Further improvement in glycemic control after switching from exenatide two times per day to exenatide once-weekly autoinjected suspension in patients with type 2 diabetes: 52-week results from the DURATION-NEO-1 study.

INTRODUCTION: Investigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year. RESEARCH DESIGN AND METHODS: In this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight. RESULTS: In total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were included in the 24-week extension (mean A1C of 7.0% and 7.3%, respectively, at week 28). From weeks 28-52, patients who switched from exenatide two times per day to exenatide QWS-AI had additional A1C reductions of approximately 0.5% (mean A1C change from baseline of -1.4% at week 52) and further reductions from baseline in FPG. Patients who continued exenatide QWS-AI treatment for 52 weeks showed clinically relevant A1C reductions (mean A1C change from baseline of -1.3% at week 52). Body-weight reductions achieved through week 28 were sustained at week 52 in both groups. There were no unexpected safety concerns or changes in the safety profile among patients who switched from exenatide two times per day to exenatide QWS-AI or those who continued exenatide QWS-AI treatment for 52 weeks. CONCLUSIONS: Switching from exenatide two times per day to exenatide QWS-AI resulted in further A1C reductions and maintenance of earlier decreases in body weight, while continued therapy with exenatide QWS-AI for 52 weeks maintained A1C and body-weight reductions, without additional safety or tolerability concerns. TRIAL REGISTRATION NUMBER: NCT01652716.

Pancreatitis Incidence in the Exenatide BID, Exenatide QW, and Exenatide QW Suspension Development Programs: Pooled Analysis of 35 Clinical Trials.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA exenatide as well as to describe patient-level data for all reported cases. METHODS: The primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks' duration) in the integrated clinical databases for exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for exenatide and non-exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences. RESULTS: The primary analysis included 5596 patients who received exenatide and 4462 in the non-exenatide group. The mean duration of study medication exposure for the exenatide and non-exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (exenatide, n = 8; non-exenatide, n = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516-0.2154] in the exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468-0.2482) in the non-exenatide treatment group. The EAIR ratio for the exenatide versus non-exenatide treatment group was 0.761 (95% CI 0.231-2.510). CONCLUSION: In this pooled analysis of 10,058 patients among studies comparing exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between exenatide and non-exenatide treatment groups. No evidence of an association between exenatide and pancreatitis was observed. FUNDING: Bristol-Myers Squibb and AstraZeneca. Plain language summary available for this article.

Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.

AIMS: To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). MATERIALS AND METHODS: This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 µg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. RESULTS: A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. CONCLUSIONS: Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

A Systematic Review and Pooled Analysis of Select Safety Parameters Among Normal Healthy Volunteers Taking Placebo in Phase 1 Clinical Trials.

A systematic review of the Bristol-Myers Squibb normal healthy volunteers (NHVs) database identified phase 1 trials that included NHVs administered placebo with the aim of characterizing normal inter- and intraindividual safety parameter variability. Twenty-five single and multiple ascending dose studies, median duration 28 (2 to 63) days, were included in the pooled analysis (355 NHVs). Laboratory evaluations, vital signs, electrocardiograms, and adverse events were assessed. The most commonly occurring adverse event was headache (28 [7.9%] NHVs; 519.5 events/100 person-years). During the dosing period (on placebo), evaluations showed 5.1 events/100 measures of alanine aminotransferase and 7.3 events/100 measures of creatine kinase 1× above the upper limit of normal. Alanine aminotransferase and creatine kinase elevations occurred in 28 (7.9%) and 39 (11.0%) NHVs, respectively; 105 (30.3%) NHVs had low and 46 (13.3%) had high diastolic blood pressure. This analysis may inform future study designs and provide a context for interpretation of safety signals in early phase clinical trials.

Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: The DURATION-NEO-2 randomized clinical study.

