Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms


Piotr Chruściel | Amirhossein Sahebkar | Magdalena Rembek-Wieliczko | Maria-Corina Serban | Sorin Ursoniu | Dimitri P. Mikhailidis | Steven R. Jones | Svetlana Mosteoru | Michael J. Blaha | Seth S. Martin | Jacek Rysz | Peter P. Toth | Gregory Y.H. Lip | Michael J. Pencina | Kausik K. Ray | Maciej Banach | Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group


Background and aims

The effect of statin therapy on plasma adiponectin levels has not been conclusively studied. Therefore, we aimed to evaluate this effect through a systematic review and meta-analysis of available randomized controlled trials (RCTs).


Quantitative data synthesis was performed using a random-effects model with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics.


In 30 studies (43 study arms) with 2953 participants, a significant increase in plasma adiponectin levels was observed after statin therapy (WMD: 0.57 μg/mL, 95% CI: 0.18, 0.95, p = 0.004). In subgroup analysis, atorvastatin, simvastatin, rosuvastatin, pravastatin and pitavastatin were found to change plasma adiponectin concentrations by 0.70 μg/mL (95% CI: −0.26, 1.65), 0.50 μg/mL (95% CI: −0.44, 1.45), −0.70 μg/mL (95% CI: −1.08, −0.33), 0.62 μg/mL (95% CI: −0.12, 1.35), and 0.51 μg/mL (95% CI: 0.30, 0.72), respectively. With respect to duration of treatment, there was a significant increase in the subset of trials lasting ≥12 weeks (WMD: 0.88 μg/mL, 95% CI: 0.19, 1.57, p = 0.012) but not in the subset of <12 weeks of duration (WMD: 0.18 μg/mL, 95% CI: −0.23, 0.58, p = 0.390). Random-effects meta-regression suggested a significant association between statin-induced elevation of plasma adiponectin and changes in plasma low density lipoprotein cholesterol levels (slope: 0.04; 95% CI: 0.01, 0.06; p = 0.002).


The meta-analysis showed a significant increase in plasma adiponectin levels following statin therapy. Although statins are known to increase the risk for new onset diabetes mellitus, our data might suggest that the mechanism for this is unlikely to be due to a reduction in adiponectin expression.

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Conflict of interest

This meta-analysis was written independently; no company or institution supported it financially. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.

Author contributions

AS designed the study, made the statistical analysis, corrected the draft of the paper; PC, MR, CS made the literature search, drafted the manuscript; MB designed the study, made the literature search, drafted the manuscript, prepared the final version, submitted the paper; SU made the literature search, drafted the manuscript; DPM, SRJ, SM, MJB, SSM, JR, PPT, GYHL, MJP, KKRcorrected the draft of the paper and prepared the final version of the manuscript. All authors read and approved the final manuscript.

