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Submaximal dose pentagastrin tests conducted in normal male volunteers with L-643.441, a novel histamine H2-receptor antagonist, indicate that it is a potent and long-acting inhibitor of gastric acid secretion. The effect appears dose-dependent and single doses of 50 mg are sufficient to reduce secretory potential by at least 50% when examined 24 h after drug administration. No adverse effects attributable to treatment were observed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. OBJECTIVE: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. RESULTS: Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001 ) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P=0.002 ) and apo A-I ( P=0.006 ). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001 ). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. CONCLUSION: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM. [ABSTRACT FROM AUTHOR]

The discovery of PCSK9 and its role in regulating the low-density lipoprotein (LDL) receptor, and the effect of loss-of-function mutations of its gene, identified it as a therapeutic target in 2006. Fully humanized monoclonal antibodies to PCSK9 (alirocumab and evolocumab) proved effective for lowering LDL cholesterol and subsequently for reducing atherosclerotic events in large outcome trials. Suppressing PCSK9 synthesis via gene silencing using inclisiran, a small interfering RNA, is another approach that effectively reduces LDL cholesterol, and a cardiovascular outcome trial is in progress. These treatments are given subcutaneously on a background of maximally tolerated statin treatment and are long-lasting: dosing is once or twice a month, self-administered, for alirocumab and evolocumab, and every 6 months for inclisiran, in the clinic, with an extra dose at 3 months in the initial year of therapy. These 3 agents produce mean LDL reductions of about 55% with no important adverse effects detectable to date. They are indicated in patients with atherosclerotic vascular disease or familial hypercholesterolemia who cannot achieve LDL cholesterol targets with maximally tolerated statin treatment. Such therapy can produce very low plasma LDL cholesterol and PCSK9, but there is no evidence this is harmful. Introduction into clinical practice has been impeded by economic considerations. The barrier to their use has not been scientific or medical, but rather the impact on healthcare resources. Prices have been reduced, but whether they are now cost-effective varies from country to country., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Combinations of lipid-lowering agents can often bring LDL cholesterol down to around 40 mg/dL (1 mmol/L). Randomized controlled trials indicate that this reduces the risk of atherosclerotic vascular events with minimal adverse effects. This has raised the question of whether there is any concentration of LDL cholesterol below which further lowering is futile and/or a source of new adverse effects. This article examines several lines of evidence that lead to the conclusion that there is no known threshold below which lowering LDL cholesterol is harmful, but reduction of LDL cholesterol below 25 mg/dL may provide little if any further benefit., (Copyright © 2022 Elsevier Inc. All rights reserved.)

One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied. In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority. Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.

The nocebo effect, the inverse of the placebo effect, is a well-established phenomenon that is under-appreciated in cardiovascular medicine. It refers to adverse events, usually purely subjective, that result from expectations of harm from a drug, placebo, other therapeutic intervention or a nonmedical situation. These expectations can be driven by many factors including the informed consent form in a clinical trial, warnings about adverse effects communicated by clinicians when prescribing a drug, and information in the media about the dangers of certain treatments. The nocebo effect is the best explanation for the high rate of muscle and other symptoms attributed to statins in observational studies and clinical practice, but not in randomized controlled trials, where muscle symptoms, and rates of discontinuation due to any adverse event, are generally similar in the statin and placebo groups. Statin-intolerant patients usually tolerate statins under double-blind conditions, indicating that the intolerance has little if any pharmacological basis. Known techniques for minimizing the nocebo effect can be applied to the prevention and management of statin intolerance., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Statin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant., Methods: Examination of differences between statin and placebo in withdrawal rates due to adverse events - a good measure of tolerability - in statin cardiovascular outcome trials in patients with advanced disease and complex medical histories, who may be more vulnerable to adverse effects. The arguments commonly used to dismiss safety and tolerability data in statin clinical trials are examined., Results: Rates of withdrawal due to adverse events in trials in patients with advanced disease and complex medical histories are consistently similar in the statin and placebo groups. We find no support for arguments that statin cardiovascular outcome trials do not translate to clinical practice., Conclusions: Given the absence of any signal of intolerance in clinical trials, it appears that statin intolerance in the clinic is commonly due to the nocebo effect causing patients to attribute background symptoms to the statin. Consistent with this, over 90% of patients who have stopped treatment because of an adverse event can tolerate a statin if re-challenged. Consequently, new agents, including monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, will be useful when added to statin therapy but should rarely be used as a statin substitute., (© The European Society of Cardiology 2015.)

