To compare the impact of different statins therapies on the reduction of carotid intima-media thickness (CIMT) may reflect their cardiovascular benefits which is useful in clinical decision.
PubMed, EMBASE, Cochrane Library, and Web of Science were searched, and 3539 articles published from 1992 to 2020 were retrieved. CIMT in randomized controlled trials for statins therapies were included for traditional and network meta-analyses analyzed by Stata 16. The quality of included studies was assessed by the Cochrane Collaboration’s tool.
Thirty-three randomized controlled trials (n=8762) were eligible for network meta-analysis, of which 18 randomized controlled trials (n=5252) were included for comparison between statins and no statins and 11 randomized controlled trials (n=1338) were included for comparison between high-intensity statins or combination with niacin/ezetimibe and moderate/low-intensity statins in 2 traditional meta-analyses. In the traditional meta-analyses, the statins groups significantly reduce CIMT compared to no statins (standard mean difference=−0.207, 95% confidence interval: −0.291 to −0.123, p<0.001), while high-intensity statins or combination with niacin/ezetimibe performed significant CIMT reduction compared to moderate/low-intensity statins (standard mean difference=−0.287, 95% confidence interval: −0.460 to −0.114, p=0.001). In the network meta-analysis, a relative rank for the ability to reduce CIMT was given as follows: combination therapy with niacin (mean rank: 1.7), high-intensity statins, combination therapy with ezetimibe, and moderate/low-intensity statins.
Statins combined with niacin performed a greater CIMT reduction compared to high-intensity statins alone and combination therapies with ezetimibe. The advantage of niacin-combined statins therapies to improve cardiovascular endpoint needs further validation through randomized controlled trials.
Clinical trial registration
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Mach FBC, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, ESC Scientific Document Group (2020) 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 41(1):111–188. https://doi.org/10.1093/eurheartj/ehz45510 1093/eurheartj/ehz455/5556353 10.1093/eurheartj/ehz455#supplementary-data
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J (2019) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 73(24):e285–e350. https://doi.org/10.1016/j.jacc.2018.11.003
Zhao SP, Yu BL, Peng DQ, Huo Y (2014) The effect of moderate-dose versus double-dose statins on patients with acute coronary syndrome in China: results of the CHILLAS trial. Atherosclerosis 233(2):707–712. https://doi.org/10.1016/j.atherosclerosis.2013.12.003
Dai W, Huang XS, Zhao SP (2016) No evidence to support high-intensity statin in Chinese patients with coronary heart disease. Int J Cardiol 204:57–58. https://doi.org/10.1016/j.ijcard.2015.11.164
Ji MS, Jeong MH, Ahn YK, Kim SH, Kim YJ, Chae SC, Hong TJ, Seong IW, Chae JK, Kim CJ, Cho MC, Rha SW, Bae JH, Seung KB, Park SJ, other Korea Acute Myocardial Infarction Registry I (2016) Clinical outcome of statin plus ezetimibe versus high-intensity statin therapy in patients with acute myocardial infarction propensity-score matching analysis. Int J Cardiol 225:50–59. https://doi.org/10.1016/j.ijcard.2016.09.082
Ran D, Nie HJ, Gao YL, Deng SB, Du JL, Liu YJ, Jing XD, She Q (2017) A randomized, controlled comparison of different intensive lipid-lowering therapies in Chinese patients with non-ST-elevation acute coronary syndrome (NSTE-ACS): ezetimibe and rosuvastatin versus high-dose rosuvastatin. Int J Cardiol 235:49–55. https://doi.org/10.1016/j.ijcard.2017.02.099
Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W (2011) Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 365(24):2255–2267. https://doi.org/10.1056/NEJMoa1107579
Lavigne PM, Karas RH (2013) The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol 61(4):440–446. https://doi.org/10.1016/j.jacc.2012.10.030
Smilde TJ, van Wissen S, Awollersheim H, Trip MD, Kastelein JJP, Stalenhoef AFH (2001) Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357(9256):577–581. https://doi.org/10.1016/s0140-6736(00)04053-8
Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, Silverman A, Galloway JM, Henderson JA, Weir MR, Wilson C, Stylianou M, Howard WJ (2008) Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol 52(25):2198–2205. https://doi.org/10.1016/j.jacc.2008.10.031
Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, Griffen L, Taylor AJ (2010) The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 55(24):2721–2726. https://doi.org/10.1016/j.jacc.2010.03.017
Kastelein JJPAF, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH, Visseren FLJ, Sijbrands EJG, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E, ENHANCE Investigators (2008) Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 358(14):1431–1443
Meaney A, Ceballos G, Asbun J, Solache G, Mendoza E, Vela A, Meaney E (2009) The VYtorin on Carotid intima-media thickness and overall arterial rigidity (VYCTOR) study. J Clin Pharmacol 49(7):838–847. https://doi.org/10.1177/0091270009337011
Cholesterol Treatment Trialists’ (CTT) Collaboration BC, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 376(9753):1670–1681. https://doi.org/10.1016/s0140-6736(10)61350-5
