Statin escape phenomenon: Does it really exist?

Statin escape phenomenon: Does it really exist?

European Journal of Internal Medicine 16 (2005) 192 – 194 Original article Statin escape phenomenon: Does it really exi...

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European Journal of Internal Medicine 16 (2005) 192 – 194

Original article

Statin escape phenomenon: Does it really exist? D. Yeshurun*, G. Slobodin, D. Keren, N. Elias The Clinic for Hyperlipidemic Patients, Department of Medicine A, Bnai Zion Medical Center, Bruce Rapoport Faculty of Medicine, Technion, P.O. Box 4940, 47, Golomb Street, Haifa 31048, Israel Received 27 April 2004; received in revised form 14 October 2004; accepted 4 November 2004

Abstract Background: The normalization of blood lipid profile has become an accepted method of primary and secondary prevention of vascular disease, with statins being the most popular group of medicines prescribed to lower cholesterol and LDL cholesterol levels. The failure of statins, administered in an appropriate dose, to maintain the optimal level of LDL cholesterol is a rare phenomenon, and is still not well understood in patients compliant for both medication and diet. The entity of ‘‘statin escape phenomenon’’, proposed to explain the failure of statins in some of these patients, has not been studied or characterized extensively, and reports of its prevalence are scarce. Methods: Patients with hyperlipidemia type 2a or 2b who had been treated with statins for at least 1 year and who were followed up in the lipid clinic on a regular basis every 3 – 4 months were included in this study. The charts of patients whose LDL cholesterol levels were elevated by 15% or more while receiving the same treatment were analyzed, and patients with putative statin escape phenomenon were included in the study and further characterized. Results: Forty-five of 358 statin-treated patients demonstrated a 15% increase in LDL cholesterol levels, leading to suspicion of statin escape phenomenon. However, a strict exclusion analysis left only two patients without evident potential triggers for the observed elevation in LDL cholesterol. Conclusions: Whether a statin escape phenomenon really exists is still not certain, but if it does exist, it is probably an uncommon event with a low prevalence. D 2005 Elsevier B.V. All rights reserved. Keywords: Statins; LDL cholesterol; Escape

1. Introduction Hydroxy-3-methyl-glutaryl coenzyme A (HMGCoA) reductase inhibitors, or statins, have recently become one of the most frequently prescribed groups of medicines. The efficacy of statins for patients with hyperlipidemia, mainly hypercholesterolemia, in primary and secondary prevention of coronary heart disease and in stroke prevention has been repeatedly acknowledged. A broad range of individuals can benefit from such therapy [1]. The low incidence of side effects and fairly predictable positive effect of statins have led to the explosive character of statin consumption. In this setting, knowing about the possibility of the so-called ‘‘statin escape’’ phenomenon is important for both physician

* Corresponding author. Tel.: +972 4 8359359; fax: +972 4 8371393. 0953-6205/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.11.007

and patient in order to achieve the maximal efficacy of statin treatment. The existence of the statin escape phenomenon was first suspected and reported in 1991, as an extended clinical evaluation of the big EXCEL study that reported some increase in LDL cholesterol towards the end of the first year of treatment with statin [2]. Since that time, only one case series has acknowledged this phenomenon [3]. It is generally thought that it is not statin escape but poor compliance by patients to their medication or diet that is responsible for the increase in LDL cholesterol levels over time [4]. The aim of this communication is to summarize the experience at our lipid clinic with regard to the putative phenomenon of statin escape and to try to define the prevalence of, and risk factors for this phenomenon if, indeed, it exists.

D. Yeshurun et al. / European Journal of Internal Medicine 16 (2005) 192 – 194



2. Methods

3. Results Of the 358 patients followed up at our lipid clinic during the period 1993 – 2003, 161 (97 females and 64 males) were treated with statins for hyperlipidemia type 2a or 2b. Fortyfive of these patients (28%) demonstrated an increase of 15% or more in LDL cholesterol levels compared to the highest level registered at the three previous visits, although



The study was carried out on patients followed up at the lipid clinic of Bnai Zion Medical Center (Haifa, Israel) and was approved by the local ethics committee. Patients with hyperlipidemia type 2a or 2b who had been treated with statins for at least 1 year and followed up on a regular basis every 3– 4 months were included. At every visit, serum total cholesterol, HDL cholesterol, and triglycerides were determined; the LDL cholesterol was calculated according to the Friedwald formula [5]. The charts of the patients were analyzed retrospectively, but the evaluation of the suspected ‘‘escape’’ patients was done at their follow-up visits to the clinic. Escape phenomenon was defined as an elevation of LDL cholesterol levels by 15% or more, which is stricter than the previously suggested elevation of 10% [3]. In order to identify and exclude patients with ‘‘pseudo-escape’’ due to noncompliance to a prescribed diet or medicine, poorly controlled diabetes, or weight gain, we decided to analyze these factors as a two-step process. First, one of the authors who followed the patients in the lipid clinic detected the patients with suspected escape phenomenon and took a thorough history with regard to dietary habits and regularity of medicine consumption. Then, patients were asked to fill out a typical 1-day diet list, including all medications taken. They were also asked about the presence of potential triggers to a sudden increase in LDL cholesterol levels, such as alcohol consumption and weight change. Just prior to writing this paper, the second investigator went back to the eight selected patients who were highly suspected of having escape and evaluated them with regard to other possible causes of elevated cholesterol. The patients with putative statin escape phenomenon were characterized in terms of age, comorbidities, statin treatment time before the escape, and complete lipid profile at three visits preceding their escape.


