act-058362 and Diabetes-Mellitus--Type-2

Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations.. Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS.. We conducted a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers.. Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT).. Mifepristone was administered at doses of 300-1200 mg daily.. We evaluated change in area under the curve for glucose on 2-h oral glucose test for C-DM and change in diastolic blood pressure from baseline to wk 24 for C-HT.. In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P < 0.0001). Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P < 0.001); fasting plasma glucose decreased from 149.0 ± 75.7 mg/dl (8.3 ± 4.1 mmol/liter) to 104.7 ± 37.5 mg/dl (5.8 ± 2.1 mmol/liter, P < 0.03). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). Mean weight change was -5.7 ± 7.4% (P < 0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P < 0.001) in women and -8.44 ± 5.9 cm (P < 0.001) in men. Overall, 87% (P < 0.0001) had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women.. Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.

Topics: Adult; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Composition; Body Weight; Cushing Syndrome; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Hormone Antagonists; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Mifepristone; Quality of Life; Quinolines; Receptors, Glucocorticoid; Urea

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypertension; Male; Middle Aged; Placebos; Quinolines; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Urea; Urotensins

To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study.. After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d.,effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake.. Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of -1.8 microU ml(-1), 95% confidence interval (CI) -7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean C(max) and AUC(tau) (95% CI) and median t(max) (range) in this patient population were 180 ng ml(-1) (125, 260), 581 ng.h ml(-1) (422, 800) and 3.0 h (0.67, 4.3), respectively.. The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Quinolines; Receptors, G-Protein-Coupled; Treatment Outcome; Urea; Urotensins

In patients with renal disease increased urotensin II plasma levels have been observed. We have investigated whether palosuran, a potent, selective, and competitive antagonist of the urotensin II receptor, has effects in patients who are prone to the development of renal disease.. Macroalbuminuric, diabetic patients, categorized by renal function, were treated with oral doses of 125 mg palosuran twice daily for 13.5 days in addition to treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The 24-hour urinary albumin excretion rate was determined twice at baseline and after 13.5 days of treatment. Plasma concentrations of palosuran were determined for 12 hours after the first and last drug intake. Renal hemodynamics was measured before and after 12.5 days of treatment. Tolerability and safety parameters were monitored.. An overall clinically significant reduction of 24.3% (geometric mean) (95% confidence interval, 4.1 to 45.0) in the 24-hour urinary albumin excretion rate was observed (P = .014). No effect was observed on renal hemodynamic parameters. Palosuran was rapidly absorbed with maximum plasma concentrations at 1 hour after drug administration. The accumulation factor was 1.7 (geometric mean) (95% confidence interval, 1.3 to 2.1). Palosuran was well tolerated.. The good tolerability profile and the decrease in the 24-hour urinary albumin excretion rate may benefit diabetic patients with renal failure with regard to their disease progression. Larger placebo-controlled trials in this patient population are needed to investigate whether urotensin II receptor antagonists, given as monotherapy or combination therapy, may improve the current treatment of diabetic nephropathy.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fatigue; Female; Glomerular Filtration Rate; Headache; Humans; Hypertension; Male; Middle Aged; Nasopharyngitis; Quinolines; Receptors, G-Protein-Coupled; Renal Circulation; Treatment Outcome; Urea