Mcpbecker

Simvastatin vs Therapeutic Lifestyle Changes and Supplements:
Randomized Primary Prevention Trial
DAVID J. BECKER, MD; RAM Y. GORDON, MD; PATTI B. MORRIS, RD; JACQUELINE YORKO, MED; Y. JEROLD GORDON, MD; MINGYAO LI, PHD; AND NAYYAR IQBAL, MD, MSCE OBJECTIVE: To compare the lipid-lowering effects of an alternative We have used a combination of fish oil and red yeast regimen (lifestyle changes, red yeast rice, and fish oil) with a rice (RYR) as an alternative regimen for hyperlipidemia.
standard dose of a 3-hydroxy-3-methylglutaryl coenzyme A reduc-tase inhibitor (statin).
This regimen is nonprescription, is readily available, and PATIENTS AND METHODS: This randomized trial enrolled 74 pa- seems to be tolerated with few adverse effects. However, tients with hypercholesterolemia who met Adult Treatment Panel to date, no data show a benefit to patients.
III criteria for primary prevention using statin therapy. All partici- The primary purpose of this study was to test whether an pants were randomized to an alternative treatment group (AG) orto receive simvastatin (40 mg/d) in this open-label trial con- “alternative” regimen reduced serum low-density lipopro- ducted between April 1, 2006, and June 30, 2006. The alternative tein cholesterol (LDL-C) in a primary prevention popula- treatment included therapeutic lifestyle changes, ingestion of red tion. Specifically, the efficacy and safety of RYR, fish oil, yeast rice, and fish oil supplements for 12 weeks. The simvastatingroup received medication and traditional counseling. The primary and therapeutic lifestyle changes (alternative regimen) was outcome measure was the percentage change in low-density lipo- compared to those of a standard dose of a cholesterol- protein cholesterol (LDL-C). Secondary measures were changes in lowering agent (simvastatin, 40 mg/d) and traditional diet RESULTS: There was a statistically significant reduction in LDL-Clevels in both the AG (–42.4%±15%) (P<.001) and the simvastatingroup (–39.6%±20%) (P<.001). No significant differences were noted between groups. The AG also demonstrated significantreductions in triglycerides (–29% vs –9.3%; 95% confidence inter- Patients were recruited from a cardiology practice in sub- val, –61 to –11.7; P=.003) and weight (–5.5% vs –0.4%; 95%confidence interval, –5.5 to –3.4; P<.001) compared with the urban Philadelphia, PA. The trial was approved by the Institutional Review Board of Chestnut Hill Healthcare, CONCLUSION: Lifestyle changes combined with ingestion of red and written informed consent was obtained from all par- yeast rice and fish oil reduced LDL-C in proportions similar to ticipants. All authors had complete access to the primary standard therapy with simvastatin. Pending confirmation in larger trials, this multifactorial, alternative approach to lipid loweringhas promise for a subset of patients unwilling or unable to take Men and women aged 18 to 80 years with known or newly detected hypercholesterolemia were eligible for en- Trial Registration: clinicaltrials.gov identifier: NCT0042 rollment if they met the Adult Treatment Panel III guide- lines.8 Inclusion criteria included baseline LDL-C of 130mg/dL or more (to convert to mmol/L, multiply by 0.0259) AG = alternative treatment group; CI = confidence interval; CK = and 2 or more cardiovascular risk factors or baseline LDL- creatine kinase; HDL-C = high-density lipoprotein cholesterol; LDL-C =low-density lipoprotein cholesterol; RYR = red yeast rice; TC = total C between 160 and 210 mg/dL for patients with no or 1 risk factor. Risk factors included age (men >45 years or women>55 years or postmenopausal), hypertension requiring Overwhelming scientific evidence shows that 3-hy- medical treatment, high-density lipoprotein cholesterol droxy-3-methylglutaryl coenzyme A reductase in- (HDL-C) less than 40 mg/dL, current cigarette smoking, hibitors (statins) are beneficial to patients for primary pre-vention of coronary artery disease.1 Although the safety of From the Division of Cardiology, Chestnut Hill Hospital, University of Pennsyl- these medications is established,2 adherence can be trouble- vania Health System, Philadelphia (D.J.B., R.Y.G., P.B.M., J.Y.); Departmentof Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA some. As many as 40% of patients who receive a prescrip- (Y.J.G.); Department of Biostatistics and Epidemiology, University of Pennsyl- tion for a statin are thought to take it for less than 1 year.3,4 vania School of Medicine, Philadelphia (M.L.); and Division of Endocrinology,Philadelphia VA Medical Center/University of Pennsylvania, Philadelphia Possible reasons include the cost of these medications, adverse effects, poor explanations of their benefits by phy- This study was sponsored by an unrestricted grant from the State of sicians, and patients’ reluctance to take prescription or long-term medications.5 It is difficult to estimate the num- Address reprint requests and correspondence to David J. Becker, MD, 1722 ber of patients who seek alternative therapies to statins, and Bethlehem Pike, Flourtown, PA 19095 (dbeckerchcardiology@hotmail.com).
