Skip to main content
Top
Published in: Endocrine 2/2018

01-05-2018 | Meta-Analysis

Effect of ezetimibe on glycemic control: a systematic review and meta-analysis of randomized controlled trials

Authors: Huijin Wu, Hua Shang, Jing Wu

Published in: Endocrine | Issue 2/2018

Login to get access

Abstract

Purpose

Given the increased risk of incident diabetes and the side effects on glycemic control with statin treatment, statin and ezetimibe combination therapy has been widely used. However, whether the same concern exists in ezetimibe remains uncertain. This meta-analysis aimed to investigate the influence of ezetimibe treatment on glycemic control.

Methods

Articles were searched from PubMed, EMBASE, and Cochrane Library. Randomized controlled trials (RCTs) were included if they compared the effects of ezetimibe with placebo, ezetimibe plus statin with the same statin, or low-dose stain plus ezetimibe with high-dose statin on FBG and glycosylated hemoglobin A1c (HbA1c).

Results

Of the 2440 articles retrieved, 16 RCTs were included. Ezetimibe did not cause side effects on FBG (WMD −0.62, 95% CI: −3.13 to 1.90) and HbA1c (WMD 0.07, 95% CI: −0.07 to 0.20%). No significant changes in FBG (WMD −1.78, 95% CI: −6.33 to 2.77%) and HbA1c (WMD −0.05, 95% CI: −0.14 to 0.05%) were observed in ezetimibe plus low-dose statin treatment compared with high-dose statin. According to subgroup analysis, in comparison with high-dose statin, ezetimibe plus low-dose statin taken for more than 3 months showed a significant decrease in FBG (WMD −7.12, 95% CI: −13.86 to −0.38%) compared with that taken for less than 3 months (WMD 0.90, 95% CI: −2.91 to 4.71%). Nevertheless, this difference was invalid when the study conducted by Dagli et al. was removed.

