Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients

Accepted Manuscript Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients Olivier Descamps, Joanne E. Tomassini, Jianxin Lin, Adam B. Polis, Arvind Shah, Philippe Brudi, Mary E. Hanson, Andrew M. Tershakovec PII:

S0021-9150(15)00163-X

DOI:

10.1016/j.atherosclerosis.2015.03.004

Reference:

ATH 13980

To appear in:

Atherosclerosis

Received Date: 24 December 2014 Revised Date:

20 February 2015

Accepted Date: 3 March 2015

Please cite this article as: Descamps O, Tomassini JE, Lin J, Polis AB, Shah A, Brudi P, Hanson ME, Tershakovec AM, Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients, Atherosclerosis (2015), doi: 10.1016/j.atherosclerosis.2015.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in

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hypercholesterolemic patients

Olivier Descampsa, Joanne E. Tomassinib, Jianxin Linb, Adam B. Polisb, Arvind Shahb, Philippe Brudib,

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Mary E. Hansonb, and Andrew M. Tershakovecb

Centre de Recherche Médicale de Jolimont, 159, Rue Ferrer, 7100 Haine Saint-Paul, Belgium;

b

Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033 USA

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E-mails of authors: [email protected]; [email protected];

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[email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]

Olivier Descamps

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*Corresponding Author:

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Centre de Recherche Médicale de Jolimont, 159, Rue Ferrer

Haine Saint-Paul, Belgium 7100 Phone: 00 32 64 23 3167 E-mail: [email protected]

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Funding: This work was supported by Merck & Co., Inc., Kenilworth, NJ, USA. The funding organization was involved in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, and the preparation, review, approval of and decision to submit the

Keywords: Ezetimibe; hypercholesterolemia; LDL-C; Statin; Variability

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Manuscript Word Count: 2946 words

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manuscript.

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Number of Figures: 2 / Number of Tables: 4 / Supplemental Materials

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Abstract Objective: We compared the variability of LDL-C-lowering responses to treatment with

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ezetimibe+statins versus statins in hypercholesterolemic patients. Methods: An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled studies in 21,671 patients treated with ezetimibe+statins versus statins on 1st-line (statin-naïve/wash-out) or 2nd-line (on statin, randomized to ezetimibe versus placebo [add-on] or ezetimibe versus uptitrated

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statin [uptitrate]) for 6-24 wks. Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were

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compared.

Results: In 1st-line and 2nd-line add-on studies, the variability (SD, RMSE) of % change from baseline in LDL-C was lower in ezetimibe+statin-treated patients versus statin-treated patients, +/-covariates. Differences were small but statistically significant due to the large sample size. In 2nd-line uptitrate studies, ezetimibe+statin treatment resulted in greater unadjusted variability (SD) versus statin therapy,

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while the adjusted variability (RMSE) was significantly lower. Relative variability (CV=SD/mean) was lower for ezetimibe+statins versus statin therapy for all study types, being more pronounced in 2nd-line add-on and uptitrate studies, attributed to larger mean LDL-C reductions for ezetimibe+statins versus

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statin groups. When assessed by individual study/type, statin brand, potency or dose, the CVs remained lower for ezetimibe+statins versus statins in 2nd-line studies. The SDs showed no consistent trend for

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either therapy.

Conclusion: In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses to ezetimibe+statins was not greater versus statins alone and appeared lower when adjusted for other factors. Relative variability was lower in patients treated with statins+ezetimibe. A better understanding of the variability of the LDL-C lowering response may help guide clinicians in making therapeutic decisions.

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Introduction Reduction of low-density lipoprotein cholesterol (LDL-C) with statin therapy significantly reduces the risk of major cardiovascular disease (CVD) -related events.[1, 2] Consequently, several

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treatment guidelines recommend statin uptitration, switching to a more potent statin and/or combination therapy for high-risk patients. Moreover, combination therapy may be considered for high-risk patients who cannot achieve adequate LDL-C lowering on statin monotherapy.[3-6] The recent update to the

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guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults from the American College of Cardiology/American Heart Association recommend moderate- or high-

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intensive statin therapy on the basis of underlying risk categories to achieve at least a 50% reduction in LDL-C. The addition of a non-statin cholesterol-lowering drug to statin therapy may be considered for high-risk patients who have a less-than-anticipated therapeutic response to the recommended maximum tolerated dose of statin if the risk-reduction benefit outweighs the safety risk.[7] There is considerable inter-individual variation in the extent of LDL-C lowering achieved with

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statin therapy,[8, 9] and many high-risk patients do not attain sufficient LDL-C lowering.[10-12] The LDL-C lowering response to statin treatment can vary due to diverse inherited and acquired patient characteristics including age, race/ethnicity, gender, baseline lipid and hsCRP levels and various

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metabolic factors.[13-18] Differences in methods and/or standardization of LDL-C measurement, along with day-to-day biological variability, may also influence the results of LDL-C lowering response to

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treatment.[19] Patient non-compliance/intolerance of statin therapy, as well as physician non-adherence to guidelines, and/or cost factors can also hinder attainment of LDL-C targets on statin therapy.[20-22] A better understanding of the variability in response to lipid-lowering therapy is one way to help guide clinicians in making therapeutic decisions. Little is known about the potential differences in the variability of treatment responses to lipidlowering regimens including statin combination therapy and statin monotherapy. Based on mathematical rationale, it could be hypothesized that the variability of the response to combination therapy with two

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different lipid-lowering therapies having independent effects, may be greater than those of the individual components. Such variability may have an impact on patient therapy targeted to specific LDL-C levels, wherein greater variability in treatment response may result in suboptimal LDL-C lowering in some

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patientslevels. Conversely, less variability may offer the advantage of better precision and accuracy in predicting response to treatment and achieving specific target lipid levels.[23]

A preliminary examination of some isolated studies [24, 25] suggested that combination therapy

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with ezetimibe plus statins may have less variability in LDL-C lowering response than statins alone. In the current analysis, we compared the variability of the LDL-C lowering response to treatment with

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ezetimibe combined with statins with statins alone in patients with hypercholesterolemia using patientlevel data (N=21,671) pooled from 27 double-blind, placebo-and/or active-controlled clinical studies. Variability was assessed separately in 1st-line (statin-naïve/drug wash-out) and 2nd-line (patients on statin

Methods

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therapy) add-on and uptitration study types.

