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Tolerability of Red Yeast Rice (2,400 mg Twice Daily) Versus Pravastatin (20 mg Twice Daily) in Patients With Previous Statin Intolerance

Published:November 30, 2009DOI:https://doi.org/10.1016/j.amjcard.2009.08.672
      Currently, no consensus has been reached regarding the management of hyperlipidemia in patients who develop statin-associated myalgia (SAM). Many statin-intolerant patients use alternative lipid-lowering therapies, including red yeast rice. The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia. The study was conducted in a community-based setting in Philadelphia, Pennsylvania. A total of 43 adults with dyslipidemia and a history of statin discontinuation because of myalgia were randomly assigned to red yeast rice 2,400 mg twice daily or pravastatin 20 mg twice daily for 12 weeks. All subjects were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcomes included the incidence of treatment discontinuation because of myalgia and a daily pain severity score. The secondary outcomes were muscle strength and plasma lipids. The incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.
      In patients with a history of statin-associated myalgia (SAM), muscle symptoms often recur when another statin drug is initiated.
      • Thompson P.D.
      • Clarkson P.
      • Karas R.H.
      Statin-associated myopathy.
      Because no definitive approach has been determined for treating patients with recurrent SAM, many patients seek complementary or alternative therapies to manage their dyslipidemia. One such treatment is red yeast rice, a popular lipid-lowering dietary supplement that contains low levels of statin-like metabolites, including monacolin K (lovastatin).
      • Li Y.G.
      • Zhang F.
      • Wang Z.T.
      • Hu Z.B.
      Identification and chemical profiling of monacolins in red yeast rice using high-performance liquid chromatography with photodiode array detector and mass spectrometry.
      • Ma J.
      • Li Y.
      • Ye Q.
      • Li J.
      • Hua Y.
      • Ju D.
      • Zhang D.
      • Cooper R.
      • Chang M.
      Constituents of red yeast rice, a traditional Chinese food and medicine.
      Consumer spending on red yeast rice grew nearly 80% from 2005 to 2008 in the United States, with sales of $20 million in 2008.
      Studies in the United States and China have documented the lipid-lowering efficacy of red yeast rice.
      • Becker D.J.
      • Gordon R.Y.
      • Morris P.B.
      • Yorko J.
      • Gordon Y.J.
      • Li M.
      • Iqbal N.
      Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial.
      • Heber D.
      • Yip I.
      • Ashley J.M.
      • Elashoff D.A.
      • Elashoff R.M.
      • Go V.L.
      Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.
      • Lu Z.
      • Kou W.
      • Du B.
      • Wu Y.
      • Zhao S.
      • Brusco O.A.
      • Morgan J.M.
      • Capuzzi D.M.
      • Li S.
      Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.
      • Becker D.J.
      • Gordon J.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast rice versus placebo in dyslipidemic, statin-intolerant patients enrolled in a therapeutic lifestyle program: a randomized, controlled trial.
      In a previous placebo-controlled study, we demonstrated that 93% of subjects with a history of SAM were able to tolerate red yeast rice for 24 weeks without a recurrence of myalgia.
      • Becker D.J.
      • Gordon J.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast rice versus placebo in dyslipidemic, statin-intolerant patients enrolled in a therapeutic lifestyle program: a randomized, controlled trial.
      However, no trials have addressed whether red yeast rice is associated with a reduced incidence of myalgia compared to statin therapy. The primary goal of the present study was to compare the effect of red yeast rice versus pravastatin on the rate of myalgia recurrence in subjects with a history of SAM.

      Methods

      This study was conducted from January to September 2008 in a community-based setting in the Philadelphia, PA area (trial registration at clinicaltrials.gov, identifier NCT00639223). The institutional review boards at the University of Pennsylvania and Chestnut Hill Hospitals approved the study. All participants provided written informed consent. The subjects were recruited from preventive cardiology clinics at University of Pennsylvania and Thomas Jefferson University Hospitals, and 2 suburban Philadelphia cardiology practices. The subjects were eligible if they had had previous, documented SAM leading to discontinuation of at least one statin other than pravastatin, with resolution of myalgia after discontinuation. The exclusion criteria included statin or red yeast rice use during the month before randomization, a history of statin-associated myositis or rhabdomyolysis, a history of generalized chronic pain, the use of medications that inhibit cytochrome P450 CYP3A4, the use of dietary supplements that could mitigate SAM or lower lipids, abnormal baseline laboratory values (creatine phosphokinase >500 U/L, triglycerides ≥400 mg/dl, aspartate aminotransferase or alanine aminotransferase >2.5 times normal, serum creatinine >2 mg/dl, thyroid-stimulating hormone >4.5 μU/ml), and pregnancy.
