The Effect of Adding Plant Sterols or Stanols to StatinTherapy in Hypercholesterolemic Patients: SystematicReview and Meta-Analysis Jennifer M. Scholle, BS, William L. Baker, PharmD, BCPS, Ripple Talati, PharmD, Craig I. Coleman, PharmD University of Connecticut School of Pharmacy, Storrs (J.M.S., R.T., C.I.C.), Department of Drug Information, Hartford Hospital,Hartford (W.L.B., R.T.), Connecticut Key words: phytosterols, statins, hypercholesterolemia, meta-analysis Objective: To characterize the effect of plant sterols/stanols on serum lipids in hypercholesterolemic patients on concurrent statin therapy, we conducted a meta-analysis of randomized controlled trials.
Methods: A systematic literature search of MEDLINE, EMBASE, Cochrane CENTRAL, and the Natural Medicines Comprehensive Database was conducted from the earliest possible date through May 2008. Trials were included in the analysis if they were randomized controlled trials evaluating the use of plant sterols/stanols in combination with statins in hypercholesterolemic patients that reported efficacy data on total cholesterol, low- density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides. The weighted mean difference (WMD) of the change from baseline (in mg/dL) with 95% confidence interval (CI) was calculated as the difference between the mean in the plant sterol/stanol groups and the control groups, using Results: Eight studies (n 5 306 patients) met the inclusion criteria. Upon meta-analysis, the use of plant sterols/stanols in combination with statin therapy significantly lowered total cholesterol (WMD, 214.01 mg/dL [95% CI, 218.66 to 29.37], p , 0.0001) and LDL cholesterol (WMD, 213.26 mg/dL [95% CI, 217.34 to 29.18], p , 0.0001) but not HDL cholesterol or triglycerides.
Conclusions: Based upon the current literature, we can only say that plant sterols/stanols, when administered in addition to statins, favorably affect total and LDL cholesterol with 95% confidence.
Randomized trials examining the impact of plant sterols/stanols in combinatation with statins on patient creasing intake of viscous soluble fiber ($5–10 g/day) and plant sterols or stanols (2 g/day) to help achieve treatment Elevated serum lipids, including total cholesterol, low- density lipoprotein (LDL) cholesterol, and triglycerides, as Plant sterols and stanols are plant steroids with a chemical well as decreased high-density lipoprotein (HDL) cholesterol structure and cellular function similar to that of human are associated with an increased risk for the development of cholesterol. Plant sterols and stanols have lower bioavailability coronary heart disease (CHD) [1]. The National Cholesterol than dietary cholesterol and can displace cholesterol from Education Program (NCEP) Adult Treatment Panel (ATP) III mixed micelles in the intestine, reducing the absorption of guidelines recommend a number of dietary modifications such as decreasing the intake of saturated fat (,7% of daily A previous meta-analysis of randomized trials evaluated the calories) and dietary cholesterol (,200 mg/day) while in- ability of foods containing plant sterols or stanols to alter Address correspondence to: Craig I. Coleman, PharmD, Assistant Professor of Pharmacy Practice, University of Connecticut School of Pharmacy, and Director,Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102-5037. E-mail: ccolema@harthosp.org Financial Disclosures: We certify that none of the material in this manuscript has been previously published. The study was not funded and we have no conflicts to declaregermane to this manuscript.
Abbreviations: CI 5 confidence interval, HDL 5 high-density lipoprotein, LDL 5 low-density lipoprotein, WMD 5 weighted mean difference.
Journal of the American College of Nutrition, Vol. 28, No. 5, 517–524 (2009)Published by the American College of Nutrition serum lipid levels [3]. The meta-analysis found that foods allows for the effect of the previous therapy to dissipate, the containing plant sterols or stanols were able to reduce LDL effects of the newer therapy to manifest, and patients to reach cholesterol by a mean of 6.7% at doses of 0.7–1.1 g/day and by new steady-state lipid levels. We included trials individually as much as 11.3% at doses $2.5 g/day.
evaluating multiple treatment arms by including each pairwise Until recently, there was a paucity of data evaluating plant comparison separately, but with the repeated placebo groups’ sterols or stanols in combination with a 3-hydroxy-3- sample size divided out evenly among the comparisons. Three methylglutaryl coenzyme A reductase inhibitor (statin) in investigators (J.M.S., R.T., C.I.C.) reviewed potentially hypercholesterolemic patients. As many patients are already relevant articles independently and abstracted necessary data, receiving statins to reduce LDL cholesterol, but are not with differences resolved through discussion. When applica- achieving NCEP goals, it is important to better quantify the ble, efforts were made to contact investigators for clarification additional LDL cholesterol–lowering benefit achieved with adjuvant plant sterol or stanol ingestion.
