Simvastatin side effects and benefit for cholesterol reduction - Combining this cholesterol drug with fish oils, psyllium or niacin by Ray Sahelian, M.D.
March 4 2016

Simvastatin is a cholesterol- lowering drug. Simvastatin inhibits the production of cholesterol by the liver. Lowering cholesterol levels may slow progression and may even reverse coronary artery disease, however there is no evidence that overall lifespan is increased by the use of statin drugs such as simvastatin. Vytorin is a new prescription medication combination of ezetimibe (Zetia) and simvastatin (Zocor). Early research indicates beta glucan may be helpful for cholesterol reduction.
    A study raises fresh concerns about Zetia and its cousin, Vytorin, drugs that are still taken by millions of Americans to lower cholesterol, despite questions raised in 2009 about how well they work. In the study, Zetia failed to shrink buildups in artery walls while a rival drug, Niaspan, did so significantly. Zetia users also suffered more heart attacks and other problems although the numbers of these events are too small to draw firm conclusions. "This study provides no evidence that would reassure us that this drug is beneficial, and it provides some evidence that it may be harmful," said Yale University cardiologist Dr. Harlan Krumholz, who had no role in the study. Vytorin is a pill that combines Zetia with a statin. Both are sold by Merck & Co. of Whitehouse Station, N.J.

Simvastatin side effects, safety, risks, danger
Statins are among the most commonly prescribed drugs and they play a role in the prevention of cardiovascular disease. However, they have been associated with mitochondrial abnormalities and may cause myopathy, which can progress to rhabdomyolysis -- a potentially fatal condition.

BMJ Case Rep. 2013. Should anyone still be taking simvastatin 80 mg? A 64-year-old woman who previously suffered myalgia with lower dose simvastatin was given just one high dose of simvastatin and developed rhabdomyolysis. This was a potentially life-threatening complication. Fortunately she recovered with conservative management and did not require haemofiltration. This case reminds us of the risks of statins and the caution that needs to be exercised when prescribing these medications to patients with a history of intolerances.

CNS Drugs. 2014. Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management. Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin, may cause neuropsychiatric reactions. They include behavioural alterations (severe irritability, homicidal impulses, threats to others, road rage, depression and violence, paranoia, alienation, antisocial behaviour); cognitive and memory impairments; sleep disturbance (frequent awakenings, shorter sleep duration, early morning awakenings, nightmares, sleepwalking, night terrors); and sexual dysfunction (impotence and decreased libido). Studies designed to investigate specific neuropsychiatric endpoints have yielded conflicting results. Several mechanisms, mainly related to inhibition of cholesterol biosynthesis, have been proposed to explain the detrimental effects of statins on the central nervous system. Approaches to prevent and manage such adverse effects may include drug discontinuation and introduction of dietary restrictions; maintenance of statin treatment for some weeks with close patient monitoring; switching to a different statin; dose reduction; and use of ω-3 fatty acids or coenzyme Q10 supplements. The available information suggests that neuropsychiatric effects associated with statins are rare events that likely occur in sensitive patients.

Patients on the highest approved dose of the cholesterol-lowering drug Zocor may be at increased risk of muscle injury. Made by Merck & Co and sold under the brand name Zocor, simvastatin is also sold in combination with ezetimibe as Vytorin, and in combination with niacin as Abbott Laboratories Simcor. The FDA said its review of simvastatin is part of an ongoing effort to evaluate the risk of statin-associated muscle injury. The warning follows an FDA review of new information on the risk of muscle injury from clinical trials, studies, adverse event reports and prescription use data, Rhabdomyolysis is the most serious form of muscle disease and can lead to severe kidney damage, kidney failure, and sometimes death.

Brain function
Simvastatin and other statins (HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors) are extensively used in clinical practices and are effective in decreasing serum low-density lipoprotein cholesterol. However, their effect on cholesterol synthesis in central nervous system and its behavioral consequences have not been fully understood yet.

