Statin-Related New-Onset Diabetes Appears Driven by Increased Insulin Resistance: Are There Clinical Implications?
See accompanying article on page 2786
Statins (HMG CoA-reductase inhibitors) are universally acknowledged as first-line treatment for medical prevention of atherosclerotic cardiovascular disease (ASCVD) events in essentially all patients either with or without established disease. Statins are generally safe and well-tolerated but have been repeatedly associated with increased insulin resistance (IR) and increased incidence of new-onset diabetes type 2 (NOD2). This association has been consistently shown in large cohort studies1–5 and more importantly, in meta-analyses of randomized clinical trials of statin versus placebo.6–9 Furthermore, a Mendelian randomization study of genetic variants of the HMG CoA-reductase gene showed that genetically reduced HMG CoA-reductase activity associates with increased NOD2.10 Finally, meta-analyses of randomized statin-dosing trials have shown that higher-intensity treatment (whether by higher doses or with higher-efficacy agents) associates with increased NOD2 risk,11 while statin treatment to LDL-C (low-density lipoprotein-cholesterol) goals of <100 or <70 mg/dL was associated with adjusted 16% or 33% increases in NOD2, respectively.12 Together, these data establish that an increase in NOD2 risk is causally related to statin use, likely as an on-target effect.
Given the convincing evidence that statins can cause NOD2, Abbasi et al13 explored the mechanisms of this adverse effect in a study published in this issue of ATVB. Using detailed, gold-standard methods, they measured IR (or its reciprocal, insulin sensitivity) as well as insulin secretion in the largest subject group ever to be tested in such a definitive way. Their cohort of 71 subjects was recruited for an absence of prevalent diabetes type 2, although they were over-recruited for elevated plasma triglycerides, associated with both increased IR and with increased NOD2 risk with statin use. At baseline, all subjects were off statins for at least 4 weeks and underwent 3 advanced studies of insulin and glucose metabolism: (1) a standard 75 g oral glucose tolerance test, (2) a graded glucose infusion test, and (3) a modified insulin suppression test. All tests were repeated after 12 weeks of high-intensity statin treatment, atorvastatin 40 mg daily, with each subject serving as his/her own control. The primary result was a modest, but convincing, 8% increase in IR (P=0.002).
Most other published studies have also shown an increase in IR with statin treatment, although using somewhat less precise methods. These include a retrospective cohort of 27 155 subjects on atorvastatin versus nonstatin treatment,14 a cohort of 938 subjects after taking various statins for 30 days or longer15 and a prospective cohort of 8749 subjects treated with various doses of simvastatin and atorvastatin for nearly 6 years.16 Importantly, both this third cohort and also a trial of 213 subjects randomized to atorvastatin, 10 through 80 mg/d versus placebo for 2 months, showed dose-dependent increases in IR at all doses (P=0.008).17 Given these prior publications and the new data from Abbasi et al,13 increased IR can now be considered likely the primary means by which statins cause NOD2 (Figure [A through D]).
Figure. Schema of statin effects on insulin resistance, insulin secretion and glycemia, as they likely contribute to other diabetogenic factors, across the spectrum from metabolically normal (column A) through early and late stages of the metabolic syndrome (columns B and C) to diabetes type 2 (column D). Arrows (top three rows) denote the direction, degree and/or range of changes. Pie graphs (bottom row) show the approximate degree of compensatory increase in insulin secretion in response to increased insulin resistance.
Meanwhile, the effects of statins on insulin secretion are less consistent in the scientific literature. Abbasi et al13 found a 9% increase in insulin secretion, which appeared compensatory to the increase in IR. An additional published study found increased insulin secretion with statin treatment,18 but several others have reported a decrease.14–16 This apparent variability in the effects of statins on insulin secretion may be due, in part, to the variability in insulin secretion response during sustained IR (Figure [B through D]). That is, initially insulin secretion increases to compensate for the increased IR (Figure [B]) but if IR is sustained over time that compensatory increase may later start to decline (Figure [C]) and eventually may fail to match insulin requirements, causing NOD2 (Figure [D]). The published variability in statin effects on insulin secretion may also be due to differences in study populations or perhaps in methods used for its measurement or calculation. Importantly, this tendency towards decreased insulin secretion in most in vivo studies of statins concurs with data from in vitro studies of statin exposure to beta cells (see Carmena and Betteridge19 for a review). Additional research is needed to further validate this schema regarding the sequence of the evolution of NOD2 with statins, as well as to refine its predictors and treatments to prevent it.