This was an analysis of patient-level data that was pooled from 27 double-blind, placebo and/or

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active-controlled clinical studies of patients with hypercholesterolemia (N=21,671) who were treated with ezetimibe+statin versus statin therapy in 1st-line (statin-naïve/drug wash-out) and 2nd-line (on-statin)

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studies during 6-24 weeks. Second line study types included add-on therapy, in which patients on a stable dose of statin were then randomized to ezetimibe versus placebo while continuing the same dose of statin; and uptitration therapy, which included patients on a statin at baseline who were then randomized to ezetimibe added to their current statin versus uptitrating (doubling) the statin dose. An initial survey showed differences in the variability of the percent change from baseline in LDL-C in the individual studies/study types and that variability was more consistent among studies within each type; thus, the analyses were conducted using patient data pooled separately from 1st-line, 2nd-line add-on and uptitration study types (Table 1). The research hypothesis of this analysis, based on the assumption of the negatively

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correlated effects of the 2 drugs was that the variability of the LDL-C lowering response to combined therapy is equal to or lower than that of statins alone. The variability of percent change from baseline in LDL-C was assessed in the full cohort and among subgroups (age, race/ethnicity, gender, body mass

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index [BMI], metabolic syndrome, diabetes, baseline LDL-C, triglycerides and hsCRP levels, statin brand and potency) in the 3 study types.

All analyses were separately performed by 1st-line, 2nd-line add-on and 2nd-line uptitrate (double-

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dose including switch statin) study types. Variability of percent change from baseline in LDL-C for

ezetimibe+statin and statin treatments was evaluated by three methods including standard deviation (SD),

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which is the unadjusted sample variance estimates of % change from baseline in LDL-C; coefficient of variation (CV),which is the ratio of the SD to the mean of % change from baseline in LDL-C; and root mean squared error (RMSE), which is the adjusted variance estimate, calculated from a model with a factor for treatment group, and covariates of gender, race, diabetes, statin potency, extent of LDL-C reduction (low, med, high by tertiles), age, BMI, baseline LDL-C, triglycerides and hsCRP. Each method

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offered different information regarding variance (Supplemental Data). Briefly, the SD, the square root of the variance, has the same dimension as the data and thus is comparable to deviations from the mean. The CV, which is the ratio of the standard deviation to the mean, is useful when comparing between data sets

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with different units or widely different means. However, CV is sensitive to small changes in the mean when the mean value is close to zero. Two (or more) variances (ie. SDs) can be compared while

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controlling for covariates in a model and is reported as the RMSE. An F test was used to compare the ratio (statin: ezetimibe+statin) of the variance estimates (SD and RMSE). Statistical comparisons were not performed for CV. Many statistical tests were performed with no adjustment to control the type-1 error rate.

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Results The baseline characteristics for the pooled 1st-line (n=12,157), 2nd-line add-on (n=4,796) and uptitration (n=4,327) study cohorts were generally balanced across treatment groups (Table 2). Baseline

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means for LDL-C, non-HDL-C, total cholesterol, triglycerides, and Apo B were higher in 1st-line studies than those in 2nd-line add-on and uptitration studies (Table 2).

The percent changes from baseline in LDL-C, pooled for each study type, were significantly greater

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(p<0.001) in patients treated with ezetimibe+statin therapy compared with patients treated with statin treatment (Figure 1). For 1st-line and 2nd-line add-on studies, the absolute variability (unadjusted SD,

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adjusted RMSE) of LDL-C lowering responses with ezetimibe+statin was statistically significantly lower than with statin therapies (Table 3). However, these differences were small and could be attributable to large sample sizes. For 2nd-line uptitration studies, the unadjusted variance (SD) was significantly lower in the statin versus ezetimibe+statin groups, while the adjusted variance (RMSE) was significantly lower in patients treated with ezetimibe+statin vs statins alone. The relative variability (CV) was lower for

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ezetimibe+statins versus statins alone for all study types. The variability of LDL-C lowering efficacy in terms of the unadjusted SDs were generally similar in 1st- and 2nd-line add-on studies for ezetimibe+statin therapies and in the 1st-line studies for statin therapies,

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regardless of the degree of LDL-C lowering, across statin brands and doses (Figure 2). However, in the 2nd-line add-on studies for statin therapies, it appears that the SD decreased with increases in LDL-C

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(Figure 2). The relative variability (CV) decreased with increasing LDL-C lowering efficacy and was lower for ezetimibe+statin versus statin therapy due to larger mean LDL-C reductions. Similar results were observed in 2nd-line uptitration studies (Supplemental Figure1). The percent change from baseline, SD and RMSE for percent change from baseline for most subgroups, including statin brand and potency (Supplementary Table 1) as well as age, gender, race, diabetes mellitus, metabolic syndrome, BMI, and baseline LDL-C, triglycerides and hsCRP (Table 4) were generally similar to the full cohorts for the study types. When assessed by statin brand and potency,

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the CVs and RMSEs remained lower for ezetimibe+statin vs statin in 2nd-line studies, while the SDs showed no consistent trend for either therapy.

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Discussion In this analysis, although the absolute variability (SD, RMSE) of LDL-C lowering responses to

ezetimibe+statin was statistically significantly lower, the difference was not considered meaningfully different between ezetimibe+statin and statin monotherapy in all study types, regardless of the degree of

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LDL-C lowering efficacy. The relative variability (CV) was related to the degree of LDL-C lowering efficacy and was lower when patients were treated concomitantly with ezetimibe+statins vs statins alone

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for all study types, attributed to larger mean LDL-C reductions achieved with ezetimibe+statins vs statins The variability within subgroups was generally consistent with those observed in the full cohort for each study type.

Although both statins and the cholesterol absorption inhibitor, ezetimibe, reduce LDL-C levels via a

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common pathway of LDL-receptor, it has been suggested in some studies using cholesterol synthesis and absorption markers that the LDL-C lowering response of ezetimibe is inversely related to that of statins; however the data remain controversial.[15, 26-29] In the present study, the reduced variability in LDL-C lowering response observed with the combination of ezetimibe plus statins compared with statins alone

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would appear to be consistent with the idea of this inverse relationship (Supplemental Figure 2). The difference in variability between the two treatment regimens appears to be generally small and the

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statistical significance may likely be related to the large sample sizes. Additionally, variability appeared to be related to the LDL-C lowering efficacy. That is, the variability was lower for the combination therapy, most notably in the add-on studies, and was attributed to a greater magnitude of LDL-C lowering compared with statins. However, it is important to consider that the day-to-day biological variability that contributes to the variability in LDL-C response may impact the precise assessment of this difference. In principle, biological variability that is independent of the treatment effect, could affect the estimate of the variability associated with responses to both therapies, resulting in larger or smaller differences between

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the two regimens. Therefore, in the current analysis, the variability is considered to be similar with combination ezetimibe+statins versus statins, but certainly not greater as may be expected from combined therapy. This finding is important as it allows a better prediction of the effect of lipid-lowering treatment,