  1. Tilg H., Moschen A.R.
    Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
    Nat. Rev. Immunol. 2006; 6: 772-783
  2. Jung U.J., Choi M.-S.
    Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease.
    Int. J. Mol. Sci. 2014; 15: 6184-6223
  3. Zhang L., Li M.-M. Corcoran M.
    et al.
    Essential roles of insulin, AMPK signaling and lysyl and prolyl hydroxylases in the biosynthesis and multimerization of adiponectin.
    Mol. Cell. Endocrinol. 2015; 399: 164-177
  4. Park S.E., Park C.-Y., Sweeney G.
    Biomarkers of insulin sensitivity and insulin resistance: past, present and future.
    Crit. Rev. Clin. Lab. Sci. 2015; 52: 180-190
  5. Heid I.M., Henneman P., Hicks A., et al.
    Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4659 European individuals.
    Atherosclerosis. 2010; 208: 412-420
  6. Khan U.I., Wang D., Sowers M.R., et al.
    Race–ethnic differences in adipokine levels: the Study of Women’s Health across the Nation (SWAN).
    Metabol. Clin. Exp. 2012; 61: 1261-1269
  7. Karastergiou K.
    The interplay between sex, ethnicity, and adipose tissue characteristics.
    Curr. Obes. Rep. 2015; : 1-10
  8. Stumvoll M., Tschritter O., Fritsche A., et al.
    Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes.
    Diabetes. 2002; 51: 37-41
  9. Kadowaki T., Yamauchi T., Kubota N., et al.
    Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
    J. Clin. Invest. 2006; 116: 1784-1792
  10. Greenhill C.
    Epigenetics: obesity-induced hypermethylation of adiponectin gene, nature reviews.
    Endocrinology. 2015; 11 (504–504)
  11. Ohashi K., Yuasa D., Shibata R., et al.
    Adiponectin as a target in obesity-related inflammatory state, endocrine.
    Metabol. Immune Disorders Drug Targets Formerly Curr. Drug Targets ImmuneEndocr. Metabol. Disord. 2015; 15: 145-150
  12. Stępień M., Stępień A., Banach M., et al.
    New obesity indices and adipokines in normotensive patients and patients with hypertension comparative pilot analysis.
    Angiology. 2014; 65: 333-342
  13. Stępień M., Wlazeł R.N., Paradowski M., et al.
    Serum concentrations of adiponectin, leptin, resistin, ghrelin and insulin and their association with obesity indices in obese normo-and hypertensive patients–pilot study.
    Arch. Med. Sci. 2012; 8: 431-436
  14. Stepien M., Rosniak-Bak K., Paradowski M., et al.
    Waist circumference, ghrelin and selected adipose tissue-derived adipokines as predictors of insulin resistance in obese patients: preliminary results.
    Med. Sci. Monit. Basic Res. 2011; 17: PR13-PR18
  15. Nigro E., Scudiero O., Monaco M.L., et al.
    New insight into adiponectin role in obesity and obesity-related diseases.
    BioMed Res. Int. 2014; 2014: 658913
  16. Hui X., Lam K.S., Vanhoutte P.M., et al.
    Adiponectin and cardiovascular health: an update.
    Br. J. Pharmacol. 2012; 165: 574-590
  17. Brochu-Gaudreau K., Rehfeldt C., Blouin R., et al.
    Adiponectin action from head to toe.
    Endocrine. 2010; 37: 11-32
  18. Hossain M.M., Mukheem A., Kamarul T.
    The prevention and treatment of hypoadiponectinemia-associated human diseases by up-regulation of plasma adiponectin.
    Life Sci. 2015; 135: 55-67
  19. Lee S., Hong H., Han T., et al.
    Aerobic training increases the expression of adiponectin receptor genes in the peripheral blood mononuclear cells of young men.
    Biol. sport. 2015; 32: 181
  20. Banach M., Serban C., Sahebkar A., et al.
    Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies.
    BMC Med. 2015; 13: 229
  21. Sahebkar A., Kotani K., Serban C., et al.
    Statin therapy reduces plasma endothelin-1 concentrations: a meta-analysis of 15 randomized controlled trials.
    Atherosclerosis. 2015; 241: 433-442
  22. Banach M., Malodobra-Mazur M., Gluba A., et al.
    Statin therapy and new-onset diabetes: molecular mechanisms and clinical relevance.
    Curr. Pharm. Des. 2013; 19: 4904-4912
  23. Moher D., Liberati A., Tetzlaff J., et al.
    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
    BMJ. 2009; 339: b2535
  24. Higgins J., Green S.
    Cochrane handbook for systematic reviews of interventions version 5.1. 0.
    Cochrane Collab. 2011; 5
  25. Borenstein M., Hedges L., Higgins J.
    et al.
    Comprehensive Meta-analysis Version 2.
    Biostat, Englewood, NJ2005: 104
  26. Hozo S.P., Djulbegovic B., Hozo I.
    Estimating the mean and variance from the median, range, and the size of a sample.
    BMC Med. Res. Methodol. 2005; 5: 13
  27. Sutton A.J., Abrams K.R., Jones D.R., et al.
    Methods for Meta-analysis in Medical Research.
    J. Wiley Chichester, New York2000
  28. Duval S., Tweedie R.
    Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis.
