This study assessed the effects of tesaglitazar (0.5 or 1 mg/day), a dual peroxisome proliferator-activated receptor α/γ agonist, when added to maximally tolerated metformin (2–2.5 g/day) in patients with poorly controlled type 2 diabetes. The primary end point of this 24-week, randomised, placebo-controlled study was the absolute change from baseline in glycosylated haemoglobin (HbA1C).
Tesaglitazar significantly reduced HbA1C, fasting plasma glucose and insulin levels compared with placebo (p<0.0001 for all) when added to metformin. Triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels also improved with tesaglitazar treatment (p<0.0001 for all). Adverse events were generally similar across treatments, except for higher frequencies of peripheral oedema and weight gain in the tesaglitazar 1 mg group. Although reversibility was not fully evaluated, dose-dependent changes in mean serum crea-tinine levels and haematology measures tended to return towards baseline at follow-up.
Despite the clinical discontinuation of tesaglitazar, this study has demonstrated the potential benefits of dual PPAR agonism as add-on therapy to metformin, in patients with poorly controlled type 2 diabetes.
1. Position statements & American Diabetes Association statements.Diabetes Care2007;30(suppl 1):S93–S95.
2.
2. Wakabayashi I, Masuda H.Association of acute-phase reactants with arterial stiffness in patients with type 2 diabetes mellitus. Clin Chim Acta2006;365:230–5.
3.
3. Goodarzi MO, Bryer-Ash M.Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab2005;7:654–65.
4.
4. United Kingdom Prospective Diabetes Study (UKPDS) 13.Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ1995;310:83–8.
5.
5. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).UK Prospective Diabetes Study (UKPDS) Group. Lancet1998;352:854–65.
6.
6. Wulffele MG, Kooy A, de Zeeuw D et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med2004;256:1–14.
7.
7. Ferre P.The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes2004;53(suppl 1):S43–S50.
8.
8. Staels B, Dallongeville J, Auwerx J. et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation1998;98:2088–93.
9.
9. Yki-Jarvinen H.Thiazolidinediones. N Engl J Med2004;351:1106–18.
10.
10. Kahn SE, Haffner SM, Heise MA. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med2006;355:2427–43.
11.
11. Bell DS.Beta-cell rejuvenation with thiazolidinediones. Am J Med2003;115(suppl 8A):20S–23S.
12.
12. Xiang AH, Peters RK, Kjos SL. et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes2006;55:517–22.
13.
13. Fagerberg B, Edwards S, Halmos T. et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia2005;48:1716–25.
14.
14. Goldstein BJ, Rosenstock J, Anzalone D. et al. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial. Curr Med Res Opin2006;22:2575–90.
15.
15. Bays H, Bryzinski BS, McElhattan J.A double-blind, randomised trial of tesaglitazar versus poglitazone in patients with type 2 diabetes mellitus. Diabetes Vasc Dis Res2007;4:181–93, doi:10.3132/dvdr.2007.039.
16.
16. CPMP, Committee for Proprietary Medicinal Products. Note for guidance on clinical investigation of medicinal products in the treatment of diabetes mellitus. CPMP/EWP/1080/00, 2002.
18. Walldius G, Jungner I.Rationale for using apolipoprotein B and apolipoprotein A-I as indicators of cardiac risk and as targets for lipid-lowering therapy. Eur Heart J2005;26:210–12.
19.
19. Walldius G, Jungner I, Holme I. et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet2001;358:2026–33.
20.
20. Sacks FM, Tonkin AM, Shepherd J. et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation2000;102:1893–900.
21.
21. Nesto RW.Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. Am J Cardiovasc Drugs2005;5:379–87.
22.
22. Ridker PM, Hennekens CH, Buring JE, Rifai N.C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med2000;342:836–43.
23.
23. Carter AM, Bennett CE, Bostock JA, Grant PJ.Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus. Diabet Med2005;22:1282–4.
24.
24. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI.Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation2002;106:679–84.
25.
25. Festa A, Hanley AJ, Tracy RP, D'Agostino R Jr, Haffner SM.Inflammation in the prediabetic state is related to increased insulin resistance rather than decreased insulin secretion. Circulation2003;108:1822–30.
27. Nesto RW, Bell D, Bonow RO. et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care2004;27:256–63.
28.
28. Nichols GA, Gomez-Caminero A.Weight changes following the initiation of new anti-hyperglycaemic therapies. Diabetes Obes Metab2007;9:96–102.
29.
29. Basu A, Jensen MD, McCann F. et al. Effects of pioglitazone versus glip-izide on body fat distribution, body water content, and hemodynamics in type 2 diabetes. Diabetes Care2006;29:510–14.
30.
30. Purnell JQ, Weyer C.Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity. Treat Endocrinol2003;2:33–47.
31.
31. Bays H, Mandarino L, DeFronzo RA.Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab2004;89:463–78.
32.
32. Johansen K.Efficacy of metformin in the treatment of NIDDM. Meta-analysis. Diabetes Care1999;22:33–7.
33.
33. Belcher G, Lambert C, Edwards G. et al. Safety and tolerability of pioglitazone, metformin, and gliclazide in the treatment of type 2 diabetes. Diabetes Res Clin Pract2005;70:53–62.
34.
34. Samuelsson O, Ottosson P, Alaupovic P, Gause-Nilsson I.The effects of tesaglitazar, a dual PPARalpha/gamma agonist, on renal dyslipidaemia. J Am Soc Nephrol2006;Abstract Issue:112A.
35.
35. Broeders N, Knoop C, Antoine M. et al. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent?Nephrol Dial Transplant2000;15:1993–9.
36.
36. Kazumi T HT, Yoshino G.Effects of fenofibrate on albuminuria in patients with hypertriglyceridemia and/or hyperuricemia: a multicenter, randomized, double-blind, placebo-controlled, crossover study. Curr Ther Res2003;64:434–46.
37.
37. 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. Lancet2005;366:1849–61.
38.
38. Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H.Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes2004;53:2169–76.
39.
39. Knowler WC, Barrett-Connor E, Fowler SE. et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med2002;346:393–403.
