Lovastatin

Brand Names: Mevacor, Cholestin

Clinical Names: Lovastatin

Summary

generic name: Lovastatin

trade names: Mevacor®, Cholestin®

type of drug: Antihyperlipidemic; HMG-CoA (hydroxymethyl glutaryl coenzyme A) reductase inhibitor; statin.

note: Cholestin® is a dietary supplement which contains naturally-occurring lovastatin and several other constituents with HMG-CoA reductase inhibitor activity.

used to treat: Hypercholesterolemia (high cholesterol).

mode of action: Lovastatin, as with all HMG-CoA reductase inhibitor drugs, blocks the normal production of cholesterol in the body.

overview of interactions:
• nutrient affected by drug: Coenzyme Q10 (Ubiquinone)

• nutrient affected by drug: Vitamin A (Retinol)

• nutrient affecting drug performance and toxicity: Vitamin B3 (Niacin, Nicotinic Acid, Inositol Hexaniacinate)

• nutrient affected by drug: Alpha-tocopherol (Vitamin E)

• nutrient affecting drug toxicity: Vitamin E

• diet affecting drug performance: Soluble Fiber

• diet affecting drug activity: Food

• food affecting drug performance: Grapefruit Juice



Interactions

nutrient affected by drug: Coenzyme Q10 (Ubiquinone)

• mechanism: Lovastatin functions by inhibiting the enzyme HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, that is required for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonic acid. Biosynthesis of both cholesterol and coenzyme Q (CoQ) requires mevalonic acid as a precursor. Consequently, lovastatin therapy could also result in a lowering of cellular CoQ levels.

• metabolic/nutrient concern: In 1990 Folkers et al suggested liver dysfunction, among the many known side effects of lovastatin, can be caused by the lovastatin-induced deficiency of CoQ10. Coenzyme Q10 is a component of the LDL + VLDL fractions of cholesterol which plays a key role as an essential mitochondrial redox-component and endogenous antioxidant. Much attention has been given to its role in reducing the risk of atherosclerosis based on the theory that the pathological changes result from oxidative processes. Likewise Q10 is often used in the treatment of cardiovascular disease.

• research: Folkers et al conducted a small study on the depletion of CoQ10 by lovastatin and concluded that oral administration of CoQ10 increased blood levels of CoQ10 and was generally accompanied by an improvement in cardiac function. In 1994 Laaksonen et al conducted the further inquiries into the effects of statin drugs, specifically the HMG-CoA reductase inhibitors lovaststain and simvastatin, upon serum ubiquinone concentrations. They found that after short-term lovastatin treatment, and after long-term simvastatin treatment, average serum ubiquinone levels were similar to those observed in a group of apparently healthy middle-aged men. However, in 1997 Mortensen et al conducted a randomized, double-blind clinical trial where serum levels of Coenzyme Q10 were measured over a period of eighteen weeks in forty-five hypercholesterolemic individuals who had been prescribed the statin drugs lovastatin and pravastatin. A dose-related significant decline of the total serum level of coenzyme Q10 was found in both groups, with those taking lovastatin, at 20-80 mg/day, demonstrating the more pronounced decline. Likewise Palomaki et al conducted a double-blinded, placebo-controlled cross-over trial with twenty-seven hypercholesterolemic men suffering from coronary heart disease. During the 6-week treatment period using lovastatin (60 mg/day) ubiquinol content diminished by 13% as measured per LDL phosphorus. However, in a later randomized, double-masked, placebo-controlled cross-over trial Palomaki et al found that supplementation with 180 mg of Coenzyme Q10 daily did not convincingly correct impaired defense against initiation of oxidation of low density lipoprotein (LDL) due to lovastatin treatment at 60 mg per day. They concluded that supplementation with Coenzyme Q10 only partially restored the drug-induced depletion of LDL ubiquinol.
(Folkers K, et al. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8931-8934; Willis RA, et al. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8928-8930; Laaksonen R, et al. Eur J Clin Pharmacol 1994;46(4):313-317; Mortensen SA, et al. Mol Aspects Med. 1997;18 Suppl:S137-144; Palomaki A, et al. FEBS Lett 1997 Jun 30;410(2-3):254-258; Palomaki A, et al. J Lipid Res. 1998 Jul;39(7):1430-1437.)

nutrient affecting drug performance and toxicity: Vitamin B3 (Niacin, Nicotinic Acid, Inositol Hexaniacinate)

• mechanism: Niacin and Lovastatin are both used to treat high cholesterol. There has been conflicting evidence as to whether their interaction could be beneficial or harmful.

• research: In a much-cited review article Garnett noted that the four commonly used HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, and fluvastatin, could interact with high-dose niacin, cyclosporine, erythromycin, and gemfibrozil in a way which may result in myopathy with or without rhabdomyolysis. While the basis of these reports has been limited, it has drawn attention to the issue of potential interactions. However, other researchers have found niacin to be effective in lowering cholesterol, especially as inositol hexoniacinate, which appears to provide therapeutic efficacy with minimal risk of adverse side effects. In contrast, niacinamide is not effective for lowering cholesterol. A wide range of researchers and clinicians has supported a therapeutic approach combining niacin (or inositol hexoniacinate) and statin drugs such as lovastatin as complementary tools within an integrative approach.
(Garnett WR. Am J Health Syst Pharm 1995 Aug 1;52(15):1639-1645; Berge KG, et al. Eur J Clin Pharmacol. 1991;40 Suppl 1:S49-51; Canner PL, et al. J Am Coll Cardiol. 1986 Dec;8(6):1245-1255; Malloy MJ, et al. Ann Intern Med 1987;Nov;107(5):616-623;
Brown BG, et al. Am J Cardiol. 1997 Jul 15;80(2):111-115.)