Conclusions

Compared with high-dose statin therapy, ezetimibe with low-dose statin for more than 3 months may have a beneficial tendency of effects on glycemic control.
Literature
2.
go back to reference C. Baigent, A. Keech, P.M. Kearney, L. Blackwell, G. Buck, C. Pollicino, A. Kirby, T. Sourjina, R. Peto, R. Collins, R. Simes; Cholesterol Treatment, C. Trialists, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366(9493), 1267–1278 (2005). https://doi.org/10.1016/S0140-6736(05)67394-1 CrossRefPubMed C. Baigent, A. Keech, P.M. Kearney, L. Blackwell, G. Buck, C. Pollicino, A. Kirby, T. Sourjina, R. Peto, R. Collins, R. Simes; Cholesterol Treatment, C. Trialists, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366(9493), 1267–1278 (2005). https://​doi.​org/​10.​1016/​S0140-6736(05)67394-1 CrossRefPubMed
3.
go back to reference Cholesterol Treatment Trialists, C., P.M. Kearney, L. Blackwell, R. Collins, A. Keech, J. Simes, R. Peto, J. Armitage, C. Baigent, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371(9607), 117–125 (2008). https://doi.org/10.1016/S0140-6736(08)60104-X CrossRef Cholesterol Treatment Trialists, C., P.M. Kearney, L. Blackwell, R. Collins, A. Keech, J. Simes, R. Peto, J. Armitage, C. Baigent, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371(9607), 117–125 (2008). https://​doi.​org/​10.​1016/​S0140-6736(08)60104-X CrossRef
4.
go back to reference N. Sattar, D. Preiss, H.M. Murray, P. Welsh, B.M. Buckley, A.J. de Craen, S.R. Seshasai, J.J. McMurray, D.J. Freeman, J.W. Jukema, P.W. Macfarlane, C.J. Packard, D.J. Stott, R.G. Westendorp, J. Shepherd, B.R. Davis, S.L. Pressel, R. Marchioli, R.M. Marfisi, A.P. Maggioni, L. Tavazzi, G. Tognoni, J. Kjekshus, T.R. Pedersen, T.J. Cook, A.M. Gotto, M.B. Clearfield, J.R. Downs, H. Nakamura, Y. Ohashi, K. Mizuno, K.K. Ray, I. Ford, Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375(9716), 735–742 (2010). https://doi.org/10.1016/S0140-6736(09)61965-6 CrossRefPubMed N. Sattar, D. Preiss, H.M. Murray, P. Welsh, B.M. Buckley, A.J. de Craen, S.R. Seshasai, J.J. McMurray, D.J. Freeman, J.W. Jukema, P.W. Macfarlane, C.J. Packard, D.J. Stott, R.G. Westendorp, J. Shepherd, B.R. Davis, S.L. Pressel, R. Marchioli, R.M. Marfisi, A.P. Maggioni, L. Tavazzi, G. Tognoni, J. Kjekshus, T.R. Pedersen, T.J. Cook, A.M. Gotto, M.B. Clearfield, J.R. Downs, H. Nakamura, Y. Ohashi, K. Mizuno, K.K. Ray, I. Ford, Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375(9716), 735–742 (2010). https://​doi.​org/​10.​1016/​S0140-6736(09)61965-6 CrossRefPubMed
6.
go back to reference E.A. Nutescu, N.L. Shapiro, Ezetimibe: a selective cholesterol absorption inhibitor. Pharmacotherapy 23(11), 1463–1474 (2003)CrossRefPubMed E.A. Nutescu, N.L. Shapiro, Ezetimibe: a selective cholesterol absorption inhibitor. Pharmacotherapy 23(11), 1463–1474 (2003)CrossRefPubMed
7.
go back to reference M. Garcia-Calvo, J. Lisnock, H.G. Bull, B.E. Hawes, D.A. Burnett, M.P. Braun, J.H. Crona, H.R. Davis Jr., D.C. Dean, P.A. Detmers, M.P. Graziano, M. Hughes, D.E. Macintyre, A. Ogawa, A. O’Neill K., S.P. Iyer, D.E. Shevell, M.M. Smith, Y.S. Tang, A.M. Makarewicz, F. Ujjainwalla, S.W. Altmann, K.T. Chapman, N.A. Thornberry, The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc. Natl Acad. Sci. USA 102(23), 8132–8137 (2005). https://doi.org/10.1073/pnas.0500269102 CrossRefPubMedPubMedCentral M. Garcia-Calvo, J. Lisnock, H.G. Bull, B.E. Hawes, D.A. Burnett, M.P. Braun, J.H. Crona, H.R. Davis Jr., D.C. Dean, P.A. Detmers, M.P. Graziano, M. Hughes, D.E. Macintyre, A. Ogawa, A. O’Neill K., S.P. Iyer, D.E. Shevell, M.M. Smith, Y.S. Tang, A.M. Makarewicz, F. Ujjainwalla, S.W. Altmann, K.T. Chapman, N.A. Thornberry, The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc. Natl Acad. Sci. USA 102(23), 8132–8137 (2005). https://​doi.​org/​10.​1073/​pnas.​0500269102 CrossRefPubMedPubMedCentral
