C10AA: HMG CoA reductase inhibitors
Statins (or HMG-CoA reductase inhibitors) are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease [1].
In 1971, Akira Endo’s group at Sankyo in Tokyo began screening culture broths of fungi for inhibitors of HMG-CoA reductase. In 1972 they found an active broth of the mold Penicillium citrinum, isolated from a rice sample collected at a grain shop in Kyoto. In July 1973 they isolated ML-236B from it, the compound known as compactin and the first statin [2].
How do statins work?
Statins act by competitively inhibiting HMG-CoA reductase: they occupy part of the enzyme’s binding site for HMG-CoA, which blocks the substrate’s access [3]. By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver [4].
HMG-CoA reductase converts HMG-CoA to mevalonate, an early rate-limiting step in cholesterol synthesis. With less cholesterol made, the cells express more low-density lipoprotein (LDL) receptors, and take up more LDL cholesterol from the blood [5]. The uptake transporter OATP1B1, encoded by the gene SLCO1B1, facilitates the entry of all statins into the liver [6].
Efficacy
The main clinical measure of statin effect is LDL cholesterol in plasma, a continuous variable. There is no simple way to measure the inhibition of HMG-CoA reductase itself in human pharmacodynamic studies. LDL cholesterol takes 4 to 6 weeks to show a reduction after the start of treatment. For these reasons, Lennernäs and Fager considered a dose-effect relationship more appropriate than a concentration-effect relationship for describing statin pharmacodynamics [5].
An indirect response model, in which the drug inhibits or stimulates the production or loss of the response, accounts for such delays [7]. One such model was built from 2863 LDL cholesterol values of 378 patients on statins, taken from electronic medical records. In it, adding ezetimibe (C10AX09) reduced the LDL synthesis rate by 10.9% [8].
The clinical outcomes are cardiovascular events and death, which trials report as risk ratios or hazard ratios. An umbrella review of 20 randomized statin trials, with a median follow-up of 4.85 years, found that statins improved all the clinical outcomes studied. However, the size of each trial’s LDL cholesterol reduction explained little of the difference in its effect on outcomes, with a trial-level R2 of 0 to 0.1. The authors concluded that LDL cholesterol should not be used as pivotal evidence in drug trials [1].
Safety
Statins are generally well tolerated, but they can cause muscle toxicity, which can lead to severe rhabdomyolysis, a breakdown of muscle tissue. The phenotypes of statin-related muscle toxicity include muscle pain (myalgia), muscle disease (myopathy), rhabdomyolysis and muscle damage caused by the immune system (necrotizing autoimmune myopathy) [9]. In placebo-controlled trials in people aged 65 and over, myalgia was no more frequent on a statin than on placebo (odds ratio 1.03) [10].
The adverse effects of statins may depend partly on how much they act outside the liver, so systemic exposure may be clinically important [5]. Simvastatin (C10AA01), lovastatin (C10AA02) and atorvastatin (C10AA05) are metabolized by CYP3A4. Strong CYP3A4 inhibitors greatly increase their plasma concentrations and the risk of muscle toxicity. Pravastatin (C10AA03), rosuvastatin (C10AA07) and pitavastatin (C10AA08) are excreted mainly unchanged, and pure CYP3A4 inhibitors do not significantly raise their concentrations. Ciclosporin (L04AD01) inhibits OATP1B1, along with CYP3A4 and P-glycoprotein. Gemfibrozil (C10AB04) inhibits OATP1B1 and CYP2C8. Both raise plasma statin concentrations and the risk of muscle toxicity. OATP1B1 inhibitors may also worsen the benefit-risk ratio, by interfering with statin entry into the liver cells where they act [11].
Statin-associated musculoskeletal symptoms affect adherence, and so can impede the long-term effectiveness of treatment. Genetic variants in SLCO1B1, ABCG2 and CYP2C9 alter systemic exposure to statins, which can increase the risk of these symptoms. The Clinical Pharmacogenetics Implementation Consortium (CPIC) gives recommendations for statin therapy based on these genotypes [6].