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PUBLICATION OF THE HDL ATHEROSCLEROSIS TREATMENT STUDY (HATS) in the New England Journal of Medicine follows presentation of preliminary data at the annual American College of Cardiology meeting in March [...]

Atherosclerotic vascular disease is the major cause of death and disability in adult men and women living in the United States, where 13-14 million adults have a history of coronary artery disease (CAD). One-third of the 1.5 million individuals who experience a myocardial infarction (MI) each year will die and one half of these deaths will occur within 60 minutes of the event. The relation between elevated serum lipids and CAD has been corroborated by epidemiologic as well as pathologic evidence. Approximately 96 million people have total cholesterol levels [is greater than] 200 mg/dL, with 38 million of these individuals having values [is greater than] 240 mg/ dL. The National Cholesterol Education Program (NCEP) identified elevated low-density lipoprotein (LDL) cholesterol as a primary risk factor for CAD in 1988. This conclusion, along with recommendations for assessment and treatment, was reaffirmed in 1993. The NCEP also recommended mat high-risk patients, with or without clinical manifestations of coronary atherosclerosis, should substantially lower their serum cholesterol levels. Specifically, the NCEP recommends that patients with CAD need to maintain serum LDL cholesterol levels of [is less than or equal to] 100 mg/dL, this means that the vast majority of patients need to decrease LDL cholesterol levels by [is greater than or equal to] 30%. Aggressive dietary and/or drug therapy are recommended to achieve these reductions. In recent years, clinical trials have demon-strated the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('stating') in lowering elevated levels of LDL cholesterol and decreasing the risk for clinical coronary events. Am J Med. 1998;104(2A):2S-5S. [C] 1998 by Excerpta Medica, Inc.

Background: Few studies have been performed to compare fenofibrate, a second-generation fibrate, and simvastatin a 3-hydroxy-3-methylglutaryl coenzyme A reductase dlictasc iiihibiior. This study was aimed to compare the of both drugs in reducing atherogenic risk factors in type IIa or Ila hyperlipidemia. Methods: Sixty-three patients entered this single-center, double-blind, crossover trial. Sixty patients (32 with type Ila, and 28 with type Ilb hyperlipidemia) were randomized to treatment for 3 months with a single daily 200-mg dose of micronized fenofibrate or 20 mg of simvastatin and then changed to the alternative treatment for a further 3-month period. Results: After the first treatment period, in both types IIa and Ilb, fenofibrate and simvastatin produced similar significant reductions in levels of total cholesterol and low- density lipoproten cholesterol; high-density lipoprotein cholesterol levels were increased with both drugs in type Ilb. Only fenolibrate decreased total triglyceride levels in type Ilb, Lp(a) lipoprotein levels in patients with high baseline values, and fibrinogen. After the second period of treatment, in both types Ila and Ilb, switching from fenofibrate to simvastatin resulted in a further reduction in total cholesterol and low-density lipoprotein cholesterol levels. The difference in the response of the two treatments on levels of total triglycerides, Lp(a) lipoprotein, and fibrinogen was confirmed after changing over to the alternative treatment. This short-term study showed few adverse effects for both drugs. Conclusions: Fenofibrate and simvastatin provide similar variations on total cholesterol and low-density, lipoprotein cholesterol levels after a 3-month treatment period, with simvastatin having the capacity to decrease these measures further when administered after fenofibrate. However, fenofibrate exhibits a significant effect on other established risk factors, such as total triglyceride, fibrinogen, and Lp(a) lipoprotein levels, and accordingly has a broader spectrum of activity than simvastatin.

