The first generation statins were introduced during the late 1980s and 1990s, and had the lowest potency. Among them, pravastatin was the most studied statin, and several clinical trials showed reduction in LDL-C levels, cardiac mortality, and coronary events as well as efficiency in secondary prevention and symptomatic coronary disease. Though the adequate evidence is lacking, lovastatin and fluvastatin also demonstrated benefited cardiovascular risk reduction. Among thoese first statins, pravastatin and fluvastatin commanded much attention because of their low drug interaction as they are not metabolized by CYP450 isoenzyme systems. Hence, in spite of their low potency, they are still used as an alternative in patients who are intolerant to potent statins, although in 2001, one of the first statins, cerivastatin was withdrawn from market worldwide after confirmed reports of serious myopathy/rhabdomyolysis.
The second generation of statins was marked by introduction of atorvastatin and simvastatin. Even today, they are considered as the best selling statins. These statins had superior efficacy in lowering plasma LDL-C levels than the 1st generation and required lower doses. The pharmacological demonstration of atorvastatin and simvastatin drug-drug interaction is now well-established. Wider information on statin drug interactions and monitoring of the statin adverse effects would further help in minimizing statin-induced myopathy.
Third generation statins included rosuvastatin and pitavastatin, which had high potency and efficacy and thus termed as super statins. Rosuvastatin owes remarkable potency and efficacy due to its fluorinated phenyl group and hydrophilic methane sulphonamide group in addition to the common dihydroxyheptenoic acid side chain. Its unique chemical structure enables multiple and strong binding with HMG-CoA reductase enzyme. It has low drug interaction potential due to its hydrophilic nature, which avoids biotransformation for conversion into water-soluble intermediates for elimination. Pitavastatin also have several clinical advantages over 1st and 2nd generation statins. It's lowering potentiality of serum LDL-C was greater than pravastatin but was similar to atorvastatin. It is primarily metabolized through glucuronidation, and only minor fractions are metabolized by CYP2C9 and CYP3A4. Therefore, pitavastatin is hardly metabolized by microsomal cytochrome P450 system compared to other statins and hence has an advantage of not having unexpected interactions with other drugs. These TGSs are used as an alternative to other statins in high-risk patients who more often develop statin intolerance.
Almost all the statin trials reported statins to be safe and tolerable.