AIMS: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors treat type 2 diabetes through incretin-signaling pathways. This study compared the efficacy and safety of the glucagon-like peptide-1 receptor agonist exenatide once-weekly (Miglyol) suspension for autoinjection (QWS-AI) with the dipeptidyl peptidase-4 inhibitor sitagliptin or placebo. MATERIALS AND METHODS: In this open-label, multicentre study of patients with type 2 diabetes who had suboptimal glycaemic control on metformin monotherapy, 365 patients were randomized to receive exenatide 2.0 mg QWS-AI, sitagliptin 100 mg once daily or oral placebo (3:2:1 ratio). The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to 28 weeks. RESULTS: At 28 weeks, exenatide QWS-AI significantly reduced HbA1c from baseline compared to sitagliptin (-1.13% vs -0.75% [baseline values, 8.42% and 8.50%, respectively]; P = .02) and placebo (-0.40% [baseline value, 8.50%]; P = .001). More exenatide QWS-AI-treated patients achieved HbA1c <7.0% than did sitagliptin- or placebo-treated patients (43.1% vs 32.0% and 24.6%; both P < .05). Exenatide QWS-AI and sitagliptin reduced fasting plasma glucose from baseline to 28 weeks (-21.3 and -11.3 mg/dL) vs placebo (+9.6 mg/dL), with no significant difference between the 2 active treatments. Body weight decreased with both active treatments (-1.12 and -1.19 kg), but not with placebo (+0.15 kg). No improvement in blood pressure was observed in any group. The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions. CONCLUSIONS: This study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well tolerated.

Changes in Fasting and Prandial Gut and Adiposity Hormones Following Vertical Sleeve Gastrectomy or Roux-en-Y-Gastric Bypass: an 18-Month Prospective Study.

BACKGROUND: Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) produce substantial weight loss, both primarily through gastric restriction but with potentially different hormonal signaling. This prospective, observational study compared changes in gut-derived hormones in VSG, RYGB, and weight-stable participants at 6 and 18 months post-surgery. METHODS: Sixty-four obese, non-diabetic women, including 18 VSG, 23 RYGB, and 23 weight-stable controls completed assessments at baseline and 6 months, before and after consuming a mixed-nutrient meal; blood sampling occurred for 180 min post-meal. Fifty-one participants completed the 18-month outcome. Change from baseline in post-prandial area under the curve (over 180 min) for GLP-1, PYY3-36, ghrelin, and leptin was measured at 6 and 18 months post-surgery. RESULTS: At 18 months, VSG and RYGB participants lost a mean (±SEM) of 25.5 ± 2.3% and 34.2 ± 4.2% of initial weight, respectively (p < 0.156), which both differed (p < 0.001) from the +1.7 ± 1.0% gain in the control group. Fasting ghrelin declined significantly more in VSG than RYGB participants at both months 6 (p = 0.0199) and 18 (p = 0.0003). In response to the mixed-nutrient meal, GLP-1 and PYY3-36 demonstrated an exaggerated post-prandial response that was significantly greater in RYGB than VSG at 6 months (p < 0.0001 and p = 0.0062, respectively) but not 18 months (p = 0.0296 and p = 0.1210). CONCLUSIONS: VSG and RYGB both produced substantial weight losses at 18 months. The data suggest a role of gastrointestinal hormones as mediators of weight loss.

Effects of a 2-year behavioral weight loss intervention on sleep and mood in obese individuals treated in primary care practice.