• nutritional support: As a pharmacological apsproach to the treatment of hypercholesterolemia niaicin has often been used in dosages ranging from one to six grams per day, usually starting with 100 mg three times daily. At such levels niacin could potentially produce adverse effects in some patients with extended use and consulting with a nutritionally-informed physician would be advisable. In particular, individuals who are also taking lovastatin should consult with their prescribing physician and/or a nutritionally oriented healthcare professional to supervise and monitor the course of treatment. While research is still limited, evidence is growing that use of inositol hexoniacinate poses fewer, though potentially similar risks; it is commonly prescribed at levels of 500 mg three times daily for the initial two weeks, and then increased to 1000 mg three times per day. Again, monitoring by an appropriate healthcare provided would be prudent.
(Head KA. Alt Med Rev 1996;1:176-184; Murray M. Am J Natural Med 1995;2:9-12; Murray and Pizzorno, 1998, p. 354; Dorner Von G, et al. Arzneimittelforschung 1961;11:110-113; Grundy SM, et al. J Lipid Res. 1981 Jan;22(1):24-36; Carlson LA, Oro L. Atherosclerosis 1973 Jul-Aug;18(1):1-9; Canner PL, et al. J Am Coll Cardiol. 1986 Dec;8(6):1245-1255.)

nutrient affected by drug: Alpha-tocopherol (Vitamin E)

• metabolic/nutrient concern: Alpha-tocopherol is a potent endogenous antioxidant. Much attention has been given to its role in reducing the risk of atherosclerosis based on the theory that the pathological changes result from oxidative processes. Likewise alpha-tocopherol is often used in the treatment of cardiovascular disease.

• research: Chen et al conducted initial research into the antiatherosclerotic effects of vitamin E, through preservation of endogenous antioxidant activity and inhibition of lipid peroxidation, when used with lovastatin and amlodipine. Later, in a randomized, double-masked, crossover clinical trial Palomaki et al evaluated whether lovastatin therapy (60 mg daily) affected the initiation of oxidation of low density lipoprotein (LDL) in cardiac patients on alpha-tocopherol supplementation therapy. Twenty-eight men with verified coronary heart disease and hypercholesterolemia received 450 IU alpha-tocopherol daily with lovastatin or with placebo. They concluded that alpha-tocopherol supplementation significantly increased the antioxidative capacity of LDL when measured ex vivo, but that this benefit was partially abolished by concomitant lovastatin therapy.
(Chen L, et al. J Am Coll Cardiol. 1997 Aug;30(2):569-575; Palomaki A, et al. Arterioscler Thromb Vasc Biol 1999 Jun;19(6):1541-1548.)

• nutritional support: 400 IU of alpha-tocopherol, twice daily, would be an appropriate dose to counter the adverse effects of lovastatin and provide some additional benefit to the cardiovascular system. Individuals who are also taking lovastatin should consult with their prescribing physician and/or a nutritionally oriented healthcare professional to supervise and monitor the course of treatment.

nutrient affecting drug toxicity: Vitamin E

• mechanism: As discussed above lovastatin has been found to deplete Coenzyme Q10.

• nutritional support: Vitamin E supplementation of may offset the loss of Coenzyme Q10. 400 IU of alpha-tocopherol, twice daily, would be an appropriate dose.
(Baum H. New Scientist May 24, 1991, 24.)

diet affecting drug performance: Soluble Fiber

• mechanism: Research indicates that dietary fiber, from foods such as oatmeal or fruit, can reduce gastrointestinal absorption, and thereby effectiveness, of lovastatin by binding the drug. The resulting reduction in effectiveness could increase LDL cholesterol levels.
(Pronsky ZM. 1995, 121.)

• report: Richter et al have reported that fruit pectin and oat bran have a particular tendency to interact with lovastatin.
(Richter W, et al. Lancet 1991;Sep 14;338(8768):706.)

• dietary concerns: While the consumption of oat bran and whole fruit might in themselves contribute to lowering cholesterol, individuals taking lovastatin should separate taking the drug from the consumption of foods high in soluble fiber by at least two hours. Foods high in soluble fiber include fruit, oats and beans; oat bran, pectin and glucomannan are highly concentrated fiber sources.

diet affecting drug activity: Food

• mechanism: The simultaneous consumption of food and lovastatin results in increased blood levels of the drug.
(Threlkeld DS, ed. Sep 1998; Pronsky ZM. 1995, 121.)