      Eligible participants were randomized to receive red yeast rice 4,800 mg daily (four 600-mg capsules twice daily; Sylvan Bioproducts, Kittanning, Pennsylvania) or pravastatin 40 mg/day (1 overencapsulated 20-mg tablet to appear identical to the red yeast rice capsules and 3 identical-appearing placebo capsules twice daily) for 12 weeks. A sample of red yeast rice was independently analyzed for chemical composition (Eurofins Scientific, Petaluma, California; Table 1). An investigational new drug application for using red yeast rice in the present trial was approved by the Food and Drug Administration. Adherence to the study medication was determined by pill counts of the returned study medication every 4 weeks. The mean adherence to pravastatin and red yeast rice (excluding dropouts and subjects who withdrew from medication) was 97% and 93%, respectively (p = 0.10). To ensure that both groups received identical lifestyle education, all participants attended weekly 3.5-hour sessions of a therapeutic lifestyle change program
      • Becker D.J.
      • Gordon R.Y.
      • Morris P.B.
      • Yorko J.
      • Gordon Y.J.
      • Li M.
      • Iqbal N.
      Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial.
      (see Appendix [on-line only]). Attendance at these meetings averaged 83%, with no significant difference in attendance between the 2 groups.
      Table 1Chemical analysis of red yeast rice (600 mg/capsule)
      Performed by Eurofins Scientific, Inc., Petaluma, California.
      Two bottles of 120 capsules/bottle (600 mg/capsule) were sent for analysis; manufactured by Sylvan Bioproducts, Inc., Kittanning, Pennsylvania.
      ComponentQuantity
      Active monacolins
       Monacolin K (lovastatin) (mg/capsule)1.245
       Monacolin KA (mg/capsule)0.54
      Potential contaminants
      All microbial counts were less than the detectable levels.
       Citrinin (ppb)<10
       Arsenic (mg/kg)0.21
       Lead (mg/kg)0.06
       Cadmium (mg/kg)0.03
       Mercury (mg/kg)<0.01
      low asterisk Performed by Eurofins Scientific, Inc., Petaluma, California.
      Two bottles of 120 capsules/bottle (600 mg/capsule) were sent for analysis; manufactured by Sylvan Bioproducts, Inc., Kittanning, Pennsylvania.
      All microbial counts were less than the detectable levels.
      The primary outcome of the present study was the rate of withdrawal from treatment because of intolerable muscle symptoms. The co-primary outcome was the daily pain severity score measured using one question adapted from the Brief Pain Inventory
      • Keller S.
      • Bann C.M.
      • Dodd S.L.
      • Schein J.
      • Mendoza T.R.
      • Cleeland C.S.
      Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain.
      regarding the average pain during the past 24 hours (on a 0 to 10 scale). Participants rated both nonmyalgic and myalgic pain using this scale. The same blinded physician reviewed these pain scales weekly. If the subjects reported intolerable myalgia, their study treatment was discontinued, but all planned measurements were obtained. Isometric hip flexor muscle strength was determined by the same blinded physical therapist at baseline and every 4 weeks using a standard protocol with a hand-held dynamometer (model 01163, Lafayette Industries, Lafayette, Indiana). The hand-held dynamometer has a high correlation (0.91) with isokinetic muscle testing and is useful in comparing serial muscle strength tests.
      • Martin H.J.
      • Yule V.
      • Syddall H.E.
      • Dennison E.M.
      • Cooper C.
      • Aihie S.A.
      Is hand-held dynamometry useful for the measurement of quadriceps strength in older people? A comparison with the gold standard Bodex dynamometry.
      A fasting blood sample was obtained at baseline and week 12 to determine the low-density lipoprotein (LDL) cholesterol, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, and thyroid-stimulating hormone (baseline only) levels. Analyses were performed by the Hospital of the University of Pennsylvania.
      Adherence to the dietary recommendations was assessed by collecting two 24-hour diet recalls
      • Thomson C.A.
      • Giuliano A.
      • Rock C.L.
      • Ritenbaugh C.K.
      • Flatt S.W.
      • Faerber S.
      • Newman V.
      • Caan B.
      • Graver E.
      • Hartz V.
      • Whitacre R.
      • Parker F.
      • Piece J.P.
      • Marshall J.R.
      Measuring dietary change in a diet intervention trial: comparing food frequency questionnaire and dietary recalls.
      (1 weekend day and 1 weekday) at baseline and week 12. Blinded, trained staff collected the dietary survey by telephone interview, with data collection centralized at the Penn State Department of Nutritional Sciences (University Park, Pennsylvania). The dietary intake data were analyzed using Nutrition Data System, version 2007 (Nutrition Coordinating Center, Minneapolis, Minnesota). Physical activity was assessed using the Paffenbarger Physical Activity Questionnaire at baseline and week 12. This validated, reliable, self-administered questionnaire quantifies the number of kilocalories subjects expend per week in sports, leisure, and recreational activities.
      • Paffenbarger Jr, R.S.
      • Hyde R.T.
      • Wing A.L.
      • Hsieh C.C.
