Retrospective Study Evaluating the Association Between Rosiglitazone Use and Clinical Course of Diabetic Nephropathy: Population-Based Study

Background Type 2 diabetes mellitus is a public health concern, and projections of its future effect are alarming. According to the World Health Organization, diabetes affects more than 170 million people worldwide, and this number will rise to 370 million by 2030 [1]. About one third of those affected will eventually have progressive deterioration of renal function [2, 3]. The first clinical sign of renal dysfunction in patients with diabetes is generally microalbuminuria (a sign of endothelial dysfunction that is not necessarily confined to the kidney)[4], which develops in 2 to 5 percent of patients per year [5,6]. In type 2 diabetes, unlike type 1 diabetes [7], microalbuminuria is seldom reversible [8], but, instead, progresses to overt proteinuria in 20 to 40 percent of patients.[9,10]. In 10 to 50 percent of patients with proteinuria, chronic kidney disease develops that ultimately requires dialysis or transplantation [11,12,13]. Forty to 50 percent of patients with type 2 diabetes who have microalbuminuria eventually die of cardiovascular disease [14,15]; this is three times as high a rate of death from cardiac causes as among patients who have diabetes but have no evidence of renal disease [6].

In patients with diabetes and renal disease, lowering blood pressure and the levels of urinary albumin is effective in reducing the risk of end-stage renal disease as well as that of myocardial infarction, heart failure, and stroke [16]. Angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II antagonists appear to be the most effective renoprotective and antihypertensive agents [11, 12, 17-21] . Treatment with the ACE inhibitor enalapril over a period of six years decreased the incidence of microalbuminuria in patients with type 2 diabetes who were normotensive and not obese [22].

Preventing (or delaying) the development of microalbuminuria is a key treatment goal for renoprotection [23] and, possibly, for cardioprotection [4]. Recent clinical trials suggested that inhibition of the renin-angiotensin system may actually prevent nephropathy. The post hoc analyses of the reduction in hypertension in the Heart Outcomes Prevention Evaluation study [18] and in the Losartan Intervention for Endpoint study [24] found a lower incidence of overt nephropathy in subjects with type 2 diabetes who received therapy that inhibited the renin-angiotensin system than in controls.

Recent BENEDICT study indicates that treatment with trandolapril with or without verapamil significantly reduces the incidence of microalbuminuria in patients with type 2 diabetes and normal urinary albumin excretion, as compared with placebo [25]. Trandolapril alone also appeared to decrease the incidence of microalbuminuria, whereas verapamil had no effect. Thiseffect of trandolapril plus verapamil and trandolapril alone in preventing microalbuminuria exceeded expectations based on changes in blood pressure alone.

Unfortunately, even with the appropriate use of available therapy, diabetic nephropathy still remains the leading cause of ESRD [2]. More effective strategies are needed in order to retard the progression of diabetic nephropathy and to reduce cardiovascular mortality in diabetic population.