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particularly as LDL-C levels become lower. This is important with regard to ezetimibe+statin therapy, which has been shown in numerous clinical trials to provide greater LDL-C lowering versus statins alone, and thus provides an optional therapy for those patients who cannot achieve sufficient LDL-C lowering

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on statin therapy alone.[30-34]

Observational studies have shown that a large proportion of patients do not achieve sufficient LDL-C

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lowering despite treatment.[8] This may be due in part to variable responses by patients to statin therapy, which is the first-line therapy for hypercholesterolemia. For example, >40% of patients prescribed high dose statin did not reach LDL-C <70 mg/dL while taking high dose statins.[8, 35] This variability may be related to non-compliance (e.g., because of dose-related toxicity or adverse effects), patient characteristics (e.g., gender, race, presence of diabetes, age, body mass index, baseline lipid levels), or genetic

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variability.[17, 18, 35-37] However, a pooled analysis that included data from more than 11,000 subjects treated with combination of ezetimibe+statin therapy reported consistent LDL-C lowering across a wide range of patient characteristics and risk factors, and modest subgroup effects on LDL-C lowering

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response.[33] This is consistent with the results from the current analysis that showed generally consistent LDL-C lowering across study types for most subgroups, including statin brand and potency as

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well as age, gender, race, diabetes mellitus, metabolic syndrome, BMI, and baseline LDL-C, triglycerides and hsCRP. While the absolute variability of LDL-C lowering was not found to be meaningfully different between statin monotherapy and ezetimibe+statin, there was variability between patients’ response to therapy. For example, with ezetimibe+statin first line therapy, the mean reduction was 52.2% (+/- 15.3%). This means that for any patient who initiates treatment with ezetimibe+statin, it would be very reasonable to expect a response which ranges from a 36.9% reduction (mean – 1 SD) to 67.5% (mean+1 SD). Other studies with statin monotherapy have shown variability in LDL-C reductions in subjects with genetic mutations, diabetes mellitus, in women, black subjects, and in older patients.[17, 18,

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33, 35-37] Of note, some genetic mutations (such as missense mutations of the PCSK9 gene) may cause not only high LDL-C levels, but also hyper-responsivity to statin therapy.[36] Individualized patient therapy that includes consideration of risk reduction, baseline lipid levels, choosing the right statin/dose

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or other lipid-lowering therapy regimen, safety concerns and patient preferences is needed to optimize LDL-C lowering therapy. [38-41]

Several guidelines specify treatment target levels for lipids based on CVD risk.[3-6] The evidencebased US guidelines no longer specify targets, but focus on treatment with high-intensity statin therapy to

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reduce LDL-C levels by ≥50% or moderate-intensity statin therapy to reduce LDL-C levels by 30-<50%

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based on 4 risk groups.[7] It is important to note that individual variability in LDL-C response demonstrated for the full range of statin doses may limit the ability of physicians to make informed decisions about appropriate therapeutic regimens toward CVD risk reduction.[8, 9, 39, 42] For example, a subanalysis of the Voyager trial demonstrated individual variability in LDL-C response with all statin brands across doses, with standard deviations ranging from 12.8–17.9% for the LDL-C reductions.[9, 42]

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Physicians should consider that in order to achieve a 50% reduction in LDL-C, an adequate lipid-lowering therapy with a mean 50% LDL-C lowering efficacy may need to be prescribed. Monitoring of LDL-C lowering response is important to ensure the adequacy of lipid-lowering therapy, as well as adherence to

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medication/lifestyle changes and in guiding therapeutic decisions.[9, 39, 43] This analysis was limited to short-term lipid-altering efficacy studies 6-24 weeks in duration and did

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not assess clinical outcomes. Therefore, generalizing to longer-term use should be made with caution. However, the recently completed IMPROVE-IT trial assessed the incremental cardiovascular benefit of LDL-C lowering with ezetimibe 10 mg added to simvastatin (mainly 40 mg) compared with simvastatin monotherapy over 6 years in patients presenting with acute coronary syndromes.[44-46] The study investigators reported that the trial met its primary and secondary composite efficacy endpoints. In conclusion, these results indicate that the addition of ezetimibe to statin therapy does not increase the variability of the LDL-C lowering response to statin treatment in patients with hypercholesterolemia. This is of clinical importance given that the combination of ezetimibe+statin is considered an optional

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lipid-lowering therapy for high-risk patients who do not reach recommended LDL-C goals with high-dose statin monotherapy. Knowledge of the variability of the LDL-C lowering response in these patients when being treated with these therapies should allow healthcare providers to make therapeutic decisions with

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greater confidence.

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Conflict of interest

O Descamps has received research grants from AstraZeneca, MSD, Bayer, and Pfizer and Amgen, and

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serves as an advisory board member for MSD, AstraZeneca, Abbot, Sanofi and Amgen, as well as a clinical trial investigator for Amgen and Sanofi; he has also received conference fees from AstraZeneca, MSD, Pfizer, BMS, and Abbott. P Brudi, J Lin, AB Polis, A Shah, ME Hanson, AM Tershakovec and JE Tomassini are employees of Merck & Co., Inc., Kenilworth, NJ and may own stock or hold stock options

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in the company.

Author contributions: OD, JET, JL, ABP, AS, PB, MEH and AMT are responsible for the work described in this paper. All authors were involved in at least one of the following:

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[conception, design, acquisition, analysis, statistical analysis, interpretation of data] and [drafting the manuscript and/or revising/reviewing the manuscript for important intellectual content]. All

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authors provided final approval of the version to be published and they agree to be accountable for all aspects of the work ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Acknowledgements The authors wish to thank Sheila Erespe of Merck & Co., Inc. for editorial assistance. This work was supported by Merck & Co., Inc., Kenilworth, NJ, USA.

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39. Karlson BW, Nicholls SJ, Lundman P, Palmer MK, Barter PJ. Achievement of 2011 European lowdensity lipoprotein cholesterol (LDL-C) goals of either <70 mg/dl or >/= 50% reduction in high-risk patients: results from VOYAGER. Atherosclerosis 2013;228:265-9

M AN U

40. Blaha MJ, Blumenthal RS. Risk factors: new risk-assessment guidelines-more or less personalized? Nat Rev Cardiol 2014;11:136-7 41. Martin SS, Abd TT, Jones SR, Michos ED, Blumenthal RS, Blaha MJ. 2013 ACC/AHA cholesterol treatment guideline: what was done well and what could be done better. J Am Coll Cardiol 2014;63:2674-8

TE D

42. Karlson BW, Palmer MK, Nicholls SJ, Lundman P, Barter PJ. Attainment of the anticipated >=50% reduction in LDL-C in the four ACC/AHA guidelines statin benefit groups: A voyager meta-analysis. Atherosclerosis 2014;235:e11-e12 (Abstract) 43. Grundy SM. Statins for all? Am J Cardiol 2014;114:1443-6

EP

44. Blazing MA, Giugliano RP, Cannon CP, et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: Final baseline characteristics of the IMPROVE-IT study population. Am Heart J 2014;168:205-12

AC C

45. Blazing MA, Guigliano R, Cannon CP, et al. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial: On-treatment analysis. Presented at the American Heart Association Scientific Sessions 2014; November 15-19, 2014; Chicago, IL (Abstract) 46. Cannon CP, On behalf of the IMPROVE-IT investigators. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. Presented at the American Heart Association Scientific Sessions 2014; November 15-19, 2014; Chicago, IL (Abstract)

15

ACCEPTED MANUSCRIPT

Table 1 Description of included studies.

