Atorvastatin

Abstract

High cholesterol, in particular increased low-density lipoprotein (LDL), is a significant, modifiable risk factor in the development of cardiovascular disease (CVD). In people with diabetes, the risk of CVD is greatly increased and is the leading cause of morbidity and mortality. People with diabetes typically have a triad of elevated fasting and postprandial triglycerides, elevated LDL cholesterol and a relative reduction in high-density lipoprotein (HDL) cholesterol. While exercise, diet and tighter glycaemic control can contribute to improvements in the lipid profile, statins offer the biggest risk reduction with respect to CVD; every 1mmol/L reduction in LDL-C with statin therapy is associated with a 22% reduction in cardiovascular events.1 Statins may also have additional cardiovascular protective effects via their action on platelets, endothelium and atherosclerotic plaques. Statins therefore have an important role in the primary and secondary prevention of CVD. The pharmacology of atorvastatin is shown in Figure 1. HMG-CoA reductase catalyses the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, the rate limiting step of the hepatic pathway of cholesterol synthesis. Shorter-acting statins such as simvastatin should be taken at night as most cholesterol synthesis takes place when dietary intake is lowest. Atorvastatin has a longer half-life and can be taken at any time. Atorvastatin has oral bioavailability of 14% after first pass metabolism and is highly plasma protein bound. It is metabolised by the CYP450 system (CYP3A4) and eliminated in bile. CYP3A4 inhibitors such as clarithromycin, ciclosporin and ketoconazole can significantly increase plasma concentrations of atorvastatin and co-administration should be avoided or the dose of atorvastatin reduced. Atorvastatin has been studied in people with and without diabetes. It is well tolerated, efficacious and has minimal adverse events. A Cochrane review of 296 trials in 38,817 participants found that treatment with 10–80mg of atorvastatin was associated with a reduction in LDL-C of 37.1–51.7%.2 The Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA) examined the effect on atorvastatin on the primary prevention of CVD. In all, 10,305 patients with hypertension and at least three cardiovascular risk factors were randomised to 10mg atorvastatin or placebo. The primary outcome was the combined endpoint of non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD). The trial was terminated early because of the reduction in coronary events and stroke. Treatment with atorvastatin was associated with a relative risk reduction in the primary endpoint of 36% compared with placebo (HR 0.64, 95% CI 0.5–0.83, p=000.5) and a 27% risk reduction in stroke (HR 0.73, 95% CI 0.56–00.96, p=0.0236).3 The efficacy of atorvastatin in the secondary prevention of CVD was demonstrated in the Treating to New Targets (TNT) trial. In this large-scale randomised trial, over 1000 patients with established CHD were randomised to 10mg or 80mg atorvastatin for a median of 4.9 years. Treatment with high dose atorvastatin was associated with a 22% relative reduction in risk of major cardiovascular events. This trial was also significant because it was the first to demonstrate the beneficial effects of achieving a target LDL-C of 2.0mmol/L and below in patients with CHD.4 Atorvastatin is largely well tolerated. The most common reason for discontinuation is due to statin-associated muscle symptoms such as myalgia, reported to occur in 10–15% of trial participants. Despite this, less than 0.1% of patients treated with atorvastatin experience true myopathy and rhabdomyolysis. Asymptomatic mild rises in liver transaminases occur in up to 2% of patients. Statins are associated with increased insulin resistance and new onset diabetes. In patients treated with atorvastatin, this risk appears dose related and is increased in the presence of risk factors such as obesity, hypertension and impaired fasting glucose. In patients with diabetes, statin use has also been associated with diabetes progression, increased risk of hyperglycaemia and initiation of insulin.5 Atorvastatin has proven efficacy in the primary and secondary prevention in patients with diabetes. Participants in the Collaborative Atorvastatin Diabetes Study (CARDS) had type 2 diabetes and at least one cardiovascular risk factor but no history of CVD. Treatment with 10mg atorvastatin was associated with a 37% reduction in cardiovascular events compared to placebo regardless of baseline LDL-C level.6 The study was terminated early as a consequence of the benefits seen. In contrast, the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-insulin-dependent diabetes mellitus (ASPEN) failed to show any effect on the primary endpoint (composite of time to cardiovascular death, non-fatal MI, non-fatal stroke, coronary artery bypass surgery, cardiac arrest and hospitalisation for unstable angina) in patients with type 2 diabetes treated with atorvastatin despite significant reductions in LDL-C.7 It is likely that issues with the study design, change in protocol, different endpoints and use of lipid-lowering therapy in both groups influenced the results. The ASCOT-LLA trial included 2532 patients with type 2 diabetes randomised to treatment with 10mg atorvastatin or placebo. The subgroup analysis did not show a statistically significant reduction in the primary endpoint of fatal CHD and non-fatal MI in patients with diabetes treated with atorvastatin which may have related to the limited power to detect a significant difference.3 A subsequent analysis of this group demonstrated that atorvastatin significantly reduced the risk of all cardiovascular events and procedures by 23% (HR 0.77, 95% CI 0.01–0.98, p=0.036).8 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study investigated the use of 80mg atorvastatin in patients with recent stroke or TIA but no CHD. A subgroup analysis of patients with type 2 diabetes in this trial found a reduction in major cardiovascular events, coronary events and revascularisation procedures.9 Atorvastatin is an effective and safe treatment for lipid-lowering therapy and prevention of cardiovascular adverse events in patients with and without diabetes. Current guidelines recommend use of 20mg or 80mg atorvastatin for the primary and secondary prevention of CVD respectively. While the increased incidence of new onset diabetes or worsening glycaemic control is an important consideration, the risk of not using lipid-lowering therapy in people who are at significant cardiovascular risk is arguably more important. There are no conflicts of interest declared.