The Korean Journal of Medicine

The Korean Association of Internal Medicine (대한내과학회)
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Peroxisome Proliferator-Activated Receptor (PPAR) ${\alpha}/{\gamma}$ Agonist

Peroxisome Proliferator-Activated Receptor (PPAR) ${\alpha}/{\gamma}$ 작용제

  • Lee, Jihyun (Department of Internal Medicine, Catholic University of Daegu School of Medicine)
  • 이지현 (대구가톨릭대학교 의과대학 내과학교실)
  • Published : 2014.07.01
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Abstract

Peroxisome proliferator-activated receptor (PPAR) agonists improve glucose control and insulin sensitivity, reduce concentrations of atherogenic lipoproteins, and decrease circulating levels of inflammatory mediators. PPAR activation is considered an important pharmacologic target for patients with type 2 diabetes. However, the PPAR agonists in clinical use have undesirable side effects, including weight gain, heart failure, and bone fractures. PPAR ${\alpha}/{\gamma}$ dual agonists each target one or more of the key cardiometabolic risk factors of diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation; thus, combining their benefits to provide glucose control and ameliorate cardiovascular risks has emerged as an attractive treatment option. Aleglitazar, which was designed to balance the activation of PPAR ${\alpha}/{\gamma}$, proved efficacious in improving glycemic control and lipid homeostasis and is anticipated to minimize PPAR-related side effects. Whether the effects of aleglitazar on cardiometabolic risk factors translate into improved cardiovascular outcomes, particularly in high-risk patients, is currently being evaluated by AleCardio, a large, long-term, time-, and event-driven outcome study of type 2 diabetics with recent acute coronary syndrome.

PPAR을 활성화시키는 약제는 혈당을 낮추고 인슐린저항성을 감소시키며 동맥경화증 발생에 관여하는 지질대사를 개선하고 염증 반응을 줄여주는 효과가 있어 중요한 당뇨병 치료약제로 생각된다. 하지만 기존의 약제들은 체중증가, 심부전 발생, 심혈관 질환 발생과 골절 등이 증가하여 임상에서의 사용에 제약이 많다. 새로운 PPAR ${\alpha}/{\gamma}$ 이중 작용제는 당뇨병성 이상지질혈증, 인슐린저항성, 고혈당, 염증반응 등과 같은 심혈관 질환 발생 위험인자를 주 치료 타겟으로 하는 약제이므로 이들 약제의 복합적인 효과는 혈당 조절과 더불어 심혈관 질환 발생을 줄여줄 수 있는 새로운 흥미로운 치료 약제로 기대해 볼 수 있다. 현재 임상연구가 진행되고 있는 약제인 aleglitazar의 최근 연구 결과는 적절한 용량에서 충분한 혈당 조절과 지질대사의 효과가 있으며 상대적으로 부작용의 발생을 최소화하는 결과를 보여주고 있다. 최근에는 급성 관상동맥 질환이 발생한 고위험군의 당뇨병 환자를 대상으로 aleglitazar 약제가 심혈관 질환 발생에 미치는 영향에 대한 연구가 진행되고 있으며 연구 결과에 따라 새로운 약제에 대한 임상 적용이 가능해질 것으로 기대된다.