The mean change in lipid parameters from baseline was Therefore, we performed a meta-analysis of randomized treated as a continuous variable and the weighted mean controlled trials of plant sterols or stanols in combination with difference (WMD) was calculated as the difference between statins to better characterize their impact on serum lipids in the mean in the plant sterol/stanol and control groups. Accepted statistical methods were used to impute change scores as suggested by Follmann and colleagues [6]. We conducted subgroup analyses to determine whether plant stanols or sterols had differing effects on lipid parameters and whether the use of concomitant dietary modification affected plant sterol/stanol A systematic literature search of MEDLINE, EMBASE, efficacy. We also conducted sensitivity analyses to assess Cochrane CENTRAL, and the Natural Medicines Comprehen- whether study design characteristics or the inclusion of a study sive Database was conducted from the earliest possible date enrolling patients with familial hypercholesterolemia had an through May 2008. A search strategy was performed using the effect on our results. A DerSimonian and Laird random-effects Medical Subject Headings and the following text key words: model was used to calculate the WMD and 95% confidence sterol, stanol, sitosterol, sitostanol, beta-sitosterol, beta-sitos- intervals (CIs) [7]. Statistical heterogeneity was addressed using tanol, phytosterol, phytostanol, stanol ester, sterol ester and the I2 statistic. Visual inspection of funnel plots and Egger’s simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin, weighted regression statistics were used to assess for the lovastatin, rosuvastatin, statin, HMG-CoA reductase inhibitor, presence of publication bias. Statistics were performed using hydroxymethylglutaryl coenzyme A reductase inhibitor, and 3- StatsDirect, version 2.5.8 (StatsDirect, Cheshire, England).
hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in combination with lipids, cholesterol, hypercholesterolemia, hypercholesterolemic, hyperlipidemia, hyperlipidemic, low- density lipoproteins, high-density lipoproteins, LDL, HDL, and triglycerides. For our MEDLINE search, we used the Cochrane Collaboration’s Highly Sensitive Search Strategy sensitivity- A total of eight randomized controlled trials (n 5 306 maximizing version [4]. The McMaster University Health patients) met all inclusion criteria [8–15]. All 8 trials [8–15] Information Research Unit search strategy was used for the reported useable data for total and LDL cholesterol while 7 EMBASE search [5]. No language restrictions were imposed.
trials [8–12,14,15] reported useable data for HDL cholesterol In addition, a manual search of references from primary or and triglycerides (Fig. 1). All trials enrolled patients with mild- review articles was performed to identify relevant trials.
to-moderate hypercholesterolemia and randomized them to be Trials were included in the analysis if they were treated with either plant sterol/stanol (dosing range: 1.8–6 g/ randomized controlled trials evaluating the use of plant sterols day) or control for a period of 4–14 weeks (Table 1). Five or stanols in combination with statins in hypercholesterolemic trials were double-blinded [8,9,11–13], one single-blinded patients that reported efficacy data (suitable for calculation of [10], one open-label [15], and one was unclear in reporting the change from baseline) on at least one of the following lipid extent of blinding [14]. Five were parallel trials [9–11,13,15] endpoints: (1) total cholesterol, (2) LDL cholesterol, (3) HDL and 3 were crossover trials [8,12,14]. Only 4 studies required cholesterol, or (4) triglycerides. Both parallel and crossover patients to undergo concurrent dietary modification trials were eligible for inclusion. To be included, crossover [8,11,12,15]. The use or absence of use of dietary modification studies needed to have at least a 2-week washout period or, if was similar between plant sterol/stanol– and control-treated the washout was shorter or absent, needed to measure lipid patients in each trial; however, one trial provided what levels at least 4 weeks after therapies had been switched. This appeared to be more intensive dietary counseling to the plant Fig. 1. QUOROM flow diagram of study identification, inclusion, and exclusion.
sterol/stanol group compared to the control group, although no right of the composite effect line may not have been included dietary modification was mandated in either group [10].