      Physical activity, all-cause mortality, and longevity of college alumni.
      The subjects were randomized to the study medication in blocks of 4. Although all participants had a history of myalgia with at least one statin drug, many had previously been challenged with other statins. Therefore, the randomization was stratified into 3 groups: those who had not developed myalgia on challenge with a different statin, those who had developed intolerable myalgia with all previous statin challenges, and those who had never been challenged with another statin drug. The randomization sequence was computer-generated using a randomization program available on the Internet (www.randomization.com)
      • Dallal G.
      Randomization.com.
      with the fixed block option. All subjects and study team members were kept unaware of treatment allocation throughout the 12-week study. To assess blinding, the participants guessed their treatment allocation at the end of the study; 37% of those taking pravastatin and 67% of those taking red yeast rice guessed their treatment assignment correctly.
      Sample size calculations were performed on the basis of the 7% rate of intolerable myalgias seen with red yeast rice in our previous study
      • Becker D.J.
      • Gordon J.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast rice versus placebo in dyslipidemic, statin-intolerant patients enrolled in a therapeutic lifestyle program: a randomized, controlled trial.
      and rates of approximately 50% reported in the published data
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
      with a statin rechallenge, assuming a 20% dropout rate. According to these rates, a sample size of 20 to 22 subjects per group would provide 80% power to detect a difference of 40% between the 2 groups for intolerable myalgic symptoms, with α = 0.05. All primary analyses were conducted using the intention-to-treat approach. We compared the incidence of withdrawal from the study medication because of intolerable myalgia between the 2 groups using Fisher's exact test. A linear regression model was used to compare the difference between the treatment groups in the mean Brief Pain Inventory pain severity score, defined as the maximum reported score for myalgic and nonmyalgic pain during each day. The robust variance estimator was used to adjust the standard error estimates for correlation due to repeated measurements.
      • Liang K.-Y.
      • Zeger S.L.
      Longitudinal data analysis using generalized linear models.
      Missing pain scores were treated as missing, because only 2 subjects (dropouts) had missing data (<5%). A linear mixed-effects model was used to analyze hip flexor strength at baseline and weeks 4, 8, and 12. The covariates in the models for pain and muscle strength included stratification assignment,
      • Simon R.
      Patient subsets and variation in therapeutic efficacy.
      age, baseline thyroid-stimulating hormone level, and baseline physical activity. A secondary analysis was performed to assess the differences between groups in the occurrence of myalgic pain during the intervention period. For participants who reported myalgic pain, we created dichotomous outcomes, defined a priori, indicating whether the subjects had persistent myalgia starting after >2 weeks of study treatment and of ≥1 week's duration. Comparisons between treatment groups were made using Fisher's exact tests.
      To evaluate treatment efficacy, descriptive statistics were computed for LDL cholesterol, total cholesterol, HDL cholesterol, and triglycerides at baseline and week 12. Linear regression models quantified the differences in the mean LDL cholesterol, total cholesterol, HDL cholesterol, and triglycerides at week 12 across the treatment groups. Each model was adjusted for its respective baseline lipoprotein measure and baseline body mass index. To assess the adherence to the therapeutic lifestyle change program, we compared the mean percentage of change from baseline to week 12 across the treatment groups for the following outcomes using 2-sample t tests: total energy intake, total fat, saturated fat, percentage of energy from fat, fiber, weight, and total kilocalories expended per week. Safety parameters, including liver-associated enzymes and creatine phosphokinase, were analyzed for differences between the 2 groups using 2-sample t tests. The differences in the adverse event rates were compared between treatment groups using Fisher's exact tests. Statistical analyses were performed using Stata version 9.2 (StataCorp, College Station, Texas). All comparisons were 2-tailed, and the level of significance was set at p = 0.05.

      Results

      During a 3-month period, 180 patients with a history of SAM completed the screening. Of those, 54 met the eligibility criteria and 43 agreed to participate (Figure 1). The red yeast rice and pravastatin groups had similar baseline characteristics (Table 2). The incidence of treatment discontinuation because of myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). Of the 21 subjects in the red yeast rice group and 22 in the pravastatin group, 14 (67%) and 15 (68%) reported pain at some point during the study period. Figure 2 displays the maximum pain severity scores for each subject and the average trend for each treatment group during the study period. In the linear regression analysis that was controlled for stratification assignment, age, and baseline thyroid-stimulating hormone level, no significant difference was found between the 2 treatment groups in the mean pain severity score. The estimated difference in the mean pain severity score between the 2 groups was 0.02 (95% confidence interval [CI] −0.12 to 0.15; p = 0.81). Also, in the linear mixed-effects model for hip flexor strength, adjusted for stratification assignment and age, no difference was found in the mean strength scores between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). Figure 3 displays the mean and 95% CIs for muscle strength at baseline and weeks 4, 8, and 12 for the red yeast rice and pravastatin groups. In a secondary analysis of myalgic pain (Table 3), the reports of myalgia were fewer in the red yeast rice group.