Simvastatin is a long-established hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, first introduced in 1988. At the maximal recommended dose of 80 mg/day, it produces an average reduction in low-density lipoprotein cholesterol (LDL-C) of 47%, accompanied by reductions in very LDL-C, triglycerides and apolipoprotein B, and a modest increase in high-density lipoprotein cholesterol. The only important, although rare, adverse effect of simvastatin is myopathy, an effect shared by all members of the class; when severe, this can take the form of rhabdomyolysis, which may lead to acute renal failure. The mechanism of the myopathy is not understood. The risk is increased by certain concomitant drugs, including gemfibrozil and potent inhibitors of cytochrome P450 3A4. Simvastatin has been studied in two large outcome trials, the Scandinavian Simvastatin Survival Study (4S), and the Heart Protection Study (HPS), both of which demonstrated strikingly beneficial effects on a variety of cardiovascular outcomes, with minimal adverse effects. 4S was the first study with a cholesterol-lowering agent to demonstrate an unequivocal reduction in all-cause mortality (30%; p = 0.0003). HPS showed that the beneficial effects of simvastatin were obtainable in a broad array of patients with, or at high risk of, coronary heart disease (CHD) in categories previously little studied, including women, the elderly, patients with diabetes without known CHD, and, perhaps most importantly, patients with LDL-C well below the UK population average. Simvastatin has recently become available in many countries as a combination product with the cholesterol absorption inhibitor, ezetimibe. Because of its long record of safety and demonstrated ability to reduce cardiovascular risk, simvastatin has recently become available without a prescription in the UK at the 10 mg dosage level.

In the 1950s and 1960s, it became apparent that elevated concentrations of plasma cholesterol were a major risk factor for the development of coronary heart disease, which led to the search for drugs that could reduce plasma cholesterol. One possibility was to reduce cholesterol biosynthesis, and the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, was a natural target. Here, I describe the discovery and development of lovastatin--the first approved inhibitor of HMG-CoA reductase--and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease.

The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.

A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins.

Background: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed., Methods and Results: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001)., Conclusions: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.

In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.

The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to <100 mg/dl. However, in some patients this cannot be achieved using monotherapy with simvastatin 40 mg/day, the current maximal recommended dose. To evaluate the effectiveness of extending the dosage range, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80, and 160 mg/day in a 26 week, double-blind, 3-period, complete block crossover study. Each active treatment period was 6 weeks in duration with intervening 2 week washout periods. Median reductions from baseline in LDL cholesterol were 41%, 47%, and 53% in the 40-, 80-, and 160-mg groups, respectively. The corresponding reductions in plasma TG were 21%, 23%, and 33%. High-density lipoprotein (HDL) cholesterol increased by 6% to 8% in each group. One patient (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg, and 3 (2.1%) taking 160 mg had transaminase elevations > 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.

Several studies have shown that effective lipid-lowering therapy slows the progression of atherosclerotic lesions in the coronary and carotid arteries. Recent clinical trials have confirmed and extended previous work showing that lowering cholesterol reduces the risk of coronary events. A clear reduction in major coronary events during treatment for 5 years with the hydroxymethylglutaryl-coenzyme A reductase inhibitor pravastatin was observed in the West of Scotland study and in the preliminary results of the Cholesterol and Recurrent Events study. The Scandinavian Simvastatin Survival Study has provided the first unequivocal demonstration of improved survival as a result of lipid-lowering therapy. These three trials, which together included over 15,000 patients studied for 5 years, have provided good evidence that noncardiovascular mortality is not affected by substantial reductions in blood cholesterol.

BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. METHODS AND RESULTS: In this multicenter, prospective, randomized trial, 180 patients with hypercholesterolemia and hypertriglyceridemia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total, low-density lipoprotein, and very low-density lipoprotein cholesterol and triglycerides by 24%, 29%, 45%, and 31%, respectively, while increasing high-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol-lowering effect of simvastatin; however, the combination was more effective than either monotherapy at raising high-density lipoprotein cholesterol and lowering very low-density lipoprotein cholesterol (P <.05). More patients discontinued treatment because of an adverse event in the niacin (P <.03) and combination groups (P =.06) than the simvastatin group. CONCLUSIONS: Treatment of patients with combined hyperlipidemia and/or low high-density lipoprotein with combination low-dose simvastatin and niacin resulted in large reductions in total, low-density lipoprotein, and very low-density lipoprotein cholesterol and increases in HDL cholesterol. Although the combination was well tolerated in the current trial, its safety needs to be evaluated in larger trials of longer duration.

Although several cholesterol-lowering interventions have reduced coronary heart disease (CHD) events in clinical trials, drug therapy for hypercholesterolaemia has not been as widely used as the US and European guidelines recommend, mainly because until recently there was insufficient clinical trial evidence for improved survival. The Scandinavian Simvastatin Survival Study (4S) is the first trial of lipid-lowering therapy to demonstrate an unequivocal reduction in total mortality. Largely as a result of this study, there is now little disagreement on the necessity to reduce low density lipoprotein (LDL) cholesterol effectively in hypercholesterolaemic patients with CHD. Many physicians believe it is also important to reduce elevated levels of LDL cholesterol in patients without overt coronary disease, but more clinical trial evidence will be required before this is universally accepted. Inhibitors of HMG-CoA reductase are the most effective class of agents for this purpose, and have become widely used. It is likely that the magnitude of risk reduction produced by lipid-lowering therapy is proportional to the degree of cholesterol lowering achieved, which is an important consideration when selecting an agent and deciding the dosage to use. The results of several multicentre comparative trials have clearly established that the 4 members of the class are not all equipotent on a mg basis in terms of their effects on lowering LDL cholesterol. They have shown that the hypolipidaemic effect of simvastatin 5 mg approximately equals that of pravastatin 15 mg and lovastatin 15 mg and that of fluvastatin 40 mg, all given once daily. The tolerability profiles of HMG-CoA reductase inhibitors are excellent. Five-year data are available for simvastatin and lovastatin, and to date there is no good evidence for important differences in safety or tolerability among the class.

BACKGROUND: Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used for the treatment of hypercholesterolemia. Physicians and third-party payers need an accurate measure of their relative potency and hypolipidemic efficacy. We have therefore compared simvastatin against fluvastatin, the newest member of this class. METHODS AND RESULTS: One hundred fifty-eight hypercholesterolemic patients in seven United States lipid clinics participated in this balanced double-blind incomplete block study. After a placebo-diet run-in period, patients received treatment with active drug for three consecutive 5-week periods, with measurement of lipids in a NHLBI-CDC standardized central laboratory at the end of each period. Each patient was randomly assigned to three of the following five treatments: simvastatin 5 mg, 10 mg, and 20 mg and fluvastatin 20 mg and 40 mg. The mean percent reductions in low density lipoprotein cholesterol from baseline were 21, 27, 32, 16, and 23 respectively. The simvastatin/fluvastatin milligram potency ratio was 6.8 (95% CI, 5.3-9.3). At the same 20 mg dose, simvastatin produced an effect on LDL cholesterol approximately double that of fluvastatin and resulted in 46% of patients achieving their National Cholesterol Education Program low density lipoprotein cholesterol target levels, compared to 12% for fluvastatin. CONCLUSIONS: Fluvastatin at its maximal dose of 40 mg daily is approximately equivalent to simvastatin 5 mg daily. Higher doses of simvastatin are considerably more effective in the treatment of primary hypercholesterolemia.