Manufacturers of plant sterol/stanol products funded 2 trials Subgroup and sensitivity analyses are presented in Table 2.
[12,13]; research foundations funded 4 trials [8,9,11,14], an No noteworthy changes in our meta-analysis’ conclusions were academic institution funded 1 trial [10] and one did not state the Upon meta-analysis, the use of plant sterol or stanols added Our meta-analysis of 8 randomized controlled trials [8–15] to statin therapy significantly lowered total cholesterol (WMD, evalutating the addition of plant sterols/stanols at doses of 1.7– 214.01 mg/dL [95% CI, 218.66 to 29.37], p , 0.0001) and 6 g/day to statin therapy in hypercholesterolemic patients LDL cholesterol (WMD, 213.26 mg/dL [95% CI, 217.34 to showed significant lowering of both total cholesterol (14 mg/ 29.18], p , 0.0001), but not HDL cholesterol or triglycerides dL) and LDL cholesterol (13 mg/dL) as compared with a statin (p . 0.10 for all) as compared with statin use alone (Fig. 2).
alone. No significant impact on either HDL cholesterol or No statistical heterogeneity was observed in any of the lipid triglycerides was seen. Subgroup analyses revealed no endpoint analyses (I2 5 0% for all).
significant difference in lipid lowering when plant sterols Review of funnel plots (not shown) and the Egger’s versus stanols were used or whether or not diet modification weighted regression statistic p values suggested a low potential was present. According to the NCEP ATP III 2004 update [16], for publication bias for the total cholesterol, LDL cholesterol, a 1-mg/dL decrease in LDL cholesterol reduces a patient’s and HDL cholesterol analyses (p . 0.31 for all). Both an relative risk of having a coronary event by approximately 1%.
asymmetrical funnel plot and the Egger’s p value (p 5 0.02) Thus, the LDL cholesterol reductions seen in our meta-analysis for triglycerides suggested a higher likelihood of publication with sterols/stanols above and beyond that achieved with bias. The funnel plot suggested that at least one study to the statins is likely clinically important.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Table 1. Characteristics of Included Randomized, Controlled Trials of Statins Plus Plant Sterols or Stanols in Patientswith Hypercholesterolemia a Presented as plant sterol and/or stanols value(s) at baseline; placebo value(s) at baseline.
b Diet modifications (or lack thereof) were applied equally to the plant sterol or stanols groups and placebo groups except for Cabezas et al. [10], where the stanol estergroup received ‘‘intensive dietary education’’ and the control group received only a ‘‘healthy eating’’ leaflet and answering of questions.
AHA 5 American Heart Association, HDL-C 5 high-density lipoprotein cholesterol, LDL-C 5 low-density lipoprotein cholesterol, MUFA 5 monounsaturated fatty acids, PUFA 5 polyunsaturated fatty acids, TC 5 total cholesterol, TG 5 triglycerides.
Unfortunately, many patients receiving statin therapy are synthesis of 38–53% is seen [18]. This increase in cholesterol not reaching the LDL cholesterol goals. Foley and colleagues biosynthesis may be attenutated by the concurrent use of a demonstrated that only 48% of patients reached their LDL statin [14]. Simons and colleagues showed that LDL cholesterol goal following initiation of a statin, and of those cholesterol reductions attributable to plant sterols were similar who required further dose titration, only an additional 14% when plant sterols were used either alone (,8%) or added to achieved their goals [17]. Thus, most patients may require statin therapy (,6%), suggesting an additive rather than either increased doses of their statin or additional drug therapy synergistic effect [19]. This reduction in LDL cholesterol is in an attempt to reach their goal. The addition of plant sterols similar to that seen by doubling the dose of a statin. The results and stanols to statin therapy may provide the additional of our meta-analysis support this theory, with additional cholesterol lowering needed to reach LDL cholesterol goals.