most do not discuss this choice with their physicians.6,7 2008 Mayo Foundation for Medical Education and Research
Mayo Clin Proc. • July 2008;83(7):758-764 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Pr a Two bottles of 200 capsules/bottle were sent for analysis.
13 Excluded 11 LDL-C <130 mg/dLa 2 Abnormal LFT results phase. Before the trial began, 3 patients dropped out of thesimvastatin group, and 2 patients dropped out of the alterna- tive treatment group (AG). Of the 79 patients randomized,74 were included in the analysis. By using a computer- generated simple randomization list, patients were allocated to either the simvastatin group or the AG. Men and women were separately randomized to ensure equal numbers in both groups. The study was conducted between April 1, 2006, andJune 30, 2006. No patients were lost to follow-up.
Group 1 patients received simvastatin (40 mg/d) and traditional counseling regarding diet and exercise in theform of preprinted material. These handouts were based onAmerican Heart Association diet and lifestyle recommen-dations. Group 2 received fish oil and RYR supplements.
The fish oil (Res-Q 1250; N3 Oceanic, Palm, PA) was
purchased directly from the manufacturer, and each patienttook 3 capsules twice daily (Table 1). The RYR (Res-QLDL-X, 600-mg [by weight] capsules, N3 Oceanic) was FIGURE. Flow of participants through trial. LDL-C = low-density lipo- also purchased directly from the manufacturer. Each cap- protein cholesterol; LFT = liver function test.
a SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259.
sule had a total monacolin content of 5.3 mg, of which 2.53mg was monacolin K (lovastatin) (Table 2). Two strengths diabetes mellitus, or family history of premature coronary of RYR were used. If the initial LDL-C measurement was higher than 160 mg/dL, a total dose of 3.6 g was given in 2 Exclusion criteria included known coronary artery dis- divided doses. If the initial LDL-C measurement was 160 ease or a procedure to treat such disease (angina pectoris, mg/dL or less, a total dose of 2.4 g was given in 2 divided myocardial infarction, percutaneous transluminal angio- doses. No other medications were adjusted other than dis- plasty, or coronary artery bypass grafting), triglyceride (TG) continuation of prestudy statin therapy.
levels at baseline testing higher than 400 mg/dL, use of Group 2 patients were also enrolled in a 12-week warfarin, severe liver or kidney disease, an orthopedic condi- multidisciplinary lifestyle program that involved weekly tion that would prevent aerobic exercise, or other systemic 31/2-hour meetings. The group was taught about the impor- tance of lifestyle changes by a board-certified cardiologist.
Participants learned about coronary plaque formation, pre- ventive measures, and standard cardiac testing techniques.
The flow of participants through the trial is shown in the In addition to the cardiologist, the team consisted of a Figure. Patients were recruited between December 1, 2005, dietitian, exercise physiologist, and several alternative or and March 31, 2006. Of the 227 eligible patients, 135 met relaxation practitioners. A certified dietitian taught basic the initial screening criteria but chose not to participate.
principles of nutrition and encouraged the group to follow a Ninety-two patients signed the informed consent form and Mediterranean diet that was modified by reducing satu- were screened. Thirteen patients failed screening, most rated fat and by limiting total fat to less than 25% of daily because LDL-C levels were less than 130 mg/dL. A total of caloric intake. Sugars and simple carbohydrates were re- 79 patients were eligible to be randomized to the treatment stricted, and participants were taught how to count calories, Mayo Clin Proc. • July 2008;83(7):758-764 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Pr (www.consumerlab.com, White Plains, NY). We provided the testing facility with 400 capsules of fish oil and 360 capsules of RYR. The commercial laboratory ran- domly selected 20 capsules of each product, made this sample into a single composite, and then analyzed the composite for total content of each chemical. The results were then calculated and reported to us on a per capsule basis (Tables 1 and 2). Variability estimates for these samples based on how the facility performed its analysis The fish oil capsules were assessed by gas chromatogra- phy. The RYR was tested for its amount of individual and total monacolins by high-performance liquid chromatogra- phy. Citrinin was analyzed using thin-layer chromatogra- a Three bottles of 120 capsules/bottle were sent for analysis.