10.
11.
go back to reference S. Hiramitsu, Y. Ishiguro, H. Matsuyama, K. Yamada, K. Kato, M. Noba, A. Uemura, S. Yoshida, Y. Matsubara, A. Kani, K. Hasegawa, H. Hishida, Y. Ozaki, The effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis in Japanese patients with dyslipidemia. J. Atheroscler. Thromb. 17(1), 106–114 (2010)CrossRefPubMed S. Hiramitsu, Y. Ishiguro, H. Matsuyama, K. Yamada, K. Kato, M. Noba, A. Uemura, S. Yoshida, Y. Matsubara, A. Kani, K. Hasegawa, H. Hishida, Y. Ozaki, The effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis in Japanese patients with dyslipidemia. J. Atheroscler. Thromb. 17(1), 106–114 (2010)CrossRefPubMed
12.
go back to reference S. Yagi, M. Akaike, K. Aihara, T. Iwase, K. Ishikawa, S. Yoshida, Y. Sumitomo-Ueda, K. Kusunose, T. Niki, K. Yamaguchi, K. Koshiba, Y. Hirata, M. Dagvasumberel, Y. Taketani, N. Tomita, H. Yamada, T. Soeki, T. Wakatsuki, T. Matsumoto, M. Sata, Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia. J. Atheroscler. Thromb. 17(2), 173–180 (2010)CrossRefPubMed S. Yagi, M. Akaike, K. Aihara, T. Iwase, K. Ishikawa, S. Yoshida, Y. Sumitomo-Ueda, K. Kusunose, T. Niki, K. Yamaguchi, K. Koshiba, Y. Hirata, M. Dagvasumberel, Y. Taketani, N. Tomita, H. Yamada, T. Soeki, T. Wakatsuki, T. Matsumoto, M. Sata, Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia. J. Atheroscler. Thromb. 17(2), 173–180 (2010)CrossRefPubMed
14.
go back to reference N. Tamaki, H. Ueno, Y. Morinaga, T. Shiiya, M. Nakazato, Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. J. Atheroscler. Thromb. 19(6), 532–538 (2012)CrossRefPubMed N. Tamaki, H. Ueno, Y. Morinaga, T. Shiiya, M. Nakazato, Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. J. Atheroscler. Thromb. 19(6), 532–538 (2012)CrossRefPubMed
15.
go back to reference Y. Takeshita, T. Takamura, M. Honda, Y. Kita, Y. Zen, K. Kato, H. Misu, T. Ota, M. Nakamura, K. Yamada, H. Sunagozaka, K. Arai, T. Yamashita, E. Mizukoshi, S. Kaneko, The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57(5), 878–890 (2014). https://doi.org/10.1007/s00125-013-3149-9 CrossRefPubMed Y. Takeshita, T. Takamura, M. Honda, Y. Kita, Y. Zen, K. Kato, H. Misu, T. Ota, M. Nakamura, K. Yamada, H. Sunagozaka, K. Arai, T. Yamashita, E. Mizukoshi, S. Kaneko, The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57(5), 878–890 (2014). https://​doi.​org/​10.​1007/​s00125-013-3149-9 CrossRefPubMed
17.
go back to reference K. Kikuchi, U. Nezu, K. Inazumi, T. Miyazaki, K. Ono, K. Orime, J. Shirakawa, K. Sato, H. Koike, T. Wakasugi, M. Sato, C. Kawakami, S. Watanabe, T. Yamakawa, Y. Terauchi, Double-blind randomized clinical trial of the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia. J. Atheroscler. Thromb. 19(12), 1093–1101 (2012)CrossRefPubMed K. Kikuchi, U. Nezu, K. Inazumi, T. Miyazaki, K. Ono, K. Orime, J. Shirakawa, K. Sato, H. Koike, T. Wakasugi, M. Sato, C. Kawakami, S. Watanabe, T. Yamakawa, Y. Terauchi, Double-blind randomized clinical trial of the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia. J. Atheroscler. Thromb. 19(12), 1093–1101 (2012)CrossRefPubMed