There is substantial evidence that drug treatment of hypemholesterolemia in patients without known coronary artery disease (CAD) can reduce fatal and nonfatal CAD events. Two trials, the Lipid Research Clinics Coronary Primary Prevention Trial and the Heisinki Heart Study used cholestyramine and gemfibrozil, respectively, to alter lipoprotein levels; their demonstrated efficacy and safety have led to their widespread use in hyperlipidemic patients. Recently, a new class of hypolipidemic agents has been shown to be extremely effective in lowering total and low-density lipaprotein cholesterol levels. These drugs, including govastatin and simvastatin, competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of intracellular cholesterol synthesis. Results of safety and efficacy studies suggest that they may be valuable first-line treatment options for high-risk hypemholesterolemic patients. Two long-term clinical trials are planned with lovastatin and simvastatin. in the United States, lovastatin will be used in a double-blind, placebo-controlled, primary prevention trial involving 8,000 patients without clinical evidence of CAD, slight to moderate elevations of total cholesterol, and low-and high-density lipoprotein cholesterol to establish whether 5 years of treatment will decrease the rate of fatal CAD or nonfatal myocardial infarction. A Scandinavian study of 4,000 patients with ischemic heart disease and hypecholesterolemia will determine if simvastatin will improve total survival and reduce fatal or nonfatal myocardial infarction and sudden death for at least 3 years. These study designs will be discussed and compared with other studies, and the expected impact on CAD event rates presented. (Am J Cardiol 1990;66:39B-43B), Lovastatin is a naturally occurring drug, derived from the fungus Aspergillus terreus. It serves as the basis for the chemical synthesis of simvastatin; both drugs are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Previous studies have demonstrated that lovastatin and simvastatin are effective in reducing total serum cholesterol. In addition, the reduction occurs in a manner that is deemed to be especially favorable in terms of lowering the risk of heart disease. Low-density lipoprotein (LDL) cholesterol is reduced, while high-density lipoprotein (HDL) cholesterol, which is thought to exert a protective effect, is actually increased. It is well established that elevated levels of LDL cholesterol are associated with an increased risk of coronary artery disease. Furthermore, it is well established that the treatment of hypercholesterolemia (high serum cholesterol) with drugs like cholestyramine, gemfibrozil, and niacin reduces the risk of coronary death. It is important to demonstrate that the favorable levels of cholesterol reduction achieved with lovastatin and simvastatin actually translate into proportional improvements in the rate of coronary death. Two long-term trials are presently being initiated; one in the United States involving 8,000 patients without evidence of coronary artery disease, and one in Sweden involving 4,000 patients who already have ischemic heart disease and for whom the risk of coronary death is particularly high. These studies should establish if lovastatin and simvastatin have a beneficial effect on coronary artery disease mortality. (Consumer Summary produced by Reliance Medical Information, Inc.)

A variety of double-blind studies have compared the efficacy of hydroxymethylglutaryl coenzyme A reductase inhibitors (lovastatin and simvastatin) with that of control agents (cholestyramine, fibrates and probucol) in patients with type IIA or IIB primary hypercholesterolemia. Results have shown that both lovastatin and simvastatin are more effective than the standard therapies with regard to reducing total and low-density lipoprotein cholesterol. Decreases in triglycerides and increases in high-density lipoprotein cholesterol were generally greater with fibrates. Ongoing studies are assessing the benefits of lovastatin and simvastatin in reducing the incidence of mortality from coronary artery disease, as well as causing regression of coronary atheroma. (Am J Cardiol 1990;65:19F-22F), Until recently, when treating patients with elevated cholesterol (hypercholesterolemia) the physician was faced with choosing an effective, but poorly tolerated drug or a well-tolerated agent with limited effectiveness. This situation is changing with the introduction of a group of agents which inhibit the enzyme hydroxymethylglutaryl coenzyme A (HMG CoA) reductase. Lovastatin, available in the United States and Canada, and simvastatin, available in a number of European nations, are the two most widely used HMG CoA reductase inhibitors. Lovastatin or simvastatin is used as monotherapy (a single drug) to reduce elevated cholesterol. These drugs act by inhibiting the pathway of intracellular cholesterol synthesis, or production. When cholesterol synthesis is inhibited, the cells increase their low-density lipoprotein (LDL) receptors to remove more LDL cholesterol from the blood. (LDL cholesterol is associated with an increased risk of cardiovascular disease.) As a result, the blood levels of cholesterol and LDL cholesterol fall. An important feature of taking an HMG CoA reductase inhibitor orally is that the liver removes a great quantity of the drug before it can enter the general circulation. While this might be a problem for many other types of medication, it is ideal in this case because the liver is the primary site of cholesterol synthesis. Most of the drug goes directly to where it does the most good. Clinical studies have indicated that while another group of antilipidemic agents known as fibrates (such as gemfibrozil and bezafibrate) are more effective at reducing blood levels of triglycerides (another group of lipids or fats), lovastatin and simvastatin are more effective than standard therapies for reducing blood levels of LDL cholesterol. (Consumer Summary produced by Reliance Medical Information, Inc.)

Simvastatin is a drug that lowers blood cholesterol and specifically acts to decrease levels of low-density lipoprotein cholesterol (LDL-C). Elevated LDL-C has been shown to be a major risk factor for disease of the coronary arteries, the major blood vessels supplying the heart. This cholesterol-lowering agent is given once daily along with a low-fat diet for treating hypercholesterolemia, high blood levels of cholesterol, particularly LDL-C. Disorders associated with high LDL-C levels were previously treated with agents called resins, such as cholestyramine and colestipol, which were not well accepted by patients. The effectiveness of simvastatin was compared with that of cholestyramine in a 12-week study of 251 patients with hypercholesterolemia. Twenty and 40 milligrams (mg) of simvastatin given daily decreased total cholesterol by 26 and 33 percent respectively, and LDL-C by 32 and 40 percent respectively. Four to 12 mg of cholestyramine resin given twice daily reduced total cholesterol and LDL-C by 15 and 21 percent, respectively. Both agents increased high-density lipoprotein cholesterol, whereas triglyceride levels were decreased by simvastatin and increased by cholestyramine. Patients tolerated simvastatin more easily than cholestyramine, which caused several gastrointestinal side effects, although neither drug caused severe adverse reactions. (Consumer Summary produced by Reliance Medical Information, Inc.)