Population

Weeks

Baseline LDL-C

Treatment

HC

12

12

12

EP

HC

12

177

HC

P 10, 20, 40

218

191

203

204

246

253

AC C

12

345

353

246

446

250

505

Eze+P 10, 20, 40

176-182

Eze, PBO A 10, 20, 40, 80 Eze+A 10, 20, 40, 80

174-176

Eze, PBO Eze+S 20, 40, 80

HC, high risk

S 20, 40, 80 6

165-174

S 20,

Feldman et al (2004) 025

269

Eze, PBO

Goldberg et al (2004) 023

261

Eze, PBO

TE D

Melani et al (2003)

005

(N=11423)

Eze+L 10, 20, 40

HC

Ballantyne et al (2003)

178-179

L 10, 20, 40

Kerzner et al (2003)

692

(N=10248)

Eze+S 10, 20, 40, 80

HC

691

Randomized to Eze+Statin

Eze, PBO

S10, 20, 40, 80

Davidson et al (2002)

679

179-183

M AN U

011

Randomized to Statin

SC

First-line studies†: Ezetimibe+statins coadministered in statin-naïve patients

Subjects

RI PT

Study

Subjects

HC

Eze+S 20, 40, 80 12

179-181

A 10-80

Ballantyne et al (2004)

Eze/S 10-80

16

ACCEPTED MANUSCRIPT

HC

12

176-180

Eze, PBO Eze/S 10, 20, 40, 80

Bays et al (2004) 051

6

178-179

A 10 20, 40, 80 HC

6

172-173

Eze/S 20, 40, 80

Catapano et al (2006) 6

145

1428

1427

Eze/S 20, 40

Goldberg et al (2006)

718

480

123

124

647

436

316

311

894

1836

207

204

186

119

224

219

12

Rodney et al (2006)

M AN U

A 10, 20, 40 HC, africanamerican

107

923

SC

R 10, 20, 40 HC, T2DM

3377

927

Eze/S 20, 40, 80

Ballantyne et al (2005)

077

612

S 10, 20, 40, 80 HC

058

604

RI PT

038

175-177

Eze+S 20 S 20

HC, MetS

6

Robinson et al (2009)

134-142

Eze/S 20, 40 A10, 20, 40

Add-on to statins

Gagne et al (2002) 040

HC

AC C

Pearson et al (2005) 801

HC

8

EP

2173/2246

TE D

Second-line studies‡: Ezetimibe added-on to ongoing statin therapy

Established CHD

8

138-139

129

Established CHD

Ongoing statin 6

122-123

Eze+S 10, 20 S10, 20

6

121-123

Eze + S 10, 20

Farnier et al (2005) 803/804

Ongoing statin

Eze+ongoing statin

Brohet et al (2005) 802

Eze+ongoing statin

S 10, 20 Established CHD

6

121-123

Eze + A 10, 20

17

ACCEPTED MANUSCRIPT

CruzFernandez et al (2005)

A 10, 20

Uptitration (doubling statin dose)

030 Stein et al (2004) 021

14

57-79% HeFH; 3032% CHD;37-39% ≥2RF

4

T2DM

24

167-171

Eze S 20, 40

186-187

Eze+A 10, 20, 40 A 10, 20, 40, 80

92-94

Barrios et a 2005

CHD

807

T2DM

6

107

103

123-125

210

217

213

425

92

92

279

277

297

305

515

515

Eze/S 20

6

91-96

Eze/S 20, 40

HC; moderate CHD risk

6

6

EP

HC; high CHD risk

TE D

A 20

Conard et al (2008)

AC C

HC; high CHD risk

6

118-120

89-90

HL; ≥65 years

Eze+A 20 A 40

Eze+A 40 A 80

124-125

Eze/S 20

Farnier et al (2009) 112

293

A 20

Constance et al (2007)

809

M AN U

Atherosclerosis/

Leiter et al (2008)

303

S 40

806

090

62

Eze+S 20

Gaudiani et al (2005)

079

34

RI PT

Dobs et al (2003)

22% HeFH, 42%CHD; 40% ≥2RF

SC

700

R10 6

102-103

Eze+A 10

Zieve et al (2010)

A 20/40

Pbo=placebo; Eze=ezetimibe 10mg; S=simvastatin; L=lovastatin; Pravastatin; A=atorvastatin; CHD=coronary heart disease; HC=hypercholesterolemia; HeFH=heterologous familial hypercholesterolemia; MetS=metabolic syndrome; T2DM=type 2 diabetes. †Baseline measured following placebo run-in prior to active treatment; ‡Subjects were on statin at baseline or received stain during run-in therapy; baseline was measured at time of ezetimibe or placebo added-on to onto statin therapy, ezetimibe added-on versus doubling the statin dose

18

ACCEPTED MANUSCRIPT

Table 2 Baseline characteristics.

Characteristics (%)

Second Line Add-on Studies‡

Second Line Uptitration Studies‡

RI PT

First Line Studies† Statin (n=6080)

Eze +Statin (n=6077)

Statin (n=1929)

Eze +Statin (n=2867)

Statin (n=2046)

Eze +Statin (n=2281)

Mean

57.3

57.9

61.6

62.0

62.5

62.5

< 65

72.8

71.5

57.9

56.2

47.4

49.2

65 – 74

22.3

22.5

29.0

29.4

≥ 75

4.9

5.9

13.2

14.4

Male

48.1

49.4

58.2

57.2

Female

51.9

50.6

41.8

42.8

Race 82.1

83.0

Non-caucasian

17.9

17.0

CHD

16.3

19.1

Diabetes Mellitus

28.0

25.1

Metabolic Syndrome§

49.3

46.0

BMI (kg/m2 ) mean (SD)

30.2

≥ 30

43.9 (n=6224)