What are the clinical implications of this tendency of statins to nudge most patients towards NOD2, to the point of causing frank diabetes in many patients with preexisting risk factors?20,21 First of all, as correctly stated by Abbasi et al,13 and others, the overall risk-benefit ratio remains strongly in favor of statin therapy as first-line ASCVD prevention, even in patients who later develop NOD2 because of that treatment. The optimal approach to statin use, however, is not simply to accept increased NOD2 risk in patients with metabolic syndrome and other risk factors,20,21 but instead to actively reduce that risk by employing mitigation measures. As noted by Abbasi et al,13 diet and lifestyle recommendations are clearly warranted. If, however, these measures are insufficient, as is often the case, medical prevention should next be considered. Pioglitazone should generally be first choice since it is very effective in NOD2 prevention,22 improves the lipid profile,23,24 and reduces CVD risk.25 Furthermore, pioglitazone is inexpensive, well-tolerated, and generally safe, although it is contraindicated in patients with moderately to severely symptomatic (New York Heart Association stage 3–4) congestive heart failure.26 Adding metformin to pioglitazone may enhance NOD2 prevention,27 and metformin alone may also reduce NOD2.28 In addition, 2 uncommonly used statins, pravastatin,29 or especially pitavastatin30,31 may be favored over other statins in patients at elevated risk of NOD2, due to their apparently lower tendency to cause diabetes (see Carmena and Betteridge19 and Laakso and Kuusisto29 for reviews).
Finally, it seems appropriate at this time to question the ardent and widespread advocacy for maximally tolerated statin intensity, since such softening could provide another means to reduce the risk of statin-induced NOD2. Statin efficacy for ASCVD prevention is strongly related to LDL-lowering when comparing lower- versus higher-intensity statin regimens,32 which is the rationale for the preference for higher-intensity statin treatment and the concept of maximally tolerated statin therapy. The latter has been widely encouraged for ASCVD prevention in high-risk patients since the 2013 American College of Cardiology/American Heart Association Cholesterol guidelines,33 which favored maximization of statin intensity over achievement of any particular on-treatment LDL-C level. Unfortunately, in any patient not tolerant of maximal statin intensity, pursuit of a maximally tolerated regimen by definition may induce statin intolerance. This pursuit can be time-consuming at best for both patient and prescriber and may result in abandonment of statin treatment unless a somewhat cumbersome rechallenge is performed.34,35 Fortunately, since 2013, there can be less urgency for high-intensity statins due to advances in statin adjuncts, both in number of available agents and in documentation of their efficacy for LDL-lowering and ASCVD prevention, as well as safety. For this reason, cholesterol treatment recommendations since 2013 have reverted to (or continued) less emphasis on maximal statin intensity and more focus on levels of on-treatment LDL-C, either as a goal of treatment or a threshold for treatment intensification.36–38
Meanwhile, although higher-intensity statin therapy does help further prevent ASCVD, it also increases the risk of statin-induced NOD2, as detailed above.11,12,17,39 Unfortunately, patients who develop compensated IR (Figure [B]), late-stage metabolic syndrome (Figure [C]) or even NOD2 (Figure [D]) on a statin, may have few or no symptoms and thus would not ordinarily be considered statin-intolerant. In such cases, statin back-titration to a “tolerable” dose seems unlikely. Statin adjuncts are already universally endorsed when maximally tolerated statin therapy fails to adequately lower LDL-C, but why not consider statin adjuncts preemptively as statin-sparing agents? Since doubling a statin dose provides only an additional 6% or so of LDL-C lowering,40 initiating a statin at moderate- or even low-intensity along with a statin adjunct is appealing when asymptomatic IR or NOD2 threaten, even if high-intensity statins might otherwise be well-tolerated. Alternatively, monitoring for progression of IR towards NOD2 could be done,41 triggering back-titration of the statin regimen with addition of a statin adjunct as needed. Lower-intensity statins plus statin adjuncts clearly can match or exceed the LDL-lowering available with statin monotherapy.42–44 More importantly, addition of ezetimibe or PCSK9 (proprotein convertase subtilisin/kexin type 9)-inhibitor mAbs decrease ASCVD as much as does statin uptitration, without raising NOD2 risk.45–47 A trial directly comparing ASCVD and NOD2 outcomes of high-intensity versus lower-intensity statin therapy plus nondiabetogenic adjuncts is needed to prove this novel strategy superior to the conventional one but would be costly and impractical to conduct. It currently seems likely, however, that “less is more” regarding statin intensity (plus statin adjuncts, as needed) for most patients at elevated NOD2 risk, as an alternative to one-size-fits-all maximally tolerated statin regimens.
