Optimal Prescribing of Statins to Reduce Cardiovascular Disease

Cardiovascular disease is the most common cause of death in the United States and worldwide. Most of this disease is preventable with improvement of lifestyle and medication to reduce circulating cholesterol. The most common medications prescribed to reduce cholesterol are statins, which inhibit the hepatic enzyme HMG CoA reductase, the limiting enzyme in cholesterol synthesis. Unfortunately, statins are rarely prescribed correctly, resulting in excessive adverse events and very poor patient compliance. In fact, studies have demonstrated that approximately 50% of patients prescribed statins are no longer taking the medication within one year of obtaining a prescription1Benner JS Glynn RJ Mogun H Neumann PJ Weinstein MC Avorn J. Long-term persistence in use of statin therapy in elderly patients.JAMA. 2002; 288: 455-461https://doi.org/10.1001/jama.288.4.455Crossref PubMed Scopus (1056) Google Scholar. This omission results in less than half of all “at risk” patients achieving national guideline LDL cholesterol goals thereby resulting in excessive cardiovascular mortality. In 2019, a description of the pitfalls of statin prescribing was published2Schade DS Shey L Eaton RP. Prescribing statins to reduce cardiovascular disease: 10 common misconceptions.Am J Med. 2019; 132: 897-899https://doi.org/10.1016/j.amjmed.2019.01.042Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar. Since this Commentary, new studies of statin use have shown additional advantages of maintaining a lower statin dose with the addition of ezetimibe to enhance statins’ LDL cholesterol's lowering activity3Kim B-K Hong S-J Lee Y-J Hong SJ Yun KH Gon B-K et al.RACING Investigators. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity monotherapy in patients with atherosclerotic cardiovascular disease (RACING): A randomized, open-label, non-inferiority trial.Lancet. 2022; 400: 380-390https://doi.org/10.1016/S0140-6736(22)00916-3Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar. Correct statin prescribing is not difficult but does require an understanding of statins’ metabolic effects at the liver, the intestine, and the muscle. The goal of this Commentary is to update the optimal approach to limiting the adverse effects of statins while simultaneously optimizing the benefits of statin therapy. Although many adverse effects have been attributed to statin therapy, there are only two observed statin adverse effects in randomized, placebo controlled clinical trials: myalgias and glucose intolerance4Preiss D Kondapally Seshasai SR Welsh P Murphy SA Ho JE Waters DD et al.Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: A meta-analysis.JAMA. 2011; 305: 2556-2564https://doi.org/10.1001/jama.2011.860Crossref PubMed Scopus (1155) Google Scholar, 5Mach F Ray KK Wiklund O Corsini A Catapano AL Bruckert E et al.European Atherosclerosis Society Consensus Panel. Adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract.Eur Heart J. 2018; 39: 2526-2539https://doi.org/10.1093/eurheartj/ehy182Crossref PubMed Scopus (214) Google Scholar. The magnitude of these adverse effects is dependent on the dose and type of statin prescribed and the blood level of circulating statin concentration achieved. Therefore, using the lowest dose possible that still achieves the LDL desired goal should be the underlying strategy for all caregivers. Understanding the various metabolic effects of statins results in their correct use. When statins inhibit the synthesis of cholesterol at the liver, the hepatic content of cholesterol diminishes. This condition results in the activation of several lipogenic genes resulting in an increase in the uptake of LDL cholesterol from the circulation via increasing the number of hepatic cell surface LDL receptors6Schade DS Gonzales K Kaminsky N Adolphe A Shey L Eaton RP Resolving the egg and cholesterol intake controversy: New clinical insights into cholesterol regulation by the liver and intestine.Endocr Pract. 2022; 28: 102-109https://doi.org/10.1016/j.eprac.2021.09.004Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar. What is under appreciated are the other two gene-induced effects to increase hepatic cholesterol content by increasing the intestinal absorption of cholesterol and increasing the hepatic reuptake of cholesterol from the bile6Schade DS Gonzales K Kaminsky N Adolphe A Shey L Eaton RP Resolving the egg and cholesterol intake controversy: New clinical insights into cholesterol regulation by the liver and intestine.Endocr Pract. 2022; 28: 102-109https://doi.org/10.1016/j.eprac.2021.09.004Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar. Understanding this response can be effectively utilized clinically to optimize statin therapy. One important question is “Which statin should be prescribed?” Since all statins are available in generic formulation, cost is usually not a prime consideration. Most important is LDL cholesterol-lowering potency versus potential adverse drug-drug interactions and direct adverse effects (myalgia and diabetes). Considering these parameters, rosuvastatin has several advantages not shared with several other statins (e.g., atorvastatin). When some statins are metabolized in the liver, the common enzyme cytochrome P4503A4 is activated but may also be simultaneously functioning to metabolize other drugs. P4503A4 catalyzes more than 50% of clinically used drugs. Rosuvastatin has the advantage that it is 90% excreted metabolically unchanged (primarily in the bile) so that minimal drug-drug interactions occur7Kostapanos MS Milionis HJ Elisaf MS. Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia.Am J Cardiovasc Drugs. 2010; 10: 11-28https://doi.org/10.2165/13168600-000000000-00000Crossref Scopus (83) Google Scholar. In addition, rosuvastatin is the most potent of available statins such that 10 mg/day provides the same LDL reduction as 40 mg/day of atorvastatin8Brewer Jr, HB Benefit-risk assessment of rosuvastatin 10 to 40 milligrams.Am J Cardiol. 