• dietary concerns: Individuals using lovastatin should take the drug at the same time every day, preferably with a meal, or at least in consistent relationship to the intake of food. Many physicians and pharmacists advise taking lovastatin with food to obtain the increased levels associated with this interaction. If prescribed a single daily dose, it should be taken with the evening meal. However, as per the above concern with fiber decreasing absorption, individuals taking lovastatin should avoid eating fiber, pectin or oat bran within two hours before or after taking the drug.

food affecting drug performance: Grapefruit Juice

• mechanism: Grapefruit juice increases the bioavailability of many drugs by preventing CYP3A4-mediated first-pass metabolism in the small intestine.
(Bailey DG, et al. Br J Clin Pharmacol. 1998 Aug;46(2):101-110.)

• research: Kantola et al conducted an open, randomized, two-phase crossover study with ten subjects looking at the interaction between lovastatin and grapefruit juice. They concluded that, compared to placebo, grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid.
(Kantola T, et al. Clin Pharmacol Ther 1998;Mar;63(4):397-402.)

• nutritional concerns and possible synergy: Individuals taking lovastatin should avoid drinking grapefruit juice, especially within two hours of taking lovastatin. Any regular consumption of grapefruit juice should be discussed with the prescribing physician so they are aware of the potential interaction. Kantola et al recommended that the dose of lovastatin be reduced accordingly in individuals who continued to consume grapefruit juice. While the consumption of grapefruit juice with lovastatin might theoretically enable the use of lower doses of the drug to achieve the same therapeutic effect, no conclusive research on this potential synergistic approach has been published. Any such attempt at combining lovastatin and grapefruit therapeutically would require close monitoring by the prescribing physician. Therefore anyone taking lovastatin should avoid changing their dose of the medication based on their consumption of grapefruit juice without first consulting their prescribing physician.

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References

[No authors listed]  MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J. 1999 May;20(10):725-741.
Abstract: AIMS: In observational studies, prolonged lower blood total cholesterol levels - down at least to 3 mmol. l-1 - are associated with lower risks of coronary heart disease. Cholesterol-lowering therapy may, therefore, be worthwhile for individuals at high risk of coronary heart disease events irrespective of their presenting cholesterol levels. Observational studies also suggest that increased dietary intake of antioxidant vitamins may be associated with lower risks of coronary heart disease. The present randomized trial aims to assess reliably the effects on mortality and major morbidity of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of different categories of high-risk patients. METHODS AND RESULTS: Men and women aged 40 to 80 years were eligible provided they were considered to be at elevated risk of coronary heart disease death because of past history of myocardial infarction or other coronary heart disease, occlusive disease of non-coronary arteries, diabetes mellitus or treated hypertension; had baseline blood total cholesterol of 3.5 mmol. l-1 or greater; and no clear indications for, or contraindications to, either of the study treatments. Eligible patients who completed a pre-randomization run-in phase on active treatment were randomly allocated to receive simvastatin (40 mg daily) or matching placebo tablets and, in a '2x2 factorial' design, antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily) or matching placebo capsules. Follow-up visits after randomization are scheduled at 4, 8 and 12 months, and then 6-monthly, for at least 5 years.Between July 1994 and May 1997, 15 454 men and 5082 women were randomized, with 9515 aged over 65 years at entry. Diagnostic criteria overlapped, with 8510 (41%) having had myocardial infarction (most of whom were either female, or elderly or with low blood cholesterol), 4869 (24%) some other history of coronary heart disease, 3288 (16%) cerebrovascular disease, 6748 (33%) peripheral vascular disease, 5963 (29%) diabetes mellitus (of whom 3985 had no history of coronary heart disease) and 8455 (41%) treated hypertension. Baseline non-fasting total cholesterol levels were less than 5.5 mmol. l-1 in 7882 (38%) participants, and LDL (low density lipoprotein) cholesterol less than 3.0 mmol. l-1 in 6888 (34%).During a mean follow-up of 25 months (range: 13 to 47 months), no significant differences had been observed between the treatment groups in the numbers of patients with muscle symptoms, other possible side-effects leading to termination of study treatment, or elevated liver and muscle enzymes. After 30 months of follow-up, 81% of randomized patients remained compliant with taking their study simvastatin or placebo tablets, and allocation to simvastatin produced average reductions in non-fasting blood total and LDL cholesterol of about 1.5-1.6 mmol. l-1 and 1.1-1.2 mmol. l-1 respectively. Eighty-seven per cent of patients remained compliant with taking their vitamin or placebo capsules, and allocation to the vitamin supplement produced an average increase in plasma vitamin E levels of about 24 micromol. l-1. Based on this initial follow-up period, the estimated annual rate of non-fatal myocardial infarction or fatal coronary heart disease is 2.4%, annual stroke rate is 1.3%, and annual all-cause mortality rate is 2. 2%. CONCLUSION: The Heart Protection Study is large, it has included a wide range of patients at high risk of vascular events, and the treatment regimens being studied are well-tolerated and produce substantial effects on blood lipid and vitamin levels. The study should, therefore, provide reliable evidence about the effects of cholesterol-lowering therapy and of antioxidant vitamin supplements on all-cause or cause-specific mortality and major morbidity in a range of different categories of individuals for whom uncertainty remains about the balance of benefits and risks of these treatments.

Bailey DG, et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol. 1998 Aug;46(2):101-110. (Review)

Baum H. New Scientist May 24, 1991, 24.