11.7

11.8

54.1

54.4

45.9

45.6

88.6

86.6

86.8

85.8

13.4

13.2

14.2

67.2

59.7

46.4

50.7

29.7

31.2

35.9

42.1

55.7

57.5

51.6

51.6

29.9

29.4

29.8

29.0

29.1

41.6

36.4

40.4

35.7

35.6

(n=6215)

(n=1973)

(n=2917)

(n=2050)

(n=2289)

EP

Lipids [mg/dL]

39.0

11.4

TE D

Caucasian

40.9

M AN U

Gender

SC

Age (y)

LDL-C

169 ± 34

170 ± 33

129 ± 30

129 ± 29

119 ± 41

117 ± 42

Non-HDL-C

205 ± 36

206 ± 36

161 ± 33

161 ± 33

147 ± 44

146 ± 44

49 ± 12

49 ± 12

50 ±12

49 ±11

52 ±13

52 ± 13

Total C

254 ± 38

255 ± 37

211 ± 34

210 ± 34

199 ± 45

197 ± 45

165 ± 93

166 ± 92

142 ± 81

146 ± 84

127 ± 74

126 ± 73

AC C

HDL-C Triglycerides§ Apo B Apo AI

hs-CRP [mg/L]

║

158 ± 28

159 ± 28

131 ± 25

130 ± 25

118 ± 33

118 ± 33

153 ± 27

154 ± 27

158 ± 28

158 ± 27

158 ± 27

157 ± 28

2.3 ± 3.6

2.3 ± 3.4

2.3 ± 3.5

2.2 ± 3.4

1.6 ± 2.6

1.7 ± 2.8

† st

Eze=ezetimibe 10mg; CHD=coronary heart disease; BMI=body mass index; 1 line studies: Statin-naïve or wash-out prior to randomization; ‡2nd line studies: On-statin treatment at study-entry, patients were randomized to (1) Ezetimibe or placebo (add-on) or (2) Ezetimibe or uptitrated statin dose (uptitrate); §Defined as having 3 or more of the following 5 criteria: (i) waist circumference>102 cm (males) or >88 cm (females); (ii) triglycerides ≥159 mg/dl; (iii) HDL-C <39.8 mg/dl for men or <49.8 mg/dl for women; (iv) systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mmHg or drug treatment for hypertension; (v) fasting glucose ≥100.9 mg/dl or drug treatment for elevated blood glucose. ║Median ± robust SD

19

ACCEPTED MANUSCRIPT Table 3 Variability of % change from baseline in LDL-C in pooled 1st-line and 2nd line add-on and uptitrate studies.

Variability

N type 1st line†

Unadjusted §

CV

Adjusted RMSE║

16.4

-0.4

7.4

6215

-52.2

14.3

2917

-25.7

¶

LDL-C

Mean % change

SD

6224

-42.3

1973

-2.8

17.5

-6.4

2050

-12.1

19.2

-1.6

2nd line‡

2nd line‡ Uptitration

15.7

Unadjusted

CV¶

Adjusted RMSE║

15.3*

-0.3

7.0*

16.5*

-0.6

10.0*

21.0*

-0.8

14.4*

LDL-C

M AN U

Add-on

N

Variability

§

SD

SC

Mean % change

Study

Ezetimibe+Statin Combination Therapy

RI PT

Statin Monotherapy

2289

-27.0

TE D

CV=coefficient of covariance; SD=standard deviation; RMSE=root mean squared error, estimated SD adjusted for covariates; †Statinnaïve/wash-out and ‡on-statin treatment at study-entry; 2nd-line studies are a mix of study design wherein patients on a background of statin therapy were randomized to (1) Ezetimibe or placebo (add-on) or (2) Ezetimibe or uptitrated statin dose (uptitrate). §Unadjusted variance comparison between Ezetimibe +Statin and Statin groups based on SDs of % change from baseline in LDL-C; ¶CV=SD/mean; ║Adjusted variance comparison between Ezetimibe+Statin and Statin groups while controlling for covariates of gender, race, diabetes, statin potency, extent of LDL-C reduction (low, med, high by tertiles), age, BMI, baseline LDL-C, TG and CRP in the full cohort.

AC C

EP

*p<0.05 for the ratio of variances in Ezetimibe + statin vs Statin groups for unadjusted SD and adjusted RMSE.

20

ACCEPTED MANUSCRIPT

Table 4. Variability of % change from baseline in statin brand and statin potency subgroups and subgroups by baseline demographics and clinical characteristics.