OBJECTIVE: To examine the effect of weight loss on sleep duration, sleep quality, and mood in 390 obese men and women who received one of three behavioral weight loss interventions in the Practice-based Opportunities for Weight Reduction trial at the University of Pennsylvania (POWER-UP). METHODS: Sleep duration and quality were assessed at baseline and months 6 and 24 by the Pittsburgh Sleep Quality Index (PSQI) questionnaire and mood by the Patient Health Questionnaire-8 (PHQ-8). Changes in sleep and mood were examined according to treatment group and based on participants' having lost ≥5% of initial weight vs. <5%. RESULTS: There were few significant differences between treatment groups in changes in sleep or mood. At month 6, however, mean (±SD) min of sleep increased significantly more in participants who lost ≥5% vs. <5% (21.6 ± 7.2 vs. 1.2 ± 6.0 min, P = 0.0031). PSQI total scores similarly improved (declined) more in those who lost ≥5% vs. <5% (-1.2 ± 0.2 vs. -0.4 ± 0.2, P < 0.001), as did PHQ-8 scores (-2.5 ± 0.4 vs. -0.1 ± 0.3, P < 0.0001). At month 24, only the differences in mood remained statistically significant (P < 0.05). CONCLUSION: Losing ≥5% of initial weight was associated with short-term improvements in sleep duration and sleep quality, as well as favorable short- and long-term changes in mood.

GLP-1 plays a limited role in improved glycemia shortly after Roux-en-Y gastric bypass: a comparison with intensive lifestyle modification.

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9-39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Bioequivalence of saxagliptin/dapagliflozin fixed-dose combination tablets compared with coadministration of the individual tablets to healthy subjects.

Saxagliptin and dapagliflozin are individually indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The bioequivalence of saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg fixed-dose combination (FDC) tablets compared with coadministration of the individual tablets and the food effect on both strengths of saxagliptin/dapagliflozin FDCs were evaluated in this open-label, randomized, single-dose crossover study. Healthy subjects were randomized to saxagliptin 2.5 mg + dapagliflozin 5 mg fasted, 2.5/5 mg FDC fasted, 2.5/5 mg FDC fed (Cohort 1) or saxagliptin 5 mg + dapagliflozin 10 mg fasted, 5/10 mg FDC fasted, 5/10 mg FDC fed (Cohort 2). Serial blood samples for pharmacokinetics of saxagliptin and dapagliflozin were obtained predose and up to 60 h postdose. Bioequivalence of FDC tablets versus individual components was concluded if the 90% CIs for FDC to individual component geometric mean ratios of C max, AUC 0-T, and AUC inf of both analytes were between 0.80 and 1.25. Seventy-two subjects were randomized; 71 (98.6%) completed the study. Saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg FDC tablets were bioequivalent to the individual tablets administered concomitantly. Food had no clinically meaningful effect on saxagliptin or dapagliflozin overall systemic exposure. Saxagliptin/dapagliflozin FDC tablets were bioequivalent to coadministration of the individual components in healthy subjects under fasted conditions and food had no clinically meaningful effect on bioavailability.

Nutritional management of type 2 diabetes mellitus and obesity and pharmacologic therapies to facilitate weight loss.

Diet plays an integral role in the treatment of type 2 diabetes mellitus (T2DM). Unfortunately, many patients with T2DM do not have access to a registered dietitian or certified diabetes educator, and rates of physician counseling about diet remain low. This article provides an overview of the current recommendations for the nutritional management of T2DM, which are endorsed by the American Diabetes Association (ADA). Medical nutrition therapy, which provides a flexible and individualized approach to diet, emphasizes the total number (rather than the type) of carbohydrate consumed. Because fat intake also affects glycemia and cardiovascular risk, a reduction in daily mono- and polyunsaturated fat intake is recommended for most patients with T2DM. Weight loss plays an important adjunct role in treating patients with T2DM, because the majority of individuals with T2DM are overweight or obese. Patient lifestyle modification, which encompasses diet, physical activity, and behavioral therapy, can be used to facilitate weight loss in conjunction with several different dietary approaches. These include low-carbohydrate, low-fat, low-glycemic index, and Mediterranean diets. Studies have demonstrated that modest weight loss (5%-10% of body weight) is associated with significant improvements in patient measures of glycemic control, lipids, blood pressure, and other cardiovascular risk factors. Furthermore, a modest weight loss of as little as 4.5 kg can result in reducing the glycated hemoglobin level by approximately 0.5%. Pharmacologic agents, when combined with these approaches, may further augment weight loss. Familiarity with these principles can help physicians provide dietary counseling to their patients with T2DM and obesity.

Attitudes about the safety and efficacy of bariatric surgery among patients with type 2 diabetes and a body mass index of 30-40 kg/m2.

BACKGROUND: Despite increasing awareness within the medical community about the benefits of bariatric surgery for type 2 diabetes mellitus (T2DM), little is known about patients' attitudes toward bariatric surgery as a treatment for T2DM. The objective of this study was to investigate the attitudes of individuals with T2DM and a body mass index of 30 to 40 kg/m(2) concerning bariatric surgery for the treatment of T2DM. METHODS: Patients identified from the Pennsylvania Integrated Clinical and Administrative Research Database (PICARD) were surveyed about perceptions of the safety profile and efficacy of bariatric surgery as a treatment for obesity and T2DM and their willingness to be randomly assigned to receive a surgical procedure. RESULTS: A total of 130 individuals of 513 (25.3%) responded. Respondents had a median (interquartile range) age of 58.0 (range 51.0-63.0) years and self-reported body mass index of 32.9 (range 30.9-35.2) kg/m(2). Roughly half (66 of 130) were female. Overall, only 20.3% of respondents had positive views of bariatric surgery, with few reporting that it is a safe (14.3%) and effective (28.5%) treatment for T2DM. Less than 20% of respondents were willing to be randomly assigned to undergo a surgical procedure for the treatment of diabetes (16.1%) or obesity (17.5%). CONCLUSIONS: Few obese individuals with T2DM who responded to the survey had positive views about bariatric surgery. Patients' concerns about the procedure's safety profile and efficacy must be addressed to improve the acceptability of bariatric surgery as well as the feasibility of randomized, controlled trials of bariatric surgery for these individuals.

Comparison of Bariatric Surgical Procedures for Diabetes Remission: Efficacy and Mechanisms.

Bariatric surgery induces a mean weight loss of 15-30% of initial body weight (depending on the procedure), as well as a 45-95% rate of diabetes remission. Procedures that induce greater weight loss are associated with higher rates of diabetes remission. Improvements in glucose homeostasis after bariatric surgery are likely mediated by a combination of caloric restriction (followed by weight loss) and the effects of altered gut anatomy on the secretion of glucoregulatory gut hormones.

Lifestyle modifications and surgical options in the treatment of patients with obesity and type 2 diabetes mellitus.

This article reviews recent developments in the behavioral and surgical treatment of obesity and type 2 diabetes mellitus (T2DM). Randomized controlled trials of comprehensive lifestyle-modification programs, which include dietary interventions, physical activity, and behavioral therapy, have shown weight losses of 7% to 10% of initial body weight within 4 to 6 months after treatment. These programs also reduce the likelihood of developing T2DM by 58% for individuals with impaired glucose tolerance. Long-term maintenance of these improvements requires continued implementation of the program diet, physical activity, and self-regulatory behaviors. This can be successfully facilitated by continued patient-provider contact, which is frequently delivered by phone, mail, email, or online. However, these benefits may have less impact on those with extreme obesity or more significant health problems. For these individuals, bariatric surgery may be a more appropriate treatment. Bariatric surgical procedures induce mean weight losses of 15% to 30% of initial body weight (depending on the procedure) within 2 years after surgery, as well as a 45% to 95% rate of diabetes remission. Familiarity with these developments can help physicians and patients to determine which combinations of behavioral, medical, and surgical interventions are appropriate for the treatment of obesity and T2DM.

Physicians' attitudes about referring their type 2 diabetes patients for bariatric surgery.