Berge KG, Canner PL. Coronary drug project: experience with niacin. Coronary Drug Project Research Group. Eur J Clin Pharmacol. 1991;40 Suppl 1:S49-51.
Abstract: Niacin was one of the treatments compared in the Coronary Drug Project, a placebo-controlled, multicenter trial of lipid-lowering drugs in the secondary prevention of coronary heart disease. A total of 1119 men, aged 30-64 at entry, were randomized to niacin and 2789 to placebo by the end of recruitment in March 1969. Although side-effects interfered with adherence to the niacin regimen, it was the most effective agent in achieving cholesterol-lowering (10% overall); other agents in the trial were clofibrate, dextrothyroxine, and conjugated equine estrogens. At the scheduled conclusion of the trial in February 1975, the niacin-treated group exhibited a statistically significantly lower incidence of definite, non-fatal myocardial infarction (MI) than the placebo group. There was a trend toward improvement in the life-table mortality curve, but this was not statistically significant. In 1981 an extended follow-up was carried out concerning vital status for the 6008 men who were still alive at the end of treatment and active follow-up in the trial in 1975 (827 in the niacin group and 2008 in placebo groups). Vital status was determined for 99.1% of these men after a mean of 9 years from conclusion of the trial. In the group previously randomized to niacin, there were 69 (11%) fewer deaths than were expected on the basis of mortality in the placebo group. This difference was significant (z = -3.52; P = 0.0004). The data also suggested that patients with a higher baseline cholesterol experienced greater benefit from niacin therapy, as did those with the best response to the drug.

Brown BG, Bardsley J, Poulin D, Hillger LA, Dowdy A, Maher VM, Zhao XQ, Albers JJ, Knopp RH.  Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol. 1997 Jul 15;80(2):111-115.
Abstract: The efficacy, safety, and tolerability of a moderate dose, 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease. In an initial 12-month phase, regular niacin, 500 mg qid, lovastatin, 20 mg bid, and colestipol, 10 g/bid, were given with dose adjustment for lipid targets and side effects. This was followed by 2 random sequence crossover phases (8 months each) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen. Lipid, lipoprotein, apoprotein, and clinical chemistry determinations were obtained at baseline, during the initial phase, at the 2 crossover phases, and at 6 weeks after therapy. A final questionnaire queried specific side effects and overall preferences. Low-/high-density lipoprotein (LDL/HDL) changed from means of 215/46 mg/dl at baseline, to 94/59 mg/dl after run-in, to 85/52 mg/dl after 8 months of controlled-release niacin, and to 98/56 mg/dl after 8 months of regular niacin (regular niacin vs controlled-release niacin, p <0.005/<0.05). The target of LDL < or = 100 mg/dl was achieved at 8 months by 83% of these patients with controlled-release niacin and by 52% with regular niacin (p <0.01). Compliance was 95% with controlled-release niacin versus 85% with regular niacin (p <0.001). The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid, glucose, insulin, or asparate aminotransferase levels. Overall, 21% of patients called the 3 drugs "very easy" and 72% "fairly easy" to take. The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4. In conclusion, these regimens achieve striking lipid changes among hyperlipidemic patients. Controlled release is the preferred niacin preparation in terms of LDL reduction, compliance, patient preference, and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl. The 2 niacin preparations did not differ in evidence of toxicity.

Brown WV. Niacin for lipid disorders. Indications, effectiveness, and safety. Postgrad Med 1995 Aug;98(2):185-9, 192-193.
Abstract: Niacin can be very effective and safe in lowering low-density lipoprotein cholesterol and triglyceride levels and also in increasing high-density lipoprotein cholesterol levels. In combination with other lipid-lowering drugs (eg, bile acid sequestrants), it has reduced the incidence of cardiovascular events and stopped the progression of coronary artery lesions. It may be the most cost-effective lipid-lowering agent currently available. At lower doses, sustained-release forms of niacin may also improve patient compliance.

Brown BG, Zambon A, Poulin D, Rocha A, Maher VM, Davis JW, Albers JJ, Brunzell JD. Use of niacin, statins, and resins in patients with combined hyperlipidemia. Am J Cardiol 1998 Feb 26;81(4A):52B-59B.
Abstract: Patients in the original Familial Atherosclerosis Treatment Study (FATS) cohort were subgrouped into those with triglyceride levels < or = 120 mg/dL (n = 26) and those with triglyceride levels > or = 190 mg/dL (n = 40). Their therapeutic responses to niacin plus colestipol, lovastatin plus colestipol, colestipol alone, or placebo were determined. Therapeutic response was also determined in the same 2 triglyceride subgroups (n = 12 and n = 27, respectively) of patients selected for low levels of high-density lipoprotein (HDL) cholesterol and coronary artery disease. These triglyceride criteria were chosen to identify patient subgroups with high likelihood of "pattern A" (normal-size low-density lipoprotein [LDL] particles and triglyceride < or = 120 mg/dL) or "pattern B" (small dense LDL and triglyceride > or = 190 mg/dL). Our findings in these small patient subgroups are consistent with the emerging understanding that coronary artery disease patients presenting with high triglyceride levels have lower HDL-C, smaller less buoyant LDL-C, and greater very low-density lipoprotein (VLDL) cholesterol and VLDL apolipoprotein B, and are more responsive to therapy as assessed by an increase in HDL-C and reduction in triglycerides, VLDL-C, and VLDL apolipoprotein B. In the FATS high-triglyceride subgroup with these characteristics, a tendency toward greater therapeutic improvement in coronary stenosis severity was observed among those treated with either of the 2 forms of intensive cholesterol-lowering therapy. This improvement is associated with therapeutic reduction of LDL-C and elevation of HDL-C, but also appears to be associated with drug-induced improvement in LDL buoyancy.

Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986 Dec;8(6):1245-1255.
Abstract: Men with 1 or more MIs who took 3 g q.d.had a lower incidence of nonfatal MIs and, for several years after the study ended, a lower mortality rate.
The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

Carlson LA, Oro L. Effect of treatment of nicotinic acid for one month on serum lipids in patients with different types of hyperlipidemia. Atherosclerosis 1973 Jul-Aug;18(1):1-9.
Abstract: 188 patients with various types of hyperlipoproteinemia were given 3 gms nicotinic acid daily. Most responsive were patients with Type V. Their cholesterols decreased 70% and triglycerides decreased 90%, followed by Type lll: decreases of 50% and 60% respectively. Both lipids were also reduced in the other types, and even patients with normal lipid levels showed a 10-20% reduction in serum lipids.

Chen L, Haught WH, Yang B, Saldeen TG, Parathasarathy S, Mehta JL.Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine. J Am Coll Cardiol. 1997 Aug;30(2):569-575.
Abstract: OBJECTIVES: We sought to document the common mechanisms of the antiatherogenic effects of the cholesterol-lowering hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin, the dihydropyridine Ca2+ blocker amlodipine and the antioxidant vitamin E. BACKGROUND: Vitamin E, HMG-CoA reductase inhibitors and Ca2+ blockers each inhibit atherosclerosis in hypercholesterolemic animals. METHODS: New Zealand White rabbits were fed regular chow (Group A), chow with 1% cholesterol (Group B), 1% cholesterol diet plus lovastatin (Group C), 1% cholesterol diet plus vitamin E (Group D) or 1% cholesterol diet plus amlodipine (Group E) for 12 weeks. The extent of aortic atherosclerosis was measured by planimetry of the sudanophilic area. Malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured as indexes of lipid peroxidation and antioxidant activity, respectively. RESULTS: Group A rabbits showed no atherosclerosis, whereas Group B rabbits had 17.4 +/- 9.3% (mean +/- SD) of the aorta covered with atherosclerosis, and Groups C, D and E rabbits had significantly less atherosclerosis. Plasma SOD activity was lower in Group B than in Group A (6.9 +/- 1.1 vs. 12.8 +/- 1.5 U/ml, p < 0.01) and was preserved in the groups given lovastatin, vitamin E or amlodipine with a high cholesterol diet. The serum MDA level was higher in Group B rabbits than Group A rabbits (12.1 +/- 2.6 vs. 1.2 +/- 0.1 nmol/ml, p < 0.01) and increased minimally in rabbits given lovastatin, vitamin E or amlodipine with a high cholesterol diet. In in vitro experiments, both lovastatin and amlodipine preserved SOD activity and reduced the oxidizability of low density lipoproteins by rabbit leukocytes. CONCLUSIONS: This study suggests that a reduction in lipid peroxidation and preservation of SOD may be common mechanisms of antiatherosclerotic effects of lovastatin, vitamin E and amlodipine.

Dorner Von G, Fisher FW. Zur Beinflussung der Serumlipide und -lipoproteine durch den Hexanicotinsaureester des m- Inositol. Arzneimittelforschung 1961;11:110-113.

Folkers K, Langsjoen P, Eds. In: Folkers K, Littarru GP, Yamagami T, Eds. Biochemical and Clinical Aspects of Coenzyme Q, Volume 6. Amsterdam, Elsevier Science Publ, 1991: 449-452.

Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, Tamagawa H. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8931-8934.
Abstract: Lovastatin is clinically used to treat patients with hypercholesterolemia and successfully lowers cholesterol levels. The mechanism of action of lovastatin is inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme involved in the biosynthesis of cholesterol from acetyl-CoA. Inhibition of this enzyme could also inhibit the intrinsic biosynthesis of coenzyme Q10 (CoQ10), but there have not been definitive data on whether lovastatin reduces levels of CoQ10 as it does cholesterol. The clinical use of lovastatin is to reduce a risk of cardiac disease, and if lovastatin were to reduce levels of CoQ10, this reduction would constitute a new risk of cardiac disease, since it is established that CoQ10 is indispensable for cardiac function. We have conducted three related protocols to determine whether lovastatin does indeed inhibit the biosynthesis of CoQ10. One protocol was done on rats, and is reported in the preceding paper [Willis, R. A., Folkers, K., Tucker, J. L., Ye, C.-Q., Xia, L.-J. & Tamagawa, H. (1990) Proc. Natl. Acad. Sci. USA 87, 8928-8930]. The other two protocols are reported here. One involved patients in a hospital, and the other involved a volunteer who permitted extraordinary monitoring of CoQ10 and cholesterol levels and cardiac function. All data from the three protocols revealed that lovastatin does indeed lower levels of CoQ10. The five hospitalized patients, 43-72 years old, revealed increased cardiac disease from lovastatin, which was life-threatening for patients having class IV cardiomyopathy before lovastatin or after taking lovastatin. Oral administration of CoQ10 increased blood levels of CoQ10 and was generally accompanied by an improvement in cardiac function. Although a successful drug, lovastatin does have side effects, particularly including liver dysfunction, which presumably can be caused by the lovastatin-induced deficiency of CoQ10.

Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995 Aug 1;52(15):1639-1645. (Review)
Abstract: Drug-drug, drug-food, and drug-disease interactions involving hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are reviewed. The four available HMG-CoA reductase inhibitors-lovastatin, simvastatin, pravastatin, and fluvastatin-have different potentials for drug interactions, probably because of their different pharmacokinetic characteristics. Interactions of some of these cholesterol-lowering agents with cyclosporine, erythromycin, high-dose niacin, or gemfibrozil may produce myopathy with or without rhabdomyolysis. Interactions with other commonly prescribed agents, such as bile acid sequestrants, coumarin anticoagulants, and cardiovascular drugs, may alter the pharmacokinetics of either drug, but the clinical significance is generally minor. Food may affect plasma lovastatin concentrations, systemic pravastatin bioavailability, and the maximum serum concentration (Cmax) and time to achieve Cmax for fluvastatin. Hepatic dysfunction may influence the pharmacokinetics of pravastatin; all HMG-CoA reductase inhibitors are contraindicated in patients with liver disease or unexplained elevations in serum aminotransferases. Severe renal insufficiency may necessitate dosage modification in lovastatin recipients. Renal dysfunction seems to affect the pharmacokinetics of pravastatin, simvastatin, and fluvastatin only minimally, but caution is still warranted. Although the HMG-CoA reductase inhibitors rarely have severe adverse effects, they may interact, in some cases dangerously, with other drugs, with food, and with disease states.

Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res. 1981 Jan;22(1):24-36.
Abstract: The mechanisms for the hypolipidemic action of nicotinic acid were examined in 12 patients with hyperlipidemia. Most patients were studied in the hospital on a metabolic ward. The first month was a control period followed by 1 month on nicotinic acid. During treatment with nicotinic acid, the triglycerides (TG) decreased in total plasma by an average of 52% and in very low density lipoproteins (VLDL) by 36%. Transport rates of VLDL-TG were determined by multicompartmental analysis following injection of [3H]glycerol as a precursor. Nicotinic acid decreased transport (synthesis) of VLDL-TG by an average of 21%. Kinetic modeling of the VLDL-TG data suggested that the TG reduction was due to a decrease in TG content of VLDL and hence a reduction in lipoprotein size more than number. For the whole group, plasma cholesterol fell during nicotinic acid therapy by a mean of 22%. The drug produced no detectable changes in fecal excretions of cholesterol (neutral steroids) or bile acids. However, it induced a small but significant increment in hepatic secretion of biliary cholesterol that might have led to a net loss of cholesterol from the body even though this loss could not be detected by sterol balance. Despite this increase in outputs of biliary cholesterol, there was not a significant increase in molar % cholesterol or in % saturation of gallbladder bile. Therefore, it is doubtful that nicotinic acid enhances the risk for cholesterol gallstones.

Head KA. Inositol Hexaniacinate: A Safer Alternative to Niacin. Alt Med Rev 1996;1(3):176-184.
Abstract: Niacin has long been prescribed for the treatment of various cardiovascular conditions, particularly the hyperlipidemias. It has been proven effective at lowering VLDL, LDL, total cholesterol and triglyceride levels while raising HDL levels. The side effects of niacin which may occur at the dosages often required for therapeutic efficacy, ranging from flushing and pruritus to hepatoxicity and impaired glucose tolerance, often prove troubling for both patient and practitioner. The need for a safer approach to niacin supplementation has resulted in the investigation of niacin esters. One of the most widely studied of these is inositol hexaniacinate (IHN). In numerous trials it has been found to be virtually free of the side effects associated with conventional niacin therapy. Extensive research has found IHN to be effective in the treatment of hyperlipidemia, Raynaud's disease and intermittent claudication. A number of other conditions which respond favorably to niacin therapy such as hypertension, diabetes, dysmennorhea and alcoholism bear further investigation.

Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998;Mar;63(4):397-402.
Abstract: BACKGROUND: Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A4. We wanted to investigate a possible interaction of grapefruit juice with lovastatin, a cholesterol-lowering agent that is partially metabolized by CY P3A4. METHODS: An open, randomized, two-phase crossover study with an interval of 2 weeks between the phases was carried out. Ten healthy volunteers took either 200 ml double-strength grapefruit juice or water orally three times a day for 2 days. On day 3, each subject ingested 80 mg lovastatin with either 200 ml grapefruit juice or water, and an additional dose of 200 ml was ingested 1/2 and 1 1/2 hours after lovastatin intake. Serum concentrations of lovastatin and lovastatin acid were measured up to 12 hours. RESULTS: Grapefruit juice greatly increased the serum concentrations of both lovastatin and lovastatin acid. The mean peak serum concentration (Cmax) of lovastatin was increased about 12-fold (range, 5.2-fold to 19.7-fold; p < 0.001) and the area under the concentration-time curve [AUC(0-12)] was increased 15-fold (range, 5.7-fold to 26.3-fold; p < 0.001) by grapefruit juice. The mean Cmax and AUC(0-12) of lovastatin acid were increased about fourfold (range, 1.8-fold to 11.5-fold; p < 0.001) and fivefold (range, 2.4-fold to 23.3-fold; p < 0.001) by grapefruit juice, respectively. The half-lives of lovastatin and lovastatin acid remained unchanged. CONCLUSIONS: Grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine. The concomitant use of grapefruit juice with lovastatin and simvastatin should be avoided, or the dose of these 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Laaksonen R, Ojala JP, Tikkanen MJ, Himberg JJ. Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1994;46(4):313-317.
Abstract: Serum ubiquinone levels were studied during long- and short-term treatment with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors in 17 men with primary non-familial hypercholesterolaemia. The serum ubiquinone levels were determined after the patients had received simvastatin (20-40 mg per day) for 4.7 years, after a 4 week treatment pause and again after they had resumed treatment with lovastatin (20-40 mg per day) for 12 weeks. During the treatment pause the average serum ubiquinone levels increased by 32%; resumption of treatment caused a reduction of 25%. The changes in the levels of ubiquinone and serum total cholesterol as well as those of ubiquinone and low-density lipoprotein cholesterol were closely parallel. This suggested that changes in serum ubiquinone reflected changes in cholesterol-containing serum lipoproteins which could serve as carrier vehicles for ubiquinone. After long-term simvastatin treatment and after short-term lovastatin treatment, average serum ubiquinone levels (1.16 and 1.22 mg.l-1, respectively) were similar to that observed in a group of apparently healthy middle-aged men (1.16 mg.l-1).

Loop RA, et al. Effects of ethanol, lovastatin and coenzyme Q10 treatment on antioxidants and TBA reactive material in liver of rats. Mol Aspects Med. 1994;15 Suppl:S195-206.

Malloy MJ, Kane JP, Kunitake ST, Tun P. Complementarity of colestipol, niacin, and lovastatin in treatment of severe familial hypercholesterolemia. Ann Intern Med 1987;Nov;107(5):616-623.
Abstract: OBJECTIVE: To compare the effectiveness of the ternary-drug combination of colestipol, niacin, and lovastatin with binary combinations of those drugs in treating patients with familial hypercholesterolemia. DESIGN: An open sequential study of serum lipoprotein responses in patients receiving diet alone (mean duration, 4 months); colestipol and niacin with diet (mean duration, 9 months); and colestipol, niacin, and lovastatin with diet (mean duration, 15 months). SETTING: Metabolic ward and lipid clinic of a university medical center. PATIENTS: Twenty-two patients with clinical characteristics of familial hypercholesterolemia (low-density-lipoprotein cholesterol, greater than 8.48 mmol/L; 21 of 22 with tendon xanthomas). INTERVENTIONS: Diet: less than 200 mg/d of cholesterol and less than 8% of total calories from saturated fat; colestipol, 30 g/d; lovastatin, 40 to 60 mg/d; and niacin, 1.5 to 7.5 g/d. MEASUREMENTS AND MAIN RESULTS: Mean total serum cholesterol and low-density-lipoprotein cholesterol levels of 4.86 +/- 0.62 mmol/L (188 +/- 24 mg/dL SD) and 2.89 +/- 0.54 mmol/L (112 +/- 21 mg/dL SD), respectively, were significantly lower during ternary-drug treatment than during colestipol-niacin treatment (p less than 0.003) or during treatment in which other possible binary combinations were given. The cholesterol content of very low-density-lipoproteins was lower and high-density-lipoprotein cholesterol levels higher during this phase than during the colestipol-niacin phase. CONCLUSIONS: Colestipol, lovastatin, and niacin are mutually complementary in treating hypercholesterolemia. This regimen produces reductions in serum cholesterol levels similar to those associated with regression of atheromatous plaques in animal studies.

Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997;18 Suppl:S137-S144.
Abstract: Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.

Muggeo M, Zenti MG, Travia D, Sartori A, Trimeloni S, Grigolini L, Graziani MS, Cigolini M. Serum retinol levels throughout two years of cholesterol-lowering therapy. Metabolism 1995;Mar;44(3):398-403.
Abstract: Some studies have reported an inverse correlation between serum cholesterol level and risk of cancer. This correlation might be due to a decrease in serum retinol, a lipid-soluble vitamin that controls cell proliferation and differentiation. We evaluated the influence of cholesterol-lowering therapy on serum retinol in 102 subjects (mean +/- SE: aged 47.1 +/- 4.1 years; body mass index, 23.8 +/- 0.6 kg/m2) with primary hypercholesterolemia treated for 2 years with different therapeutic protocols. Twenty-two subjects had been treated with diet alone, 35 with diet and fibrates, 37 with diet and hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), and eight with diet and cholestyramine. Postabsorptive serum retinol, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were determined at baseline and every 3 months. Baseline TC and LDL-C were significantly lower in the diet-treated group than in other groups. No intergroup differences were found in pretreatment levels of triglycerides and serum retinol. After 2 years of treatment, TC and LDL-C serum levels were not significantly decreased in the diet-alone group, whereas they were decreased by 20% and 24%, respectively, in the gemfibrozil group, 28% and 34% in the statins group; and 21% and 27% in the cholestyramine group. In the entire population (N = 102), serum retinol was 3.46 +/- 0.08 mumol/L before therapy and 3.76 +/- 0.07 after 2 years of therapy (P < .001). Serum retinol increased in diet- and statin-treated groups, but not in fibrate- and resin-treated groups.

