Targeting PCSK9 With Antibodies and Gene Silencing to Reduce LDL Cholesterol.

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.

LDL Cholesterol-How Low Can We Go?

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.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

Aims: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period.

Methods And Results: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy.

Lipid-Modifying Agents, From Statins to PCSK9 Inhibitors: JACC Focus Seminar.

Mendelian randomization studies and randomized trials have conclusively demonstrated that lower low-density lipoprotein (LDL) cholesterol results in fewer cardiovascular events. This review describes key stages in the evolution of LDL cholesterol-lowering treatment. Data from over 25 cardiovascular outcome trials confirm that, within a few years, statins lower the relative risk of major atherosclerotic events by about 22% per 38.

Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association.

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 nocebo effect in the context of statin intolerance.

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.

Statin tolerability: In defence of placebo-controlled trials.

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 effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.

Background: Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.

Methods: This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation.

Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people.

Background: Simvastatin reduces cardiovascular mortality and morbidity but, as with other HMG-CoA reductase inhibitors, can cause significant muscle toxicity and has been associated with elevations of liver transaminases.

Methods: Muscle and liver adverse effects of simvastatin 40 mg daily were evaluated in a randomized placebo-controlled trial involving 20,536 UK patients with vascular disease or diabetes (in which a substantial reduction of cardiovascular mortality and morbidity has previously been demonstrated).

Results: The excess incidence of myopathy in the simvastatin group was < 0.

Simvastatin: a review.

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.

Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial.

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.

Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.

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.

A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).

Background And Aim: This study was conducted in preparation for the Study Evaluating Additional Reduction in Cholesterol and Homocysteine (SEARCH). SEARCH is a 12,000 patient 2X2 factorial study in post-myocardial infarction patients that will compare simvastatin 20 mg with simvastatin 80 mg to evaluate whether greater LDL-C reductions with simvastatin provide greater coronary event reductions. SEARCH will also test the hypothesis that lowering plasma homocysteine with folic acid and vitamin B12 will reduce coronary events.

Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin.

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).

Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.

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.

Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S).

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.

Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).

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.