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, Investigators I-I (2015) Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 372(25):2387–2397. https://doi.org/10.1056/NEJMoa1410489
Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA (2004) Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 110(23):3512–3517. https://doi.org/10.1161/01.CIR.0000148955.19792.8D
Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ (2007) Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 370(9582):153–160. https://doi.org/10.1016/s0140-6736(07)61088-5
Group HTC (2013) HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 34(17):1279–1291. https://doi.org/10.1093/eurheartj/eht055
Canner PLBK, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W (1986) Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 8(6):1245–1255
Taylor AJVT, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M (2009) Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 361(22):2113–2122. https://doi.org/10.1056/NEJMoa0907569
Fathi R, Haluska B, Short L, Marwick TH (2003) A randomized trial of aggressive lipid reduction for improvement of myocardial ischemia, symptom status, and vascular function in patients with coronary artery disease not amenable to intervention. Am J Med 114(6):445–453. https://doi.org/10.1016/s0002-9343(03)00052-4
Zhao S, Wang Y, Mu Y, Yu B, Ye P, Yan X, Li Z, Wei Y, Ambegaonakr BM, Hu D, Investigators DY-CS (2014) Prevalence of dyslipidaemia in patients treated with lipid-lowering agents in China: results of the DYSlipidemia International Study (DYSIS). Atherosclerosis 235(2):463–469. https://doi.org/10.1016/j.atherosclerosis.2014.05.916
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M (2007) Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115(4):459–467. https://doi.org/10.1161/CIRCULATIONAHA.106.628875
Baldassarre D, Hamsten A, Veglia F, de Faire U, Humphries SE, Smit AJ, Giral P, Kurl S, Rauramaa R, Mannarino E, Grossi E, Paoletti R, Tremoli E, Group IS (2012) Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. J Am Coll Cardiol 60(16):1489–1499. https://doi.org/10.1016/j.jacc.2012.06.034
Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, Najjar SS, Rembold CM, Post WS (2008) Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 21(2):93–111. https://doi.org/10.1016/j.echo.2007.11.011
Furberg CDAHJ, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA (1994) Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 90(4):1679–1687. https://doi.org/10.1161/01.cir.90.4.1679
Kinouchi KIA, Bokuda K, Morimoto S, Itoh H (2013) Effects of adding ezetimibe to fluvastatin on kidney function in patients with hypercholesterolemia: a randomized control trial. J Atheroscler Thromb 20(3):245–256. https://doi.org/10.5551/jat.14860
Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JM, Kushner FG, Lauer MS, Shaw LJ, Smith SC Jr, Taylor AJ, Weintraub WS, Wenger NK, Jacobs AK, Smith SC Jr, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Nishimura R, Ohman EM, Page RL, Stevenson WG, Tarkington LG, Yancy CW, American College of Cardiology F, American Heart A (2010) 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 56(25):e50–e103. https://doi.org/10.1016/j.jacc.2010.09.001
Wang D, Jackson EA, Karvonen-Gutierrez CA, Elliott MR, Harlow SD, Hood MM, Derby CA, Sternfeld B, Janssen I, Crawford SL, Huang MH, El Khoudary SR, Chae CU, Baylin A (2018) Healthy lifestyle during the midlife is prospectively associated with less subclinical carotid atherosclerosis: the study of women’s health across the nation. J Am Heart Assoc 7(23):e010405. https://doi.org/10.1161/JAHA.118.010405
Puhan MA, Schunemann HJ, Murad MH, Li T, Brignardello-Petersen R, Singh JA, Kessels AG, Guyatt GH, Group GW (2014) A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 349:g5630. https://doi.org/10.1136/bmj.g5630
Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, Kuder J, Murphy SA, Jukema JW, Lewis BS, Tokgozoglu L, Somaratne R, Sever PS, Pedersen TR, Sabatine MS (2018) Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 137(4):338–350. https://doi.org/10.1161/CIRCULATIONAHA.117.032235
Toth PP, Worthy G, Gandra SR, Sattar N, Bray S, Cheng LI, Bridges I, Worth GM, Dent R, Forbes CA, Deshpande S, Ross J, Kleijnen J, Stroes ESG (2017) Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia. J Am Heart Assoc 6(10). https://doi.org/10.1161/JAHA.116.005367
This work was supported by the National Natural Science Foundation of China (NSFC) [No. 81970388, No. 81700397, No. 81903299, No.81801719], the Natural Science Foundation of Guangdong [No. 2019A1515011682], the Key S&T Special Project of Guangzhou [No. 201704020044], and the Yat-sen Launching Project [No. YXQH202014].
Consent to participate
Consent for publication
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Li, H., Xu, X., Lu, L. et al. The comparative impact among different intensive statins and combination therapies with niacin/ezetimibe on carotid intima-media thickness: a systematic review, traditional meta-analysis, and network meta-analysis of randomized controlled trials. Eur J Clin Pharmacol (2021). https://doi.org/10.1007/s00228-021-03113-0
- Carotid intima-media thickness
- Network meta-analysis