Treatment

N

Mean % change LDLC

SD§

7.8

771

-3.8

18.9

-0.3

6.8*

1132

-27.1

17.2*

-0.5

7.3

264

N

Mean % change LDL-C

SD§

CV¶

RMSE║

Statin

2788

-43.0

16.0

-0.4

Eze+Statin

253

-56.3

17.1ns

Statin

203

-25.3

12.1

Pravastatin

Simvastatin

Other††

ns

High

¶¶

Male

Female

SD§

CV¶

RMS E║

-5.0

14.9

1612

-11.7

17.5

-1.5

14.9

-0.6

10.3*

1177

-26.2

18.3ns

-0.7

12.3*

15.5

ns

-10.6

11.8

n/a

n/a

n/a

n/a

n/a

ns

204

-38.5

13.8

-0.4

6.0*

466

-22.8

16.7

-0.7

11.3

n/a

n/a

n/a

n/a

n/a

Statin

1587

-37.3

15.2

-0.4

7.4

789

-2.5

16.5

-6.6

14.1

141

-3.0

18.7

-6.2

17.3

ns

Eze+Statin

5567

-52.9

14.8

-0.3

7.1*

1068

-26.1

15.9

-0.6

9.3*

1112

-27.9

23.5*

-0.8

16.1ns

Statin

1646

-48.1

15.8

-0.3

n/a

147

-0.9

18.0

-20.7

14.2

n/a

n/a

n/a

n/a

n/a

ns

Eze+Statin

191

-40.4

15.5

-0.4

Statin

583

-27.0

13.0

-0.5

Eze+Statin

1292

-44.3

13.5ns

-0.3

Statin

3333

-38.9

15.0

-0.4

3792

-52.6

Statin

2308

-51.1

Eze+Statin

1131

-59.9

Statin

2987

-41.4

Eze+Statin

3066

Statin

3237

14.6

-0.3

14.4

-0.3

ns

n/a

246

-23.3

13.8*

-0.6

8.9*

n/a

n/a

n/a

n/a

n/a

6.8

317

-2.2

16.0

-7.3

13.6

n/a

n/a

n/a

n/a

n/a

5.9*

489

-24.2

15.3ns

-0.6

9.3*

n/a

n/a

n/a

n/a

n/a

7.7

1312

-2.7

17.2

-6.3

14.0

1679

-12.4

19.3

-1.6

16.3

EP

Eze+Statin

ns

AC C

Medium§§

Mean % change LDL-C

Eze+Statin

Statin Potency Low‡‡

-1.5

TE D

Atorvastatin

N

M AN U

Statin Brand

2nd Line Uptitration Studies‡

RMSE║

CV¶

SC

Subgroup

2nd Line Add-on Studies‡

RI PT

1st Line Studies†

ns

7.0*

1934

-25.9

16.5

-0.6

10.1*

2012

-27.0

21.2*

-0.8

14.8*

6.7

317

-3.3

19.8

-6.0

16.4

371

-11.0

18.7

-1.7

13.7

ns

15.1*

-0.3

7.5*

471

-26.5

17.5*

-0.7

10.2*

277

-27.2

19.1

-0.7

11.7*

16.0

-0.4

7.6

1148

-2.6

16.7

-6.4

14.0

1108

-12.2

18.6

-1.5

15.2

-51.9

14.6*

-0.3

7.0*

1667

-26.3

16.2ns

-0.6

9.9*

1251

-28.4

18.9ns

-0.7

11.6*

-43.1

16.8

-0.4

7.1

825

-2.9

18.4

-6.3

14.6

942

-12.0

19.8

-1.65

16.4

21

ACCEPTED MANUSCRIPT

Diabetes No

Met syndrome Yes Met syndrome No 2

BMI <30 kg/m

BMI ≥30 kg/m

2

Baseline LDL <150 mg/dL Baseline LDL ≥150 mg/dL BL TG <150 mg/dL

7.1ns

1250

-25.0

16.8*

-0.7

10.2*

1038

-25.4

23.2*

-0.91

17.0ns

Statin

4530

-41.4

16.8

-0.41

7.6

1142

-3.0

17.3

-5.87

13.7

967

-10.9

20.5

-1.9

18.3

-0.7

10.5*

1119

-26.8

20.7

-0.8

14.2*

-7.2

15.0

1083

-13.2

17.9

-1.4

13.7

-0.6

9.3*

1170

-27.3

21.3*

-0. 8

14.5ns

-5.7

13.3

1781

-12.7

18.6

-1.5

15.0

-0.6

9.3*

1968

-27.1

21.1*

-0.8

14.6ns

Eze+Statin

4448

-51.0

16.0*

-0.31

7.1*

1638

-25.3

17.2

Statin

1694

-44.8

15.1

-0.34

6.9

831

-2.5

17.6

ns

RI PT

s

ns

Eze+Statin

1767

-55.1

13.1*

-0.24

6.7

1279

-26.2

15.4*

Statin

5112

-42.9

16.1

-0.4

7.3

1749

-2.9

16.4

Eze+Statin

5160

-52.7

14.7*

-0.28

6.9*

2527

-26.0

15.6*

Statin

1112

-39.8

17.8

-0.5

8.0

224

-1.6

24.2

-14.7

20.8

269

-8.5

22.5

-2.6

19.5

Eze+Statin

1055

-49.8

17.8ns

-0.4

7.5ns

390

-23.9

21.0*

-0.9

13.8*

321

-26.6

20.6ns

-0.8

13.4*

Statin

1746

-43.3

15.81

-0.37

7.27

584

-2.2

19.39

-8.85

14.85

735

-10.2

22.66

-2.23

18.26

ns

ns

SC

Diabetes Yes

-0.3

M AN U

Non-Caucasian

15.9*

Eze+Statin

1561

-53.9

15.3

-0.3

7.4

910

-27.3

17.1*

-0.6

10.0*

958

-27.4

24.4*

-0.9

16.3*

Statin

4478

-41.9

16.6

-0.4

7.4

1389

-3.0

16.6

-5.6

14.0

1315

-13.2

16.8

-1.3

13.6

Eze+Statin

4654

-51.6

15.3*

-0.3

6.9*

2007

-25.0

16.1ns

-0.6

10.0*

1331

-26.8

18.2*

-0.7

11.9*

Statin

2860

-43.7

16.4

-0.4

7.7

752

-2.3

19.8

-8.6

15.9

608

-12.9

18.6

-1.5

13.5

Eze+Statin

2573

-53.0

15.1*

-0.3

7.3*

1324

-25.2

17.3*

-0.7

10.7*

610

-27.6

21.2*

-0.8

13.3ns

Statin

2937

-42.2

16.3

-0.4

-1.4

15.2

Eze+Statin

3018

-52.0

15.7*

-0.3

Statin

3407

-42.5

16.7

-0.4

Eze+Statin

3551

-52.7

15.3*

-0.3

Statin

2678

-42.4

16.1

Eze+Statin

2529

-51.7

Statin

1607

-40.6

Eze+Statin

1505

-51.4

Statin

4617

-42.9

Eze+Statin

4710

Statin

2529

TE D

Caucasian

-52.5

6.9

601

-2.9

15.7

-5.4

13.2

571

-14.2

20.2

7.0ns

981

-25.1

15.9ns

-0.6

9.8*

572

-27.1

18.9ns

-0.7

11.1*

7.8

1243

-2.6

17.3

-6.6

14.7

1318

-12.3

19.5

-1.6

16.3

ns

7.1*

1726

-25.9

15.9*

-0.6

9.6*

1472

-27.6

19.6

-0.7

12.8*

-0.4

6.9

713

-3.0

17.9

-5.9

13.6

730

-11.8

18.6

-1.6

14.6

15.2*

-0.3

6.7ns

1169

-25.4

17.2ns

-0.7

10.5*

812

-26.1

23. 2*

-0.9

16.6*

17.9

-0.4

8.9

1621

-1.3

17.2

-13.1

14.6

1729

-12.1

19.8

-1.6

15.8

15.8*

-0.3

7.4*

2404

-24.9

16.4*

-0.7

10.3*

1940

-27.3

21.7*

-0.8

14.6*

15.8

-0.4

6.7

352

-9.3

16.9

-1.8

11.3

321

-12.3

15.6

-1.3

13.9

-52.5

15.1*

-0.3

6.9ns

513

-29.5

16.2

-0.6

8.4*

349

-25.9

16.8ns

-0.7

10.1*

-42.6

16.2

-0.4

7.0

1070

-2.7

16.8

-6.2

14.3

1320

-11.8

18.8

-1.6

16.0

EP

Age >65

3149

AC C

Age <65

Eze+Statin

22

ACCEPTED MANUSCRIPT

BL hsCRP <2 mg/L BL hsCRP ≥2 mg/L

Eze+Statin

2558

-52.7

15.2*

-0.3

6.9ns

1529

-26.1

15.8*

-0.6

9.6*

1472

-26.8

20.1*

-0.8

13.8*

Statin

3695

-42.1

16.6

-0.4

7.6

903

-2.8

18.2

-6.6

14.2

730

-12.6

19.9

-1.6

15.3

Eze+Statin

3657

-51.9

15.4*

-0.3

7.1*

1388

-25.3

17.1*

-0.7

10.4*

817

-27.4

22.5*

-0.8

16.0ns

Statin

2482

-44.5

15.4

-0.4

6.7

810

-3.3

16.7

-5.1

13.9

841

-12.1

19.7

-1.6

15.2

-0.6

10.3*

943

-27.2

21.3*

-0.8

13.6*

-7.4

14.6

667

-11.0

21.3

-1.9

16.4

-0.6

9.7*

804

-26.3

23.2*

-0.9

15.1*

ns

ns

Eze+Statin

2570

-54.0

13.7*

-0.3

7.0

1198

-25.4

16.3

Statin

3256

-42.0

16.7

-0.0

7.8