ABSTRACT & COMMENTARY THE HYPOTHESIS FOR THIS LARGE AND IMPORTANT STUDY IS THAT patients with increased vascular risk would benefit from LDL-cholesterol (LDL-C) lowering with a statin, irrespective of baseline [...]

Simon Ebbett GP leaders have attacked the move to make simvastatin available over the counter as unsafe and unfair. As Doctor predicted last week, the Government has now formally announced [...]

Further results from the UK Heart Protection Study show that treating diabetes sufferers with 40mg/day simvastatin reduced LDL cholesterol by an average 1mmol/l and vascular events by a quarter, irrespective [...]

The author evaluates a study of the use of simvastatin to treat hypercholesterolemia in elderly patients. Patients taking simvastatin showed reduce mortality due to cardiovascular disease.

Atorvastatin and simvastatin have been shown to be the most effective statins at reducing serum cholesterol concentration, a study in the BMJ has found. The cross-sectional survey, carried out by [...]

Cholesterol and triglycerides have been shown to predict progression of proteinuria in T1D. To examine the feasibility of a long-term/large-scale trial of the effect of lipid modulation on the progression [...]

Background: Patients with diabetes mellitus (DM) have a marked increase in coronary heart disease (CHD) events relative to those without DM. In a previous report from the Scandinavian Simvastatin Survival Study using a clinical case definition of DM (n = 202), simvastatin-treated patients had significantly fewer CHD events compared with placebo-treated control subjects. Objective: To examine the effect of simvastatin therapy on CHD in patients with DM and impaired fasting glucose levels. Methods: Using the 1997 American Diabetes Association diagnostic criteria, we assessed the effect of simvastatin therapy post hoc for an average of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483). Results: Simvastatin-treated patients with DM had significantly reduced numbers of major coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly, due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin use significantly reduced the number of major coronary events (RR = 0.62; P = .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary (RR = 0.45; P = .007) mortality. Conclusions: Our results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels ([is greater than or equal to] 6.0 mmol/L [[is greater than or equal to] 110 mg/ dL]) or DM and known CHD. Arch Intern Med. 1999;159:2661-2667

ATLANTA -- The combination of simvastatin plus niacin is particularly effective at preventing atherosclerotic progression and clinical events in patients with the metabolic syndrome, Dr. Xue-Qiao Zhao reported at the [...]

The efficacy of simvastatin, a new inhibitor of cholesterol biosynthesis, was studied in patients with familial hypercholesterolemia. A mean reduction in low-density lipoprotein cholesterol of 38 percent was observed after eight weeks of treatment with 20 mg of simvastatin; a 42 percent reduction was seen after the next 16 weeks with 40 mg. There was no difference in response whether the drug was taken in one or two doses. In another study, simvastatin (40 mg per day) was compared with cholestyramine (8 to 16 g per day). After 12 weeks, low-density lipoprotein cholesterol was reduced 43 percent by simvastatin and 29 percent by cholestyramine. Combination therapy caused a reduction in low-density lipoprotein cholesterol of 54 percent. Simvastatin appeared also to be a potent hypolipidemic drug in 10 patients with familial dysbetalipoproteinemia. The drug was well tolerated. Adverse effects were primarily composed of increases in serum transaminases and creatine phosphokinase. No effects of simvastatin on the production of steroid hormones were observed., To evaluate the effectiveness of simvastatin in reducing serum cholesterol, 43 patients with hereditary hypercholesterolemia were tested in several centers. All subjects were observing a standard lipid-lowering diet and did not receive any drug treatment for six weeks prior to the study. All patients received placebo for two weeks, after which 35 patients were randomly assigned to the simvastatin group and 8 were assigned to a placebo control group. No adverse effects were observed in the simvastatin group, and the patients reported no subjective effects. After 20 weeks, the range of reduction of low-density lipoprotein was from 39 to 71 percent. High-density lipoproteins were elevated by 10 to 14 percent. Different dose ranges were tried; 20 mg per day of simvastatin was more effective than 40 mg per day. A single evening dose seemed to be at least as effective as doses broken up throughout the day. Even in cases of severe hypercholesterolemia, simvastatin can reduce low-density lipoprotein levels to the normal range. (Consumer Summary produced by Reliance Medical Information, Inc.)