    Biometrics. 2000; 56: 455-463
  29. Sahebkar A., Watts G.F.
    Fibrate therapy and circulating adiponectin concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials.
    Atherosclerosis. 2013; 230: 110-120
  30. Jin D., Sun J., Huang J. et al.
    Peroxisome proliferator-activated receptor gamma enhances adiponectin secretion via up-regulating DsbA-L expression.
    Mol. Cell Endocrinol. 2015; 411: 97-104
  31. Serban C., Sahebkar A., Ursoniu S., et al.
    A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations.
    Sci. Rep. 2015; 5: 9902
  32. Sahebkar A., Serban C., Mikhailidis D.P., et al.
    Association between statin use and plasma D-dimer levels. A systematic review and meta-analysis of randomised controlled trials.
    Thromb. Haemost. 2015; 114: 546-557
  33. Fantuzzi G.
    Adiponectin and inflammation: consensus and controversy.
    J. Allergy Clin. Immunol. 2008; 121: 326-330
  34. Keech A., Colquhoun D., Best J., et al.
    Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial.
    Diabetes Care. 2003; 26: 2713-2721
  35. Rajpathak S.N., Kumbhani D.J., Crandall J., et al.
    Statin therapy and risk of developing type 2 diabetes: a meta-analysis.
    Diabetes care. 2009; 32: 1924-1929
  36. Kei A., Rizos E.C., Elisaf M.
    Statin use in prediabetic patients: rationale and results to date.
    Ther. Adv. Chronic Dis. 2015; 6: 246-251
  37. Elfakhani M., Torabi S., Hussein D., et al.
    Mevalonate deprivation mediates the impact of lovastatin on the differentiation of murine 3T3-F442A preadipocytes.
    Exp. Biol. Med. 2014; 239: 293-301
  38. Barylski M., Nikolic D., Banach M., et al.
    Statins and new-onset diabetes.
    Curr. Pharm. Des. 2014; 20: 3657-3664
  39. Amin R., Chen H.-Q., Tannous M., et al.
    Inhibition of glucose-and calcium-induced insulin secretion from βTC3 cells by novel inhibitors of protein isoprenylation.
    J. Pharmacol. Exp. Ther. 2002; 303: 82-88
  40. Banach M., Serban C., Ursoniu S., et al.
    Statin therapy and plasma coenzyme Q10 concentrations—A systematic review and meta-analysis of placebo-controlled trials.
    Pharmacol. Res. 2015; 99: 329-336
  41. Mabuchi H., Higashikata T., Kawashiri M., et al.
    Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients.
    J. Atheroscler. Thromb. 2005; 12: 111-119
  42. Chamberlain L.H.
    Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes.
    FEBS Lett. 2001; 507: 357-361
  43. Abel E.D., Peroni O., Kim J.K., et al.
    Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver.
    Nature. 2001; 409: 729-733
  44. Maedler K., Sergeev P., Ehses J.A., et al.
    Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets.
    Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8138-8143
  45. Kostapanos M.S., Milionis H.J., Elisaf M.S.
    An overview of the extra-lipid effects of rosuvastatin.
    J. Cardiovasc Pharmacol. Ther. 2008; 13: 157-174
  46. Arnaboldi L., Corsini A.
    Could changes in adiponectin drive the effect of statins on the risk of new-onset diabetes? The case of pitavastatin.
    Atherosclerosis. 2015; 16 (Supplements): 1-27
  47. McTaggart F.
    Comparative pharmacology of rosuvastatin.
    Atherosclerosis. 2003; 4 (Supplements): 9-14
  48. Chapman M., Orsoni A., Robillard P., et al.
    Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies.
    Curr. Med. Res. Opin. 2014; 30: 775-784
  49. Fan L.H., He Y., Xu W., et al.
    Adiponectin may be a biomarker of early atherosclerosis of smokers and decreased by nicotine through KATP channel in adipocytes.
    Nutr. (Burbank, Los Angel. Cty. Calif.). 2015; 31: 955-958
  50. Gazzerro P., Proto M.C, Gangemi G., et al.
    Pharmacological actions of statins: a critical appraisal in the management of cancer.
    Pharmacol. Rev. 2012; 64: 102-146
  51. Buldak L., Dulawa-Buldak A., Labuzek K., et al.
    Effects of 90-day hypolipidemic treatment on insulin resistance, adipokines and proinflammatory cytokines in patients with mixed hyperlipidemia and impaired fasting glucose.
    Int. J. Clin. Pharmacol. Ther. 2012; 50: 805-813
  52. Chan K.C., Chou H.H., Huang C.N.,  et al.
    Atorvastatin administration after percutaneous coronary intervention in patients with coronary artery disease and normal lipid profiles: impact on plasma adiponectin level.
    Clin. Cardiol. 2008; 31: 253-258
  53. Devaraj S., Siegel D., Jialal I.
    Simvastatin (40 mg/day), adiponectin levels, and insulin sensitivity in subjects with the metabolic syndrome.
    Am. J. Cardiol. 2007; 100: 1397-1399
  54. Doh F.M., Chang T.-I., Koo H.M., et al.
    The effect of HMG-CoA reductase inhibitor on insulin resistance in patients undergoing peritoneal dialysis.
    Cardiovasc. drugs Ther. 2012; 26: 501-509
