Nephro- and neuroprotective effects of rosiglitazone versus glimepiride in normoalbuminuric patients with type 2 diabetes mellitus: a randomized controlled trial

BACKGROUND: Thiazolidinediones represent a novel class of drugs that exert pleiotropic effects at various levels and lower blood glucose through reduction of insulin resistance in patients with type 2 diabetes mellitus. MAIN PURPOSE: The nephro- and neuroprotective effects of rosiglitazone vs. glimepiride were evaluated in normoalbuminuric patients with type 2 diabetes mellitus. The relevance of several biomarkers in the diagnosis of incipient diabetic nephropathy and cerebral microangiopathy was also assessed. METHODS: A total of 34 normoalbuminuric patients with type 2 diabetes mellitus were enrolled in a 1-year open-label randomized controlled trial. Group A comprised 17 patients (7 men, 10 women, mean age 63 +/- 8.07 years) treated with rosiglitazone plus metformin; Group B comprised 17 patients (7 men, 10 women, mean age 63.2 +/- 7.19 years) treated with glimepiride plus metformin. All patients were assessed at initiation, at 6 months and by the end of the study concerning serum and urinary beta 2-microglobulin, urinary a1-microglobulin, serum cystatin C, serum creatinine, glomerular filtration rate, C-reactive protein, fibrinogen, glycated hemoglobin, cholesterol, triglycerides, hemoglobin, and the urinary albumin/creatinine ratio (UACR). Cerebral hemodynamic parameters were also measured: pulsatility index and resistance index in the internal carotid artery and middle cerebral artery, and intima-media thickness in the common carotid artery. RESULTS: At 1 year there were differences between groups A and B regarding serum cystatin C (P < 0.04), urinary beta 2-microglobulin (P < 0.004), urinary a1-microglobulin (P < 0.0001), C-reactive protein (P < 0.0001), fibrinogen (P < 0.0001), serum creatinine (P < 0.0024), glomerular filtration rate (P < 0.0010), UACR (P < 0.0001), and the cerebral hemodynamic indices. The increase in a1- and beta 2-microglobulin preceded the occurrence of microalbuminuria. UACR correlated with urinary a1- microglobulin (r = 0.4854), urinary beta 2-microglobulin (r = 0.4867), and serum cystatin C (r = 0.3702). The cerebrovascular parameters improved in group A vs. group B and correlated with urinary beta 2- and a1-microglobulin, C-reactive protein, fibrinogen, glomerular filtration rate, and duration of diabetes. CONCLUSION: Rosiglitazone demonstrated its nephro- and neuroprotective effects in normoalbuminuric patients with type 2 diabetes mellitus by the end of the follow-up period and these effects were beyond glycemic control. Urinary beta 2- and a1-microglobulin are significant biomarkers for incipient diabetic nephropathy and diabetic cerebral microangiopathy. These biomarkers showed that proximal tubule dysfunction may develop before the stage of microalbuminuria.