Four drugs that act as specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--lovastatin, pravastatin, simvastatin, and, most recently, fluvastatin--have been approved by regulatory authorities throughout the world. In the present review, we have critically assessed the comparative hypocholesterolemic effects of these four drugs based on direct comparative studies, which were randomized, double-blind, and included more than 25 patients per treatment group. All studies were conducted in patients with primary hypercholesterolemia and the major end point of efficacy was reduction in the plasma concentrations of low-density lipoprotein (LDL)-cholesterol. Eight comparative trials have evaluated the efficacy and safety of lovastatin, simvastatin, or pravastatin, and one recently completed trial has compared lovastatin and fluvastatin. These trials confirm the log-linear dose response curves for all four of these drugs but indicate that on a milligram-for-milligram basis, lovastatin and pravastatin are approximately equipotent, whereas simvastatin is at least twice as effective per milligram of drug administered as lovastatin and pravastatin. Lovastatin at doses of 20 and 40 mg/d was of similar efficacy to fluvastatin at doses of 40 and 80 mg/d and would suggest that on a milligram-for-milligram basis, fluvastatin is half as potent as lovastatin. The side-effect profiles of all four drugs appeared similar, and earlier reports that suggested a higher incidence of sleep disorders in patients treated with the more lipophilic drugs, lovastatin and simvastatin, as compared with pravastatin, are not supported by more recent, controlled clinical trials. We conclude that although the currently available HMG-CoA reductase inhibitors differ in their relative hypolipidemic effects, as a class they constitute the most effective agents available to maximally reduce elevated concentrations of LDL-cholesterol.

Background: A diet low in saturated fat and cholesterol is the standard initial treatment for hypercholesterolemia. However, little quantitative information is available about the efficacy of dietary therapy in clinical practice or about the combined effects of diet and drug therapy., Methods: One hundred eleven outpatients with moderate hypercholesterolemia were treated at five lipid clinics with the National Cholesterol Education Program Step 2 diet (which is low in fat and cholesterol) and lovastatin (20 mg once daily), both alone and together. A diet high in fat and cholesterol and a placebo identical in appearance to the lovastatin were used as the respective controls. Each of the 97 patients completing the study (58 men and 39 women) underwent four consecutive nine-week periods of treatment according to a randomized, balanced design: a high-fat diet-placebo period, a low-fat diet-placebo period, a high-fat diet-lovastatin period, and a low-fat diet-lovastatin period., Results: The level of low-density lipoprotein (LDL) cholesterol was a mean of 5 percent (95 percent confidence interval, 3 to 7 percent) lower during the low-fat diet than during the high-fat diet (P < 0.001). With lovastatin therapy as compared with placebo, the reduction was 27 percent. Together, the low-fat diet and lovastatin led to a mean reduction of 32 percent in the level of LDL cholesterol. The level of high-density lipoprotein (HDL) cholesterol fell by 6 percent (95 percent confidence interval, 4 to 8 percent) during the low-fat diet (P < 0.001) and rose by 4 percent during treatment with lovastatin (P < 0.001). The ratio of LDL to HDL cholesterol and the level of total triglycerides were reduced by lovastatin (P < 0.001), but not by the low-fat diet., Conclusions: The effects of the low-fat-low-cholesterol diet and lovastatin on lipoprotein levels were independent and additive. However, the reduction in LDL cholesterol produced by the diet was small, and its benefit was possibly offset by the accompanying reduction in the level of HDL cholesterol.

New information on the tolerability of lovastatin has emerged from an ongoing study of long-term therapy; preliminary results from a large, 48-week clinical trial; and spontaneous reports of adverse events observed during prescription use of the drug in the United States. As of June 1989, 744 patients had received lovastatin for an average duration of 3.6 years in the long-term study. Drug-attributable adverse events necessitated withdrawal of 17 patients (2.3%) from the study. These adverse effects were asymptomatic elevations of transaminases (10), skin rash (3), gastrointestinal symptoms (2), myopathy (1) and insomnia (1). No effect of lovastatin on the human lens was observed. In the 48-week study, 8,245 patients were randomized into 5 equal groups to receive placebo or lovastatin 20 or 40 mg once or twice daily on a double-blind basis. Only 3 cases of myopathy were observed, all in patients taking lovastatin 40 mg twice daily. The incidence of withdrawal from the study because of raised transaminases was approximately 0.1% in the placebo group vs 0.1, 0.7, 0.6 and 1.5% in patients taking lovastatin in doses of 20 mg once daily, 40 mg once daily, 20 mg twice daily and 40 mg twice daily, respectively. Lovastatin has been available in the United States since September 1987. By June 1989, the drug had been prescribed for approximately 1 million patients. Drug-attributable adverse events not observed in clinical trials (such as hypersensitivity reactions and symptomatic hepatitis) have been reported, but the incidence of each appears to be extremely low.