BACKGROUND: Despite increasing evidence about the beneficial effects of bariatric surgery, little is known about physicians' attitudes toward it as a treatment of type 2 diabetes. Our objective was to investigate physicians' attitudes about referring patients with type 2 diabetes for bariatric surgery. METHODS: Physicians were identified from the Pennsylvania Integrated Clinical and Administrative Research Database and other databases. Physicians at an academic medical center (n = 142) and community-based physicians (n = 197) in the Philadelphia area in specialties likely to treat type 2 diabetes were sent a survey about their perceptions of the safety and efficacy of bariatric surgery as a treatment for obesity and type 2 diabetes. RESULTS: Of the physicians, 93 returned the survey, for a combined response rate of 27.4%. Respondents reported having positive impressions of bariatric surgery as a treatment for obesity and type 2 diabetes (79.6% and 67.4%, respectively). Only 20.8% of respondents indicated that they would be likely to refer their patients with type 2 diabetes with a body mass index of 30-34.9 kg/m(2) to a randomized research trial of bariatric surgery. CONCLUSION: In general, physicians who treat patients with type 2 diabetes had favorable impressions about bariatric surgery as a treatment for obesity and type 2 diabetes. However, only a few were willing to refer their patients with type 2 diabetes and a body mass index of 30-34.9 kg/m(2) to randomized research trials of bariatric surgery. This reluctance to refer patients represents an important barrier to the successful completion of studies of the efficacy of bariatric surgery for those with type 2 diabetes and a body mass index <35 kg/m(2).

Patients' preferred terms for describing their excess weight: discussing obesity in clinical practice.

The increasing prevalence of obesity has become one of the most challenging problems facing healthcare providers. Despite recommendations from the US Preventive Services Task Force, many health professionals fail to discuss obesity with their patients. This study sought to identify terms that obese individuals who were treated in primary care would find the most and least acceptable for describing their excess weight. Three-hundred ninety obese adult primary care patients in the Philadelphia area were administered the Weight Preferences Questionnaire from January 2008 through February 2009. Ratings of 11 terms used to describe excess weight were transformed to a 5-point scale, ranging from "very desirable" (+2) to neutral (0) to "very undesirable" (-2). The term "fatness" (mean score -1.1 ± 1.3) was rated as significantly more undesirable than all other descriptors (P < 0.001). The terms "excess fat" (-0.6 ± 1.3), "large size" (-0.6 ± 1.3), "obesity" (-0.5 ± 1.4), and "heaviness" (-0.4 ± 1.2) were rated as significantly more undesirable then the remaining terms, which included weight problem, BMI, and excess weight (P < 0.001). In contrast, the term "weight" was viewed as the most desirable term for characterizing excess weight. Patients' preferences for terms were not significantly influenced by gender, race/ethnicity, or a BMI ≥40 kg/m(2). Practitioners who treat obesity are encouraged to avoid undesirable terms when discussing this condition with their patients. Instead practitioners may want to consider broaching the topic using more patient-friendly terms such as "weight," "BMI," "weight problem," or "excess weight."

A two-year randomized trial of obesity treatment in primary care practice.

BACKGROUND: Calls for primary care providers (PCPs) to offer obese patients behavioral weight-loss counseling have not been accompanied by adequate guidance on how such care could be delivered. This randomized trial compared weight loss during a 2-year period in response to three lifestyle interventions, all delivered by PCPs in collaboration with auxiliary health professionals (lifestyle coaches) in their practices. METHODS: We randomly assigned 390 obese adults in six primary care practices to one of three types of intervention: usual care, consisting of quarterly PCP visits that included education about weight management; brief lifestyle counseling, consisting of quarterly PCP visits combined with brief monthly sessions with lifestyle coaches who instructed participants about behavioral weight control; or enhanced brief lifestyle counseling, which provided the same care as described for the previous intervention but included meal replacements or weight-loss medication (orlistat or sibutramine), chosen by the participants in consultation with the PCPs, to potentially increase weight loss. RESULTS: Of the 390 participants, 86% completed the 2-year trial, at which time, the mean (±SE) weight loss with usual care, brief lifestyle counseling, and enhanced brief lifestyle counseling was 1.7±0.7, 2.9±0.7, and 4.6±0.7 kg, respectively. Initial weight decreased at least 5% in 21.5%, 26.0%, and 34.9% of the participants in the three groups, respectively. Enhanced lifestyle counseling was superior to usual care on both these measures of success (P=0.003 and P=0.02, respectively), with no other significant differences among the groups. The benefits of enhanced lifestyle counseling remained even after participants given sibutramine were excluded from the analyses. There were no significant differences between the intervention groups in the occurrence of serious adverse events. CONCLUSIONS: Enhanced weight-loss counseling helps about one third of obese patients achieve long-term, clinically meaningful weight loss. (Funded by the National Heart, Lung, and Blood Institute; POWER-UP ClinicalTrials.gov number, NCT00826774.).

