Drug interactions are possible, but studies have not shown that these statins increase exposure to ciclosporin. Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. The beneficial effects of statins are the result of their capacity to reduce cholesterol biosyntesis, mainly in the liver, where they are selectively distributed, as well as to the modulation of lipid metabolism, derived from their effect of inhibition upon HMG-CoA reductase. In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began to investigate this problem. Statins are HMG-CoA reductase inhibitors. [30], Statins are effective in decreasing mortality in people with pre-existing cardiovascular disease. [87], The relationship between statin use and risk of developing diabetes remains unclear and the results of reviews are mixed. [167] Scientists in academic settings and the pharmaceutical industry began trying to develop a drug to reduce cholesterol more effectively. [144], Click on genes, proteins and metabolites below to link to respective articles. [10] The best-selling statin is atorvastatin, also known as Lipitor, which in 2003 became the best-selling pharmaceutical in history. The beneficial effects of statins are the result of their capacity to reduce cholesterol biosyntesis, mainly in the liver, where they are selectively distributed, as well as to the modulation of lipid metabolism, derived from their effect of inhibition upon HMG‐CoA reductase. Statins act by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. This competition reduces the rate by which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol. The effect was found to be stronger among those with preexisting kidney dysfunction or diabetes mellitus. Cerivastatin is the most potent, (withdrawn from the market in August, 2001 due to risk of serious rhabdomyolysis) followed by (in order of decreasing potency), rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. COVID-19 is an emerging, rapidly evolving situation. [47] These people have defects usually in either the LDL receptor or apolipoprotein B genes, both of which are responsible for LDL clearance from the blood. [93] The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear. [48] Statins remain a first-line treatment in familial hypercholesterolemia,[47] although other cholesterol-reducing measures may be required. [82] The gene SLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for an organic anion-transporting polypeptide that is involved in the regulation of the absorption of statins. [67][68][69][70][71] Statins have been shown to decrease the risk of dementia, Alzheimer's disease, and improve cognitive impairment in some cases. Additional factors that could be used were an LDL-C ≥ 160 or a very high lifetime risk. [127] This is accomplished via proteases that cleave membrane-bound sterol regulatory element binding proteins, which then migrate to the nucleus and bind to the sterol response elements. 2020 Sep 30;8:523550. doi: 10.3389/fcell.2020.523550. [88][89][90][91] Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes. Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling[citation needed] branded drug. Combining any statin with a fibrate or niacin (other categories of lipid-lowering drugs) increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years.