Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension.

Objective: To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11ß-hydroxylase inhibitor, for treating Cushing's disease (CD). Design/methods: A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline. Results: Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1-245) and median average dose was 7.4 mg/day (range 0.8-46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension. Conclusions: Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.

Self-Monitoring of Blood Glucose: A Complementary Method Beyond the Oral Glucose Tolerance Test to Identify Hyperglycemia During Pregnancy.

OBJECTIVES: To compare: 1) 75 g oral glucose tolerance test (OGTT) and self-monitoring of blood glucose (SMBG) in identifying gestational diabetes mellitus (GDM) and other hyperglycemic statuses in pregnant women; 2) pregnancy outcomes according to glycemic status; and 3) participants' opinions regarding both methods. METHODS: A prospective study in women with a 50 g glucose load test ≥7.2 mmol/L at 24 to 28 weeks' gestation and singleton pregnancy. Women underwent OGTT (blinded) at day 1, followed by 7 days of SMBG (4 daily measurements: fasting and 2 h postprandially) without modifying diet or lifestyle. GDM (OGTT+) was diagnosed using the criteria of the International Association of the Diabetes and Pregnancy Study Groups, while pregnancy hyperglycemia (SMBG+) was defined as ≥4/7 glucose values ≥5.3 after fasting or ≥6.7 mmol/L 2 h postprandially for any meal of the day. Equivalent management was provided to women with GDM and/or pregnancy-related hyperglycemia. RESULTS: We divided 103 participants (age: 29.5±5.0 years; prepregnancy body mass index: 25.3±5.4 kg/m2) into 4 groups according to test results: OGTT+/SMBG+ (n=12, 11.7%); OGTT+/SMBG- (n=14, 13.6%); OGTT-/SMBG+ (n=9, 8.7%); and OGTT-/SMBG- (n=68, 66.0%). Clinical characteristics and maternal outcomes were statistically similar between groups. Neonatal complication rates were greater in groups with hyperglycemia than in the OGTT-/SMBG- group, notably neonatal hypoglycemia (9/12, 7/14, 5/9 vs. 6/68; p<0.001). Participants reported no convenience difference between methods but would prefer OGTT for a future pregnancy. CONCLUSIONS: More than half of the women with OGTT+ were normoglycemic in daily life. Conversely, 11.7% of women with OGTT- had pregnancy hyperglycemia. OGTT+ and/or SMBG+ were equally associated with greater neonatal complications. This study suggests that alongside OGTT, SMBG could improve the care of pregnant women.

Establishment of reference intervals for the salivary cortisol circadian cycle, by electrochemiluminescence (ECLIA), in healthy adults.

OBJECTIVES: To determine salivary cortisol reference intervals in a healthy adult population, at 6 different time points during a 24-hour (h) period. METHODS: In a prospective study, salivary cortisol concentrations were measured upon waking, one-hour post-waking and at specific times of the day: at 12 h00, 16 h00, 20 h00 and midnight. Samples were analyzed by the first and second-generation electrochemiluminescence assays (ECLIA) from Roche Cobas Cortisol®. RESULTS: Salivary cortisol values were obtained from 134 healthy volunteers. Reference intervals for the first-generation assay were 6.14-33.19 nmol/L (95% prediction interval) at waking, 5.42-28.06 nmol/L one-hour post-waking, 3.62-16.23 nmol/L at 12 h00, 2.78-15.27 nmol/L at 16 h00, 2.08-14.90 nmol/L at 20 h00 and 2.09-16.92 nmol/L at midnight. Mean salivary cortisol values were 14.63 nmol/L at waking and 6.44 nmol/L at midnight. Reference intervals for the second-generation assay were 1.50-22.02 nmol/L (2.5th to 97.5th percentiles) at waking, 1.50-20.87 nmol/L one-hour post-waking, 1.50-12.51 nmol/L at 12 h00, 1.50-13.03 nmol/L at 16 h00, 1.50-9.52 nmol/L at 20 h00 and 1.50-6.28 nmol/L at midnight. Values for the second-generation assay at all 6 different time points were almost half of the first-generation assay. The second-generation assay showed a better correlation with LC-MS/MS (r = 0,97). CONCLUSION: Our study confirms that reference intervals for salivary cortisol are not comparable across first and second-generation Roche Cobas Cortisol® assays. Furthermore, the second-generation assay has a better correlation with LC-MS/MS and a better analytical performance (accuracy and precision).