      Figure thumbnail gr1
      Figure 1Participant flow through study. *Primary end point. Those with missing data were included in analysis of primary outcome. MI = myocardial infarction; MVA = motor vehicle accident; SAM = statin-associated myalgia; TLC = therapeutic lifestyle program.
      Table 2Baseline characteristics of study participants
      CharacteristicRed Yeast Rice (n = 21)Pravastatin (n = 22)p Value
      Mean age (years)62.4 ± 8.962.9 ± 6.60.87
      Women16 (76%)16 (73%)0.80
      Mean No. of statins not tolerated1.3 ± 0.51.5 ± 0.60.27
      Statin drug not tolerated
       Atorvastatin16 (76%)
      Numbers in each column may not sum to the total number of subjects because some subjects received >1 statin.
      15 (68%)
      Numbers in each column may not sum to the total number of subjects because some subjects received >1 statin.
      0.57
       Simvastatin9 (43%)14 (64%)0.17
       Rosuvastatin2 (10%)4 (18%)0.41
       Lovastatin1 (5%)2 (9%)0.58
      Interval to onset of statin-related myalgia <12 weeks
      Subject had a history of the development of myalgias within 12 weeks of any previous statin challenge.
      15 (79%)
      Of 19 patients total.
      18 (90%)
      Of 20 patients total.
      0.34
      Family history of statin-related myalgia0.19
       Yes5 (24%)1 (5%)
       Unknown1 (5%)1 (5%)
      Education0.27
       High school or less2 (10%)7 (32%)
       Some college5 (25%)5 (23%)
       College graduate9 (45%)5 (23%)
       Postgraduate4 (20%)5 (23%)
      Medical history
       Essential hypertension8 (38%)14 (64%)0.09
       Coronary artery disease3 (14%)3 (14%)0.95
       Diabetes mellitus2 (10%)5 (23%)0.24
       Hypothyroid6 (29%)3 (14%)0.23
       Local arthritis5 (24%)6 (27%)0.80
       Low back pain5 (24%)5 (23%)0.93
      Mean body mass index (kg/m2)0.21
       18.5–24.82 (10%)2 (9%)
       25–29.910 (48%)5 (23%)
       >309 (43%)15 (68%)
      Mean blood pressure (mm Hg)
       Systolic127.9 ± 11.5133 ± 17.70.27
       Diastolic77.8 ± 6.179.5 ± 8.90.46
      Mean fasting glucose (mg/dl)98.1 ± 26.296.8 ± 26.60.87
      Mean creatine phosphokinase (U/L)124.3 ± 61.7125.1 ± 72.50.97
      Mean thyroid-stimulating hormone (μU/ml)1.32 ± 0.71.33 ± 0.90.99
      Mean baseline energy expenditure (kcal/wk)1,368.2 ± 1,536.51,074.5 ± 1,034.40.77
      Mean weight (kg)81.9 ± 21.296.3 ± 30.40.15
      Mean Brief Pain Inventory score
      Scores on Brief Pain Inventory range from 0(no pain) to 10(worst pain imaginable); score represents average pain during previous 24 hours reported at baseline.
      1.4 ± 1.91.1 ± 1.50.82
      Data are presented as mean ± SD or numbers (%).
      low asterisk Numbers in each column may not sum to the total number of subjects because some subjects received >1 statin.
      Subject had a history of the development of myalgias within 12 weeks of any previous statin challenge.
      Of 19 patients total.
      § Of 20 patients total.
      Scores on Brief Pain Inventory range from 0 (no pain) to 10 (worst pain imaginable); score represents average pain during previous 24 hours reported at baseline.
      Figure thumbnail gr2
      Figure 2Individual maximum pain severity scores (solid lines) and average trend (dashed line) during study period for each treatment group. Individual trajectories and average trend plots were obtained using scatterplot smoother.
      Figure thumbnail gr3
      Figure 3Point estimates and 95% CIs for mean muscle strength and mean LDL cholesterol for pravastatin group (white) and red yeast rice group (black).
      Table 3Descriptive analysis of myalgic pain from Brief Pain Inventory scores
      Outcome MeasureRed Yeast Rice (n = 21)Pravastatin (n = 22)p Value
      n (%)95% CIn (%)95% CI
      Persistent myalgia only
      Persistent myalgia defined as persistent myalgia starting after ≥2 weeks of study treatment and of ≥1 week's duration.
       Generalized myalgia
      Bilateral myalgia in major muscle groups.
      03 (13.6%)0–70.23
       Local myalgia
      Unilateral myalgia in a major muscle group.
      2 (9.5%)1–91 (4.6%)0–60.60
       Combined local and generalized myalgia2 (9.5%)0–54 (18.1%)0–80.66
      Persistent and intermittent myalgia
      Persistent and intermittent myalgia includes any myalgia reported during the study regardless of duration.