19.
go back to reference M. Kishimoto, T. Sugiyama, K. Osame, D. Takarabe, M. Okamoto, M. Noda, Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes. J. Med. Invest. 58(1-2), 86–94 (2011)CrossRefPubMed M. Kishimoto, T. Sugiyama, K. Osame, D. Takarabe, M. Okamoto, M. Noda, Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes. J. Med. Invest. 58(1-2), 86–94 (2011)CrossRefPubMed
23.
26.
go back to reference K.J. Kim, S.H. Kim, Y.W. Yoon, S.W. Rha, S.J. Hong, C.H. Kwak, W. Kim, C.W. Nam, M.Y. Rhee, T.H. Park, T.J. Hong, S. Park, Y. Ahn, N. Lee, H.K. Jeon, D.W. Jeon, K.R. Han, K.W. Moon, I.H. Chae, H.S. Kim, Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe). Cardiovasc. Ther. 34(5), 371–382 (2016). https://doi.org/10.1111/1755-5922.12213 CrossRefPubMedPubMedCentral K.J. Kim, S.H. Kim, Y.W. Yoon, S.W. Rha, S.J. Hong, C.H. Kwak, W. Kim, C.W. Nam, M.Y. Rhee, T.H. Park, T.J. Hong, S. Park, Y. Ahn, N. Lee, H.K. Jeon, D.W. Jeon, K.R. Han, K.W. Moon, I.H. Chae, H.S. Kim, Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe). Cardiovasc. Ther. 34(5), 371–382 (2016). https://​doi.​org/​10.​1111/​1755-5922.​12213 CrossRefPubMedPubMedCentral
28.
go back to reference P. Ruggenenti, D. Cattaneo, S. Rota, I. Iliev, A. Parvanova, O. Diadei, B. Ene-Iordache, S. Ferrari, A.C. Bossi, R. Trevisan, A. Belviso, G. Remuzzi, Ezetimibe, Simvastatin in Dyslipidemia of Diabetes Study, G.: Effects of combined ezetimibe and simvastatin therapy as compared with simvastatin alone in patients with type 2 diabetes: a prospective randomized double-blind clinical trial. Diabetes Care 33(9), 1954–1956 (2010). https://doi.org/10.2337/dc10-0320 CrossRefPubMedPubMedCentral P. Ruggenenti, D. Cattaneo, S. Rota, I. Iliev, A. Parvanova, O. Diadei, B. Ene-Iordache, S. Ferrari, A.C. Bossi, R. Trevisan, A. Belviso, G. Remuzzi, Ezetimibe, Simvastatin in Dyslipidemia of Diabetes Study, G.: Effects of combined ezetimibe and simvastatin therapy as compared with simvastatin alone in patients with type 2 diabetes: a prospective randomized double-blind clinical trial. Diabetes Care 33(9), 1954–1956 (2010). https://​doi.​org/​10.​2337/​dc10-0320 CrossRefPubMedPubMedCentral
30.
go back to reference G. Villegas-Rivera, L.M. Roman-Pintos, E.G. Cardona-Munoz, O. Arias-Carvajal, A.D. Rodriguez-Carrizalez, R. Troyo-Sanroman, F.P. Pacheco-Moises, A. Moreno-Ulloa, A.G. Miranda-Diaz, Effects of ezetimibe/simvastatin and rosuvastatin on oxidative stress in diabetic neuropathy: a randomized, double-blind, placebo-controlled clinical trial. Oxid. Med Cell Longev. 2015, 756294 (2015). https://doi.org/10.1155/2015/756294 CrossRefPubMedPubMedCentral G. Villegas-Rivera, L.M. Roman-Pintos, E.G. Cardona-Munoz, O. Arias-Carvajal, A.D. Rodriguez-Carrizalez, R. Troyo-Sanroman, F.P. Pacheco-Moises, A. Moreno-Ulloa, A.G. Miranda-Diaz, Effects of ezetimibe/simvastatin and rosuvastatin on oxidative stress in diabetic neuropathy: a randomized, double-blind, placebo-controlled clinical trial. Oxid. Med Cell Longev. 2015, 756294 (2015). https://​doi.​org/​10.​1155/​2015/​756294 CrossRefPubMedPubMedCentral
32.
go back to reference Y. Kawagoe, Y. Hattori, A. Nakano, C. Aoki, S. Tanaka, S. Ohta, T. Iijima, A. Tomizawa, T. Jojima, H. Kase, K. Kasai, Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients. Endocr. J. 58(3), 171–175 (2011)CrossRefPubMed Y. Kawagoe, Y. Hattori, A. Nakano, C. Aoki, S. Tanaka, S. Ohta, T. Iijima, A. Tomizawa, T. Jojima, H. Kase, K. Kasai, Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients. Endocr. J. 58(3), 171–175 (2011)CrossRefPubMed