phy. The identity of the products was not disclosed to thelaboratory that performed the testing.
although there was no formal caloric restriction. An exer- cise physiologist instructed the group to gradually increase The primary end point was percentage change of LDL-C exercise to 5 to 6 times per week. Aerobic exercise was from baseline levels. A sample of 35 patients was required encouraged and included walking, swimming, or jogging for each group for an 80% power and an α level of .05 to for 30 to 45 minutes at a time. Patients in this group were detect a 20% difference in the percentage change between exposed to relaxation methods including yoga and tai chi.
Adherence to the program was documented by the Statistical analyses included mean ± SD of baseline study coordinators at the weekly meetings. Patients in characteristics by treatment group, a between–treatment both treatment groups received a 30-day supply of medi- group comparison at baseline, a within–treatment group cation at each of 3 monthly visits, and pill counts were comparison for the percentage change from baseline, and a performed to ascertain adherence. Although the 2 groups between–treatment group comparison for the percentage ran concurrently, there was no contact between them dur- change from baseline for all variables. The between–treat- ment group comparison at baseline was performed using a2-sample t test, and the within–treatment group comparison at baseline and at week 12 was performed using a 1-sample The primary efficacy parameter was percentage change t test. Multiple linear regression, with treatment group in- from baseline levels of LDL-C. The secondary parameters cluded as a factor and adjusting for baseline weight, was included percentage change from baseline levels of HDL-C used for between–treatment group comparison. Analyses and TG at 12 weeks. A fasting blood sample was drawn were performed using SAS software, version 9.2 (SAS from all study participants for lipid profile, liver function Institute, Cary, NC). All tests were 2-sided; P<.05 was tests, and creatine kinase (CK) levels at baseline and at the considered statistically significant.
end of the study (week 12). If patients in either group experi-enced severe muscle pain during the study, CK level was obtained, and supplements or simvastatin was withheld for 2days until the laboratory result was available. The dose of simvastatin or RYR was halved if patients continued to Baseline characteristics of patients randomized to each experience symptoms but had a normal CK level.
group are shown in Table 3. There were 20 women and 17men in each treatment group. Fifteen patients (41%) in the simvastatin group and 12 patients (32%) in the AG were Serum laboratory analyses were performed by Laboratory receiving a statin (which was stopped at least 30 days Corporation of America (LabCorp, Burlington, NC). The before initial blood testing and randomization) before the lipid panel (total cholesterol [TC], LDL-C, HDL-C, and TG) study. The mean age was 55.9±8.4 years in the AG and and serum glucose levels were determined enzymatically.
59.3±9.6 years in the simvastatin group. No statistically Laboratory analysis of the fish oil (Table 1) and RYR significant differences between the baseline groups were capsules (Table 2) was performed by ConsumerLab apparent other than borderline significance of weights. The Mayo Clin Proc. • July 2008;83(7):758-764 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Pr TABLE 3. Baseline Characteristics by Treatment Groupa EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS Table 4 shows the changes from baseline in the 2 treatment groups. Weight decreased by 4.7±2.4 kg (–5.5%) in the AG (P<.001) and by 0.3±2.2 kg (–0.4%) in the simvastatin group (P=.42). Mean difference between the 2 groups was –4.4 kg (95% CI, –5.5 to –3.4 kg; P<.001). Body mass index also decreased significantly more in the AG than in the simvastatin group (95% CI, –1.9 to –1.2; P<.001). No significant differences in systolic blood pressure (95% CI, –7.0 to 7.2 mm Hg; P=.59), diastolic blood pressure (95% CI, –6.1 to 4.0 mm Hg; P=.89) or fasting glucose (95% CI, –11.2 to 5.2 mg/dL; P=.57) appeared between the groups.
