Objective: To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients. Design: Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N ¼ 442) were advised a hypocaloric diet (deficient by 500 kcal per day, 30% of calories from fat) for a 2-week run-in period. Patients who satisfied the entry criteria (N ¼ 371) continued on the hypocaloric diet and were randomized to either placebo or one of three different doses of cetilistat (60 mg three times daily t.i.d., 120 mg t.i.d. and 240 mg t.i.d.) for 12 weeks, followed by a 4-week post-treatment follow-up. Safety, tolerability and body weight were assessed, together with other parameters associated with obesity. Outcome measures: The primary outcome measure was absolute change in body weight from baseline. Secondary outcomes included the proportion of patients achieving pre-defined weight loss targets, changes from baseline in waist circumference and in blood lipids. GI tolerability criteria were specifically assessed, as was safety. Results: Treatment with cetilistat reduced mean body weight to similar extents at all doses, which were statistically significant compared with placebo (60 mg t.i.d. 3.3 kg, Po0.03; 120 mg t.i.d. 3.5 kg, P ¼ 0.02; 240 mg t.i.d. 4.1 kg, Po0.001). Total serum and low-density lipoprotein cholesterol levels were likewise significantly reduced by 3-11% at all doses of cetilistat. Cetilistat was well tolerated. The frequency of withdrawal owing to treatment-emergent adverse events was similar between cetilistat-treated groups (5.3-7.6%) and placebo (7.6%). Adverse events were generally mild to moderate in intensity, occurred on only one occasion and were mostly GI in nature. The incidence of GI adverse events was increased in the cetilistat-treated groups compared to placebo. However, those GI adverse events, such as flatus with discharge and oily spotting, only occurred in 1.8-2.8% of subjects in the cetilistat-treated groups. Conclusions: Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

Eleven hundred and sixty-nine young women were prospectively examined for the presence of mitral-valve prolapse as manifested by midsystolic non-ejection click or late systolic murmur (or both). Of the 1169 women 74 (6.3%) had physical findings consistent with mitral-valve prolapse. Sixty-eight of the 74 (92%) had midsystolic non-ejection click, and in 57 the click was accompanied by a late systolic murmur. In six (8%) only a late systolic murmur was heard. Echocardiography on all patients with clinical diagnosis of mitral-valve prolapse showed patterns of prolapse in 60 of 74 (81%). Fourteen (19%) had negative echocardiograms. We conclude that mitral-valve prolapse is clinically present in approximately 6.3% of otherwise healthy young women.

IntroductIonWeight control plays an important role in the management of patients with type 2 diabetes and is typically addressed by lifestyle modifications. These focus on a nutritionally balanced, moderately hypocaloric diet, with a reduced intake of saturated fat and an increase in physical activity (1-6). Current pharmacological options for weight management are limited, with only three agents, orlistat (an inhibitor of gastric and pancreatic lipases) (7-10), sibutramine (a combined reuptake inhibitor of both serotonin and norepinephrine) that acts centrally to enhance satiety (11), and phentermine (a sympathomimetic) currently approved in some countries for use in obese patients with or without diabetes (12-15). Rimonabant (a cannabinoid-1 receptor blocker) was recently removed from the market. Cetilistat is a novel, highly lipophilic benzoxazinone inhibitor of gastrointestinal (GI) and pancreatic lipases, which is currently under development for the management of weight loss in obese patients with or without medical complications. In a 12-week, randomized, placebo-controlled, phase 2 clinical study in obese patients without pharmacologically treated comorbidities, administration of 60, 120, or 240 mg cetilistat three times daily (t.i.d.) in combination with a hypocaloric diet produced significantly greater weight loss than placebo at all doses tested (16). In addition, cetilistat was well tolerated, with a similar proportion of discontinuations due to adverse events (AEs) in both the cetilistat and the placebo groups (16). AEs were predominantly GI in nature and mild or moderate in severity.We report here the results from a randomized, placebocontrolled study investigating the efficacy and tolerability of three cetilistat doses (40, 80, and 120 mg t.i.d.) compared to placebo, in obese patients with type 2 diabetes on metformin. The study also included an active treatment comparator arm, with patients in this group receiving orlistat (120 mg t.i.d. The objective of this multicenter, randomized, double-blind study was to determine the efficacy and safety of cetilistat and orlistat relative to placebo in obese patients with type 2 diabetes, on metformin. Following a 2-week run-in, patients were randomized to placebo, cetilistat (40, 80, or 120 mg three times daily), or orlistat 120 mg t.i.d., for 12 weeks. The primary endpoint was absolute change in body weight from baseline. Secondary endpoints included other measures of obesity and glycemic control. Similar reductions in body weight were observed in patients receiving cetilistat 80 or 120 mg t.i.d. or 120 mg t.i.d. orlistat; these reductions were significant vs. placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). In the 40 mg t.i.d. and placebo groups, reductions were 2.94 kg, P = 0.958 and 2.86 kg, respectively. Statistically significant reductions in glycosylated hemoglobin (HbA 1c ) were noted. Cetilistat was well tolerated, and showed fewer discontinuations due to adverse events (AEs) than in the placebo and orlistat groups. Discontinua...

Teneligliptin co-administered with metformin produced significant reductions in HbA1c in patients with T2DM without increasing the risk of hypoglycemia.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Obesity is a significant and growing problem for which many patients seek pharmacological intervention.• Orlistat, a lipase inhibitor, is licensed for the treatment of obesity.• In combination with diet, orlistat is an effective product, but is associated with a number of adverse gastrointestinal adverse events. WHAT THIS STUDY ADDS• This study demonstrates that cetilistat is an effective inhibitor of gastrointestinal lipases, substantially increasing the amount of faecal fat excreted at all doses studied. • In addition, cetilistat is well tolerated, and a comparison with orlistat suggests an improved tolerability profile. AIMSTo assess the efficacy, pharmacodynamics, safety and tolerability of a range of doses of cetilistat, a novel inhibitor of gastrointestinal lipases, in healthy volunteers. METHODSThree Phase I, randomized, placebo-controlled, parallel-group studies were conducted. Enrolled subjects in the three studies (n = 99) received a controlled calorie diet (total intake 2160 calories daily, 30% from fat). Twenty-four subjects were randomized to placebo and 66 were randomized to the following cetilistat doses: 50 mg three times daily