       Generalized myalgia1 (4.8%)0–36 (27.3%)2–100.10
       Local myalgia4 (19.1%)1–83 (13.6%)0–60.70
       Combined local and generalized myalgia5 (23.8%)1–98 (36.4%)
      Total did not sum to total number in column because 1 subject reported both local and generalized myalgia.
      4–120.51
      low asterisk Persistent myalgia defined as persistent myalgia starting after ≥2 weeks of study treatment and of ≥1 week's duration.
      Bilateral myalgia in major muscle groups.
      Unilateral myalgia in a major muscle group.
      § Persistent and intermittent myalgia includes any myalgia reported during the study regardless of duration.
      Total did not sum to total number in column because 1 subject reported both local and generalized myalgia.
      The descriptive statistics for the lipid outcome measurements are listed in Table 4. Figure 3 displays the mean and 95% CIs for LDL cholesterol at baseline and week 12 for both treatment groups. In the linear regression models adjusted for baseline lipoprotein measure and body mass index, no significant differences were found between the 2 groups in the mean LDL cholesterol (−10.7 mg/dl, 95% CI −27.2 to 5.7; p = 0.194) total cholesterol (−9.6 mg/dl, 95% CI −25.9 to 6.6; p = 0.23), triglycerides (0.5 mg/dl, 95% CI −21.2 to 22.3; p = 0.96), or HDL cholesterol (−2.5 mg/dl, 95% CI −5.7 to 0.63; p = 0.114).
      Table 4Descriptive analysis of secondary outcome measures between groups at baseline and week 12
      Outcome MeasureRed Yeast RicePravastatin
      Patients (n)Mean ± SDPatients (n)Mean ± SD
      Low-density lipoprotein cholesterol (mg/dl)
       Baseline21181.2 ± 38.922163.6 ± 32.7
       12 weeks17126.1 ± 37.622120.3 ± 38.7
       Mean percentage of change−30.2 ± 10.5−27.0 ± 15.4
      Total cholesterol (mg/dl)
       Baseline21260.7 ± 41.522253.4 ± 40.4
       12 weeks17200.9 ± 41.722198.6 ± 44.9
       Mean percentage of change−23.0 ± 7.3−19.6 ± 11.0
      High-density lipoprotein cholesterol (mg/dl)
       Baseline2151.1 ± 16.62253.1 ± 16.7
       12 weeks1750.8 ± 14.72253.0 ± 16.9
       Mean percentage change−3.8 ± 9.00.2 ± 8.7
      Triglyceride (mg/dl)
       Baseline21142.2 ± 78.922148.4 ± 65.0
       12 weeks17120.9 ± 68.422126.1 ± 45.4
       Mean percentage change−7.8 ± 30.5−7.0 ± 32.2
      Hip flexor strength (kg)
       Baseline2120.1 ± 4.32220.4 ± 5.2
       4 weeks2020.8 ± 6.32120.5 ± 4.9
       8 weeks1819.7 ± 5.31920.3 ± 4.4
       12 weeks1820.7 ± 5.42220.6 ± 5.2
      No significant differences were found between the red rice yeast group and the pravastatin group in the percentage of change from baseline to week 12 in any measure of adherence to the lifestyle change program (Table 5). The incidence of treatment discontinuation owing to all adverse events (including myalgia) was 10% (2 of 21) in the red yeast rice group and 18% (4 of 22) in the pravastatin group (p = 0.66). No statistically significant differences were found between the 2 groups in the incidence of adverse events (Table 6) or in mean values of safety measures at week 12.
      Table 5Changes in selected dietary measures and physical activity between groups at baseline and week 12
      Red Yeast RicePravastatinp Value
      From 2-sample t tests for mean percentage of change in each outcome from baseline to week 12; no statistically significant differences found in baseline variables between the 2 groups.
      BaselineWeek 12Mean Change (%)BaselineWeek 12Mean Change (%)
      Energy (kcal/day)1,650.1 ± 671.81,310.6 ± 474.4−10.31,727.5 ± 630.51,564.4 ± 693.0−7.40.76
      Fat (g/d)54.3 ± 30.536.7 ± 18.8−17.568.5 ± 33.852.0 ± 30.5−21.10.73
      Calories from fat (%)28.0 ± 7.224.0 ± 6.3−9.634.7 ± 7.028.8 ± 7.5−16.50.30
      Saturated fat (g/day)18.5 ± 14.110.6 ± 5.8)−23.522.0 ± 10.415.3 ± 13.2−30.10.57
      Fiber (g/day)18.5 ± 9.821.7 ± 10.3)23.417.0 ± 6.919.7 ± 8.137.70.55
      Weight (kg)81.9 ± 21.276.9 ± 19.0)−2.296.3 ± 30.495.0 ± 30.4−1.40.45
      Energy expenditure (kcal/wk)1,368.2 ± 1,536. 42,009.5 ± 1,596. 4237.91,074.5 ± 1,034.41,510.1 ± 1,015.3171.70.49
      low asterisk From 2-sample t tests for mean percentage of change in each outcome from baseline to week 12; no statistically significant differences found in baseline variables between the 2 groups.
