BACKGROUNDDespite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIMThe 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODSA multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTSGiven its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ‡40 kg/m 2 ) and in those with class II obesity (BMI 35.0-39.9 kg/m 2 ) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m 2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m 2 for Asian patients. CONCLUSIONSAlthough additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long‐term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight‐related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose‐dependent insulinotropic polypeptide (GIP)/GLP‐1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight‐loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long‐term obesity management and position them in a framework according to their weight loss effects.

Background: Central obesity is associated with increased risk of cardiometabolic disease. Weight loss reduces lean muscle mass, potentially impacting resting energy expenditure and/or physical functioning. This analysis of the STEP 1 trial evaluated the impact of subcutaneous (s.c.) semaglutide, a glucagon-like peptide-1 analogue, on body composition in adults with overweight/obesity using dual energy X-ray absorptiometry (DEXA). Methods: In STEP 1, 1961 adults aged ≥18 years with body mass index (BMI) ≥27 kg/m2 with ≥1 weight-related comorbidity or BMI ≥30 kg/m2, without diabetes, were randomized to s.c. semaglutide 2.4 mg once-weekly or matched placebo (2:1) for 68 weeks, plus lifestyle intervention. Participants with BMI ≤40 kg/m2 from 9 sites were eligible for the substudy. Total fat mass, total lean body mass and regional visceral fat mass were measured using DEXA at screening and week 68; visceral fat mass was calculated in the L4 region (both males/females), android region (males), or gynoid region (females), depending on site scanner methodology. Proportions of total fat and lean body mass are shown relative to total body mass; proportion of visceral fat mass is expressed relative to region assessed. Results: This analysis included 140 participants (semaglutide n=95; placebo n=45) (mean weight 98.4 kg, BMI 34.8 kg/m2; 76% female). Baseline body composition was similar in those receiving semaglutide and placebo (total fat mass proportion: 43.4% vs 44.6%; regional visceral fat mass proportion: 33.8% vs 36.3%; total lean body mass proportion: 53.9% vs 52.7%; respectively). Percentage change in body weight from baseline to week 68 was -15.0% with semaglutide vs -3.6% with placebo. This resulted in reductions from baseline with semaglutide in total fat mass (-19.3%) and regional visceral fat mass (-27.4%), leading to 3.5%-point and 2.0%-point reductions in the proportions of total fat mass and visceral fat mass, respectively. Total lean body mass decreased from baseline (-9.7%); however, the proportion relative to total body mass increased by 3.0%-points. An increasing improvement in lean body mass:fat mass ratio was seen with semaglutide with increasing weight loss from baseline to week 68 (continuous data). Overall, the ratio increased from baseline (1.34 [95% CI: 1.22, 1.47]) to week 68 by 0.23 [0.14, 0.32], with greater improvement in those with ≥15% weight loss (n=44; 0.41 [0.28, 0.53]) vs <15% weight loss (n=39; 0.03 [-0.05, 0.12]) (observed, dichotomized data; no imputation for missing data). There were no major changes in body composition with placebo from baseline to week 68. Conclusion: In adults with overweight/obesity, semaglutide 2.4 mg was associated with reduced total fat mass and regional visceral fat mass, and an increased proportion of lean body mass. Greater weight loss was associated with greater improvement in body composition (lean body mass:fat mass ratio).

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