In summary, confirmation of the IR-raising effect of statins enhances our knowledge about statin-induced NOD2 in susceptible patients. Greater attention to diabetes prevention during statin treatment in these patients is warranted, by traditional diet and lifestyle measures, use of inexpensive medications effective in diabetes prevention, choice of less-commonly used statins and/or softening the widely endorsed paradigm of maximally tolerated statin intensity in favor of lower-intensity statins plus greater use of nondiabetogenic statin-sparing adjuncts.
Article Information
Disclosures
E. Brinton is a speaker and consultant for Amgen, Esperion, Kowa, and Medicure, has received research support from Kowa and Regeneron, and served as an expert witness for Robins Cloud.
Footnotes
References
- 1.
Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM . Risk of incident diabetes among patients treated with statins: population based study.BMJ. 2013; 346:f2610. doi: 10.1136/bmj.f2610CrossrefMedlineGoogle Scholar - 2.
Yoon D, Sheen SS, Lee S, Choi YJ, Park RW, Lim HS . Statins and risk for new-onset diabetes mellitus: a real-world cohort study using a clinical research database.Medicine (Baltimore). 2016; 95:e5429. doi: 10.1097/MD.0000000000005429CrossrefMedlineGoogle Scholar - 3.
Casula M, Mozzanica F, Scotti L, Tragni E, Pirillo A, Corrao G, Catapano AL . Statin use and risk of new-onset diabetes: a meta-analysis of observational studies.Nutr Metab Cardiovasc Dis. 2017; 27:396–406. doi: 10.1016/j.numecd.2017.03.001CrossrefMedlineGoogle Scholar - 4.
Angelidi AM, Stambolliu E, Adamopoulou KI, Kousoulis AA . Is atorvastatin associated with new onset diabetes or deterioration of glycemic control? Systematic review using data from 1.9 Million Patients.Int J Endocrinol. 2018; 2018:8380192. doi: 10.1155/2018/8380192CrossrefMedlineGoogle Scholar - 5.
Ko MJ, Jo AJ, Kim YJ, Kang SH, Cho S, Jo SH, Park CY, Yun SC, Lee WJ, Park DW . Time- and dose-dependent association of statin use with risk of clinically relevant new-onset diabetes mellitus in primary prevention: a Nationwide Observational Cohort Study.J Am Heart Assoc. 2019; 8:e011320. doi: 10.1161/JAHA.118.011320LinkGoogle Scholar - 6.
Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, Sofat R, Stender S, Johnson PC, Scott RA, ; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium. HMG-coenzyme a reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2015; 385:351–361. doi: 10.1016/S0140-6736(14)61183-1CrossrefMedlineGoogle Scholar - 7.
Thakker D, Nair S, Pagada A, Jamdade V, Malik A . Statin use and the risk of developing diabetes: a network meta-analysis.Pharmacoepidemiol Drug Saf. 2016; 25:1131–1149. doi: 10.1002/pds.4020CrossrefMedlineGoogle Scholar - 8.
Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, ; American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association.Arterioscler Thromb Vasc Biol. 2019; 39:e38–e81. doi: 10.1161/ATV.0000000000000073LinkGoogle Scholar - 9.
Khan SU, Rahman H, Okunrintemi V, Riaz H, Khan MS, Sattur S, Kaluski E, Lincoff AM, Martin SS, Blaha MJ . Association of lowering low-density lipoprotein cholesterol with contemporary lipid-lowering therapies and risk of diabetes mellitus: a systematic review and meta-analysis.J Am Heart Assoc. 2019; 8:e011581. doi: 10.1161/JAHA.118.011581LinkGoogle Scholar - 10.
Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, . Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes.N Engl J Med. 2016; 375:2144–2153. doi: 10.1056/NEJMoa1604304CrossrefMedlineGoogle Scholar - 11.
Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, . Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.JAMA. 2011; 305:2556–2564. doi: 10.1001/jama.2011.860CrossrefMedlineGoogle Scholar - 12.