      Table 6Nonmyalgic adverse events
      SymptomRed Yeast Rice (n = 21)Pravastatin (n = 22)
      Muscular weakness11
      Abdominal gas, bloating20
      Alopecia20
      Arthralgia11
      Back pain56
      Diarrhea20
      Dizziness02
      Dyspepsia10
      Fatigue03
      Fracture, extremity10
      Headache22
      Motor coordination decreased, L hand01

      Discussion

      This is the first randomized, double-blind trial comparing the tolerability of red yeast rice to a statin drug in a population with SAM. Our results showed that red yeast rice was as well tolerated as pravastatin in patients with a history of SAM. Both treatments were associated with a low incidence of treatment discontinuation because of myalgia, no evidence of muscle weakness, and a similar level of LDL cholesterol reduction.
      Few studies have evaluated the rates of myalgia on statin rechallenge in patients with statin intolerance. Depending on the definition of myopathic events used in these studies, the reported incidence of myalgia recurrence has varied from 0% to 57%.
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
      • Hansen K.E.
      • Hildebrand J.P.
      • Ferguson E.E.
      • Stein J.H.
      Outcomes in 45 patients with statin-associated myopathy.
      • Backes J.M.
      • Moriarty P.M.
      • Ruisinger J.F.
      • Gibson C.A.
      Effects of once weekly rosuvastatin among patients with a prior statin intolerance.
      • Gadarla M.
      • Kearns A.K.
      • Thompson P.D.
      Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins.
      • Backes J.M.
      • Venero C.V.
      • Gibson C.A.
      • Ruisinger J.F.
      • Howard P.A.
      • Thompson P.D.
      • Moriarty P.M.
      Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance.
      • Glueck C.J.
      • Aregawi D.
      • Agloria M.
      • Khalil Q.
      • Winiarska M.
      • Munjal J.
      • Gogineni S.
      • Wang P.
      Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
      • Stein E.A.
      • Ballantyne C.M.
      • Windler E.
      • Simes P.A.
      • Sussekov A.
      • Yigit Z.
      • Seper C.
      • Gimpelewicz C.R.
      Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins.
      • Mackie B.D.
      • Satija S.
      • Nell C.
      • Miller J.
      • Sperling L.S.
      Monday, Wednesday and Friday dosing of rosuvastatin in patients previously intolerant to statin therapy.
      The lack of a well-defined and consistently applied outcome measure for SAM has contributed to the conflicting results. Our trial used a validated measure of pain severity and a specific definition of recurrent myalgia to address this methodologic issue.
      Our results have shown that both the red yeast rice and the pravastatin groups had very low rates of recurrent myalgia. The 12-week therapeutic lifestyle program intervention, which emphasized improved nutrition (increasing dietary omega-3 fatty acids and plant-based antioxidants), regular exercise, and relaxation methods, might have had positive effects on muscle function and pain perception in both groups. The 5% rate of recurrent intolerable myalgia from red yeast rice is consistent with the results from our earlier study showing a 7% incidence of this end point.
      • Becker D.J.
      • Gordon J.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast rice versus placebo in dyslipidemic, statin-intolerant patients enrolled in a therapeutic lifestyle program: a randomized, controlled trial.
      Because the risk of SAM is known to increase with higher doses of statins,
      • Thompson P.D.
      • Clarkson P.
      • Karas R.H.
      Statin-associated myopathy.
      • Jacobson T.A.
      Statin safety: lessons from new drug applications for marketed statins.
      this low rate might have been due to the reduced quantities of monacolin K (lovastatin <10 mg/day in this study) in red yeast rice.
      • Li Z.
      • Seeram N.P.
      • Lee R.
      • Thames G.
      • Minutti C.
      • Wang H.J.
      • Heber D.
      Plasma clearance of lovastatin versus Chinese red yeast rice in healthy volunteers.
      In addition, red yeast rice contains 13 other monacolins
      • Li Y.G.
      • Zhang F.
      • Wang Z.T.
      • Hu Z.B.
      Identification and chemical profiling of monacolins in red yeast rice using high-performance liquid chromatography with photodiode array detector and mass spectrometry.
      that might act synergistically to lower LDL cholesterol but have less myotoxicity.
      Although both groups reported low rates of recurrent myalgia, we were unable to demonstrate a significantly reduced incidence with red yeast rice compared to pravastatin. Possible explanations for this include that the published 50% myalgia recurrence rate for statins used in our power calculation was overestimated; the true recurrence rates for both treatments were not detected in our small, short-term study; pravastatin might have a lower recurrence rate compared to other statins owing to its hydrophilic properties
      • Thompson P.D.