1004

-2.4

17.8

Eze+Statin

3178

-51.5

15.8*

-0.3

7.1*

1417

-25.9

16.1*

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BL TG ≥150 mg/dL

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BL=baseline; BMI=body mass index; CRP=c-reactive protein; LDL-C=low-density lipoprotein cholesterol; MetS=metabolic syndrome; RMSE=root mean squared error, estimated SD adjusted for covariates; SD= standard deviation; TG=triglyceride level; †Statin-naïve/wash-out and ‡on-statin treatment at study-entry; 2nd-line studies are a mix of study design wherein patients on a background of statin therapy were randomized to (1) Ezetimibe or placebo (add-on) or (2) Ezetimibe or uptitrated statin dose (uptitration). §Unadjusted variance comparison between Ezetimibe+Statin and Statin groups based on SDs of LDL-C at study-end and % change from baseline; ¶CV=SD/mean; ║Adjusted variance comparison between Ezetimibe+Statin and Statin groups while controlling for covariates of gender, race, diabetes, statin potency, extent of LDL-C reduction (low, med, high by tertiles), age, BMI, baseline LDL-C, TG and CRP in the full cohort. *p<0.05 and ns=p>0.05 for variance comparison for SD and RSME; ††lovastatin, fluvastatin, cerivastatin; ‡‡Simvastatin 10mg, lovastatin 10 and 20mg, pravastatin 10 and 20mg; §§Atorvastatin 10 and 20mg, lovastatin 40mg, pravastatin 40 and 80mg, rosuvastatin 10mg, simvastatin 20 and 40mg; ¶¶Atorvastatin 40 and 80mg, simvastatin 80mg

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ACCEPTED MANUSCRIPT Figure legends Fig. 1. Mean % change from baseline in LDL-C. † st

1 line studies: Statin-naïve or wash-out prior to randomization; ‡2nd line studies: On-statin treatment at study-entry, patients were randomized to (1) Ezetimibe or placebo (add-on) or (2) Ezetimibe or uptitrated statin dose (uptitration)*p<0.001 for Eze+statin vs statin treatment group difference

Fig. 2. Variability (SD and CV) by LDL-C lowering efficacy† †

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Note that % reductions from baseline are relative to pre-statin baseline LDL-C values for 1st-line studies, and relative to statin-treated baseline LDL-C values for 2nd line add-on and uptitration studies

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Each data point represents pooled estimate for a given statin brand and dose across each study type; insets scaled to relevant range for data points for each study type

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Highlights • Variability of LDL-C lowering response to ezetimibe+statins vs statins was compared • Absolute variability was not greater with ezetimibe+statin vs statins

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• Relative variability was lower for ezetimibe+statin vs statins attributed to larger LDL-C reductions • Variability within subgroups was generally consistent with the full cohort

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• Ezetimibe added to statins does not increase the variability of LDL-C lowering response

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Supplemental Materials for: “Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients”

ACCEPTED MANUSCRIPT Supplemental Data 1. Statistical analyses - Measures of Variability

Variability refers to how "spread out" a group of scores is and can be defined in terms of how close

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the scores in the distribution are to the middle of the distribution. Using the mean as the measure of the middle of the distribution, variance is defined as the average squared difference of the scores from the mean. In the present study, variance was assessed using the variance or standard deviation

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(SD), which is simply the square root of the variance, and the coefficient of variation (CV), which is the ratio of the standard deviation to the mean. The CV is useful because the standard deviation of

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data must always be understood in the context of the mean of the data. The CV is a dimensionless number, and so when comparing between data sets with different units or widely different means, one should use the CV for comparison rather than the standard deviation. The disadvantage of CV is that CV is sensitive to small changes in the mean when the mean value is close to zero.

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It is easy to compare two (or more) CVs or two (or more) variances. We are also able to compare two (or more) variances (ie. SDs) while controlling for covariates such as gender, race, diabetes, statin potency, extent of LDL-C reduction, age, BMI, baseline LDL-C, triglycerides and CRP.

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The variances (SDs) calculated from a model including these factors is reported as the Root of Mean Squared Errors (RMSEs). However, comparing two (or more) CVs is more difficult while controlling for

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covariates. Therefore, in this analysis, we provide CVs for patients with ezetimibe+statin and patients with statin alone. At the same time we make statistical inferences about the hypothesis by comparing two variances with (RMSE) and without (SDs) controlling for covariates.

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Supplemental Figure 1. Variability (SD and CV) by LDL-C lowering efficacy of Uptitration studies

†Each data point represents pooled es3mate for a given sta3n brand and dose across each study type

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Supplemental Table 1. Variability of LDL-C % change from baseline in subgroups

Race Caucasian Non-caucasian Diabetes Yes No Met syndrome Yes No BMI 2 <30 kg/m ≥30 kg/m

