Diabetes Metab J.  2016 Feb;40(1):70-78. 10.4093/dmj.2016.40.1.70.

Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia

• Kim JM
• Back MK
• Yi HS
• Joung KH
• Kim HJ
• Ku BJ

• KMID: 2383317
• DOI: http://doi.org/10.4093/dmj.2016.40.1.70

Abstract

BACKGROUND
Elevated serum levels of growth differentiation factor-15 (GDF-15) are associated with type 2 diabetes. Therefore, the effects of atorvastatin on metabolic parameters and GDF-15 levels in patients with type 2 diabetes and dyslipidemia were evaluated.
METHODS
In this prospective randomized trial from February 2013 to March 2014, 50 consecutive type 2 diabetic patients with a low density lipoprotein cholesterol (LDL-C) levels > or =100 mg/dL were enrolled. The patients were divided into two groups based on the amount of atorvastatin prescribed, 10 mg/day (n=23) or 40 mg/day (n=27). The effect of atorvastatin on metabolic parameters, including lipid profiles and GDF-15 levels, at baseline and after 8 weeks of treatment were compared.
RESULTS
The baseline metabolic parameters and GDF-15 levels were not significantly different between the two groups. After 8 weeks of treatment, the total cholesterol (TC) and LDL-C levels were significantly decreased in both groups. The mean changes in TC and LDL-C levels were more significant in the 40 mg atorvastatin group. The GDF-15 level was decreased in the 10 mg atorvastatin group, from 1,460.6+/-874.8 to 1,451.0+/-770.8 pg/mL, and was increased in the 40 mg atorvastatin group, from 1,271.6+/-801.0 to 1,341.4+/-855.2 pg/mL. However, the change in the GDF-15 level was not statistically significant in the 10 or 40 mg atorvastatin group (P=0.665 and P=0.745, respectively).
CONCLUSION
The GDF-15 levels were not significantly changed after an 8-week treatment with atorvastatin in type 2 diabetic patients.

Keyword

Atorvastatin; Dyslipidemias; Growth differentiation factor 15; Type 2 diabetes

MeSH Terms

Cholesterol
Cholesterol, LDL
Diabetes Mellitus, Type 2*
Dyslipidemias*
Growth Differentiation Factor 15
Humans
Prospective Studies
Atorvastatin Calcium
Cholesterol
Cholesterol, LDL
Growth Differentiation Factor 15

Figure

• 

  Fig. 1 Flow diagram of the study patients. LDL-C, low density lipoprotein cholesterol; F/U, follow-up; Premed, before medication; Postmed, after medication.

Reference

1. Li J, Yang L, Qin W, Zhang G, Yuan J, Wang F. Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus. PLoS One. 2013; 8:e65549.

2. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A. 1997; 94:11514–11519.

3. Tan M, Wang Y, Guan K, Sun Y. PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway. Proc Natl Acad Sci U S A. 2000; 97:109–114.

4. Breit SN, Johnen H, Cook AD, Tsai VW, Mohammad MG, Kuffner T, Zhang HP, Marquis CP, Jiang L, Lockwood G, Lee-Ng M, Husaini Y, Wu L, Hamilton JA, Brown DA. The TGF-beta superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism. Growth Factors. 2011; 29:187–195.

5. Lindahl B. The story of growth differentiation factor 15: another piece of the puzzle. Clin Chem. 2013; 59:1550–1552.

6. Wallentin L, Zethelius B, Berglund L, Eggers KM, Lind L, Lindahl B, Wollert KC, Siegbahn A. GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men. PLoS One. 2013; 8:e78797.

7. Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int. 2003; 63:12–23.

8. Hornung RS. Reducing cholesterol and atherosclerosis. QJM. 2002; 95:339–341.

9. Cholesterol Treatment Trialists' (CTT) Collaborators. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008; 371:117–125.

10. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366:1267–1278.

11. Albert MA, Danielson E, Rifai N, Ridker PM. PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001; 286:64–70.

12. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001; 344:1959–1965.

13. Ascer E, Bertolami MC, Venturinelli ML, Buccheri V, Souza J, Nicolau JC, Ramires JA, Serrano CV Jr. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis. 2004; 177:161–166.

14. Mirmiran P, Bahadoran Z, Azizi F. Lipid accumulation product is associated with insulin resistance, lipid peroxidation, and systemic inflammation in type 2 diabetic patients. Endocrinol Metab (Seoul). 2014; 29:443–449.

15. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014; 13:465–476.

