Table 10.

Drug-Effectiveness for Low-Density Lipoprotein CholesteroleLowering Therapy

Drug	Dose			% LDL-C lowering 318,324,*	Mechanism	Potential adverse effects
Statins	Dose intensity (mg/d; po)
	Low	Mod	High	Typical LDL-C decline basedon statin and dose intensity: Low <30% Mod 30% to 45% High ≥50%	Inhibits HMG-CoA reductase, alters intracellular cholesterol metabolism resulting in LDL-R upregulation	Myalgias, fatigue, diabetogenic effect for both new onset T2D and increase in A1C,327,328 rare rhabdomyolysis (1–4/10,000 per year)
Simvastatin	10	20 to 40
Pravastatin	10 to 20	40 to 80
Lovastatin	20	40
Fluvastatin	20 to 40	80b
Pitavastatin		2 to 4 mg
Atorvastatin		10 to 20	40 to 80
Rosuvastatin		5 to 10	20 to 40
Cholesterol absorption inhibitor
Ezetimibe329,330	10 mg orally every day			12% to 25% as mono-Rx(329–332); 25% when added to statin330,331	Inhibits intestinal and biliary cholesterol absorption, decreasing hepatic stores and increasing LDL-R upregulation	Myalgias, fatigue, URI symptoms, GI symptoms
Bile acid sequestrants
Colesevelam	625 mg/tab; 3 tabs bid			8% to 16% as mono-Rx	Efficient binding of bile acids, lowering hepatic cholesterol, promoting LDL-R upregulation	GI symptoms, constipation, can bind other drugs; avoid if TG >300mg
Colestipol	1 g/tab; 2 to 6 g/d
Cholestyramine	4 g/packet; 8 to 16 g/d
PCSK9i	Initial dose		Max dose
Alirocumab	75 mg sc every 2 weeks		300 mg sc every 4 weeks	48% to 58%c	Decreases PCSK9 levels, leading to reduced hepatic LDL-R degradation and increased expression
Evolocumab	140 mg sc every 2 weeks		420 mg sc every 4 weeks	63% to 71%c
ACL inhibitor
Bempedoic acida	180 mg orally every day			17% to 18% as mono-Rx. Further lowering when added to statin (+22%)(333) or ezetimibe (+13%)(329)	Inhibits ACLY, an upstream enzyme of HMG-CoA reductase	Myalgias, fatigue, URI symptoms, uric acid increase
PCSK9 siRNA
Inclisirana,334	284 mg every 6 months sc X2, then 284 mg every 6 months sc			38% to 52%	small interfering	RNA directs breakdown of PCSK9 mRNA

Abbreviations: A1C = hemoglobin A1c; ACLY = adenosine triphosphate (ATP) citrate lyase; bid = twice a day; d = day; g = grams; GI = gastrointestinal; HMG-CoA = 3-hydroxy 3-methylglutaryl coenzyme A; IV = intravenous; LDL-C = low-density lipoprotein cholesterol; LDL-R = LDL receptor; Max = maximal; mg = milligrams; Mod = moderate; mono-Rx = monotherapy; mRNA = messenger RNA; PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitor; RNA = ribonucleic acid; sc = subcutaneous; siRNA = small interfering RNA; T2D = type 2 diabetes; TG = triglyceride; tab = tablet; URI = upper respiratory infection

^*Additional sources: Casula M, Mozzanica F, Scotti L, et al. Statin use and risk of new-onset diabetes: A meta-analysis of observational studies. Nutr Metab Cardiovasc Dis. 2017;27(5):396–406. doi: 10.1016/j.numecd.2017.03.001 [EL 2; MNRCT]; Mansi IA, Chansard M, Lingvay I, Zhang S, Halm EA, Alvarez CA. Association of statin therapy initiation with diabetes progression: A retrospective matched-cohort study. JAMA Intern Med. 2021;181(12):1562–1574. doi: 10.1001/jamainternmed.2021.5714 [EL 2; CS]; Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27(6):593–603. doi: 10.1177/2047487319864671 [EL 1; RCT]; Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397. doi: 10.1056/NEJMoa1410489 [EL 1; RCT]; Wu NQ, Guo YL, Zhu CG, et al. Comparison of statin plus ezetimibe with double-dose statin on lipid profiles and inflammation markers. Lipids Health Dis. 2018;17(1):265. doi: 10.1186/s12944–018-0909-z [EL 1; RCT]; Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75 or older (ewtopia 75): A randomized, controlled trial. Circulation. 2019;140(12):992–1003. doi: 10.1161/circulationaha.118.039415 [EL 1; RCT]; Lalwani ND, Hanselman JC, MacDougall DE, Sterling LR, Cramer CT. Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: A randomized placebo-controlled trial. J Clin Lipidol. 2019;13(4):568–579. doi: 10.1016/j.jacl.2019.05.003 [EL 1; RCT]; US Food & Drug Administration (FDA). Inclisiran prescribing information/package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214012lbl.pdf Accessed February 19, 2022.[EL 4; NE].

^aFood and Drug Administration-approved for use in persons with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who are taking maximally tolerated statin dose and require additional LDL-C lowering.

^b40 mg bid or XL-80 mg

^cIn combination with statin therapy