Usefulness of Nutraceuticals (Armolipid Plus) Versus Ezetimibe and Combination in Statin-Intolerant Patients With Dyslipidemia With Coronary Heart Disease

Accepted Manuscript Usefulness of Nutraceuticals (Armolipid Plus®) Versus Ezetimibe and Combination in Statin-Intolerant Dyslipidemia Patients with Coronary Heart Disease Giuseppe Marazzi, MD, PhD, Francesco Pelliccia, MD, PhD, Giuseppe Campolongo, MD, Silvia Quattrino, MD, Luca Cacciotti, MD, Maurizio Volterrani, MD, PhD, Carlo Gaudio, MD, Giuseppe Rosano, MD, PhD PII:

S0002-9149(15)02002-0

DOI:

10.1016/j.amjcard.2015.09.023

Reference:

AJC 21425

To appear in:

The American Journal of Cardiology

Received Date: 7 July 2015 Revised Date:

13 September 2015

Accepted Date: 15 September 2015

Please cite this article as: Marazzi G, Pelliccia F, Campolongo G, Quattrino S, Cacciotti L, Volterrani M, Gaudio C, Rosano G, Usefulness of Nutraceuticals (Armolipid Plus®) Versus Ezetimibe and Combination in Statin-Intolerant Dyslipidemia Patients with Coronary Heart Disease, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.09.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Usefulness of Nutraceuticals (Armolipid Plus®) Versus Ezetimibe and Combination in Statin-Intolerant Dyslipidemia

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Patients with Coronary Heart Disease

Giuseppe Marazzi, MD, PhDa,*, Francesco Pelliccia, MD, PhDb, Giuseppe Campolongo,

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MDa, Silvia Quattrino, MDa, Luca Cacciotti, MDc, Maurizio Volterrani, MD, PhDa, Carlo

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Gaudio, MDb, Giuseppe Rosano, MD, PhDa

a

IRCCS San Raffaele Pisana, Rome, Italy; bDepartment of Cardiovascular Sciences,

Sapienza University, Rome, Italy; cInstitute of Cardiology, Madre Giuseppina Vannini Hospital, Rome, Italy.

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Running title: Nutraceuticals in statin-intolerance

Corresponding author:

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Tel: (3906) 5225.1; fax: (3906) 99322931. E-mail address: [email protected]

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Abstract Statins are extensively used to treat dyslipidaemia, but, due to their low tolerability

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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. Single blind, single centre, randomised, prospective,

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parallel group trial comparing a combination of nutraceuticals (red yeast rice,

policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin), called Armolipid

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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 dyslipidemic patients with ischemic heart disease treated with percutaneous coronary intervention were enrolled (ezetimibe n=50, nutraceutical

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n=50). Efficacy (lipid profile) and tolerability (adverse events, transaminases, creatine kinase) were assessed after 3 and 12 months. After 3 months 14 patients in the

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nutraceutical group achieved their therapeutic target, whereas none of the patients in the exetinibe group did. At 1-year follow-up, 58 patients (72.5%) of the combined

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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 CHD. Further studies are needed to assess long-term effects of nutraceuticals on mortality. Key Words: Coronary heart disease; Nutraceuticals; Statin intolerance.

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Nutraceuticals are natural compounds derived from food, with cholesterol lowering actions.1 Randomized trials have consistently shown that red yeast rice, which has the

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same structure as the drug lovastatin,2 reduces cholesterol levels in statin-intolerant patients.3-7 The lipid-lowering effects of berberine and other nutraceutical combinations have also been demonstrated.8-11 A randomized study found that a nutraceutical tablet

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containing red yeast rice and berberine was more effective and better tolerated than ezetimibe in subjects with familial hypercholesterolemia intolerant to statins.12 Also, in a

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prospective single-blind, placebo-controlled randomised study,13 we demonstrated that a commercially available product containing berberine and red yeast rice significantly reduced cholesterol levels in older hypercholesterolemic patients compared to 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

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randomized trial aimed at assessing the efficacy and tolerability of nutraceuticals versus ezetimibe, and in combination, in hypercholesterolemic patients with CHD and

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previous percutaneous coronary intervention (PCI) who were intolerant to statins and refused other drugs.