Surgical treatments for obesity.

Bariatric surgery is currently the most effective and durable treatment option for extreme obesity. Restrictive procedures, such as AGB and SG, limit gastric capacity and, thus, food intake while leaving the gastrointestinal tract intact. Malabsorptive procedures, such as BPD, shorten the length of the intestine to decrease nutrient absorption. Combined procedures, such as RYGB, include restriction and gastrointestinal rearrangement. Procedures that bypass segments of the gut are associated with greater weight loss and greater improvements in comorbid conditions than is gastric banding. This may be due, in part, to the differential effects of gastrointestinal rearrangement on the secretion of orexigenic and anorexigenic gut peptides that regulate appetite, glucose homeostasis, and body weight. Bariatric surgery is generally associated with low rates of perioperative and postoperative morbidity and mortality, although rigorous comparative safety data are lacking. High-quality, long-term, randomized, controlled trials are needed to compare the efficacy, safety, and cost effectiveness of the various bariatric surgery procedures with each other, as well as with intensive nonsurgical weight loss interventions.

Behavioral and pharmacologic therapies for obesity.

This article reviews novel developments in the behavioral and pharmacologic treatment of obesity and explores the potential contribution of genomics research to weight control. A comprehensive program of lifestyle modification, comprised of diet, physical activity and behavior therapy, induces a mean loss of 7-10% of initial weight in individuals with obesity. Two trials demonstrated that weight loss of this magnitude, combined with increased physical activity, substantially reduced the risk of developing type 2 diabetes mellitus in individuals with impaired glucose tolerance. A third trial is now investigating whether lifestyle intervention will reduce cardiovascular morbidity and mortality in overweight individuals who already have diabetes mellitus. Pharmacotherapy is recommended, in some patients, as an adjunct to lifestyle modification. Two medications-orlistat and sibutramine-are currently approved in the US for long-term weight loss. Both are efficacious when combined with lifestyle modification, although health concerns have been raised about the use of sibutramine. Several novel combination therapies, which target multiple hypothalamic pathways that regulate appetite and body weight, are currently under investigation. Genomic studies provide further evidence for the role of these pathways in the regulation of body weight. Identification of new genes controlling satiety and energy expenditure may yield valuable clues for the development of novel pharmacologic treatments.

Effect of a low-carbohydrate diet versus a low-fat, calorie-restricted diet on adipokine levels in obese, diabetic participants.

The effect of dietary macronutrient composition on adipokine concentrations remains unclear. Greater reductions in leptin have been reported in participants who followed low-carbohydrate versus low-fat diets, although these studies did not adjust for the important effects of weight loss on adipokines. We investigated the effect of macronutrient composition on adipokine levels in 144 obese, diabetic participants who were randomly assigned to a low- carbohydrate (< 30 g/day) or low-fat diet (≤ 30% of calories from fat with a deficit of 500 kcal/day). Weight, adipokines, and dietary intake were assessed at baseline and 6 months. Complete data were available for 79 participants. At month 6, weight, leptin, adiponectin, and tumor necrosis factor-α concentrations did not differ significantly between groups (P > 0.05 for all variables). However, significant changes in leptin and adiponectin occurred over time (P < 0.001 and P < 0.012, respectively). Modest weight loss, rather than macronutrient composition, likely accounted for the favorable changes observed in leptin and adiponectin over time.