Gestational diabetes mellitus identification based on self-monitoring of blood glucose.

In Sherbrooke, the gestational diabetes mellitus (GDM) Regional Committee proposed GDM screening during the first trimester for all pregnant women based on a 50 g glucose challenge test (50 g GCT) followed directly by capillary self-monitoring blood glucose (SMBG) at home. We evaluated implementation of committee's recommendations on the clinical trajectory of women receiving prenatal care at our institution. We analyzed data collected systematically by the Blood Sampling in Pregnancy clinic from 2008 to 2011. We evaluated the clinical trajectory of 7710 pregnant women to assess GDM screening/diagnoses and referral rates to the diabetes care centre (DCC) for education and treatment during both the first and second trimesters. The Canadian Diabetes Association glycemic treatment targets in women with GDM were used as diagnosis thresholds and DCC referral decisions: Fasting glucose of 5.3 mmol/L and postprandial 2 h glucose of 6.7 mmol/L. We found that pregnant women were 28.0±4.8 years old, and their body mass indexes were 24.5±5.5 kg/m(2). During the first trimester, 47% of women were screened for GDM, mostly (84%) using the 50 g GCT. Following SMBG, 5.7% were referred to the DCC. Only 32% of women with early GDM had >1 GDM risk factor. Thereafter, 67% of normoglycemic women screened during the first trimester were screened again during the second trimester. Among women screened during the second trimester, most screening was done using 50 g GCT, and 8.8% were referred to the DCC following SMBG. Implementation of 50 g GCT testing followed by direct home SMBG was well implemented in our area. The importance of early GDM screening and rescreening during the second trimester still needs to be emphasized.

Lower vitamin D levels at first trimester are associated with higher risk of developing gestational diabetes mellitus.

The progressive increase of insulin resistance observed in pregnancy contributes to the pathophysiology of gestational diabetes mellitus (GDM). There is controversy whether vitamin D deficiency contributes to abnormal glycemic regulation in pregnancy. We tested the associations between first trimester 25-hydroxyvitamin D (25OHD) levels and: 1) the risk of developing GDM; 2) insulin resistance/sensitivity, beta cell function and compensation indices in a large population-based prospective cohort of pregnant women. Participants (n = 655) were seen at first (6-13 weeks) and second (24-28 weeks) trimesters for blood samples. At first trimester, 25OHD levels were measured. At second trimester, glucose and insulin were measured 3 times during the oral glucose tolerance test to estimate insulin resistance (HOMA-IR), beta cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUCins/gluc) and beta cell compensation (ISSI-2). Based on IADPSG criteria, 54 participants (8.2 %) developed GDM. Lower first trimester 25OHD levels were associated with higher risk of developing GDM even after adjustment for vitamin D confounding factors and GDM risk factors (OR = 1.48 per decrease of one SD in 25OHD levels; P = 0.04). Lower first trimester 25OHD levels were associated with higher HOMA-IR (r = - 0.08; P = 0.03), lower Matsuda index (r = 0.13; P = 0.001) and lower ISSI-2 (r = 0.08; P = 0.04). After adjustment for confounders, we found no significant association with HOMA-B and AUCins/gluc. Our results suggest that low levels of 25OHD at first trimester are (1) an independent risk factor for developing GDM and (2) associated with insulin resistance at second trimester.

Dietitian-coached management in combination with annual endocrinologist follow up improves global metabolic and cardiovascular health in diabetic participants after 24 months.