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Methods

In this single-blind, single centre, randomized, prospective, parallel-group trial we compared a nutraceutical combination with ezetimibe in terms of efficacy and tolerability, in statin-intolerant dyslipidemic patients 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,

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coenzyme Q10 2.0 mg, and astaxanthin 0.5 mg (Armolipid Plus®, Rottapharm Srl, Italy). Armolipid Plus® fulfills the European Union Good Manufacturing Practice (EU

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GMP) requirements and is available, at present, in European countries only. The study population included patients with CHD consecutively enrolled after PCI. Non-pharmacologic measures and standard medical therapy were prescribed after the

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procedure. Inclusion criteria were: a) documented CHD treated with PCI; b) high levels (over 200 mg/dl) of total cholesterol (TC); c) high levels (over 160 mg/dL) of low density

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lipoprotein cholesterol (LDL-C); d) statin intolerance and refusal of other treatments for hypercholesterolemia. Statin intolerance was defined as myalgia, i.e. muscle complaints without serum creatine kinase (CK) elevations, myositis, i.e. muscle symptoms with CK elevations, rhabdomyolysis, i.e. CK levels>10 times the upper limit of normal with an elevated creatinine level consistent with pigment-induced nephropathy, or

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gastrointestinal disorders, i.e. alanine aminotransferase or aspartate aminotransferase>2 times the upper limit of normal. Exclusion criteria included glomerular filtration rate less than 30 mUmin/1.73m2 (based on creatinine measured at

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the screening visit, and calculated by standard formula)14 and use of lipid-lowering

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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,

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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 two therapies was

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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

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assessment, and laboratory blood tests (TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, transaminases and CK). All these examinations were repeated at

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3 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, triglycerides) and treatment tolerability. In the event of an adverse event, subjects were counselled to stop taking the product permanently or temporarily. The study was carried out during routine clinical practice,

Declaration of Helsinki.

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following the international guidelines and in line with the principles outlined in the

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Data for continuous variables were expressed as mean values and standard deviation; categorical data were expressed as number of patients and percentage.

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Kolmogorov–Smirnov test for goodness of adaptation was used to verify distribution normality. On the basis of the results of Kolmogorov–Smirnov test, statistical transformations were applied if needed. Baseline characteristics between groups at the start of the treatment were compared using Student's t Test for independent samples or chi-square test. The analyses of the treatment intra-group associated changes were performed by using a series of repeated measures analysis of variance. A p-value less than 0.05 was considered as statistically significant for all tests.

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Results One hundred patients were enrolled consecutively. Of this study population, 64%

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had stable angina and 36% 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).

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At 3-month visit, the two groups differed for LDL-C, TC and triglycerides, with lower levels in the nutraceutical combination group than in the ezetimibe group (all <0.0001):

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The two 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, while 14 patients (28%) in the nutraceutical combination group reached this target

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(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.

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At 1-year follow-up, 58 patients (73%) of the combined therapy group (n= 86) and 14 (100%) of the nutraceutical combination group reached the therapeutic goal.

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Treatment effects on the lipid profile after 12 months are shown in Table 3. In both groups, LDL-C, TC and triglycerides values progressively and significantly decreased from baseline throughout treatment (all p<0.001), whereas HDL-C values progressively and significantly increased in both groups (p<0.001). During the study, no patient discontinued study treatment and no important adverse events were reported. In particular, no important increase in transaminases or CK were recorded (Table 4).

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Discussion In the present study, we assessed the effects of two alternative treatments to statins,

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ezetimibe and a combination of nutraceuticals (Armolipid Plus®) in patients with CHD and previous PCI. We found that the combination of nutriceuticals was significantly more effective than ezetimibe, as there were significantly greater reductions in TC, LDLThis is consistent with the

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C and triglycerides with Armolipid Plus® than ezetimibe.

outcome of a previous trial11 and was expected, since the nutraceutical combination

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contains 3 lipid-lowering compounds, namely policosanol, red yeast rice and berberine, with complementary mechanisms of action: red yeast rice and berberine target the HMG-CoA enzyme reducing cholesterol synthesis (the active ingredient of red yeast rice, monacholin K, inhibits HMG-CoA reductase activity competitively, whereas polycosanol decreases HMG-CoA reductase synthesis) and berberine targets also

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triglyceride synthesis and LDL liver uptake.15-19 The results related to ezetimibe are fairly consistent with previous studies. A metaanalysis of 8 randomized, double-blind, placebo-controlled trials of similar duration (12

