Merck & Co.

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

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Introduction Overweight men with diabetes often report erectile dysfunction, but few studies have examined effects of weight loss on this problem. Aim This study examined 1-year changes in erectile function in overweight/obese men with type 2 diabetes participating in the Look AHEAD trial. Methods Participants in Look AHEAD were randomly assigned to a control condition involving diabetes support and education (DSE) or to Intensive Lifestyle Intervention (ILI) involving group and individual sessions to reduce weight and increase physical activity. Men from 5 of the clinical sites in Look AHEAD completed the International Index of Erectile Function (IIEF) at baseline (N = 372) and at 1 year (N = 306) (82%). Main Outcome Measures Changes in erectile function as reported on the EF subscale of the IIEF. Results At 1 year, the ILI group lost a greater percent of initial body weight (9.9% vs 0.6 %) and had greater improvements in fitness (22.7% vs 4.6%) than DSE. Erectile function improved more in ILI (17.3 ± 7.6 at baseline; 18.6 ± 8.1 at 1-year) than in DSE (18.3 ± 7.6 at baseline; 18.4 ± 8.0 at 1-year); p=.04, and p=.06 after adjusting for baseline differences. Using established norms for none (i.e., normal erectile function), and three grades (i.e., mild, moderate and severe) ED, 8% of men in ILI reported a worsening of erectile function from baseline to 1 year, 70% stayed in the same category, and 22% reported improvements. In contrast, 20% of DSE reported worsening, 57% stayed in the same category, and 23% improved (p=.006). Conclusion In this sample of older overweight/obese diabetic men, weight loss intervention was mildly helpful in maintaining erectile function.

Introduction Determinants of erectile dysfunction in diabetic men have not been adequately investigated as potential mediators of change. Aim To determine the prevalence and correlates of erectile dysfunction (ED) in overweight men with type 2 diabetes in the multicenter, Look AHEAD trial (Action for Health in Diabetes). Main Outcome Measures International Index of Erectile Function (IIEF), self-reported use of phosphodiesterase type 5 inhibitors, laboratory measures of adiposity, cardiometabolic parameters, and exercise fitness. Methods Male participants aged 45–75 in the Look AHEAD trial in a committed relationship were recruited for an ongoing study of sexual function and diabetes. Eligible participants completed the IIEF questionnaire and provided updated information on use of medical treatments for sexual dysfunction. Baseline sexual function results for participants in the male ancillary study are reported here; intervention data and results for female participants are presented elsewhere. Results A total of 373 eligible male participants completed all sexual function questionnaires, of whom 263 (68.7%) were sexually active at the time of the study. Almost half (49.8%) of the men reported mild or moderate degrees of ED, and 24.8% had complete ED. Among sexually active participants, 42.6% had sought medical help for their problem, and 39.7% reported use of ED medications. ED was significantly associated with age (odds ratio [OR] = 1.05; confidence interval [CI]: 1.01–1.10) baseline HbA1c (OR = 1.31; CI: 1.05–1.63), hypertension history (OR = 2.41; CI: 1.34–4.36), and metabolic syndrome (OR = 3.05, CI: 1.31–7.11). Of note, cardiorespiratory fitness was found to be protective of ED in a multivariable analysis (OR = 0.61; P < 0.001). Conclusions ED is prevalent in this sample of obese, type 2 diabetic men in the Look AHEAD study. Cardiovascular risk factors were highly associated with ED in this population, and cardiorespiratory fitness was protective in this analysis.

OBJECTIVESexual dysfunction is a prevalent problem in obese women with type 2 diabetes. This study examined the effects of intensive lifestyle intervention (ILI) in these women.RESEARCH DESIGN AND METHODSLook AHEAD is a 16-center, randomized, controlled trial evaluating the health effects of ILI compared with a control group (diabetes support and education [DSE]). The Look AHEAD Sexual Function Ancillary study included 375 female participants at five Look AHEAD sites. Participants completed the Female Sexual Function Inventory (FSFI) and Beck Depression Inventory (BDI), and assessments of weight and cardiovascular risk factors at baseline and 1 year were made.RESULTSAt baseline, 50% of the 229 participants who reported being sexually active met criteria for female sexual dysfunction (FSD); only BDI score was related to FSD. One-year weight losses were greater in the ILI group than in the DSE group (7.6 vs. 0.45 kg; P < 0.001). Among women with FSD at baseline, those in the ILI group (N = 60) compared with those in the DSE group (N = 53) were significantly more likely to remain sexually active (83 vs. 64%; P < 0.008), reported greater improvement in total FSFI scores and in most FSFI domains (P < 0.05), and were more likely to experience remission of FSD (28 vs. 11%; P < 0.04) at 1 year. No significant differences between ILI and DSE were seen in women who did not have FSD at baseline.CONCLUSIONSParticipation in ILI appeared to have beneficial effects on sexual functioning among obese women with diabetes, particularly in those who had FSD at baseline.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

Although the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weekly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.