In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH).43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-mg increments from 200 mg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 mg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results.A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7--12.2; p50.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect.Our results encourage the further investigation of selexipag for the treatment of PAH.

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Animal studies have demonstrated lower levels of 1,25(OH)2D3 in a type 2 diabetes model compared with controls (1). Alterations in circulating vitamin D3 metabolites, such as decreased 1␣-hydroxylase activity and enhanced renal 25-hydroxylase activity, have been found in both experimental and human diabetes. These alterations in vitamin D metabolism may be associated with the deranged mineral homeostasis and skeletal morphology observed in rats and people with chronic insulin deficiency (2). Experimentally, vitamin D deficiency progressively reduces insulin secretion, and this reduction soon becomes irreversible (3). It was also shown that insulin deficiency may be associated with lower vitamin D-binding protein and 1,25(OH)2D3 serum levels in rats. These decreases are somewhat dependent on androgen concentration, but they are counteracted by estrogens (4).Several studies have demonstrated abnormalities in calcium, phosphate, and vitamin D metabolism in diabetic patients. In particular, Pietschmann et al. (5) evaluated 25(OH)D levels in type 1 and type 2 diabetic patients and found no difference in 25(OH)D levels between type 1 diabetic patients and control subjects, whereas 25(OH)D levels were significantly decreased in type 2 diabetic patients (5).We conducted an observational study in 799 ambulatory postmenopausal Italian women in order to assess the prevalence of hypovitaminosis D and dietary calcium insufficiency. In all patients, the levels of 25(OH)D3 (obtained by radioimmunoassay method with double antibody provided by DiaSorin), calcium intake (obtained by a questionnaire filled in by a general practitioner), and several Activity Daily Living (ADL) criteria were assessed. The samples were collected in February and March 2000.We identified 66 type 2 diabetic patients based on medical history. Female patients and control subjects were comparable for age and years since menopause, but BMI was significantly higher in diabetic patients. The ADL score was significantly worse in diabetic patients than in control subjects (P Ͻ 0.01). The 25(OH)D levels (means Ϯ SD) were significantly lower in diabetic patients than in control subjects (11 Ϯ 9.8 vs. 9 Ϯ 11.3 ng/ml, P Ͻ 0.008), and the prevalence of 25(OH) deficiency (Ͻ5 ng/ml) was significantly higher in diabetic patients than in control subjects (39 vs. 25%). Dietary calcium intake was significantly lower in diabetic patients than in control subjects (792.9 Ϯ 400.9 vs. 679 Ϯ 316.9 mg/day, P Ͻ 0.020). The significance of these findings remains unclear. The general recommendation for overweight diabetic patients to lower fat dairy product consumption may explain the lower calcium intake. We have no data that might explain the higher prevalence of hypovitaminosis D among diabetic patients. We believe our results will lead to additional studies on the hypothetical circular relationship among diabetes, vitamin D repletion, and calcium intake and absorption. We believe this relationship leads to both a worsening of diabetes and an increased risk of fractures (6), d...

In order to evaluate the prevalence, risk factors, and clinical consequences of hypovitaminosis D in elderly Italian women a multicenter study of 43 osteoporosis centers from all regions of Italy was carried out. Study population included 700 women aged 60-80 years in whom blood was taken for 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) measurements. All subjects were also questioned to assess the prevalence of several risk factors for hypovitaminosis D, osteoporotic fractures and activities of daily living (ADL). Values of 25OHD lower than 5 ng/ml were found in 27% of the women and lower than 12 ng/ml in 76%. 25OHD and PTH levels were negatively correlated ( r=-0.38, after logarithmic transformation of both variables). 25OHD levels significantly declined with advancing age and number of pregnancies and were positively correlated with educational level (years spent at school), dairy calcium intake, and days spent on holiday by the sea. In a multivariate model including all these variables, the only one that remained significant was the level of education. The lowest age-adjusted 25OH D levels were found in smokers or in women living in central Italy as compared with those living in northern or southern Italy. The mean (+/-SD) age-adjusted 25OH D values were significantly lower in women who sustained a hip fracture (7.1+/-2.2 versus 11.0+/-9.9). Women with low 25OHD levels (<12 ng/ml) had worse scores for ADL and mobility ADL (move outdoors, use stairs, walk at least 400 m, carry a heavy object). Vitamin D deficiency is extremely common among elderly Italian women. Women with lower educational level, living in central Italy, smokers or with lower intake of dairy products are at greater risk. Hypovitaminosis D is associated with worsening of the ability to perform activities of daily living and higher hip fracture prevalence. This finding should lead to an urgent population-based strategy to remedy this condition.

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