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weeks)20 showed that the mean reduction achieved in TC was -13.4% versus 11.4%

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here, the mean reduction in LDL-C was -18.6% versus 16% here and the mean increase in HDL-C was 3.0% versus 4.3% here; only the mean reduction in triglycerides was somewhat greater in our study (-13.2% versus -8.0%). Also, the results with the nutraceutical combination were similar to those of previous randomized, blinded studies:13,21-25 here the mean reduction in TC was -18.8% versus a range of -11 to 21%; the mean reduction in LDL-C was -26.8% versus a range of -15 to -31%; the mean increase in HDL-C was +8.3% versus a range of 0-10%, and the mean reduction

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in triglycerides was -13.2% versus a range of 0.5-13%. Of particular interest is the additional improvement in the lipid profile that was obtained with the association of the

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nutraceutical combination and ezetimibe which determined further considerable reductions in TC, LDL-C and triglycerides (-12.1%, -19.1%, and -9.6%, respectively), and a further increase in HDL-C (+10.8%) that were maintained up to 1 year.

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Limitations of this trial include the relative small study population, the fact that the data regard only surrogate variables, i.e. the lipid profile, the inadequacy of current

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definitions of statin intolerance,25 and the lack of a control group treated with ezetimibe only. Therefore further studies are needed in order to assess the long-term effects of nutraceuticals on mortality and clarify whether nutraceuticals are effective in preventing

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cardiovascular events.

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11. Barrat E, Zaïr Y, Ogier N, Housez B, Vergara C, Maudet C, Lescuyer JF, Bard JM, Carpentier YA, Cazaubiel M, Peltier SL. A combined natural supplement lowers LDL cholesterol in subjects with moderate untreated hypercholesterolemia: a randomized placebo-controlled trial. Int J Food Sci Nutr 2013;64:882-889. 12. Pisciotta L, Bellocchio A, Bertolini S. Nutraceutical pill containing berberine versus

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ACCEPTED MANUSCRIPT Table 1 Baseline characteristics in the two groups groups

Variable

Nutraceutical

Ezetimibe

combination

(n=50)

p-value

Male

26 (52%)

Age (years)

64±11

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(n=50) 28 (56%)

0.688

63±10

0.772

18 (36%)

0.523

20 (40%)

0.685

15 (30%)

Hypertension

22 (44%)

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

166±31

171±25

0.381

54±8

55±11

0.815

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Diabetes mellitus

Triglycerides (mg/dl)

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Ejection fraction (%)

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Table 2 Comparisons between groups for lipid profile after 3 months of treatment

Nutraceutical

Ezetimibe

combination

(n=50)

p-value

194±16

<0.0001

126±11

<0.0001

Total cholesterol (mg/dl)

177±12

Low-density lipoprotein cholesterol (mg/dl)

109±8

High-density lipoprotein cholesterol (mg/dl)

39±8

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Variable

36±7

0.0203

144±25

163±26

0.0003

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Triglycerides (mg/dl)

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(n=50)

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Table 3 Effects of the two treatments on lipid profile after 12 months of treatment

Variable

Emetizibe plus

combination

p-value

(n=14) Base-

3

12

Base-

3

12

line

months

months

line

months

months

205±11

165±7

163±7

136±6

98±3

36±8

39±7

High-density lipoprotein cholesterol (mg/dl)

161±22

139±20

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Triglycerides (mg/dl)

189±15

166±12

164±13

<0.0001

95±3

<0.0001

120±11

97±9

95±10

<0.0001

40±7

<0.0001

37±8

41±8

41±8

<0.0001

<0.0001

157±27

142±22

140±21

<0.0001

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(mg/dl)

<0.0001

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lipoprotein cholesterol

p-value

(n=86)

(mg/dl)

Low-density

Nutraceuticals

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Total cholesterol

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Nutraceutical

140±21

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Table 4 Laboratory safety variables

Ezetimibe plus

Combination

Nutraceuticals

(n=14) 12 months

24±7

aminotransferase (U/L)

Alanine aminotransferase

26±4

Creatine kinase

139±34

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(mU/mL)

Baseline

12 months

p-value

25±5

0.062

26±8

25±6

0.099

25±3

0.104

25±5

26±4

0.154

0.074

130±28

126±31

0.073

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(U/L)

pvalue

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Aspartate

(n=86)

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Baseline

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Nutraceutical

137±23