16. Ding Q, Mracek T, Gonzalez-Muniesa P, Kos K, Wilding J, Trayhurn P, Bing C. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology. 2009; 150:1688–1696.

17. Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M, Wollert KC. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol. 2012; 167:671–678.

18. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95:2409–2415.

19. Hong JH, Chung HK, Park HY, Joung KH, Lee JH, Jung JG, Kim KS, Kim HJ, Ku BJ, Shong M. GDF15 is a novel biomarker for impaired fasting glucose. Diabetes Metab J. 2014; 38:472–479.

20. Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation. 2011; 123:2101–2110.

21. Rohatgi A, Patel P, Das SR, Ayers CR, Khera A, Martinez-Rumayor A, Berry JD, McGuire DK, de Lemos JA. Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. Clin Chem. 2012; 58:172–182.

22. Xu XY, Nie Y, Wang FF, Bai Y, Lv ZZ, Zhang YY, Li ZJ, Gao W. Growth differentiation factor (GDF)-15 blocks norepinephrine-induced myocardial hypertrophy via a novel pathway involving inhibition of epidermal growth factor receptor transactivation. J Biol Chem. 2014; 289:10084–10094.

23. Chen B, Lu D, Fu Y, Zhang J, Huang X, Cao S, Xu D, Bin J, Kitakaze M, Huang Q, Liao Y. Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15 and p53. Br J Pharmacol. 2014; 171:3741–3753.

24. Dostalova I, Roubicek T, Bartlova M, Mraz M, Lacinova Z, Haluzikova D, Kavalkova P, Matoulek M, Kasalicky M, Haluzik M. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet. Eur J Endocrinol. 2009; 161:397–404.

25. Wollert KC, Kempf T. Growth differentiation factor 15 in heart failure: an update. Curr Heart Fail Rep. 2012; 9:337–345.

26. Ho JE, Hwang SJ, Wollert KC, Larson MG, Cheng S, Kempf T, Vasan RS, Januzzi JL, Wang TJ, Fox CS. Biomarkers of cardiovascular stress and incident chronic kidney disease. Clin Chem. 2013; 59:1613–1620.

27. Schlittenhardt D, Schober A, Strelau J, Bonaterra GA, Schmiedt W, Unsicker K, Metz J, Kinscherf R. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res. 2004; 318:325–333.

28. Lind L, Wallentin L, Kempf T, Tapken H, Quint A, Lindahl B, Olofsson S, Venge P, Larsson A, Hulthe J, Elmgren A, Wollert KC. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. Eur Heart J. 2009; 30:2346–2353.

29. Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M, Doehner W, Ponikowski P, Filippatos GS, Rozentryt P, Drexler H, Anker SD, Wollert KC. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol. 2007; 50:1054–1060.

30. Clerk A, Kemp TJ, Zoumpoulidou G, Sugden PH. Cardiac myocyte gene expression profiling during H2O2-induced apoptosis. Physiol Genomics. 2007; 29:118–127.

31. Han ES, Muller FL, Perez VI, Qi W, Liang H, Xi L, Fu C, Doyle E, Hickey M, Cornell J, Epstein CJ, Roberts LJ, Van Remmen H, Richardson A. The in vivo gene expression signature of oxidative stress. Physiol Genomics. 2008; 34:112–126.

32. Kim JS, Baek SJ, Sali T, Eling TE. The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15. Mol Cancer Ther. 2005; 4:487–493.

33. Bonaca MP, Morrow DA, Braunwald E, Cannon CP, Jiang S, Breher S, Sabatine MS, Kempf T, Wallentin L, Wollert KC. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: observations from PROVE IT-TIMI 22. Arterioscler Thromb Vasc Biol. 2011; 31:203–210.

34. Wang F, Guo Y, Yu H, Zheng L, Mi L, Gao W. Growth differentiation factor 15 in different stages of heart failure: potential screening implications. Biomarkers. 2010; 15:671–676.

35. Beltowski J. Statins and modulation of oxidative stress. Toxicol Mech Methods. 2005; 15:61–92.

36. Lim S, Barter P. Antioxidant effects of statins in the management of cardiometabolic disorders. J Atheroscler Thromb. 2014; 21:997–1010.

37. Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation. 2003; 108:2113–2120.

38. Nie P, Li D, Hu L, Jin S, Yu Y, Cai Z, Shao Q, Shen J, Yi J, Xiao H, Shen L, He B. Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors. PLoS One. 2014; 9:e97009.