reductions in both total and LDL cholesterol seen when plant Plant sterols and stanols have been shown to alter serum sterols/stanols were added to existing statin therapy.
lipid levels by decreasing intestinal cholesterol absorption by A similar relationship is seen between ezetimibe and 26–36%; however, a compensatory increase in cholesterol statins. Similar to plant sterols/stanols, ezetimibe lowers Plant Sterol/Stanol Dosing and Dosage Form ,0.5 g/day plant sterol from control diet 280–300 mg/day cholesterol, ,30% fat, ,10% ,0.5 g/day plant sterol from control diet No change in habitual diet other than margarine stanol ester margarine (69% sitostanolester; 31% campestanol ester) containing 62% fat and no added plantstanol (Becel) AHA Heart Healthy Diet (cholesterol ,300 mg/ day, 25–35% fat, ,7% saturated fat, ,1%trans fat) Cholesterol ,300 mg/day, saturated fat ,10% content of 18 g and no added plant stanol No change in habitual diet other than margarine content of 18 g and no added plant stanol 3 g/day sitostanol margarine (228 mg/100 g No change in habitual diet other than margarine 1138 mg/100 g sitosterol, 11,400 mg/100 g Cholesterol-lowering diet as recommended by the European Atherosclerosis Society(reduction of total fat to ,30% of energy, ofwhich less than 1/3 is saturated) cholesterol by inhibiting cholesterol absorption within the supplement to lower cholesterol might be warranted [27].
brush border of the small intestine by approximately 54% Although plant sterols and stanols were only indirectly [20,21]. When added to prior statin therapy, ezetimibe lowers compared, we found that they had similar effects on lipid total cholesterol and LDL cholesterol by an additional 16% parameters, further supporting the preferential use of plant stanols over plant sterols. In addition, plant sterol and stanol Although not evaluated in our meta-analysis, a few safety use has been assoicated with decreases in carotenoids [3] (e.g., concerns may exist regarding the increased intake of plant beta-carotene) that may be associated with increased risk of sterols and stanols. Patients with inherited phytosterolemia CHD [28], although the true extent of this increased risk, if have a defect in intestinal cholesterol transport proteins, causing a hyperabsorption of plant sterols [23]. These patients There are some limitations of the meta-analysis. When are known to develop premature atherosclerosis and CHD due performing a meta-analysis, the potential for publication bias is to the increased absorption of plant sterols [24]. Further study always a concern. A visual inspection of our analyses funnel is need to determine whether there is a risk of atherosclerosis plot’s and Egger’s weighted regression statistics revealed a low in normal patients taking increased amounts of plant sterols level of publication bias for all endpoints with the exception of through dietary supplementation [25,26]. Since plant stanols triglycerides. Inspection of the funnel plot for triglyceride are absorbed into the bloodstream to a lesser extent than plant analysis suggests that a trial to the right of the effect line may sterols, the preferential use of plant stanols as a dietary exsist but is not included and therefore, our analyses may be JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Fig. 2. Forest plots depicting the effect of plant sterols or stanols on (A) total cholesterol, (B) low-density lipoprotein cholesterol, (C) high-density lipoprotein cholesterol, and (D) triglycerides. All results reported as weighted mean differences (in mg/dL) and 95% confidence intervals.
overestimating the effect of plant sterols and stanols on inclusion of crossover trials without adequate washout periods triglyceride levels. This potential bias is not overly concerning, may also be a limitation. To minimize the effect of insufficient since plant sterols and stanols did not seem to have a significant washout periods, we only included crossover trials that impact on triglyceride levels in the base-case analysis. The evaluated lipid levels after a minimum of 4 weeks to allow Table 2. Results of Meta-Analysis of Randomized Controlled Trials Evaluating Plant Sterols or Stanols in Addition to Statins inPatients with Hypercholesterolemiaa a A DerSimonian and Laird random-effects model was used in calculating the weighted mean difference and its 95% confidence interval (CI).
To convert values for cholesterol from mg/dL to mmol/L, multiply by 0.0286; to convert values for triglycerides from mg/dL to mmol/L, multiply by 0.01129.
HDL-C 5 high-density lipoprotein cholesterol, LDL-C 5 low-density lipoprotein cholesterol.
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