This 24 month study evaluated the effect of dietitian coaching combined with minimal endocrinologist follow up on the glycemic control and cardiovascular risks of diabetic participants, compared with conventional endocrinologist follow up. Participants with type 1 or type 2 diabetes were assigned to either the control group with conventional endocrinologist follow up (C; n = 50) or the dietitian-coached group (DC; n = 51) with on-site diabetes self-management education every 3 months combined with annual endocrinologist followup. Over the 24 month intervention, weight (-0.7 vs. +2.1 kg; p = 0.04), BMI (+0.3 vs. +0.7 kg/m(2); p = 0.009), and waist circumference (-1.3 vs. +2.4 cm; p = 0.01) significantly differed between the DC and control groups. HbA(1C) dropped significantly in participants of the DC versus the control group (-0.6% vs.-0.3%; p = 0.04). This was accompanied by improved overall energy intake (-548 vs. -74 kcal/day; p = 0.04). However, no link associated glycemic control to nutrient intake or intensiveness of pharmacotherapy. Coaching by a dietitian improves glycemic control and reduces certain cardiovascular risk factors in diabetic subjects, demonstrating that a joint dietitian-endocrinologist model of care provides a convenient strategy for cardiovascular risk management in the diabetic population.

Effectiveness of a multidisciplinary program for management of obesity: the Unité d'Enseignement, de Traitement et de Recherche sur l'Obésité (UETRO) database study.

BACKGROUND: Obesity is a worldwide health problem assuming epidemic proportions. Development of effective clinical interventions is needed to lower the impact of associated morbidity and mortality, without forgetting related costs. We have established an interdisciplinary clinic for obesity management, Unité d'Enseignement, de Traitement et de Recherche sur l'Obésité (UETRO), which consists of individual consultations combined with group sessions. We report here the effectiveness of this program for weight reduction over the first year of follow up. METHODS: We performed retrospective analysis of standardized patient records of the first 115 consecutive subjects referred to UETRO with available follow up for 1 year. RESULTS: Mean age, body mass index (BMI), and waist circumference (WC) of our cohort were 46 +/- 13 years, 44.7 +/- 0.9 kg/m(2), and 120.5 +/- 1.9 cm, respectively. Hypertension and diabetes were present in 46% and 23% of our patients. Weight and WC loss were gradual over 1 year and were significantly reduced by 6.6 +/- 0.8 kg and 6.7 +/- 0.7 cm, respectively (P < 0.001), without attainment of a plateau. Blood pressure and lipid profile significantly improved after 1 year of follow up. However, the proportion of patients taking metformin, lipid-lowering, antihypertensive, or antiobesity drugs increased significantly over follow up, reflecting intensification of treatment of co-morbidities and weight management. Significant weight and WC loss occurred independently of diabetes status and use of antiobesity medications. CONCLUSIONS: This program appears to be as effective for treating obesity as more intensive treatment programs. Future prospective studies are needed to evaluate the benefits and costs of this therapeutic approach.

Long-term cabergoline therapy is not associated with valvular heart disease in patients with prolactinomas.

Ergot-derived dopamine receptor agonists, especially pergolide and cabergoline, have been associated with an increased risk of valvular heart disease in patients treated for Parkinson's disease. Cabergoline at lower doses than those employed in Parkinson's disease is widely used in patients with prolactinomas, because of its high efficacy and tolerability; however, its safety with regard to cardiac valve disease is unknown. In order to assess the prevalence of cardiac valve regurgitation in patients with prolactinomas treated with long-term cabergoline, we performed a prospective and multicentric study including four university centers in the province of Quebec. A transthoracic echocardiogram was performed in 70 patients with prolactinomas treated with cabergoline for at least 1 year (duration of treatment, 55 +/- 22 months; cumulative dose 282 +/- 271 mg, mean +/- SD) and 70 control subjects matched for age and sex. Valvular regurgitation was graded according to the American Society of Echocardiography recommendations as mild, moderate, or severe. Moderate valvular regurgitation was found in four patients (5.7%) and five control subjects (7.1%) (P = 0.73). No patient had severe valvular regurgitation. There was no correlation between the presence of significant heart-valve regurgitation and cabergoline cumulative dose, duration of cabergoline treatment, prior use of bromocriptine, age, adenoma size, or prolactin levels. Our results show that low doses of cabergoline seem to be a safe treatment of hyperprolactinemic patients. However, in patients with prolonged cabergoline treatment, we suggest that echocardiographic surveillance may be warranted.