − 23.6(11.3)% on low-dose simvastatin treatment.
because of the relatively long plasma half-lives, which render them potentially suitable for non-daily dosing regimens to lower LDL-c levels while possibly reducing adverse events [5]. The potential of every other day treatments was shown for atorvastatin in 35 patients with hyperlipidemia. In a double-blind, placebo-controlled trial, treatment with 10 mg of atorvastatin every other day resulted in LDL-c reductions of 27% [14]. This regimen has not been studied in statin-intolerant patients [6]. Non-daily dosing of rosuvastatin was reported in 40 patients with statin-intolerance. Rosuvastatin 5 mg or 10 mg twice weekly alone or added to other lipid lowering medication decreased LDL-c by 26%. Eight patients discontinued twice weekly rosuvastatin treatment because of muscle-related symptoms [16]. We chose to combine an increased dose interval with a strong reduction in dose, using simvastatin. The potential of simvastatin to decrease LDL-c at lower than usual applied doses was already shown in a publication of Mol et al.: doses of 1.25, 2.5 and 5 mg daily resulted in LDL-c reductions of respectively 8%, 17.7% and 26.5% in patients with familial hypercholesterolemia [20]. The LDL-c lowering effect of statins is dose-dependent, which also holds for statin induced side effects. Some patients may be more sensitive to statin effects than others. Considering that patients presenting with statin side effects are very sensitive to statin treatment, we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. Our results are compatible with this hypothesis and now suggest that different statin-intolerant phenotypes may exist. Psychological components may be present in some patients. The patients not tolerating 2.5 mg simvastatin every other day may also include the most sensitive subgroup potentially with a small individual therapeutic window. Another group seems to tolerate low-dose simvastatin with a significant response on LDL-c levels, without side effects. Low-dose effectiveness at least suggests a leftward shift of the dose effect curve, the width of the therapeutic window remains to be established in these patients. Intriguingly, phenotypic differences have not yet been related to different pathophysiological mechanisms. Mechanisms of statin intolerance are now being discovered. Recently, evidence was provided that variance in the SLCO1B1 gene
Table 2 Efficacy of the low-dose statin treatment.
Before treatment — mmol/l After treatment — mmol/l Absolute change — mmol/l Change — percentages Data are given as mean (standard deviation). a p b 0.001.
LDL-c
TC
TG
HDL-c
Non-HDL
5.27(1.33) 3.85(1.20) − 1.42(0.68) − 25.9(12.1)a
7.76(1.39) 6.32(1.22) − 1.44(0.74) − 18.3(8.6)a
2.03(0.87) 1.96(1.07) − 0.07(6.13) − 3.7(34.1)
1.57(0.34) 1.59(0.40) 0.02(0.26) 2.0(18.2)
6.19(1.39) 4.73(1.25) − 1.46(0.73) − 23.6(11.3)a
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• Up titration of a very low dose is a feasible procedure in almost all patients • Variability exists among response of statin-intolerant patients to the here described approach suggesting different phenotypic expressions. • If statin induced LDL-cholesterol lowering is the mechanism relating statin treatment to beneficial cardiovascular outcome, low-dose treatment may prove beneficial given the observed significant 25.9% LDL-cholesterol lowering.
References
Fig. 2. Percentage change of LDL-c levels in individual patients. The maximal observed response on normal dose statin in a patient is shown on the left side, the response to low-dose simvastatin treatment in the same patients is shown on the right side (see text for further explication). Black symbol: patients that did not tolerate low-dose statin and stopped its use. Open symbol: patients tolerating low-dose simvastatin and on treatment.
substantially alters the risk of simvastatin-induced myopathy. SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which mediates the hepatic uptake of most statins and statin acids [21]. Other proposed mechanisms for statin-related myopathy include decreased cholesterol content of skeletal myocyte membranes inducing membrane instability, depletion of isoprenoids or coenzyme Q10, and induction of mitochondrial dysfunction [5,21]. A limitation of our study is that we performed an observational study and not a blinded randomized controlled trial. This may have influenced outcome. Patients were aware of their treatment as were their doctors, both trying to “treat” statin intolerance in a real life patient care setting. Thus, tolerability and efficacy may have been overestimated. However, the mean efficacy for LDL-c decrease of 25.9(12.1)% for a mean daily dose of 4 mg as we observed is reminiscent to the 26.5% for 5 mg as described by Mol et al. [20] suggesting the observed mean pharmacological response was within an expected range. The second limitation of the study is the external validity, in other words, the applicability of our approach to other settings of patient care. However, the real life approach chosen suggests this protocol carries the potential for similar results in other patients at other outpatient wards. Another limitation is the definition of statin intolerance. We chose to accept the diagnosis as given by a referring physician. Mostly patients did not tolerate statins due to myopathy or myalgia without signs of myositis. Our approach was to take this documented clinical history as starting point for a treatment protocol aiming at introduction of simvastatin starting with an extremely low dose. For future studies, unification of the classification of statin intolerance is very important. Currently, the definition of statin myopathy varies between different organisations: The American College of Cardiology (ACC), American Heart Association (AHA), National Heart, Long and Blood Institute (NHLBI), U.S. Food and Drug Administration (FDA) and National Lipid Association (NLA) have each proposed definitions for statin-associated muscle adverse effects [6]. In summary, low-dose simvastatin starting with 2.5 mg every other day and titrated upward if possible is tolerated in more than 50% of statin-intolerant patients with good lipid lowering efficacy. This approach should be considered in patients referred for statin intolerance, and may be used in combination with other lipid lowering medication. 5. Learning points • More than half of statin-intolerant patients can be treated with lowdose simvastatin in the current study with significant efficacy.
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