      • Clarkson P.M.
      • Rosenson R.S.
      An assessment of statin safety by muscle experts.
      ; and the 40 mg/day dose of pravastatin used in the present study might have been low enough to be well-tolerated.
      Although the comparison of our primary outcome of drug discontinuation owing to intolerable myalgia showed no between-group differences, we also conducted an exploratory analysis of the rates of recurrent myalgia reported as persistent and generalized. This pattern of myalgic pain is most consistent with the clinical descriptions of SAM.
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
      • Franc S.
      • Dejager S.
      • Bruckert E.
      • Chauvenet M.
      • Giral P.
      • Turpin G.
      A comprehensive description of muscle symptoms associated with lipid-lowering drugs.
      In the latter analysis, an absolute risk reduction of 14% was found in favor of red yeast rice compared to pravastatin that we believe deserves additional investigation.
      The limitations of our study included the small sample size and short duration. Although recurrent SAM typically occurs soon after the initiation of statin therapy, ∼30% of patients can report the onset of myalgias later than 12 weeks.
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
      Also, one should not generalize our results using a rigorously analyzed red yeast rice product to other widely available red yeast rice formulations sold as food supplements. The potency differs among various products and contamination with citrinin (a potential nephrotoxin) has been reported.
      • Heber D.
      • Lembertas A.
      • Lu Q.Y.
      • Bowerman S.
      • Go V.L.
      An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents.
      Finally, no inferences could be made about the long-term effects of red yeast rice on cardiovascular morbidity or mortality from the present trial, which was limited to the tolerability of therapy and lipid-lowering effects.
      Statin-associated myalgia is an important clinical problem that will likely become more prevalent owing to the ever-expanding indications for statin use. Although no definitive conclusions could be drawn, our data showed that the red yeast rice was as well tolerated as pravastatin and achieved similar and clinically significant levels of LDL cholesterol reduction in a population with previous statin intolerance.

      Acknowledgment

      We thank Greg Fromell, MD, Executive Director of the Office of Human Research at the University of Pennsylvania School of Medicine for his help with critical revisions of the Investigational New Drug application. We are grateful to David Margolis, MD, PhD, for his participation on the Data Safety Monitoring Committee, and to Kenneth Rockwell, PharmD, MS, for technical support.

      Supplementary Data

      References

        • Thompson P.D.
        • Clarkson P.
        • Karas R.H.
        Statin-associated myopathy.
        JAMA. 2003; 289: 1681-1690
        • Li Y.G.
        • Zhang F.
        • Wang Z.T.
        • Hu Z.B.
        Identification and chemical profiling of monacolins in red yeast rice using high-performance liquid chromatography with photodiode array detector and mass spectrometry.
        J Pharm Biomed Anal. 2004; 35: 1101-1112
        • Ma J.
        • Li Y.
        • Ye Q.
        • Li J.
        • Hua Y.
        • Ju D.
        • Zhang D.
        • Cooper R.
        • Chang M.
        Constituents of red yeast rice, a traditional Chinese food and medicine.
        J Agric Food Chem. 2000; 48: 5220-5225
      1. Supplement Business Report 2009. Nutrition Business Journal, Boulder, CO2009: 44
        • Becker D.J.
        • Gordon R.Y.
        • Morris P.B.
        • Yorko J.
        • Gordon Y.J.
        • Li M.
        • Iqbal N.
        Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial.
        Mayo Clin Proc. 2008; 83: 758-764
        • Heber D.
        • Yip I.
        • Ashley J.M.
        • Elashoff D.A.
        • Elashoff R.M.
        • Go V.L.
        Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.
        Am J Clin Nutr. 1999; 69: 231-236
        • Lu Z.
        • Kou W.
        • Du B.
        • Wu Y.
        • Zhao S.
        • Brusco O.A.
        • Morgan J.M.
        • Capuzzi D.M.
        • Li S.
        Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.
        Am J Cardiol. 2008; 101: 1689-1693
        • Becker D.J.
        • Gordon J.
        • Halbert S.C.
        • French B.
        • Morris P.B.
        • Rader D.J.
        Red yeast rice versus placebo in dyslipidemic, statin-intolerant patients enrolled in a therapeutic lifestyle program: a randomized, controlled trial.
        Ann Intern Med. 2009; 150: 830-839
        • Keller S.
        • Bann C.M.
        • Dodd S.L.
        • Schein J.
        • Mendoza T.R.
        • Cleeland C.S.
        Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain.
        Clin J Pain. 2004; 20: 309-318
        • Martin H.J.
        • Yule V.
        • Syddall H.E.
        • Dennison E.M.
        • Cooper C.
        • Aihie S.A.
        Is hand-held dynamometry useful for the measurement of quadriceps strength in older people?.
        Gerontology. 2006; 52: 154-159
        • Thomson C.A.
