OBJECTIVE -It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients.RESEARCH DESIGN AND METHODS -In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI Ն30 kg/m 2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat.RESULTS -Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P Ͻ 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P ϭ 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P Ͻ 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P Ͻ 0.001).CONCLUSIONS -Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT and or NGT. Diabetes Care 27:155-161, 2004O besity is a serious health concern affecting Ͼ300 million people worldwide, representing a 50% increase in only 7 years (1). A number of studies (2-4) show that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. Indeed, ϳ90% of individuals with type 2 diabetes are either overweight or obese (5). The World Health Organization has estimated that the number of adults with diabetes will more than double from an estimated 143 million in 1997 to 300 million by 2025 (5).The Swedish Obese Subjects (SOS) study has demonstrated that large weight losses in obese patients are associated with an 80% reduction in the 8-year incidence of diabetes (6). The Finnish Diabetes Prevention Study (DPS) and the Diabetes Prevention Program (DPP) have also demonstrated that modest weight loss achieved by lifestyle changes (diet and exercise) can significantly reduce the risk of developing type 2 diabetes in obese patients with impaired glucose...

No abstract

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

HE PREVALENCE OF OVERweight in adolescents is increasing worldwide. In the United States, the proportion of adolescents with a body mass index (BMI) at or above the 95th percentile for age, a widely accepted definition of obesity in adolescents, 1,2 has increased 15.5% to 23.4% in certain ethnic minorities. 3 A similar picture is seen in European countries: the prevalence of overweight in adolescents has increased 8% to 21% in northern European countries and 17% to 23% in southern European countries. 4 Excess weight in adolescents is associated with an increased risk of disorders such as hyperlipidemia and type 2 diabetes 5 and can result in decreased emotional and physical quality of life. 6,7 In addition, childhood obesity results in increased risk of morbidity and mortality in adulthood. 8,9 Long-term follow-up studies of children and adolescents indicate that overweight children have a 15-fold greater risk of becoming overweight adults compared with those children and adolescents who were not overweight. 8 Effective weight management in children and adolescents may therefore have important immediate and future societal health benefits. Treatment of obesity in the pediatric age group, and in particular during adolescence, 10 is notoriously difficult. While behavioral therapy has had some success in treating obesity in young children (aged 6-12 years), most stud-For editorial comment see p 2932.

No abstract

The use of orlistat during periods of attempted weight maintenance minimizes weight readjustment and facilitates long-term improvement in obesity-related disease risk factors.

The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes.