Statins are extensively used to treat dyslipidemia, but, because of their low tolerability profile, they are discontinued in a significant proportion of patients. Ezetimibe and nutraceuticals have been introduced as alternative therapies and have proved to be effective and well tolerated. A single-blind, single-center, randomized, prospective, and parallel group trial comparing a combination of nutraceuticals (red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin), called Armolipid Plus, and ezetimibe for 3 months in terms of efficacy and tolerability. Patients who did not achieve their therapeutic target (low-density lipoprotein cholesterol <100 mg/dl) could add the alternative treatment on top of randomized treatment for another 12 months: 100 patients who are dyslipidemic with ischemic heart disease treated with percutaneous coronary intervention were enrolled (ezetimibe n = 50, nutraceutical n = 50). Efficacy (lipid profile) and tolerability (adverse events, transaminases, and creatine kinase) were assessed after 3 and 12 months. After 3 months, 14 patients in the nutraceutical group achieved their therapeutic target, whereas none of the patients in the ezetimibe group did. At 1-year follow-up, 58 patients (72.5%) of the combined therapy group (n = 86) and 14 (100%) of the nutraceutical group reached the therapeutic goal. No patients experienced important undesirable effects. In conclusion, nutraceuticals alone or in combination with ezetimibe are well tolerated and improve the lipid profile in statin-intolerant patients with coronary heart disease. Further studies are needed to assess long-term effects of nutraceuticals on mortality.
Nutraceuticals are natural compounds derived from food, with cholesterol-lowering actions. Randomized trials have consistently shown that red yeast rice, which has the same structure as the drug lovastatin, reduces cholesterol levels in statin-intolerant patients. The lipid-lowering effects of berberine and other nutraceutical combinations have also been demonstrated. A randomized study found that a nutraceutical tablet containing red yeast rice and berberine was more effective and better tolerated than ezetimibe in subjects with familial hypercholesterolemia intolerant to statins. Also, in a prospective single-blind, placebo-controlled randomized study, we demonstrated that a commercially available product containing berberine and red yeast rice significantly reduced cholesterol levels in older patients who are hypercholesterolemic than patients placebo. The efficacy of nutraceuticals in ameliorating the lipid profile in statin-intolerant patients with coronary heart disease (CHD) has not been established. We conducted a 12-week randomized trial aimed at assessing the efficacy and tolerability of nutraceuticals versus ezetimibe, and in combination, in patients who are hypercholesterolemic with CHD and previous percutaneous coronary intervention (PCI) who were intolerant to statins and refused other drugs.
Methods
In this single-blind, single center, randomized, prospective, and parallel group trial we compared a nutraceutical combination with ezetimibe in terms of efficacy and tolerability, in statin-intolerant patients who are dyslipidemic treated with PCI ( Clinicaltrials.gov identifier: NCT01490229 ). The composition of the nutraceutical combination was as follows: berberine 500 mg, policosanol 10 mg, red yeast rice 200 mg, folic acid 0.2 mg, coenzyme Q10 2.0 mg, and astaxanthin 0.5 mg (Armolipid Plus; Rottapharm Srl, Italy). Armolipid Plus fulfills the European Union Good Manufacturing Practice requirements and is available, at present, in European countries only.
The study population included patients with CHD consecutively enrolled after PCI. Nonpharmacologic measures and standard medical therapy were prescribed after the procedure. Inclusion criteria were: (1) documented CHD treated with PCI; (2) high levels (>200 mg/dl) of total cholesterol (TC); (3) high levels (>160 mg/dl) of low-density lipoprotein cholesterol (LDL-C); and (4) statin intolerance and refusal of other treatments for hypercholesterolemia. Statin intolerance was defined as myalgia, that is, muscle complaints without serum creatine kinase (CK) elevations, myositis, that is, muscle symptoms with CK elevations, rhabdomyolysis, that is, CK levels >10 times the upper limit of normal with an elevated creatinine level consistent with pigment-induced nephropathy, or gastrointestinal disorders, that is, alanine aminotransferase or aspartate aminotransferase >2 times the upper limit of normal. Exclusion criteria included glomerular filtration rate of <30 mUmin/1.73 m 2 (on the basis of creatinine measured at the screening visit and calculated by a standard formula) and use of lipid-lowering therapy within 30 days preceding the initial study treatment.
Subjects were randomized into the trial when they satisfied all subject selection criteria. A computer-generated randomization schedule was used to assign subjects to treatment with the nutraceutical combination or ezetimibe according to a 1:1 ratio. Eligible patients were randomized to receive ezetimibe (10 mg/day) or the nutraceutical combination for 3 months. After 3 months, patients continued the assigned therapy only if the therapeutic goal (LDL-C <100 mg/dl) was reached. In case of LDL-C >100 mg/dl, conversely, the other therapy was added to the assigned one (i.e., nutraceuticals for patients on ezetimibe and vice versa) and the combination of the 2 therapies was continued until the end of the study.
At the baseline visit, after informed consent form had been signed, efficacy and safety investigations were performed, including physical examination, vital sign assessment, and laboratory blood tests (TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, transaminases and CK). All these examinations were repeated at 3-month and 12-month follow-up visits. The primary outcome was the achievement of therapeutic target (i.e., LDL-C <100 mg/dl). Secondary outcomes were effects on the lipid profile (changes in TC, LDL-C, HDL-C, and triglycerides) and treatment tolerability. In the event of an adverse event, subjects were counseled to stop taking the product permanently or temporarily. The study was carried out during routine clinical practice, after the international guidelines and in line with the principles outlined in the Declaration of Helsinki.
Data for continuous variables were expressed as mean values and SD; categorical data were expressed as number of patients and percentage. The Kolmogorov–Smirnov test for goodness of adaptation was used to verify distribution normality. On the basis of the results of the Kolmogorov–Smirnov test, statistical transformations were applied if needed. Baseline characteristics between groups at the start of the treatment were compared using the Student t Test for independent samples or chi-square test. The analyses of the treatment intragroup associated changes were performed using a series of repeated measures analysis of variance. A p value <0.05 was considered as statistically significant for all tests.
Results
One hundred patients were enrolled consecutively. Of this study population, 64% subjects had stable angina and 36% subjects had unstable angina. Fifty patients were randomized to receive ezetimibe and 50 patients to receive the nutraceutical combination.
Baseline clinical features and lipid profiles were similar between groups ( Table 1 ).
| Variable | Nutraceutical Combination (n=50) | Ezetimibe (n=50) | p-value |
|---|---|---|---|
| Male | 26 (52%) | 28 (56%) | 0.688 |
| Age (years) | 64±11 | 63±10 | 0.772 |
| Diabetes mellitus | 15 (30%) | 18 (36%) | 0.523 |
| Hypertension | 22 (44%) | 20 (40%) | 0.685 |
| Smoker | 15 (30%) | 13 (26%) | 0.656 |
| Total cholesterol (mg/dl) | 218± 15 | 219±14 | 0.836 |
| Low-density lipoprotein cholesterol (mg/dl) | 149±16 | 150±8 | 0.600 |
| High-density lipoprotein cholesterol (mg/dl) | 36±8 | 34±7 | 0.337 |
| Triglycerides (mg/dl) | 166±31 | 171±25 | 0.381 |
| Ejection fraction (%) | 54±8 | 55±11 | 0.815 |
At 3-month visit, the 2 groups differed for LDL-C, TC, and triglycerides, with lower levels in the nutraceutical combination group than in the ezetimibe group (all <0.0001): The 2 groups differed also for HDL-C, with higher levels in the nutraceutical combination group than in the ezetimibe group (p = 0.02; Table 2 ). In particular, no patient of the ezetimibe group achieved the therapeutic target of LDL-C <100 mg/dl, whereas 14 patients (28%) in the nutraceutical combination group reached this target ( Table 3 ). Thus, all the 50 patients of the ezetimibe group plus 36 patients of the nutraceutical combination group added the other therapy on top of the one they had been randomized to.
| Variable | Nutraceutical Combination (n=50) | Ezetimibe (n=50) | p-value |
|---|---|---|---|
| Total cholesterol (mg/dl) | 177±12 | 194±16 | <0.0001 |
| Low-density lipoprotein cholesterol (mg/dl) | 109±8 | 126±11 | <0.0001 |
| High-density lipoprotein cholesterol (mg/dl) | 39±8 | 36±7 | 0.0203 |
| Triglycerides (mg/dl) | 144±25 | 163±26 | 0.0003 |
| Variable | Nutraceutical combination (n=14) | p-value | Emetizibe plus Nutraceuticals (n=86) | p-value | ||||
|---|---|---|---|---|---|---|---|---|
| Base-line | 3 months | 12 months | Base-line | 3 months | 12 months | |||
| Total cholesterol (mg/dl) | 205±11 | 165±7 | 163±7 | <0.0001 | 189±15 | 166±12 | 164±13 | <0.0001 |
| Low-density lipoprotein cholesterol (mg/dl) | 136±6 | 98±3 | 95±3 | <0.0001 | 120±11 | 97±9 | 95±10 | <0.0001 |
| High-density lipoprotein cholesterol (mg/dl) | 36±8 | 39±7 | 40±7 | <0.0001 | 37±8 | 41±8 | 41±8 | <0.0001 |
| Triglycerides (mg/dl) | 161±22 | 139±20 | 140±21 | <0.0001 | 157±27 | 142±22 | 140±21 | <0.0001 |
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