33.
go back to reference K. Sakamoto, M. Kawamura, T. Kohro, M. Omura, T. Watanabe, K. Ashidate, T. Horiuchi, H. Hara, N. Sekine, R. Chin, M. Tsujino, T. Hiyoshi, M. Tagami, A. Tanaka, Y. Mori, T. Inazawa, T. Hirano, T. Yamazaki, T. Shiba, R.S. Group, Effect of ezetimibe on LDL-C lowering and atherogenic lipoprotein profiles in type 2 diabetic patients poorly controlled by statins. PLoS ONE 10(9), e0138332 (2015). https://doi.org/10.1371/journal.pone.0138332 CrossRefPubMedPubMedCentral K. Sakamoto, M. Kawamura, T. Kohro, M. Omura, T. Watanabe, K. Ashidate, T. Horiuchi, H. Hara, N. Sekine, R. Chin, M. Tsujino, T. Hiyoshi, M. Tagami, A. Tanaka, Y. Mori, T. Inazawa, T. Hirano, T. Yamazaki, T. Shiba, R.S. Group, Effect of ezetimibe on LDL-C lowering and atherogenic lipoprotein profiles in type 2 diabetic patients poorly controlled by statins. PLoS ONE 10(9), e0138332 (2015). https://​doi.​org/​10.​1371/​journal.​pone.​0138332 CrossRefPubMedPubMedCentral
42.
go back to reference T. Nakamura, M. Hirano, Y. Kitta, D. Fujioka, Y. Saito, K. Kawabata, J.E. Obata, Y. Watanabe, K. Watanabe, K. Kugiyama, A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. J. Cardiol. 60(1), 12–17 (2012). https://doi.org/10.1016/j.jjcc.2012.02.005 CrossRefPubMed T. Nakamura, M. Hirano, Y. Kitta, D. Fujioka, Y. Saito, K. Kawabata, J.E. Obata, Y. Watanabe, K. Watanabe, K. Kugiyama, A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. J. Cardiol. 60(1), 12–17 (2012). https://​doi.​org/​10.​1016/​j.​jjcc.​2012.​02.​005 CrossRefPubMed
43.
go back to reference J.C. Sandoval, Y. Nakagawa-Toyama, D. Masuda, Y. Tochino, H. Nakaoka, R. Kawase, M. Yuasa-Kawase, K. Nakatani, M. Inagaki, K. Tsubakio-Yamamoto, T. Ohama, A. Matsuyama, M. Nishida, M. Ishigami, I. Komuro, S. Yamashita, Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. J. Atheroscler. Thromb. 17(9), 914–924 (2010)CrossRefPubMed J.C. Sandoval, Y. Nakagawa-Toyama, D. Masuda, Y. Tochino, H. Nakaoka, R. Kawase, M. Yuasa-Kawase, K. Nakatani, M. Inagaki, K. Tsubakio-Yamamoto, T. Ohama, A. Matsuyama, M. Nishida, M. Ishigami, I. Komuro, S. Yamashita, Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. J. Atheroscler. Thromb. 17(9), 914–924 (2010)CrossRefPubMed
45.
go back to reference G. Boden, M. Laakso, Lipids and glucose in type 2 diabetes: what is the cause and effect? Diabetes Care 27(9), 2253–2259 (2004)CrossRefPubMed G. Boden, M. Laakso, Lipids and glucose in type 2 diabetes: what is the cause and effect? Diabetes Care 27(9), 2253–2259 (2004)CrossRefPubMed
46.
go back to reference M. Bajaj, S. Suraamornkul, S. Kashyap, K. Cusi, L. Mandarino, R.A. DeFronzo, Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes. J. Clin. Endocrinol. Metab. 89(9), 4649–4655 (2004). https://doi.org/10.1210/jc.2004-0224 CrossRefPubMed M. Bajaj, S. Suraamornkul, S. Kashyap, K. Cusi, L. Mandarino, R.A. DeFronzo, Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes. J. Clin. Endocrinol. Metab. 89(9), 4649–4655 (2004). https://​doi.​org/​10.​1210/​jc.​2004-0224 CrossRefPubMed
Metadata
Title
Effect of ezetimibe on glycemic control: a systematic review and meta-analysis of randomized controlled trials
Authors
Huijin Wu
Hua Shang
Jing Wu
Publication date
01-05-2018
Publisher
Springer US
Published in
Endocrine / Issue 2/2018
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-018-1541-4

Other articles of this Issue 2/2018

Endocrine 2/2018 Go to the issue