Cai R, Yuan Y, Zhou Y, Xia W, Wang P, Sun H, Yang Y, Huang R, Wang S . Lower intensified target LDL-c level of statin therapy results in a higher risk of incident diabetes: a meta-analysis.PLoS One. 2014; 9:e104922. doi: 10.1371/journal.pone.0104922CrossrefMedlineGoogle Scholar - 13.
Abbasi F, Lamendola C, Harris CS, Harris V, Tsai M-S, Tripathi P, Abbas F, Reaven GM, Reaven PD, Snyder MP, . Statins are associated with increased insulin resistance and secretion.Arterioscler Thromb Vasc Biol. 2021; 41:2786–2797. doi: 10.1161/ATVBAHA.121.316159LinkGoogle Scholar - 14.
Olotu BS, Shepherd MD, Novak S, Lawson KA, Wilson JP, Richards KM, Rasu RS . Use of Statins and the Risk of Incident Diabetes: A Retrospective Cohort Study.Am J Cardiovasc Drugs. 2016; 16:377–390. doi: 10.1007/s40256-016-0176-1CrossrefMedlineGoogle Scholar - 15.
Ahmadizar F, Ochoa-Rosales C, Glisic M, Franco OH, Muka T, Stricker BH . Associations of statin use with glycaemic traits and incident type 2 diabetes.Br J Clin Pharmacol. 2019; 85:993–1002. doi: 10.1111/bcp.13898CrossrefMedlineGoogle Scholar - 16.
Cederberg H, Laakso M . Variable effects of statins on glucose homeostasis parameters and their diabetogenic role. Reply to Kostapanos MS, Agouridis AP and Elisaf MS [letter].Diabetologia. 2015; 58:1962–1963. doi: 10.1007/s00125-015-3674-9CrossrefMedlineGoogle Scholar - 17.
Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK . Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients.J Am Coll Cardiol. 2010; 55:1209–1216. doi: 10.1016/j.jacc.2009.10.053CrossrefMedlineGoogle Scholar - 18.
Puurunen J, Piltonen T, Puukka K, Ruokonen A, Savolainen MJ, Bloigu R, Morin-Papunen L, Tapanainen JS . Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study.J Clin Endocrinol Metab. 2013; 98:4798–4807. doi: 10.1210/jc.2013-2674CrossrefMedlineGoogle Scholar - 19.
Carmena R, Betteridge DJ . Diabetogenic action of statins: mechanisms.Curr Atheroscler Rep. 2019; 21:23. doi: 10.1007/s11883-019-0780-zCrossrefMedlineGoogle Scholar - 20.
Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, Kastelein JJ, Colhoun H, Barter P . Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.J Am Coll Cardiol. 2011; 57:1535–1545. doi: 10.1016/j.jacc.2010.10.047CrossrefMedlineGoogle Scholar - 21.
Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, Breazna A, Pedersen TR . Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes.J Am Coll Cardiol. 2013; 61:148–152. doi: 10.1016/j.jacc.2012.09.042CrossrefMedlineGoogle Scholar - 22.
DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, ; ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance.N Engl J Med. 2011; 364:1104–1115. doi: 10.1056/NEJMoa1010949CrossrefMedlineGoogle Scholar - 23.
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ ; GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.Diabetes Care. 2005; 28:1547–1554. doi: 10.2337/diacare.28.7.1547CrossrefMedlineGoogle Scholar - 24.
Betteridge DJ . Effects of pioglitazone on lipid and lipoprotein metabolism.Diabetes Obes Metab. 2007; 9:640–647. doi: 10.1111/j.1463-1326.2007.00715.xCrossrefMedlineGoogle Scholar - 25.
de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J . Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials.Cardiovasc Diabetol. 2017; 16:134. doi: 10.1186/s12933-017-0617-4CrossrefMedlineGoogle Scholar - 26.
Deerfield IL . Pioglitazone [FDA package insert]. Takeda Pharmaceuticals America Inc.Updated July 2011. Accessed September 22, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdfGoogle Scholar - 27.
Armato JP, DeFronzo RA, Abdul-Ghani M, Ruby RJ . Successful treatment of prediabetes in clinical practice using physiological assessment (STOP DIABETES).Lancet Diabetes Endocrinol. 2018; 6:781–789. doi: 10.1016/S2213-8587(18)30234-1CrossrefMedlineGoogle Scholar - 28.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM ; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.N Engl J Med. 2002; 346:393–403. doi: 10.1056/NEJMoa012512CrossrefMedlineGoogle Scholar - 29.