  55. El-Barbary A.M., Hussein M.S., Rageh E.M., et al.
    Effect of atorvastatin on inflammation and modification of vascular risk factors in rheumatoid arthritis.
    J. Rheumatol. 2011; 38: 229-235
  56. Fichtenbaum C.J., Yeh T.-M., Evans S.R., et al.
    Treatment with pravastatin and fenofibrate improves atherogenic lipid profiles but not inflammatory markers in ACTG 5087.
    J. Clin. Lipidol. 2010; 4: 279-287
  57. Forst T., Pfützner A., Lübben G., et al.
    Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk—the PIOSTAT Study.
    Metabolism. 2007; 56: 491-496
  58. Gannagé-Yared M.-H., Azar R.R., Amm-Azar M., et al.
    Pravastatin does not affect insulin sensitivity and adipocytokines levels in healthy nondiabetic patients.
    Metabolism. 2005; 54: 947-951
  59. Gouni-Berthold I., Berthold H.K., Chamberland J.P., et al.
    Short-term treatment with ezetimibe, simvastatin or their combination does not alter circulating adiponectin, resistin or leptin levels in healthy men.
    Clin. Endocrinol. 2008; 68: 536-541
  60. Kim J.H., Lee M.R., Shin J.A., et al.
    Effects of pravastatin on serum adiponectin levels in female patients with type 2 diabetes mellitus.
    Atherosclerosis. 2013; 227: 355-359
  61. Koh K.K., Quon M.J., Han S.H. ,et al.
    Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia.
    J. Am. Coll. Cardiol. 2005; 45: 1649-1653
  62. Koh K.K., Quon M.J., Han S.H., et al.
    Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes.
    Hypertension. 2005; 45: 1088-1093
  63. Koh K.K., Quon M.J., Han S.H., et al.
    Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients.
    Atherosclerosis. 2009; 204: 483-490
  64. Koh K.K., Quon M.J., Han S.H., et al.
    Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients.
    J. Am. Coll. Cardiol. 2010; 55: 1209-1216
  65. Koh K.K., Quon M.J., Han S.H., et al.
    Additive beneficial effects of atorvastatin combined with amlodipine in patients with mild-to-moderate hypertension.
    Int. J. Cardiol. 2011; 146: 319-325
  66. Koh K.K., Quon M.J., Sakuma I., et al., Effects of simvastatin therapy on circulating adipocytokines in patients with hypercholesterolemia.
    Int. J. Cardiol. 2011; 146: 434-437
  67. Koh K.K., Quon M.J., Sakuma I., et al.
    Differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients.
    Int. J. Cardiol. 2013; 166: 509-515
  68. Koh K.K., Lim S., Choi H., et al.
    Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia.
    Diabetes. 2013; 62: 3547-3552
  69. Koh K.K., Quon M.J., Han S.H., et al.
    Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients.
    Diabetes Care. 2008; 31: 776-782
  70. Krysiak R., Zmuda W., Okopien B.
    The effect of simvastatin–ezetimibe combination therapy on adipose tissue hormones and systemic inflammation in patients with isolated hypercholesterolemia.
    Cardiovasc. Ther. 2014; 32: 40-46
  71. Koh K.K., Quon M.J., Han S.H., et al.
    Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients.
    Circulation. 2004; 110: 3687-3692
  72. Nakamura T., Kodama Y., Takano H., et al.
    Increase in circulating levels of adiponectin after treatment with statin and fibrate in patients with coronary artery disease and hyperlipidemia.
    Atherosclerosis. 2007; 193: 449-451
  73. Nomura S., Inami N., Shouzu A., et al.
    The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients.
    Platelets. 2009; 20: 16-22
  74. Roberto C., Pasquale P., Simona B., et al.
    Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients.
    Atherosclerosis. 2010; 213: 225-234
  75. Sawara Y., Takei T., Uchida K., et al.
    Effects of lipid-lowering therapy with rosuvastatin on atherosclerotic burden in patients with chronic kidney disease.
    Intern. Med. 2008; 47: 1505-1510
  76. Shetty G.K., Economides P.A., Horton E.S., et al.
    Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes.
    Diabetes Care. 2004; 27: 2450-2457
  77. Sugiyama S., Fukushima H., Kugiyama K., et al.
    Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease.
    Atherosclerosis. 2007; 194: e43-e51
  78. van Hoek M., van Tol A., van Vark-Van der Zee L., et al.
    Role of plasma adiponectin on the HDL-cholesterol raising effect of atorvastatin in patients with type 2 diabetes*.
    Curr. Med. Res. Opinion. 2008; 25: 93-101
  79. Yokoyama H., Saito S., Daitoku K., et al.
    Effects of pravastatin and rosuvastatin on the generation of adiponectin in the visceral adipose tissue in patients with coronary artery disease.
    Fundam. Clin. Pharmacol. 2011; 25: 378-387
  80. Hu Y., Tong G., Xu W., et al.
    Anti-inflammatory effects of simvastatin on adipokines in type 2 diabetic patients with carotid atherosclerosis.
    Diabetes Vasc. Dis. Res. 2009; 6: 262-268