In the AG, all lipid values except HDL-C declined sig- nificantly from baseline. (TC, –78.5±32.6 mg/dL [–32.4%±11.8%]; P<.001; LDL-C, –66.8±28.9 mg/dL [–42.4%±14.8%]; P<.001; and TG, –50.8±65.1 mg/dL a Data are expressed as mean ± SD unless otherwise indicated. LDL-C = [–29.2%±36.3%]; P<.001) In the simvastatin group, all lipid low-density lipoprotein cholesterol; HDL-C = high-density lipoproteincholesterol.
values except HDL-C declined significantly from base- b Calculated as the weight in kilograms divided by the height in meters line (TC, –66.5±36.8 mg/dL [–27.3%±14.9%]; P<.001; LDL-C, –63.7±33.5 mg/dL [–39.6%±20.2%; P<.001; TG, SI conversion factor: To convert glucose value to mmol/L, multiply by –14.4±37.8 mg/dL; –9.3%±30.9%; P=.03). The HDL-C d SI conversion factor: To convert cholesterol values to mmol/L, multiply level decreased 2.9±9.7 mg/dL (–4.3%±16.3%; P=.08) in by 0.0259; to convert triglyceride value to mmol/L, multiply by 0.0113.
the AG and increased 0.4±6.3 mg/dL (+1.4%±11.0%;P=.70) in the simvastatin group. The difference between mean weight in the AG was 87.7±15.5 kg, and in the groups was not statistically significant (95% CI, –7.1 to simvastatin group, 80.8±14.6 kg (95% confidence interval [CI], –0.1 to 14.0; P=.05). Because of this difference, we Between-group analysis revealed a reduction in LDL-C adjusted for baseline weight when comparing the lipid, of 3.1 mg/dL greater in the AG than in the simvastatin blood pressure, and glucose levels after treatment in the AG group that was not statistically significant (95% CI, –17.6 to 11.4; P=.59). There was also no significant difference in TABLE 4. Change of Variables From Baseline by Treatment Groupa a Data are expressed as mean ± SD unless otherwise indicated. LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol.
b Calculated as the weight in kilograms divided by the height in meters squared.
c Groups are compared by adjusting for baseline weight.
d SI conversion factor: To convert glucose value to mmol/L, multiply by 0.055.
e SI conversion factor: To convert cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride value to mmol/L, multiply by 0.0113.
Mayo Clin Proc. • July 2008;83(7):758-764 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Pr the ratio of TC to HDL-C (95% CI, –0.5 to 0.4; P=.73).
garlic, and guggulipids.10-15 If these results are confirmed in However, there was a significant decrease in TG in the AG larger trials, the regimen used in this trial (although de- compared with the simvastatin group, with a mean differ- manding in terms of commitment and cost) could offer an ence between groups of –36.4 mg/dL (95% CI, –61.1 to option for patients who refuse therapy with statins.
Red yeast rice, also called hong qu, is a Chinese herbal medication first described in the Tang Dynasty in 800 AD. It is made by fermenting the yeast Monascus purpureus over Adherence was excellent, and there were no dropouts in red rice and is both a garnish for food and a traditional either arm. Average attendance of study participants was medication. Red yeast rice contains naturally occurring 90% at each of the lifestyle sessions, and adherence and lovastatin and 9 different substances called monacolins that adverse effects were reported to the study coordinator us- could inhibit 3-hydroxy-3-methylglutaryl coenzyme A re- ing standard adverse reporting forms.
ductase. Results of the current study support findings fromprevious studies with RYR that demonstrated a positive effect.15-17 The dose of RYR in our study (2.4-3.6 g/d) was In the simvastatin group, 3 patients experienced muscu- equivalent to a daily lovastatin dose of 10 to 15 mg (Table 2), loskeletal symptoms. One completed the protocol, taking less than the established therapeutic dose (20-40 mg).16 40 mg of simvastatin daily until the end of the study. Two Fish oil has been reported to decrease the risk of death, patients stopped their simvastatin regimen for 3 days, per cardiac death, and coronary events in patients who have protocol. Their CK levels were normal, and they completed had myocardial infarction.17,18 It might have an antiarrhyth- the study taking 20 mg/d. One patient had transaminase mic effect,19 and recent reviews have shown no increased elevations that were more than 2 times the upper limit of risk of bleeding.20,21 The TG-lowering effects of fish oil normal on the 12-week blood sample and reported general- have been established22 and could be responsible for the ized fatigue but completed the protocol.
results observed in the current study. Weight loss could In the AG, one patient had a baseline CK level of 232 U/L, also have contributed to the significantly lower TG levels which increased to 1532 U/L on routine testing at the completion of the study. He was completely asymptomatic, Lifestyle changes (eg, Mediterranean diet,24,25 exer- was engaged in vigorous exercise the night before his cise,26 and weight loss27,28), an important aspect of the cur- blood test, and was taking 3 capsules of RYR twice daily.
