Post-Discharge Worsening Renal Function in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome.

BACKGROUND: Worsening renal function during hospitalization for an acute coronary syndrome is strongly predictive of in-hospital and long-term outcome. However, the role of post-discharge worsening renal function has never been investigated in this setting. METHODS: We considered the placebo cohort of the AleCardio trial comparing aleglitazar with standard medical therapy among patients with type 2 diabetes mellitus and a recent acute coronary syndrome. Patients who had died or had been admitted to hospital for heart failure before the 6-month follow-up, as well as patients without complete renal function data, were excluded, leaving 2776 patients for the analysis. Worsening renal function was defined as a >20% reduction in estimated glomerular filtration rate from discharge to 6 months, or progression to macroalbuminuria. The Cox regression analysis was used to determine the prognostic impact of 6-month renal deterioration on the composite of all-cause death and hospitalization for heart failure. RESULTS: Worsening renal function occurred in 204 patients (7.34%). At a median follow-up of 2 years the estimated rates of death and hospitalization for heart failure per 100 person-years were 3.45 (95% confidence interval [CI], 2.46-6.36) for those with worsening renal function, versus 1.43 (95% CI, 1.14-1.79) for patients with stable renal function. At the adjusted analysis worsening renal function was associated with the composite endpoint (hazard ratio 2.65; 95% CI, 1.57-4.49; P <.001). CONCLUSIONS: Post-discharge worsening renal function is not infrequent among patients with type 2 diabetes and acute coronary syndromes with normal or mildly depressed renal function, and is a strong predictor of adverse cardiovascular events.

Pharmacokinetics and metabolism of tesaglitazar, a novel dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, after a single oral and intravenous dose in humans.

The pharmacokinetics of tesaglitazar (GALIDA), a novel dual-acting peroxisome proliferator-activated receptor alpha and gamma agonist, were studied in eight healthy male subjects. The subjects initially received either a single oral or intravenous (i.v.) dose of 1 mg of [(14)C]tesaglitazar. After a washout period, they received 1 mg of nonlabeled tesaglitazar via the alternative administration route. Serial blood samples and complete urine and feces were collected until 336 h postdose. Tesaglitazar absorption was rapid, with maximum plasma concentration (C(max)) at approximately 1 h postdose, and the absolute bioavailability was approximately 100%, suggesting no, or negligible, first-pass metabolism. Mean plasma clearance was 0.16 l/h and the volume of distribution at steady state was 9.1 liters. After either route of administration, the plasma concentration-time profiles of radioactivity and tesaglitazar were virtually identical, indicating low systemic metabolite concentrations and formation rate limitation of metabolite elimination. The elimination half-life of radioactivity and tesaglitazar was approximately 45 h. Radioactivity recovery was complete in all subjects, with mean values of 99.9% (i.v.) and 99.6% (oral). Tesaglitazar was mainly metabolized before excretion, and most radioactivity (91%) was recovered in urine. Approximately 20% of the dose was recovered unchanged after either administration route, resulting in a renal clearance of 0.030 l/h. Most of the radioactivity in urine was identified as acyl glucuronide of tesaglitazar. Plasma protein binding of tesaglitazar was high ( approximately 99.9%), and the mean blood-plasma partitioning ratio was 0.66, suggesting low affinity for red blood cells. There was no indication of partial inversion of the (S)-enantiomer to the corresponding (R)-form. Tesaglitazar was well tolerated.