Using a model of coronary heart disease incidence based on multivariate logistic regression functions from the Framingham Heart Study, the cost effectiveness of simvastatin was compared with that of cholestyramine in preventing such disease. For men with initial cholesterol levels of 310 mg/dl, the cost effectiveness of cholestyramine, expressed in Dutch guilders, ranges from approximately 220,000 to 510,000 guilders per year of life saved, depending on age at initiation of therapy. For simvastatin, cost-effectiveness ratios range from 50,000 to 110,000 guilders per year of life saved among this group of men. Results are similar for women, although the cost effectiveness of both agents is considerably less. These results suggest that simvastatin is substantially more cost effective than cholestyramine; that it compares well with other generally accepted medical practices, especially if therapy is initiated at an early age; and that simvastatin should become accepted as a drug of first choice in the treatment of persons with elevated serum cholesterol levels as its long-term safety record becomes more established., Cholestyramine is currently recommended by the Dutch Cholesterol Consensus Conference as the drug of first choice in the treatment of elevated blood cholesterol. Because simvastatin was registered in Holland at the end of 1988, there should now be a re-evaluation of treatment recommendations. The cost effectiveness of treatment was calculated as the cost of cholesterol-lowering treatment minus savings in the cost of treating coronary heart disease, divided by the net change in life expectancy. Using results from the 24-year follow-up of participants in the Framingham Heart Study and the Dutch national mortality statistics, the cost effectiveness was calculated. Simvastatin proved to be significantly more cost effective than cholestyramine. Other studies have also demonstrated a superior freedom from side effects with simvastatin treatment. The cost of one year of life gained by simvastatin therapy is about 50,000 Guilders, which is five times more than one year of life gained by breast cancer screening or screening for cervical cancer, and less than one year of life gained by heart transplantation or treating end-stage renal disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

A 12-week, randomized, double-blind, multicenter study was undertaken to compare the efficacy, tolerability, and safety of simvastatin and gemfibrozil in 290 patients with primary hypercholesterolemia. Patients in stratum I (initial low-density lipoprotein cholesterol level less than 195 mg/dl) received simvastatin 5 to 10 mg once every afternoon; patients in stratum 11 (initial low-density lipoprotein cholesterol level at least 195 mg/dl) received 10 to 20 mg once every afternoon. Gemfibrozil was given in a constant dosage of 600 mg twice daily in both strata. Simvastatin reduced low-density lipoprotein cholesterol levels by 26 and 34 percent in strata I and 11, respectively. The corresponding reductions brought about by gemfibrozil were 18 and 17 percent. High-density lipoprotein cholesterol was increased by 7 and 9 percent by simvastatin and by 17 and 16 percent by gemfibrozil in strata I and II, respectively. Ratios of low-density to high-density lipoprotein cholesterol were reduced by approximately 25 percent by simvastatin 5 to 10 mg once every afternoon and gemfibrozil 600 mg twice daily, but were reduced by 37 percent by simvastatin 10 to 20 mg once every afternoon. Both drugs reduced plasma triglyceride levels, but gemfibrozil was much more effective. The short-term tolerability and safety of both drugs appeared to be good during the 12-week study. The results suggest that both drugs have useful but distinctly different lipid-modifying properties., Although numerous studies have demonstrated the efficacy of simvastatin in the reduction of elevated serum cholesterol, there has not been a side-by-side comparison of simvastatin with gemfibrozil, a drug which is effective in reducing coronary heart disease in patients with elevated cholesterol. A multicenter study was undertaken in which 290 patients from Europe and South America were treated for primary hypercholesterolemia. Patients were assigned to Stratum I if their initial low-density lipoprotein (LDL) cholesterol was less than 195 milligrams per deciliter (mg/dl), and to Stratum II if their initial concentration was equal to or greater than 195 mg/dl. Within each stratum, patients were randomly assigned to either a gemfibrozil group or a simvastatin group. All patients receiving gemfibrozil received 600 milligrams (mg) twice daily. Stratum I patients were given 5 mg of simvastatin per day for six weeks. In the higher cholesterol Stratum II group, patients in the simvastatin group received 10 mg per day for six weeks. At the end of the six week period, patients in the simvastatin groups with LDL cholesterol above 140 mg/dl had their dose doubled for the next six weeks. In all cases, patients receiving simvastatin achieved a greater reduction in LDL cholesterol, though not all the observed differences were statistically significant. Gemfibrozil lowered triglycerides more than did simvastatin. Gemfibrozil may be regarded as a useful alternative in patients with type IIb hyperlipoproteinemia who also have elevated serum triglycerides. However, in the recommended dose range, simvastatin demonstrated itself to be more effective in lowering total cholesterol and LDL cholesterol. (Consumer Summary produced by Reliance Medical Information, Inc.)

'This is a landmark study. Its results make it clear that patients with diabetes and coronary heart disease benefit enormously from cholesterol lowering, which slashes the risk of a subsequent [...]