2

Statin EZE/Statin Statin EZE/Statin

2987 3066 3237 3149

16.01 14.63* 16.75 15.92*

-0.39 -0.28 -0.39 -0.30

7.61 6.98* 7.14 7.08ns

1148 1667 825 1250

16.73 ns 16.18 18.42 16.77*

-6.39 -0.62 -6.34 -0.67

Statin EZE/Statin Statin EZE/Statin

4530 4448 1694 1767

16.79 15.95* 15.09 13.09*

-0.41 -0.31 -0.34 -0.24

7.57 7.14* 6.86 6.73 ns

1142 1638 831 1279

17.32 ns 17.23 17.64 15.37*

-5.87 -0.68 -7.20 -0.59

Statin EZE/Statin Statin EZE/Statin

5112 5160 1112 1055

16.06 14.68* 17.77 ns 17.83

-0.37 -0.28 -0.45 -0.36

7.25 6.91* 7.98 ns 7.54

1749 2527 224 390

16.40 15.61* 24.17 21.00*

Statin EZE/Statin Statin EZE/Statin

1746 1561 4478 4654

15.81 ns 15.34 16.64 15.25*

-0.37 -0.28 -0.40 -0.30

7.27 ns 7.35 7.43 6.91*

584 910 1389 2007

Statin EZE/Statin Statin EZE/Statin

2860 2573 2937 3018

16.41 15.13* 16.32 15.65*

Statin EZE/Statin Statin

3407 3551 2678

16.65 15.28* 16.07

13.97 9.85* 14.58 10.16*

N

║

RMSE

1108 1251 942 1038

18.62 ns 18.89 19.80 23.16*

-1.53 -0.66 -1.65 -0.91

15.18 11.60* 16.37 ns 16.95

13.74 10.47* 15.01 9.31*

967 1119 1083 1170

20.49 ns 20.69 17.85 21.27*

-1.88 -0.77 -1.35 -0.78

18.25 14.20* 13.73 ns 14.51

-5.69 -0.60 -14.73 -0.88

13.32 9.28* 20.81 13.76*

1781 1968 269 321

18.56 21.06* 22.49 ns 20.60

-1.47 -0.78 -2.64 -0.77

14.97 ns 14.57 19.50 13.36*

19.39 17.12* 16.57 ns 16.08

-8.85 -0.63 -5.58 -0.64

14.85 10.01* 13.96 10.00*

735 958 1315 1331

22.66 24.38* 16.81 18.16*

-2.23 -0.89 -1.27 -0.68

18.26 16.33* 13.56 11.94*

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>65

N

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Age <65

RMSE║

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N

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Gender Male

Treatment

nd

2 Line ‡ Double-dose Studies § ¶ SD CV

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Subgroup

nd

2 Line ‡ Add-on Studies § ¶ ║ SD CV RMSE

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st

1 Line † Studies § ¶ SD CV

-0.38 -0.29 -0.39 -0.30

7.74 7.29* 6.89 ns 6.96

752 1324 601 981

19.79 17.31* 15.74 ns 15.87

-8.64 -0.69 -5.40 -0.63

15.90 10.71* 13.15 9.82*

608 610 571 572

18.63 21.21* 20.21 18.86ns

-1.45 -0.77 -1.43 -0.70

13.54 13.25ns 15.24 11.06*

-0.39 -0.29 -0.38

7.78 7.10* 6.88

1243 1726 713

17.25 15.94* 17.91

-6.64 -0.62 -5.90

14.74 9.63* 13.55

1318 1472 730

19.49 ns 19.59 18.58

-1.58 -0.71 -1.57

16.33 12.79* 14.64

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≥150 mg/dL

-0.29

6.95

ns

1169

17.20

Statin EZE/Statin Statin EZE/Statin

1607 1505 4617 4710

17.86 15.78* 15.84 15.14*

-0.44 -0.31 -0.37 -0.29

8.85 7.37* 6.71 ns 6.91

1621 2404 352 513

Statin

2529

16.20

-0.38

6.99

EZE/Statin

2558

15.21*

-0.29

Statin

3695

16.57

-0.39

7.63

903

18.19

-6.57

EZE/Statin

3657

15.35*

-0.30

7.13*

1388

17.08*

-0.68

Statin

2482

15.39

-0.35

6.73

810

16.72

6.89

ns

-0.68

10.45*

812

23.22*

-0.89

16.58*

17.24 16.40* 16.94 ns 16.16

-13.08 -0.66 -1.82 -0.55

14.57 10.26* 11.27 8.35*

1729 1940 321 349

19.76 21.65* 15.59 ns 16.81

-1.64 -0.79 -1.27 -0.65

15.83 14.59* 13.90 10.13*

1070

16.81

-6.19

14.30

1529

15.84*

-0.61

9.57*

BL hsCRP <2 mg/L ≥2 mg/L

ns

ns

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BL TG <150 mg/dL

15.17*

ns

1320

18.77

-1.59

15.99

1472

20.10*

-0.75

13.75*

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≥150 mg/dL

2529

14.15

730

19.87

-1.57

10.39*

817

22.51*

-0.82

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Baseline LDL <150 mg/dL

EZE/Statin

15.33 15.99

ns

-5.07

13.86

841

19.73

-1.64

15.21

EZE/Statin

2570

13.73*

-0.25

-0.64

10.31*

943

21.30*

-0.78

13.56*

Statin

3256

16.65

-0.40

7.82

1004

17.79

-7.35

14.64

667

21.27

-1.93

16.41

EZE/Statin

3178

15.79*

-0.31

7.10*

1417

16.13*

-0.62

9.73*

804

23.24*

-0.88

15.14*

6.95

1198

16.30

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SD= standard deviation; RMSE=root mean squared error, estimated SD adjusted for covariates; †Statin-naïve/wash-out and ‡on-statin treatment at study-entry; 2nd-line studies are a mix of study design wherein patients on a background of statin therapy were randomized to (1) Ezetimibe or placebo (add-on) or (2) Ezetimibe or uptitrated statin dose (uptitrate). §Unadjusted variance comparison between Ezetimibe +Statin and Statin groups based on SDs of LDL-C at study-end and % change from baseline; ¶ CV=SD/mean; ║Adjusted variance comparison between Ezetimibe+Statin and Statin groups while controlling for covariates of gender, race, diabetes, statin potency, extent of LDL-C reduction (low, med, high by tertiles), age, BMI, baseline LDL-C, TG and CRP in the full cohort. *p<0.05 and ns=p>0.05 for variance comparison for SD and RSME

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Supplemental Figure 2.

Mathematical demonstration of the effect of a negative correlation between the LDL reduction of two drugs on the final variance of LDL reduction induced by the combination of the two drugs.

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Problem: How to calculate the variance of a combination of variables that are negatively correlated? Let us define X as random variables for the LDL reduction by statins amongst a series of individuals (values = X1, X2, X3… , with mean = Xm and variance =V(X)) and Y as a random variable for the LDL

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reduction by ezetimibe amongst the same series of individuals (values = Y1, Y2, Y3… , with mean = Ym and variance = V(Y)). Let us assume that Y correlates to X by a negative correlation: Y = a + bX (with b = negative coefficient).

Solution : The variance of “X + Y” can be calculated as followed : Let < Z > denote the population mean (expected value or a long run average) of the variable Z. Then, Xm = < X >; Ym = < Y >; Var(X) = < (X - Xm)² > Assume, Y = a + bX, b < 0.

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Notice, < X + Y > = < X > + < Y > = a + (1 + b)Xm Then, Var(X+Y) = < (X+Y - < X+Y >)² > = < (a+(1+b)X-a-(1+b)Xm)² > = (1+b)² Var(X)

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So Var(X + Y ) ≤ Var(X) if and only if -1 ≤ b ≤ 0