patient 1 patient 2

150 120 90 -3 -2 -1 0




visits Fig. 1. LDL cholesterol levels of patients at the visit of registered escape and at three preceding and subsequent visits.

they had not changed their medications. We were able to disclose noncompliance to diet or medicines, a change in weight, or poorly controlled diabetes in the vast majority of patients with Fpotential_ statin escape phenomenon, but not in eight patients with a high suspicion of escape. During the second step of the exclusion process, only two females out of 161 patients treated with statins (1.2%) satisfied our criteria for statin escape phenomenon. Patient characteristics and lipid profiles at the visit when escape phenomenon was suspected are presented in Table 1. At this visit, the first patient’s treatment was switched from pravastatin 20 mg/ day to atorvastatin 10 mg/day; for the second patient, the dose of atorvastatin was increased from 20 to 40 mg/day. The curves for LDL cholesterol before and after the escape episode are presented in Fig. 1.

4. Discussion An acknowledgement of the central role of elevated LDL cholesterol levels in the pathogenesis of atherosclerosis has led to the wide use of hypolipidemic agents, particularly inhibitors of HMGCoA reductase, for primary and secondary prevention of coronary and cerebrovascular disease. Achieving the desired levels of LDL cholesterol in the majority of patients became a reality with the new generation of statins. The failure of statins to decrease the levels of LDL cholesterol on a continuous, long-term basis is thought to be related to poor compliance to medication or diet in the majority of patients. The additional potential causes of statin inefficacy, including induction of the cytochrome system, particularly CYP450-3A4 and 2C9 by other drugs or substances, were reviewed recently [4]. The slow increase in the concentration of the HMGCoA

Table 1 The characteristics and lipid profiles of patients with suspected statin escape phenomenon on the day of escape

Patient 1 Patient 2 a


TTEa (years)


Total cholesterol (mg/dl)

LDL cholesterol (mg/dl)

HDL cholesterol (mg/dl)

Triglycerides (mg/dl)

69 71

6 2

None Arterial hypertension

298 252

198 155

66 68

164 132

TTE—time of statin treatment before the escape episode.


D. Yeshurun et al. / European Journal of Internal Medicine 16 (2005) 192 – 194

reductase enzyme, or escape from the competitive inhibition by statins, was suggested as one of the mechanisms of the elevation of previously stable levels of LDL cholesterol despite continued treatment with a statin [3]. The frequency of, and risk factors for this so-called statin escape phenomenon remain unknown, and the paucity of reports on this phenomenon has led some to doubt whether it really does exist. The analysis of our cohort of 161 patients treated with statins for more than a year for hyperlipidemia type 2a or 2b revealed that only two patients satisfied our strict criteria for statin escape. It should be noted that we used escape criteria stricter than those previously proposed (a 15% versus 10% elevation in LDL cholesterol levels). The defining of risk factors or any statistical work was impossible due to the very small size of the study group. Of primary importance, however, is the fact that no study, including ours, was able to confirm the elevation in the endogenic synthesis of LDL cholesterol by LDL cholesterol metabolic studies in patients with suspected statin escape. Thus, whether a statin escape

phenomenon really exists is still uncertain. However, if it does, it is probably a rare event with a low prevalence (about 1%). Further evaluation is needed to elucidate its prevalence, underlying mechanism, and the means to overcome it.

References [1] Teo KK, Burton JR. Who should receive HMG CoA reductase inhibitors? Drugs 2002;62:1707 – 15. [2] Bradford RH, Shear CL, Chermos NA, Dujovne CA, Franklin FA, Grillo RB. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Arch Intern Med 1991;151:43 – 9. [3] Rubinstein AR, Weintraub M. Escape phenomenon of low density lipoprotein cholesterol during lovastatin treatment. Am J Cardiol 1995; 76:184 – 6. [4] Thompson GR, O’Neill F, Seed M. Why some patients respond poorly to statins and how this might be remedied. Eur Heart J 2002;23:200 – 6. [5] Friedwald WT, Levy RI, Friederickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin Chem 1972;10:499 – 502.