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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.)

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.

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.

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.

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.

The efficacy of lovastatin, a potent inhibitor of HMG CoA reductase, has been established by numerous studies. At doses of 40 mg administered twice daily, lovastatin produces a mean reduction in total plasma cholesterol of 33%, attributable to a reduction in low-density lipoprotein cholesterol of 41%. The drug also produces a mean increase in high-density lipoprotein cholesterol of 9%, and a reduction in the high- and low-density lipoprotein cholesterol ratio of 44%. The serious reported adverse effects of lovastatin are myopathy (0.5%) and asymptomatic but marked and persistent increases in transaminases (1.9%). Both are reversible when therapy is discontinued. Myopathy has occurred mainly in patients with complicated histories who were receiving concomitant therapy with immunosuppressive drugs, gemfibrozil or niacin. In an ongoing long-term safety study, 744 patients have received lovastatin for an average duration of 2.5 years up to March 1988. Fifteen patients (2.0%) have been withdrawn because of drug-attributable adverse events: raised transaminases (9), skin rash (2), gastrointestinal symptoms (2), myopathy (1) and insomnia (1). No effect of the drug on the human lens has been observed up to the date mentioned above. Lovastatin has been available in the United States since September 1987. By March 1988, the drug had been prescribed for approximately 250,000 patients. This clinical experience has confirmed the tolerability observed in clinical trials. The good adverse-effect profile of lovastatin is thus now supported both by a substantial body of data in patients treated for over 2 years in clinical trials, and by experience in clinical use with a large number of patients since the drug has been available for prescription.