Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

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Aims Treatment of prolactinomas with ergoline dopamine agonists can be complicated by intolerance and resistance. This study investigated the pharmacokinetics and pharmacodynamics of the nonergot dopamine agonist ropinirole, to assess its therapeutic potential as a novel therapy for prolactinomas. Methods Five female subjects with prolactinomas participated in this dose–response study. Subjects received up to three doses of ropinirole (0.5, 1.0 and 2.0 mg), each on separate occasions. Frequent blood samples for prolactin and ropinirole were collected for 24 h following drug administration. Data were analysed using noncompartmental and compartmental pharmacokinetic–pharmacodynamic (PKPD) techniques. Results Seven 24‐h curves revealed increased systemic drug exposure with increasing ropinirole doses. Ropinirole concentrations peaked at 4.4 ± 2.7 h and exhibited a half‐life of 5.8 ± 1.7 h. A dose‐dependent prolactin nadir occurred 4.4 ± 1.2 h after drug intake and prolactin concentrations transiently normalized in two of five subjects. PKPD modelling revealed that single‐dose PK of ropinirole is dose‐independent and can be described with a one‐compartment model with linear absorption and elimination. An indirect response model successfully captures the inhibitory effect of ropinirole on prolactin secretion and incorporates time‐dependent receptor desensitization for three of five subjects whose prolactin concentrations nadired before ropinirole reached Cmax. Conclusions This data‐rich study has informed our understanding of the clinical pharmacokinetics and pharmacodynamics of ropinirole, which are successfully captured by the proposed semi‐mechanistic PKPD model. This model can be used to further investigate the PKPD of ropinirole and may facilitate the identification of optimal dose regimens for the treatment of prolactinomas and the establishment of a new therapeutic option for patients impacted by this rare disease.

Purpose Treatment of hyperprolactinemia and prolactinomas with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. Ropinirole (ROP) is a low cost selective D2/D3 receptor non-ergot DA, approved for treatment of Parkinson’s disease and Restless Leg Syndrome, that has been shown to acutely lower prolactin levels (PRL). This study investigated the efficacy and tolerability of long-term ROP therapy in patients with hyperprolactinemia. Methods & Results Ten healthy women (21-45 yrs) with hyperprolactinemia were treated with ROP (0.25-6.0mg/d) for 6 months in an open-label dose escalation study. Clinical and biochemical status was assessed monthly and ROP doses were up-titrated to achieve normal PRL levels, restore menses, and eliminate galactorrhea. Two subjects had macroprolactinomas, 7 had microprolactinomas, and 1 had idiopathic hyperprolactinemia. 8/10 had previously been treated with cabergoline and/or bromocriptine. 5/10 were intolerant and 1/10 was resistant to ergot DAs. Pituitary MRIs were performed at baseline and 6 months.ROP was initiated at 0.25mg QHS in 9/10 subjects. One subject with severe DA intolerance was initiated on 0.125mg QHS. Subjects reaching a total daily dose (TDD) > 2.0mg/d were transitioned to ROP extended release. At study completion, TDDs ranged from 1-6mg/d, with a median TDD of 2mg/d. Baseline PRL levels were 136 ± 49ng/ml (1.9-25ng/ml). Stable PRL normalization was achieved in 50% of subjects. Of the subjects achieving normal PRL, 4 had microadenomas and 1 had idiopathic hyperprolactinemia, and the median effective TDD was 1mg/d (1-4mg/d, range). Among those not achieving PRL normalization, PRL decreased 46 ± 5.4% (Mean ± SEM) from baseline, at a median TDD of 4.0mg/d (2-6mg/d, range). In the subject with documented resistance to ergot DAs, PRL decreased from 529 to 320ng/ml, after 3 months of ROP on the maximum dose studied (6mg/d), but rose to 690ng/ml at 6 months. During ROP treatment, menses normalized in 57%, and galactorrhea resolved in 67% of affected subjects. At study completion, tumor size was unchanged in 7/8 prolactinomas. A 20% decrease in tumor size was observed in one macroadenoma, accompanied by a 30% reduction in PRL levels. There were no changes in BP, HR, weight, renal or kidney function. Mild adverse effects (AEs) were recorded in 80% of subjects. Fatigue (60%), nausea (40%), and headache (20%) were most common. Reported AEs declined after month 1 and ROP was not discontinued due to intolerance. Conclusion These data provide support for the efficacy of ROP in the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia. While further study is needed, ROP treatment for hyperprolactinemia could be considered in patients with ergot DA intolerance or significant cardiac valve disease.

Context Roux-en-Y gastric bypass (RYGB) is associated with postprandial hyperinsulinemia. Objective This study assessed whether increased blood insulin levels may be due to an increase in maximal β -cell function. Design, Setting, and Participants We performed a cross-sectional study at Columbia University Medical Center, New York, New York. Subjects without a history of diabetes were studied after surgery (n = 12) and were compared with nonsurgical controls (n = 10) who were mean matched for body mass index, insulin sensitivity, and hemoglobin A1c and with nonobese controls (n = 8). Methods Subjects underwent a mixed-meal tolerance test and on a separate day an intravenous glucose tolerance test followed by a hyperglycemic clamp (450 mg/dL; 25 mM blood glucose) and arginine stimulation. The main outcome measure was maximal insulin secretion quantified after arginine stimulation (AinsRmax). Results The RYGB group exhibited greater peak postprandial glucose levels and fourfold greater peak insulin levels than control groups; however, there were no significant differences in insulinogenic index or AinsRmax. Another finding was significantly greater postprandial glucagon levels in the RYGB group compared with controls. Conclusions Our results suggest that after RYGB, the increase in postprandial levels of insulin are not due to changes in maximal β -cell function but appear to be an appropriate response to altered nutrient flow and absorption.