Murray M. Lipid-lowering drugs vs. Inositol hexaniacinate. Am J Natural Med 1995;2:9-12.

Palomaki A, Malminiemi K, Malminiemi O, Solakivi T. Effects of lovastatin therapy on susceptibility of LDL to oxidation during alpha-tocopherol supplementation. Arterioscler Thromb Vasc Biol 1999 Jun;19(6):1541-1548.
Abstract: A randomized, double-masked, crossover clinical trial was carried out to evaluate whether lovastatin therapy (60 mg daily) affects the initiation of oxidation of low density lipoprotein (LDL) in cardiac patients on alpha-tocopherol supplementation therapy (450 IU daily). Twenty-eight men with verified coronary heart disease and hypercholesterolemia received alpha-tocopherol with lovastatin or with dummy tablets in random order. The two 6-week, active-treatment periods were preceded by a washout period of at least 8 weeks. The oxidizability of LDL was determined by 2 methods ex vivo. The depletion times for LDL ubiquinol and LDL alpha-tocopherol were determined in timed samples taken during oxidation induced by 2, 2-azobis(2,4-dimethylvaleronitrile). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated-diene formation. alpha-Tocopherol supplementation led to a 1.9-fold concentration of reduced alpha-tocopherol in LDL (P<0.0001) and to a 2.0-fold longer depletion time (P<0.0001) of alpha-tocopherol compared with determinations after the washout period. A 43% prolongation (P<0.0001) was seen in the lag time of conjugated-diene formation. Lovastatin decreased the depletion time of reduced alpha-tocopherol in metal ion-independent oxidation by 44% and shortened the lag time of conjugated-diene formation in metal ion-dependent oxidation by 7%. In conclusion, alpha-tocopherol supplementation significantly increased the antioxidative capacity of LDL when measured ex vivo, which was partially abolished by concomitant lovastatin therapy.

Palomaki A, Malminiemi K, Metsa-Ketela T. Enhanced oxidizability of ubiquinol and alpha-tocopherol during lovastatin treatment. FEBS Lett 1997 Jun 30;410(2-3):254-258.
Abstract: A double-blinded, placebo-controlled cross-over trial was carried out with 27 hypercholesterolemic men with coronary heart disease. During the 6-week treatment period lovastatin (60 mg/day) decreased fasting serum LDL cholesterol by 45%, LDL phosphorus by 38% and apoB by 33%. Ubiquinol content diminished by 13% as measured per LDL phosphorus. When LDL was oxidized ex vivo with AMVN both LDL ubiquinol and alpha-tocopherol were exhausted faster after lovastatin treatment compared to placebo, by 24% (P < 0.005) and 36% (P < 0.0001), respectively. Lag time in copper-induced oxidation of LDL decreased by 7% (P < 0.01). This suggests diminished antioxidant-dependent resistance of LDL to the early phase of oxidative stress.

Palomaki A, Malminiemi K, Solakivi T, Malminiemi O. Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo. J Lipid Res. 1998 Jul;39(7):1430-1437.
Abstract: A randomized, double-masked, placebo-controlled cross-over trial was carried out to evaluate whether ubiquinone supplementation (180 mg daily) corrects impaired defence against initiation of oxidation of low density lipoprotein (LDL) related to effective (60 mg daily) lovastatin treatment. Nineteen men with coronary heart disease and hypercholesterolemia received lovastatin with or without ubiquinone during 6-week periods after wash-out. The depletion times for LDL ubiquinol and reduced alpha-tocopherol were determined during oxidation induced by 2,2-azobis(2,4-dimethylvaleronitrile) (AMVN). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated diene formation. Compared to mere lovastatin therapy, ubiquinone supplementation lead to a 4.4-fold concentration of LDL ubiquinol (P < 0.0001). In spite of the 49% lengthening in depletion time (P < 0.0001) of LDL ubiquinol, the lag time in copper-mediated oxidation increased only by 5% (P = 0.02). Ubiquinone loading had no statistically significant effect on LDL alpha-tocopherol redox kinetics during high radical flux ex vivo. The faster depletion of LDL ubiquinol and shortened lag time in conjugated diene formation during high-dose lovastatin therapy may, at least partially, be restored with ubiquinone supplementation. However, the observed improvement in LDL antioxidative capacity was scarce, and the clinical relevance of ubiquinone supplementation during statin therapy remains open.

Pronsky ZM. Powers and Moore's Food-Medication Interactions, Ninth ed.Pottstown, PA: Food-Medication Interactions, 1995, 121.

Richter W, Jacob B, Schwandt P. Interaction between fibre and lovastatin. Lancet 1991;Sep 14;338(8768):706. (Letter)

Threlkeld DS, ed. Diuretics and Cardiovasculars, Antihyperlipidemic Agents, HMG-CoA Reductase Inhibitors. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Sep 1998.

Willis RA, Folkers K, Tucker JL, Ye CQ, Xia LJ, Tamagawa H. Lovastatin decreases coenzyme Q levels in rats. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8928-8930.