The inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (or statins) are the most effective agents currently available for lowering plasma levels of low-density lipoprotein cholesterol and are the mainstay of therapy for hyperlipidemia. These drugs are highly liver-selective and inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase – a key enzyme in the synthesis of cholesterol.

Results obtained from large controlled trials using lovastatin, simvastatin and pravastatin for the primary or secondary prevention of coronary heart disease have shown that treatment with statins is associated with a significant reduction in coronary morbidity and mortality, but also in total mortality.

Types of statins

The statins are most often grouped in two types. Natural or type 1 statins were originally identified as secondary metabolites of fungi (lovastatin, simvastatin, mevastatin and pravastatin). All the agents in this group exhibit close structural homology and differ from the type 2 or the synthetic statins.

Type 2 statins typically have a fluorophenyl group in place of the butyrl group present in type 1 statins. Examples include atorvastatin, fluvastatin, rosuvastatin, cerivastatin and pitavastatin. Furthermore, atorvastatin and rosuvastatin have additional hydrogen binding interactions.

The functional difference between the aforementioned two types of statins primarily relies on their ability to inhibit the HMG-CoA reductase, but also on their lipophilicity. Due to their specific structure, type 2 statins tend to form more robust interactions with HMG-CoA reductase.

Statins can also be present in the formulations in combinations of more than one form; that means that a statin may be present as salt (including calcium, sodium and potassium salts), acid (e.g. carboxylic acid) or in neutral, closed lactone ring form. The desired combination of statins depends upon the proposed end user, the solubility of the combination and the end-goal of the treatment.

Administration, dosing and cost-effectiveness

Statins are best given once a day in the evening to coincide with the peak cholesterol biosynthesis during night (albeit the long-acting statins atorvastatin and rosuvastatin may be given at any time of day). Lovastatin should be administered with food in order to enhance its absorption, but other statins may be taken with or without food.

Simultaneously with the start of statin therapy, patients should also begin with lifestyle change diet and planned exercise. Adequate statin dosing has important consequences for individual patient outcomes. If insufficient dose is administered, otherwise avoidable cardiovascular events may ensue; on the other hand, there can be a myriad of unnecessary side effects with excessive doses.

According to the 2013 ACC/AHA treatment guidelines (which recommend lipid-lowering therapies of varying intensity based on the predicted risk of cardiovascular events), statin therapy should be initiated at moderate or high-intensity doses, depending on the patient population. A lower starting dose may be utilized in certain extenuating circumstances (i.e.previous statin intolerance or drug interactions).

It must be noted that the duration of the cholesterol-lowering effect of statins is substantially longer than the duration of the pharmacokinetic half-life of these drugs. Such long duration of pharmacologic effects provides the rationale for the efficacy of intermittent dosing and results in almost the equivalent low-density lipoprotein cholesterol reduction in comparison with daily dosing.

Furthermore, studies comparing alternate-day dosing with daily dosing of statins indicate that the magnitude of low-density lipoprotein cholesterol reduction with alternate-day dosing is nearly the same, which also has obvious cost savings. The beneficial effect of early treatment has not yet been conclusively demonstrated.

The cost-effectiveness of statins in prevention of cardiovascular events has been evaluated in numerous studies in different countries, with incremental cost-effectiveness ratios revealing noteworthy variation. Compared with placebo, statins generally show acceptable rations according to the willingness-to-pay thresholds of most countries, namely in secondary cardiovascular prevention.