2003; 92: 23K-29Khttps://doi.org/10.1016/s0002-9149(03)00779-3Abstract Full Text Full Text PDF PubMed Google Scholar. When rosuvastatin was directly compared with atorvastatin, simvastatin, and pravastatin at all available dosages in a randomized controlled trial, rosuvastatin was superior to all other statins in lowering LDL cholesterol8Brewer Jr, HB Benefit-risk assessment of rosuvastatin 10 to 40 milligrams.Am J Cardiol. 2003; 92: 23K-29Khttps://doi.org/10.1016/s0002-9149(03)00779-3Abstract Full Text Full Text PDF PubMed Google Scholar, 9Jones PH Davidson MH Stein EA Bays HE McKenney JM Miller E et al.for the STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses.Am J Cardiol. 2003; 92: 152-160https://doi.org/10.1016/s0002-9149(03)00530-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. Because rosuvastatin is a very potent statin in lowering LDL cholesterol, it is possible to utilize a low dose of this drug (10 mg/day) to achieve a very significant reduction in LDL cholesterol (approximately 40%). In addition, rosuvastatin at a dose of 10 mg/day does not increase the risk of diabetes10Yusuf S Lonn E Pais P Bosch J Lopez-Jaramillo P Zhu J et al.HOPE-3 Investigators. Blood-pressure and cholesterol lowering in persons without cardiovascular disease.N Engl J Med. 2016; 374: 2032-2043https://doi.org/10.1056/NEJMoa1600177Crossref PubMed Scopus (283) Google Scholar. All statins can induce myalgia and, in high plasma concentration, may cause rhabdomyolysis. However, the majority of myalgia complaints cannot be duplicated when the patient is blinded to the drug versus placebo11Joy TR Monjed A Zou GY Hegele RA McDonald CG Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia.Ann Intern Med. 2014; 160: 301-310https://doi.org/10.7326/M13-1921Crossref PubMed Google Scholar. True statin-induced myalgia is dose-related and maintaining the statin dose as low as possible will minimize this adverse effect. In order to obtain the maximal benefit of a statin, two of statins’ gene-induced activities should be suppressed (the increase in cholesterol gut absorption and the reuptake of cholesterol from the bile). Both activities involve the cholesterol tissue receptor, which was identified in 1999 as the Nieman-Pick C1-Like 1 receptor. In the intestine, this receptor is specifically responsible for the uptake of dietary sterols, including cholesterol. Other sterols (particularly from plants, which do not synthesize cholesterol) are also transported by this receptor but subsequently are secreted back into the intestinal lumen for excretion. Fortunately, 50% of dietary cholesterol can be directly blocked with the concurrent prescribing of ezetimibe 10 mg/d. This receptor is also on the biliary duct endothelium of the liver and its blockage prevents the liver from re-uptaking cholesterol from the bile. The addition of this generic medication results in an approximate 18% further lowering of LDL cholesterol12Zhan S Tang M Liu F Xia P Shu M Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events.Cochrane Database Syst Rev. 2018; 11CD012502https://doi.org/10.1002/14651858.CD012502.pub2Crossref Scopus (5) Google Scholar. A recent, randomized clinical trial demonstrated that 10 mg/day of both rosuvastatin plus ezetimibe was superior to 20 mg/day of rosuvastatin in lowering LDL cholesterol and causing significantly fewer adverse effects3Kim B-K Hong S-J Lee Y-J Hong SJ Yun KH Gon B-K et al.RACING Investigators. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity monotherapy in patients with atherosclerotic cardiovascular disease (RACING): A randomized, open-label, non-inferiority trial.Lancet. 2022; 400: 380-390https://doi.org/10.1016/S0140-6736(22)00916-3Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar. The other main beneficial effect of statins is their anti-inflammatory effect. A common approach to measuring the degree of inflammation is the level of C-reactive protein. Statins’ reduction of inflammation is responsible for many of the beneficial effects of statins in acute coronary syndromes. There are no studies available that compare the anti-inflammatory effects of the available statins nor are there comparative dose response studies. However, to date, all available statins have demonstrated anti-inflammatory effects, although rosuvastatin 20 mg/d is more effective than atorvastatin 40 mg/d at lowering C-reactive protein13Khurana S Gupta S Bhalla H Nandwani S Gupta V. Comparison of anti-inflammatory effect of atorvastatin with rosuvastatin in patients of acute coronary syndrome.J Pharmacol Pharmacother. 2015; 6: 130-135https://doi.org/10.4103/0976-500X.162011Crossref PubMed Scopus (30) Google Scholar. In particular, rosuvastatin has demonstrated rapid onset anti-inflammatory effects in acute coronary syndromes14Link A Ayadhi T Bohm M Nickenig G. Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome.Eur Heart J. 2006; 27: 2945-2955https://doi.org/10.1093/eurheartj/ehl277Crossref PubMed Scopus (79) Google Scholar. In fact, addition of ezetimibe to rosuvastatin enhances the total anti-inflammatory effects15Ren Y Zhu H Fan Z Gao Y Tian N Comparison of the effect of rosuvastatin versus rosuvastatin/ezetimibe on markers of inflammation in patients with acute myocardial infarction.Exp Ther Med. 2017; 14: 4942-4950https://doi.org/10.3892/etm.2017.5175Crossref PubMed Scopus (13) Google Scholar. In summary, physicians should optimize the use of statins by considering the fact that the adverse effects are dose related but the potency in lowering LDL cholesterol is not (Figure 1). In addition, statins, which don't compete with the metabolism of other medications, should be utilized. Based on physiology, in the majority of “at risk” patients, 10 mg of rosuvastatin plus 10 mg/day of ezetimibe are a logical initial choice to optimize statin use. None