        • Giuliano A.
        • Rock C.L.
        • Ritenbaugh C.K.
        • Flatt S.W.
        • Faerber S.
        • Newman V.
        • Caan B.
        • Graver E.
        • Hartz V.
        • Whitacre R.
        • Parker F.
        • Piece J.P.
        • Marshall J.R.
        Measuring dietary change in a diet intervention trial: comparing food frequency questionnaire and dietary recalls.
        Am J Epidemiol. 2003; 157: 754-762
        • Paffenbarger Jr, R.S.
        • Hyde R.T.
        • Wing A.L.
        • Hsieh C.C.
        Physical activity, all-cause mortality, and longevity of college alumni.
        N Engl J Med. 1986; 314: 605-613
        • Dallal G.
        Randomization.com.
        (Accessed May 2, 2008)
        • Bruckert E.
        • Hayem G.
        • Dejager S.
        • Yau C.
        • Begaud B.
        Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.
        Cardiovasc Drugs Ther. 2005; 19: 403-414
        • Liang K.-Y.
        • Zeger S.L.
        Longitudinal data analysis using generalized linear models.
        Biometrika. 1986; 73: 13-22
        • Simon R.
        Patient subsets and variation in therapeutic efficacy.
        Br J Clin Pharmacol. 1982; 14: 473-482
        • Hansen K.E.
        • Hildebrand J.P.
        • Ferguson E.E.
        • Stein J.H.
        Outcomes in 45 patients with statin-associated myopathy.
        Arch Intern Med. 2005; 165: 2671-2676
        • Backes J.M.
        • Moriarty P.M.
        • Ruisinger J.F.
        • Gibson C.A.
        Effects of once weekly rosuvastatin among patients with a prior statin intolerance.
        Am J Cardiol. 2007; 100: 554-555
        • Gadarla M.
        • Kearns A.K.
        • Thompson P.D.
        Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins.
        Am J Cardiol. 2008; 101: 1747-1748
        • Backes J.M.
        • Venero C.V.
        • Gibson C.A.
        • Ruisinger J.F.
        • Howard P.A.
        • Thompson P.D.
        • Moriarty P.M.
        Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance.
        Ann Pharmacother. 2008; 42: 341-346
        • Glueck C.J.
        • Aregawi D.
        • Agloria M.
        • Khalil Q.
        • Winiarska M.
        • Munjal J.
        • Gogineni S.
        • Wang P.
        Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
        Clin Ther. 2006; 28: 933-942
        • Stein E.A.
        • Ballantyne C.M.
        • Windler E.
        • Simes P.A.
        • Sussekov A.
        • Yigit Z.
        • Seper C.
        • Gimpelewicz C.R.
        Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins.
        Am J Cardiol. 2008; 101: 490-496
        • Mackie B.D.
        • Satija S.
        • Nell C.
        • Miller J.
        • Sperling L.S.
        Monday, Wednesday and Friday dosing of rosuvastatin in patients previously intolerant to statin therapy.
        Am J Cardiol. 2007; 99: 291
        • Jacobson T.A.
        Statin safety: lessons from new drug applications for marketed statins.
        Am J Cardiol. 2006; 97: 44C-51C
        • Li Z.
        • Seeram N.P.
        • Lee R.
        • Thames G.
        • Minutti C.
        • Wang H.J.
        • Heber D.
        Plasma clearance of lovastatin versus Chinese red yeast rice in healthy volunteers.
        J Altern Complement Med. 2005; 11: 1031-1038
        • Thompson P.D.
        • Clarkson P.M.
        • Rosenson R.S.
        An assessment of statin safety by muscle experts.
        Am J Cardiol. 2006; 97: 69C-76C
        • Franc S.
        • Dejager S.
        • Bruckert E.
        • Chauvenet M.
        • Giral P.
        • Turpin G.
        A comprehensive description of muscle symptoms associated with lipid-lowering drugs.
        Cardiovasc Drugs Ther. 2003; 17: 459-465
        • Heber D.
        • Lembertas A.
        • Lu Q.Y.
        • Bowerman S.
        • Go V.L.
        An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents.
        J Altern Complement Med. 2001; 7: 133-139

      Linked Article

      • Red Yeast Rice and Statin-Intolerant Patients
        American Journal of CardiologyVol. 105Issue 10
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          We have read with attention and interest the report of Halbert et al1 recently published in The American Journal of Cardiology, as well as a previous report of the same research group published in the Annals of Internal Medicine2 concerning the tolerability of red yeast rice in statin-intolerant patients. The reported results are very similar to those already observed by our group in 48 patients intolerant to >1 statin, the last of which was prescribed in our lipid clinic, and followed for ≥12 months: only 4 patients (8.3%) dropped out of the study because of side effects (2 with asymptomatic increases in creatine phosphokinase >5 times the upper limit of normal, 1 with myalgia, and 1 with dyspepsia).
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