rent trial, are likely multifactorial and have been shown to After the study was completed, medication and exercise reduce the risk of recurrent cardiac events. In our study, were stopped, and his CK level returned to normal. Two blood pressure decreased significantly in both groups. This patients noted heartburn that resolved when they were effect was expected in the AG, which lost weight and switched to equivalent doses of a liquid form of fish oil engaged in exercise, but was somewhat unexpected in the (ResQ 1250 liquid) from the same manufacturer.
simvastatin group, which was randomized to usual care. Arecent review suggested that statins have a beneficial effecton blood pressure, although the mechanism is unknown.29 Limitations of the current trial include brief course (12 The primary purpose of this clinical trial was to compare weeks), single site, unblinded (design precluded effective the effects of an alternative regimen (a combination of masking), and limited scope. The design of the trial also RYR, fish oil, and therapeutic lifestyle changes) with the prevented delineation of the relative contribution of each effects of a standard dose of a statin and traditional diet and component of the alternative therapy. Thus, we were un- exercise counseling on LDL-C levels. We observed a simi- able to evaluate the lipid-lowering effects of the therapeutic lar reduction in serum LDL-C levels in both groups. Mem- lifestyle changes alone, without the supplements. Larger bers of the AG also had a substantial reduction in TG and future studies should address these issues. Nevertheless, lost more weight. The ratio of TC to HDL-C decreased the study was randomized, had no dropouts, had excellent equally in both groups. Finally, the HDL-C decreased in adherence in both groups, and yielded statistically signifi- the AG and increased slightly in the simvastatin group, but cant changes in unambiguous outcome measures—serum this difference was not statistically significant.
LDL-C levels and weight loss. Additional concerns in the Last year, 18.9% of US adults used natural products AG included elevated CK values in 1 asymptomatic patient with unproven efficacy,9 many taken without their physi- (attributed to vigorous exercise,30 the statinlike properties cian’s knowledge or consent. Alternative therapies for hy- of RYR, and their enhanced effect in combination31,32) and perlipidemia that have been studied and remain contro- the possible HDL-C–lowering effects of RYR. We ex- versial include policosanol, chromium, eggplant extract, pected the HDL-C to increase in the AG because members Mayo Clin Proc. • July 2008;83(7):758-764 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Pr adopted an exercise program. The unexpected, but not compared with simvastatin, we have no evidence that our statistically significant, reduction in HDL-C levels could regimen will lead to a reduction in cardiovascular events.
be partially explained by the diet followed by our patients The recent Effect of Combination Ezetimibe and High-Dose that was low in saturated fats.33,34 The decrease in HDL-C Simvastatin vs Simvastatin Alone on the Atherosclerotic levels could have been related to the supplements. Despite Process in Patients with Heterozygous Familial Hypercho- the small decrease in HDL-C levels, the ratio of TC to HDL- lesterolemia (ENHANCE) trial showed that size of reduc- C (an excellent index of cardiac risk)35-37 decreased equally tions in LDL-C levels was not necessarily associated with rate of progression in vascular disease.45 Our small, short- Our study was designed to test a comprehensive and term study did not and could not evaluate reduction in car- holistic approach to lipid lowering. The excellent adher- diovascular morbidity and mortality, which is clearly the ence in the AG was undoubtedly related to the intensive follow-up, education, and support provided for thisgroup. Long-term adherence to the alternative regimen remains to be determined, but previous studies involvingdiet and exercise have unfortunately found a high rate of In this single-center, small, randomized study, RYR and fish oil (when taken with a commitment to make lifestyle Another possible limitation of the study is the legal changes) had LDL-C lowering effects similar to those of a status of RYR as an herbal supplement. In 2001, the US standard dose of simvastatin. In addition, the lifestyle Food and Drug Administration determined that the RYR modification arm showed significant reductions in TG and product Cholestin was a drug, not a dietary supplement, weight. These results are intriguing and show a potential and asked companies to reformulate products to remove benefit of an alternative, or naturopathic, approach to a RYR.41 In fact, since completion of the current study, N3 common medical condition, hyperlipidemia. A larger, Oceanic has replaced the RYR in Res-Q LDL-X with a multicenter trial with longer follow-up is necessary, and “phytosterol ester complex and policosanol.” Policosanol the effects on cardiovascular outcomes will need to be was recently found to be no better than placebo in reducing established in the future. The risks of this alternative therapy need to be balanced against a possible therapeutic However, RYR remains widely available in stores and benefit for a subset of motivated patients who are willing to on the Internet. Although the chemical composition of adopt strict lifestyle changes and take over-the-counter RYR was known and controlled in the current study, com- position of various products and the batch consistencybetween lots from the same source make recommending unregulated supplements difficult. Heber et al42 found 1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protec-
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