Weight Loss, HbA_1c Reduction, and Tolerability of Cetilistat in a Randomized, Placebo‐controlled Phase 2 Trial in Obese Diabetics: Comparison With Orlistat (Xenical)

Abstract

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...

Treatment for overweight and obesity in adult populations: a systematic review and meta-analysis

“…51,55 The remaining 12 studies (2 studies were single-group pre-post designs, 1 study had a more active comparison group, and 9 studies reported outcomes at < 12 mo) were only included in analyses of adverse events. 24,29,57,63,[75][76][77][78][79][80][81]83 High within-group heterogeneity was common; however, the direction of treatment effect was consistent across most studies, and the confidence intervals overlapped. This statistical heterogeneity is likely due to small versus large treatment effects observed across studies.…”

“…20,27,57,59,61,66,67,[70][71][72][73]77,79,84 Gastrointestinal events were reported only in studies that used drug interventions and in the 23 studies with data that could be pooled; those taking active medications were more likely to report these events than control participants. 57,59,[61][62][63][64][65][66][67][68][69][71][72][73][74][75][76][77]79,[81][82][83][84] Likewise, participants in 25 pharmacologic studies were more likely to withdraw from their study because of adverse events compared with control participants (Table 5). 46,56,[58][59][60][61][62][63][64][65]…”

Horizons in the Pharmacotherapy of Obesity

“…It has not been launched in Japan, but is being sold by an Indian company [9]. It has similar efficacy to orlistat, but is claimed to show a reduced incidence of gastrointestinal side-effects [10,11].…”

Recent advancements in drug treatment of obesity

“…20 The adverse side effects of cetilistat are similar to those reported with orlistat, although such events were less frequent, suggesting better tolerability and therefore compliance. 20,21 Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue of the endogenous gut-derived hormone incretin. It is already known to improve glycosylated haemoglobin concentrations, beta cell function and systolic blood pressure.…”