Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients

Abstract

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.

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.…”

“…Waist circumference, total cholesterol and LDL levels were also significantly reduced by each dose of cetilistat. 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.…”

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].…”

Dinapinones, novel inhibitors of triacylglycerol synthesis in mammalian cells, produced by Penicillium pinophilum FKI-3864

“…Several approaches have been evaluated for the treatment of obesity, and two drugs have been approved for use: sibtramine, which exerts an effect centrally to inhibit serotonin and noradrenaline uptake, 1,2 and orlistat, which inhibits lipase to interfere with lipid absorption from the small intestine. 3,4 One of the potential strategies for the treatment of obesity is to block TG synthesis; 5 therefore, inhibitors of TG synthesis are considered as therapeutic agents for obesity. 6,7 TG is synthesized by a number of enzymes.…”