The following are key points to remember from this review about metabolic surgery: weight loss, diabetes, and beyond:

1. This review describes the alarming rise in the worldwide prevalence of obesity and that it is paralleled by an increasing burden of type 2 diabetes mellitus (T2DM). About 4% are severely obese (body mass index [BMI] ≥35 kg/m²), while 1% have morbid obesity (BMI ≥40 kg/m²). In the United States, more than one-third of adults are obese. Assuming unaltered trends, as much as one-fifth of the world population may have obesity by 2025, and 12% will have T2DM.
2. Metabolic abnormalities associated with obesity increase the risk of cardiovascular disease (CVD), including coronary artery disease and heart failure. Most of the deaths for which overweight is responsible can be related to CVD and T2DM. The underlying mechanisms have not been fully elucidated, but may include metabolic, hemodynamic, and inflammatory effects of having an increased adipose tissue mass.
3. While diet and exercise for weight loss have been disappointing and generally not durable, the Look AHEAD (Action for Health in Diabetes) trial is an example of a successful lifestyle intervention program. Among overweight or obese individuals with T2DM, one-half of those assigned to intensive lifestyle intervention (calorie goal of 1200-1800 kcal daily and ≥175 minutes of moderate-intensity physical activity weekly) had a clinically meaningful weight loss of ≥5% (mean 4.7%) of their initial weight at 8 years as compared with approximately one-third of patients in the control group.
4. Behavioral therapy to promote a healthy lifestyle should be provided to all individuals as primary, secondary, and tertiary prevention for overweight/obesity and associated complications. In patients with obesity, the major components of lifestyle therapy consist of reduced calorie intake, physical activity, and behavioral interventions. The energy deficit should generally be about 500-750 kcal daily. Moderate aerobic exercise of >150 minutes per week, distributed over 3-5 days, combined with resistance exercise 2-3 times per week is recommended. Self-monitoring and goal-setting should be included as part of the intervention. The weight loss goal is 10% in subjects with prediabetes or the metabolic syndrome and at least 5-15% in those who have developed T2DM.
5. Each of the five anti-obesity agents currently approved in the United States including orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide can enhance weight loss with a variety of mechanisms, and have positive effects on related comorbidities. There is significant 1-year weight loss for these drugs in comparison with placebo. In a comparative trial, weight loss ranged from 2.6 kg with orlistat to 8.8 kg with phentermine-topiramate.
6. Contemporary guidelines suggest the addition of anti-obesity medication to lifestyle measures in individuals with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one obesity-associated comorbidity who are motivated, but have failed to lose weight or maintain weight loss using high-intensity lifestyle intervention alone. Drug therapy may also be initiated concomitantly with lifestyle therapy in patients with BMI ≥27 kg/m² who have severe weight-related complications. If ≥5% of body weight has not been lost after 3 months of therapy or there are issues with tolerability or safety, the drug should be discontinued. If the weight loss criterion is met, the drug may be continued. Importantly, there is a risk of weight regain when discontinuing pharmacotherapy, particularly when behavioral measures are not used. Given the different efficacy and safety profiles, there is no general treatment algorithm, and the choice of agent should be individualized. Only liraglutide has demonstrated clinical CV benefit.
7. In patients with T2DM and overweight/obesity, the choice of glucose-lowering medications should consider their effects on weight. Antidiabetic agents associated with weight loss include biguanides (metformin), alpha-glucosidase inhibitors, and amylin analogues. Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists appear to be particularly effective. Other hypoglycemics including insulin and sulfonylureas are neutral or associated with weight gain. Antidepressants and antipsychotics are associated with weight gain and should be limited as much as possible.
8. Gastrointestinal surgery procedures are collectively referred to as bariatric (from the Greek words baros=weight and iatrikos=medicine) or metabolic (when the intent is cardiometabolic risk reduction) surgery and are among the most common gastrointestinal procedures. The International Federation for the Surgery of Obesity and Metabolic Diseases reported that almost 580,000 metabolic procedures were performed worldwide in 2014.
9. Metabolic surgery is the most effective means of obtaining substantial and durable weight loss in individuals with obesity. Randomized trials have recently shown the superiority of surgery over medical treatment alone, in achieving improved glycemic control as well as a reduction in CV risk factors and better outcomes. The mechanisms seem to extend beyond the magnitude of caloric restriction and/or malabsorption of ingested nutrients to produce weight loss. There are improvements in incretin profiles, insulin secretion, and insulin sensitivity. Many patients with T2DM who undergo these procedures experience complete remission of the diabetes, formally defined as having normal hemoglobin A1c or fasting plasma glucose without needing antidiabetic drugs for a duration of ≥1 year. In patients who underwent surgery versus those who did not, the 2-year diabetes remission rates, defined as blood glucose levels <110 mg/dl and no diabetes medications, were 72% and 16% (p < 0.001), while the corresponding rates at 15 years were 30% and 7% (p = 0.001).