Laakso M, Kuusisto J . Diabetes secondary to treatment with statins.Curr Diab Rep. 2017; 17:10. doi: 10.1007/s11892-017-0837-8CrossrefMedlineGoogle Scholar - 30.
Ray K . Statin diabetogenicity: guidance for clinicians.Cardiovasc Diabetol. 2013; 12(Suppl 1):S3. doi: 10.1186/1475-2840-12-S1-S3CrossrefMedlineGoogle Scholar - 31.
Choi JY, Choi CU, Hwang SY, Choi BG, Jang WY, Kim DY, Kim W, Park EJ, Lee S, Na JO, ; KAMIR-NIH Investigators. Effect of pitavastatin compared with atorvastatin androsuvastatin on new-onset diabetes mellitus in patientswith acute myocardial infarction.Am J Cardiol. 2018; 122:922–928. doi: 10.1016/j.amjcard.2018.06.017CrossrefMedlineGoogle Scholar - 32.
Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, ; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376:1670–1681. doi: 10.1016/S0140-6736(10)61350-5CrossrefMedlineGoogle Scholar - 33.
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2014; 129(25 suppl 2):S1–45. doi: 10.1161/01.cir.0000437738.63853.7aLinkGoogle Scholar - 34.
Mampuya WM, Frid D, Rocco M, Huang J, Brennan DM, Hazen SL, Cho L . Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience.Am Heart J. 2013; 166:597–603. doi: 10.1016/j.ahj.2013.06.004CrossrefMedlineGoogle Scholar - 35.
Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, Rajkumar CA, Connolly S, Cegla J, Stride C, . N-of-1 trial of a statin, placebo, or no treatment to assess side effects.N Engl J Med. 2020; 383:2182–2184. doi: 10.1056/NEJMc2031173CrossrefMedlineGoogle Scholar - 36.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, . 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019; 139:e1046–e1081. doi: 10.1161/CIR.0000000000000624LinkGoogle Scholar - 37.
Handelsman Y, Jellinger PS, Guerin CK, Bloomgarden ZT, Brinton EA, Budoff MJ, Davidson MH, Einhorn D, Fazio S, Fonseca VA, . Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm - 2020 Executive Summary.Endocr Pract. 2020; 26:1196–1224. doi: 10.4158/CS-2020-0490CrossrefMedlineGoogle Scholar - 38.
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, Benetos A, Biffi A, Boavida JM, Capodanno D, ; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice.Eur Heart J. 2021; 42:3227–3337. doi: 10.1093/eurheartj/ehab484CrossrefMedlineGoogle Scholar - 39.
Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M . Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort.Diabetologia. 2015; 58:1109–1117. doi: 10.1007/s00125-015-3528-5CrossrefMedlineGoogle Scholar - 40.
Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ . Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER).Am J Cardiol. 2010; 105:69–76. doi: 10.1016/j.amjcard.2009.08.651CrossrefMedlineGoogle Scholar - 41.
Wang S, Cai R, Yuan Y, Varghese Z, Moorhead J, Ruan XZ . Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis.Sci Rep. 2017; 7:39982. doi: 10.1038/srep39982CrossrefMedlineGoogle Scholar - 42.
Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J . Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study.Am Heart J. 2005; 149:464–473. doi: 10.1016/j.ahj.2004.11.023CrossrefMedlineGoogle Scholar - 43.
Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, Somaratne R, Legg JC, Nelson P, Scott R, ; LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.JAMA. 2014; 311:1870–1882. doi: 10.1001/jama.2014.4030CrossrefMedlineGoogle Scholar - 44.
Banach M, Duell PB, Gotto AM, Laufs U, Leiter LA, Mancini GBJ, Ray KK, Flaim J, Ye Z, Catapano AL . Association of Bempedoic Acid Administration With Atherogenic Lipid Levels in Phase 3 Randomized Clinical Trials of Patients With Hypercholesterolemia.JAMA Cardiol. 2020; 5:1124–1135. doi: 10.1001/jamacardio.2020.2314CrossrefMedlineGoogle Scholar - 45.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, ; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes.N Engl J Med. 2015; 372:2387–2397. doi: 10.1056/NEJMoa1410489CrossrefMedlineGoogle Scholar - 46.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, ; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376:1713–1722. doi: 10.1056/NEJMoa1615664CrossrefMedlineGoogle Scholar - 47.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, ; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.N Engl J Med. 2018; 379:2097–2107. doi: 10.1056/NEJMoa1801174CrossrefMedlineGoogle Scholar
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