Mevinolin (MK-803) is a potent inhibitor of HMG-CoA reductase. After a placebo run-in period, mevinolin 5,15 or 50 mg, or placebo was given twice daily for 7-11 days under double -blind conditions ot 4 groups of 6 normocholesterolemic male volunteers. After 7 days, mean serum cholesterol fell 14%, 25% and 24% on 5, 15 and 50 mg, respectively, which was significantly greater than the fall on placebo (4%) in the case of the two higher doses (P less than 0.01). Serum triglycerides did not change significantly. Mevinolin was generally well-tolerated and there were no serious adverse effects.

HMG-CoA reductase catalyzes the conversion of hydroxymethylglutarate to mevalonate, an important early rate-limiting step in the cholesterol biosynthesis pathway. Since the discovery of compactin, the first HMG-CoA reductase inhibitor, by Endo et al. in 1976, several other inhibitors have been described. Those that have been investigated in the clinic include mevastatin (compactin), lovastatin (mevinolin), simvastatin (synvinolin), eptastatin (CS-514, SQ-31,000), and SRI-62320. These compounds are competitive inhibitors, with Ki values of the hydroxyacid forms of around 10(-9) M. Lovastatin (mevinolin, Mevacor), which is in the late stages of clinical development and has been administered to over 1000 subjects for up to 4 years, is the inhibitor on which the most information is available. It is given in single or divided doses of 20 to 80 mg/day, and is a very effective and usually well-tolerated lipid-lowering agent. At 40 mg bid, lovastatin produces the following approximate mean changes: total plasma cholesterol, -33%; low-density lipoprotein (LDL) cholesterol, -40%; very low-density lipoprotein cholesterol, -35%; plasma triglycerides, -25%; high-density lipoprotein cholesterol, +10%; apolipoprotein B, -20%. The substantial reduction in both LDL cholesterol and apolipoprotein B (the principal protein component of LDL) indicates a reduction in the number of circulating LDL particles. The mechanism probably involves both decreased LDL production and increased LDL clearance.

Racemic indacrinone is a high-ceiling, relatively long-acting diuretic. Both enantiomers have uricosuric activity, but the diuretic activity resides predominantly in the (-) enantiomer. Usual therapeutic doses of racemic indacrinone have only transient uricosuric activity, so that, as with other diuretics, hyperuricemia occurs. Sixty-five healthy men participated in a multicenter, double-blind, randomized, balanced, incomplete-block study comparing the effects on plasma urate and urate clearance of indacrinone (-) enantiomer 10 mg given concomitantly with 0, 10, 20, 40, and 80 mg (+) enantiomer (10/0, 10/10, 10/20, 10/40, 10/80), as single daily doses for 7 days. Hydrochlorothiazide (HCTZ) 50 mg daily and ticrynafen (T) 250 mg daily were controls. Each subject received two of the seven treatments, so that there were 18 subjects per treatment. On days 7 to 8, morning (mean of 0-hr values on days 7 and 8), HCTZ, 10/0, 10/10, and 10/20 elevated plasma urate by 8% to 16%. 10/40 was approximately isouricemic, and 10/80 and T lowered plasma urate by 13% and 41%. There were corresponding changes in urate clearance.

The response of the rabbit endometrium to the copper IUD was investigated. A plastic IUD bearing copper foil (42 mm2) was inserted into one horn of the rabbit uterus and a physically similar platinum-bearing IUD in the contralateral horn served as a control. The Pt-IUD caused no tissue damage and little if any inflammatory reaction in ovariectomized, oestrous or pregnant animals, whereas the Cu-IUD produced endometrial ulcers in 14 out of 15 does in all hormonal states. The associated inflammation was particularly intense in the pregnant animals in which a unilateral pyometra was usually present. Despite the endometrial trauma produced, the Cu-IUD was only partly effective as a contraceptive agent, 36% of the ova shed from the ovary ipsilateral to the Cu-IUD implanting, compared with 63% of the ova ipsilateral to the Pt-IUD. However, almost half of the implantation swellings in the copper-bearing horns were abnormally small or distorted in shape at 9 days post coitum. The tissue destruction observed in the rabbit endometrium emphasizes the need for careful histological studies of the effect of the copper IUD on the human uterus.