10. All contemporary procedures can be done laparoscopically and include Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), adjustable gastric banding (AGB), and biliopancreatic diversion with duodenal switch. SG has recently replaced RYGB as the most commonly performed weight loss procedure worldwide. Resection of the greater curvature removes most of the oxyntic (endocrine) mucosa of the stomach, leading to alterations in neurohumoral signaling that are strikingly similar to those observed after RYGB. Weight loss after AGB is less than that seen after RYGB or SG, and as many as 75% of AGB devices require removal for lack of weight loss, substantial weight gain, or complications. Use of AGB has declined substantially over the past decade, now accounting for only 5-10% of bariatric procedures in the United States.
11. Health benefits of metabolic surgery must be carefully weighed against the possible complications. Potential risk factors for such complications include male sex, smoking, older age, greater BMI, increasing number of comorbidities, procedure type, and prolonged operative time. US patient samples have shown a stable 0.1% risk of in-hospital death and a 9% in-hospital morbidity rate. The most common cause of death is venous thromboembolism, followed by other cardiopulmonary events and complications of gastrointestinal leaks. Nutritional deficiencies due to inadequate intake, malabsorption, or both are the most common long-term complications after metabolic surgery and more often occur after RYGB than after SG. Many micronutrient deficiencies, especially of vitamin D, calcium, and iron, are prevalent preoperatively in patients with obesity and are likely to persist or worsen postoperatively. Anemia has been reported in up to three-quarters of all cases and is mainly due to deficiencies of iron and vitamin B₁₂ as well as inflammation. Other deficiencies include folate, selenium, zinc, copper, and vitamins A, B_1,2,6, C, D, E, and K can also occur, but are not common.
12. In a recent meta-analysis of 11 randomized controlled trials with 796 obese patients, metabolic surgery resulted in a 26 kg greater weight reduction than nonsurgical treatment (p < 0.001). Studies that have reported long-term (>5 years) outcomes include the prospective, matched SOS (Swedish Obese Subjects) study, in which mean weight loss at 15 years was 27% for gastric bypass and 13% for gastric banding compared with 1% for controls. Observational data suggest that the reduction in CV risk factors translates to better patient outcomes.
13. Candidates for metabolic surgery should be carefully selected using a multidisciplinary team approach. Patients must have an acceptable operative risk, be motivated to lose weight, and have responded inadequately to behaviorally based treatment. However, optimization of glycemic control should be attempted. Metabolic surgery is contraindicated in patients with current alcohol or substance abuse, uncontrolled psychiatric disorder, poor understanding of the risks and benefits, and lack of commitment to nutritional supplementation and long-term postoperative follow-up. Scoring tools, such as the Individualized Metabolic Surgery Score, may assist in clinical decision making.
14. Recent clinical guidelines have stated that metabolic surgery should be recommended in patients with a BMI ≥40 kg/m² without concomitant medical problems and in patients with a BMI ≥35 kg/m² who have at least one severe obesity-associated comorbidity (e.g., poorly controlled T2DM). Comorbidity prevalence in patients with a BMI 35-39.9 kg/m² is high, approximately 50%, 10%, and 20% for hypertension, diabetes, and dyslipidemia. Metabolic surgery should also be considered in patients with a BMI 30-34.9 kg/m² and poorly controlled T2DM. Because of the differences in the relationships among BMI, visceral fat, and CV and metabolic risk in patients of Asian descent, it has been suggested that BMI cut-offs be lowered by 2.5 kg/m² in this population.
15. In summary, metabolic surgery is highly effective in obtaining significant and durable weight loss at a low perioperative risk when appropriate patient selection and long-term follow-up are ensured. Observational data suggest that these benefits lead to less adverse CV risk profiles with a consequent reduction in macrovascular events and mortality. Additional benefits may include improved quality of life and a reduced risk for other obesity- and diabetes-related disorders, including microvascular disease, sleep apnea, fatty liver disease, and malignancies.

Keywords: Adipose Tissue, Anti-Obesity Agents, Bariatric Surgery, Body Mass Index, Caloric Restriction, Comorbidity, Coronary Artery Disease, Diabetes Mellitus, Type 2, Diet, Dyslipidemias, Exercise, Gastrectomy, Gastric Bypass, Heart Failure, Hypertension, Intra-Abdominal Fat, Life Style, Metabolic Syndrome, Metformin, Neoplasms, Obesity, Obesity, Morbid, Overweight, Primary Prevention, Quality of Life, Risk Factors, Secondary Prevention, Sleep Apnea Syndromes, Substance-Related Disorders, Elective Surgical Procedures, Venous Thromboembolism, Vitamins, Weight Gain, Weight Loss

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