Simvastatin and mitochondrial dysfunction
High-dose simvastatin treatment is associated with mitochondrial depletion, which may be the cause of statin-induced myopathy. To determine whether statins alter muscle mitochondrial DNA levels, mitochondrial DNA was analyzed in skeletal muscle biopsy specimens that had been collected as part of a previously published clinical trial investigating the effects of high-dose simvastatin or atorvastatin versus placebo. In the trial, 48 hypercholesterolemic subjects were randomly assigned to receive placebo, atorvastatin 40mg/day, or simvastatin 80mg/day for 8 weeks. Muscle biopsy specimens were collected at baseline and at follow-up, and mitochondrial DNA levels were quantified by real-time polymerase chain reaction. No subject had received prior statin therapy and none reported muscle pain during the study or had elevated serum creatine kinase levels at follow-up. The researchers found that mitochondrial DNA levels were significantly decreased in the simvastatin group at follow-up. No changes were observed in the placebo or atorvastatin groups. Results show that high-dose statin therapy can be associated with significantly reduced levels of mitochondrial DNA in skeletal muscle, after only 8 weeks of treatment, and even in the absence of muscle pain or creatine kinase elevations. The research was financially supported by unrestricted grants from AstraZeneca Canada and from the St. Paul's Hospital Foundation Healthy Heart Research Endowment Fund.

The FDA began an investigation in August 2008 regarding a possible association between Vytorin (simvastatin / ezetimibe) and an increased incidence of cancer. The link is based on preliminary results from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial.

Combining with fish oils
Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia.
Am J Cardiol. 2008. Provident Clinical Research, Glen Ellyn, Illinois, USA.
Prescription omega-3 acid ethyl esters (P-OM3) are commonly used for treatment of very high triglyceride levels, often in combination with a statin, to lower persistent hypertriglyceridemia. This randomized, crossover trial evaluated 6 weeks of combination therapy with simvastatin 20 mg/day plus P-OM3 4 g/day or placebo in 39 men and women (average age 58 years) with a triglyceride concentration 200 to 600 mg/dl and non-high-density lipoprotein (non-HDL) cholesterol greater than their National Cholesterol Education Program treatment goals after a 5-week diet lead-in. Non-HDL cholesterol decreased from baseline (209 mg/dl) by 40% for P-OM3 + simvastatin compared with 34% for placebo + simvastatin. Favorable changes for P-OM3 + simvastatin versus placebo + simvastatin were also observed for very low-density lipoprotein (VLDL) cholesterol, triglyceride, total cholesterol, HDL cholesterol (+16% vs +11%), apolipoprotein B, total cholesterol:HDL cholesterol ratio, triglyceride : HDL cholesterol ratio, and systolic and diastolic blood pressures. VLDL particle concentration and size decreased and LDL particle size increased significantly more with P-OM3 + simvastatin than with placebo + simvastatin. In conclusion, fish oils + simvastatin appears to be a useful therapeutic option for the management of mixed dyslipidemia.

Simvastatin and niacin combination
Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy;
American Heart Journal. Airan-Javia SL, Wolf RL, Wolfe ML, Tadesse M, Mohler E, Reilly MP;
Niacin has multiple lipoprotein effects that may provide cardiovascular benefit when added to statin monotherapy. In this randomized, placebo-controlled trial of magnetic resonance imaging of carotid atherosclerosis, we performed a secondary comparison of combination niacin-statin (simvastatin 20 mg / Niacin-ER 2G to monotherapy with moderate 20 mg and high-dose 80 mg simvastatin on lipids, apolipoproteins (apo), low density lipoprotein (LDL) and high density lipoprotein (HDL) particle subclasses, and inflammatory markers. We demonstrate that full-dose niacin / moderate-dose simvastatin combination has sustained benefits on atherogenic apoB lipoproteins, at least comparable to high-dose simvastatin, while also raising HDL-cholesterol.

Policosonal combination
Zhonghua Xin Xue Guan Bing Za Zhi. 2013. Effects of policosanol combined with simvastatin on serum lipids and sex hormones in male patients with hyperlipidemia. To evaluate the effects and safety of policosanol combined with simvastatin on serum lipids and sex hormones in male patients with hyperlipidemia. This randomized, single-blinded, placebo-controlled study included 120 male patients with hyperlipidemia. Patients were divided randomly into treatment group(n = 60) and control group(n = 60). Patients in the treatment group were administrated with simvastatin (40 mg/d) plus policosanol (20 mg/d),and those in the control group were treated with simvastatin (40 mg/d) plus placebo (20 mg/d).  Simvastatin / policosanol produces greater decreases in TC, LDL-C than simvastatin/placebo without resulting more side effects and changes on sex hormones.

Simvastatin and psyllium together work better
Effect of combining psyllium fiber with simvastatin in lowering cholesterol.
Arch Intern Med. 2005. Moreyra AE, Wilson AC, Koraym A. Division of Cardiology Lipid Disorder Center, Department of Medicine, Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, New Brunswick, USA.
Soluble fiber supplements are recommended to reduce levels of low-density lipoprotein cholesterol (LDL-C). We evaluated the LDL-C-lowering effect of psyllium husk added to low-dose simvastatin therapy. In a 12-week blinded placebo-controlled study, patients were randomized to receive 20 mg of simvastatin plus placebo, 10 mg of simvastatin plus placebo, or 10 mg of simvastatin plus 15 g of psyllium (Metamucil) daily. Levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were determined after 4 and 8 weeks of treatment. The study group comprised 68 patients. All treatments were well tolerated, and after 8 weeks the mean LDL-C levels in the group receiving 10 mg of simvastatin plus placebo fell by 55 mg/dL (1.4 mmol/L) from baseline, compared with 63 mg/dL (1.6 mmol/L) in the group receiving 10 mg of simvastatin plus psyllium. The mean lowering of LDL-C in the group receiving 20 mg of simvastatin plus placebo was the same as that in the group receiving 10 mg of simvastatin plus psyllium. Similar results were seen for apolipoprotein B and total cholesterol. No significant changes from baseline triglyceride or high-density lipoprotein cholesterol levels occurred. Dietary psyllium supplementation in patients taking 10 mg of simvastatin is as effective in lowering cholesterol as 20 mg of simvastatin alone. Psyllium soluble fiber should be considered as a safe and well-tolerated dietary supplement option to enhance LDL-C and apolipoprotein B lowering.

Comparison to red yeast rice and fish oil
Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial.
Mayo Clin Proc. 2008;  Becker DJ, Gordon RY, Morris PB, Yorko J, Gordon YJ, Iqbal N. Division of Cardiology, Chestnut Hill Hospital, University of Pennsylvania Health System, Philadelphia, PA.
To compare the lipid-lowering effects of an alternative regimen (lifestyle changes, red yeast rice, and fish oil) with a standard dose of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). This randomized trial enrolled 74 patients with high cholesterol levels who met Adult Treatment Panel III criteria for primary prevention using statin therapy. All participants were randomized to an alternative treatment group (AG) or to receive simvastatin (40 mg/d) in this open-label trial conducted between April 1, 2006, and June 30, 2006. The alternative treatment included therapeutic lifestyle changes, ingestion of red yeast rice, and fish oil supplements for 12 weeks. The simvastatin group received medication and traditional counseling. The primary outcome measure was the percentage change in low-density lipoprotein cholesterol (LDL-C). Secondary measures were changes in other lipoproteins and weight loss. There was a statistically significant reduction in LDL-C levels in both the AG (-42%) and the simvastatin group (-39%). No significant differences were noted between groups. The AG also demonstrated significant reductions in triglycerides (-29% vs -9%) and weight (-5.5% vs -0.4%) compared with the simvastatin group. Lifestyle changes combined with ingestion of red yeast rice and fish oil reduced LDL-C in proportions similar to standard therapy with simvastatin. Pending confirmation in larger trials, this multifactorial, alternative approach to lipid lowering has promise for a subset of patients unwilling or unable to take statins.

Combining with TriCor
Adding a drug that lowers blood fats known as triglycerides to cholesterol-fighting statins provided no additional protection from heart attack, stroke and death from heart disease in patients with Type 2 diabetes. A study run by the National Institutes of Health, dubbed Accord, aimed to see if the dual-drug therapy could reduce heart disease and stroke-related events in diabetes patients at particularly high risk of serious heart problems due to additional risk factors, such as obesity and high blood pressure. All subjects in the 5,518-patient trial took Zocor, which is available generically as simvastatin. One group also received TriCor, which is designed to lower the blood fats known as triglycerides and raise "good" HDL cholesterol. TriCor belongs to a class of drugs called fibrates. There was an 8 percent risk reduction from the combination therapy compared with the statin plus dummy pill, but researchers said the result could have been a statistical fluke. Dr. Henry Ginsberg, was study's lead investigator, who presented the data at the American College of Cardiology scientific meeting in Atlanta on 2010. Based on the results, Dr. Steven Nissen, a prominent cardiologist with the Cleveland Clinic, predicted that "the use of fenofibrates will decline precipitously. It's another troubling example of a drug that was approved that didn't work."