Keywords

References

  1. Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21:160-178. https://doi.org/10.2337/diacare.21.1.160
  2. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-418. https://doi.org/10.1056/NEJM199908053410604
  3. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci 2005;26:244-251. https://doi.org/10.1016/j.tips.2005.03.003
  4. Boden G, Laakso M. Lipids and glucose in type 2 diabetes: what is the cause and effect? Diabetes Care 2004;27:2253-2259. https://doi.org/10.2337/diacare.27.9.2253
  5. Lincoff AM, Tardif JC, Neal B, et al. Evaluation of the dual peroxisome proliferator-activated receptor ${\alpha}$/${\gamma}$ agonist aleglitazar to reduce cardiovascular events in patients with acute coronary syndrome and type 2 diabetes mellitus: rationale and design of the AleCardio trial. Am Heart J 2013;166:429-434. https://doi.org/10.1016/j.ahj.2013.05.013
  6. Rosenson RS, Wright RS, Farkouh M, Plutzky J. Modulating peroxisome proliferator-activated receptors for therapeutic benefit? biology, clinical experience, and future prospects. Am Heart J 2012;164:672-680. https://doi.org/10.1016/j.ahj.2012.06.023
  7. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409-435. https://doi.org/10.1146/annurev.med.53.082901.104018
  8. Staels B, Vu-Dac N, Kosykh VA, et al. Fibrates down-regulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase: a potential mechanism for the hypolipidemic action of fibrates. J Clin Invest 1995;95:705-712. https://doi.org/10.1172/JCI117717
  9. Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998;83:1097-1103. https://doi.org/10.1161/01.RES.83.11.1097
  10. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-1861. https://doi.org/10.1016/S0140-6736(05)67667-2
  11. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-1574. https://doi.org/10.1056/NEJMoa1001282
  12. Rubin CJ, Viraswami-Appanna K, Fiedorek FT. Efficacy and safety of muraglitazar: a double-blind, 24-week, dose-ranging study in patients with type 2 diabetes. Diab Vasc Dis Res 2009;6:205-215. https://doi.org/10.1177/1479164109336048
  13. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-2586. https://doi.org/10.1001/jama.294.20.joc50147
  14. Food and Drug Administration. Advisory Committees [Internet]. Silver Spring: Food and Drug Administration, c2012 [cited 2012 Oct 8]. Available from: http://www.fda.gov/ohrms/dockets/ac/cder05.html.
  15. Kendall DM, Rubin CJ, Mohideen P, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study. Diabetes Care 2006;29:1016-1023. https://doi.org/10.2337/dc05-1146
  16. Dietz M, Mohr P, Kuhn B, et al. Comparative molecular profiling of the PPAR${\alpha}$/${\gamma}$ activator aleglitazar: PPAR selectivity, activity and interaction with cofactors. ChemMedChem 2012;7:1101-1111. https://doi.org/10.1002/cmdc.201100598
  17. Hsiao A, Worrall DS, Olefsky JM, Subramaniam S. Variance-modeled posterior inference of microarray data: detecting gene-expression changes in 3T3-L1 adipocytes. Bioinformatics 2004;20:3108-3127. https://doi.org/10.1093/bioinformatics/bth371
  18. Bays H, McElhattan J; GALLANT 6 Study Group. A double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2007;4:181-193. https://doi.org/10.3132/dvdr.2007.039
  19. Deehan R, Maerz-Weiss P, Catlett NL, et al. Comparative transcriptional network modeling of three PPAR-${\alpha}$/${\gamma}$ co-agonists reveals distinct metabolic gene signatures in primary human hepatocytes. PLoS One 2012;7:e35012. https://doi.org/10.1371/journal.pone.0035012
  20. Younk LM, Uhl L, Davis SN. Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk. Expert Opin Drug Metab Toxicol 2011;7:753-763. https://doi.org/10.1517/17425255.2011.579561
  21. Hansen BC, Tigno XT, Benardeau A, Meyer M, Sebokova E, Mizrahi J. Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor ${\alpha}$/${\gamma}$ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome. Cardiovasc Diabetol 2011;10:7. https://doi.org/10.1186/1475-2840-10-7
  22. Benardeau A, Verry P, Atzpodien EA, et al. Effects of the dual PPAR-${\alpha}$/${\gamma}$ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat. Diabetes Obes Metab 2013;15:164-174. https://doi.org/10.1111/dom.12006
  23. Sanwald-Ducray P, Liogier D'ardhuy X, Jamois C, Banken L. Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from a randomized, placebo-controlled clinical study. Clin Pharmacol Ther 2010;88:197-203. https://doi.org/10.1038/clpt.2009.259
  24. Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009;374:126-135. https://doi.org/10.1016/S0140-6736(09)60870-9
  25. Herz M, Gaspari F, Perico N, et al. Effects of high dose aleglitazar on renal function in patients with type 2 diabetes. Int J Cardiol 2011;151:136-142. https://doi.org/10.1016/j.ijcard.2010.08.037
  26. Ruilope L, Hanefeld M, Lincoff AM, et al. Effects of aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes (ABSTR). 26th Annual General Meeting of the European Diabetic Nephropathy Study Group (EDNSG) 2013; SA-3

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