Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular disease (CVD). This complication accounts for much of the increased morbidity, mortality and costs of care associated with diabetes. Hypertension, dyslipidaemia, a pro-inflammatory phenotype, abnormal fibrinolysis and platelet activation, insulin resistance and high blood glucose concentrations all contribute to the increased risk of macrovascular disease in diabetes. Although reducing low-density lipopro-tein (LDL)-cholesterol, controlling blood pressure, angiotensin-converting enzyme (ACE) inhibitors and aspirin have been shown to decrease CVD in diabetes, it is less clear that lowering glucose levels decreases risk. The PROactive trial was undertaken to test whether treatment with the thiazolidinedione pioglitazone could decrease the number of CVD events in high-risk patients with T2DM.
1. US Department of Health and Human Services.Centers for Disease Control and Prevention. National Diabetes Fact Sheet. Prevalence of diabetes in United States, all ages 2005. Available at: http://www.cdc.gov/diabetes/pubs/estimates05.htm #prev. Accessed August 24, 2006.
2.
2. Amos A, McCarty D, Zimmet P.The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Med1997;14(suppl 5):S1–S85.
3.
3. King H, Aubert R, Herman W.Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care1998;21:1414–31.
4.
4. Kannel WB, McGee DL.Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care1979;2:120–6.
5.
5. Collins R, Armitage J, Parish S, Sleight P, Peto R.for the Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet2003;361:2005–16.
6.
6. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M.Mortality from coronary heart disease in subjects with type 2 diabetes and in nondia-betic subjects with and without prior myocardial infarction. N Engl J Med1998;339:229–34.
7.
7. Roper NA, Bilous RW, Kelly WF, Unwin NC, Connolly VM.Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study. BMJ2001;322:1389–93.
8.
8. Garcia MJ, McNamara PM, Gordon T, Kannel WB.Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes1974;23:105–11.
9.
9. UK Prospective Diabetes Study Group.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.
10.
00. Erratum in: Lancet1998;352:1558.
11.
10. UK Prospective Diabetes Study Group.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet1998;352:837–53.
12.
11. Nathan DM, Cleary PA, Backlund JY. et al. for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med2005;353:2643–53.
13.
12. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA.An antidiabeticthiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem1995;270:12953–6.
14.
13. Miyazaki Y, Mahankali A, Matsuda M. et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab2002;87:2784–91.
15.
14. Miyazaki Y, Mahankali A, Matsuda M. et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care2001;24:710–19.
16.
15. Pfützner A, Marx N, Lübben G et al. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the Pioneer study. J Am Coll Cardiol2005;45:1925–31.
17.
16. Gralinski MR, Rowse PE, Breider MA.Effects of troglitazone and pioglitazone on cytokine-mediated endothelial cell proliferation in vitro. J Cardiovasc Pharmacol1998;31:909–13.
18.
17. Goetze S, Xi XP, Kawano H. et al. PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. J Cardiovasc Pharmacol1999;33:798–806.
19.
18. Dormandy JA, Charbonnel B, Eckland DJ. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet2005;366:1279–89.
20.
19. Nathan DM, Buse JB, Davidson MB. et al. Professional Practice Committee, American Diabetes Association; European Association for the Study of Diabetes. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia2006;49:1711–21.
