Marion L. Vetter

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.).

Narrative Review: Effect of Bariatric Surgery on Type 2 Diabetes Mellitus

Key Summary Points The rapid improvement in glycemic control after bariatric surgery results from caloric restriction and alterations in the gut hormones that control insulin secretion. The enteroinsular axis includes the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), ghrelin, and peptide YY (PYY) and their subsequent effect on insulin secretion and sensitivity. Restrictive, malabsorptive, and combined bariatric surgery procedures have different effects on the enteroinsular axis. Intestinal bypass procedures increase GLP-1 and PYY levels. In contrast, restrictive procedures do not increase incretin or PYY levels. Familiarity with these changes can help physicians consider the various surgical approaches and develop postoperative treatment regimens for patients. Glycemic control in diabetic patients improves markedly within days of bariatric surgery, which suggests that the procedures alter the hormones that control insulin secretion (1). The enteroinsular axis includes the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones, also known as incretins, are secreted by intestinal L and K cells, respectively, in response to nutrients and directly enhance insulin secretion (2). Restrictive, malabsorptive, and combined bariatric surgery procedures affect the enteroinsular axis differently. The various bariatric procedures also affect the secretion of other gut hormones that affect insulin sensitivity, including ghrelin and peptide YY (PYY). Thus, an altered pattern of gut hormone secretion after bariatric surgery may profoundly affect glucose tolerance. We focus on the short-term pathophysiologic changes in the enteroinsular axis and their subsequent effect on insulin secretion and sensitivity after bariatric surgery. Familiarity with these changes can help clinicians decide among the different surgical approaches and formulate treatment regimens that avoid severe postoperative hypoglycemia. Methods We searched English-language publications in PubMed and reference lists from relevant articles published between 1967 and 2008. Our main search terms were bariatric surgery, Roux-en-Y, gastric bypass, biliopancreatic diversion, gastric banding, laparoscopic adjustable gastric banding, diabetes, enteroinsular axis, incretins, GLP-1, GIP, ghrelin, PYY, insulin, and postoperative management. To determine the rates of diabetes resolution, we included studies that enrolled at least 10 diabetic patients (alone or along with nondiabetic patients) and reported diabetes-related outcomes. We retrieved randomized, controlled trials; cohort studies; and casecontrol studies that reported weight loss, diabetes resolution, and time to restoration of normoglycemia. Because we found few such studies, we also included large case series. We evaluated study quality by using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system (3). We used our judgment to identify high-quality studies that described gut hormone levels after bariatric surgery. Types of Bariatric Procedures and Effect on Weight Loss and Diabetes Since its inception in the 1950s, bariatric surgery has become increasingly refined. More recently, it has been touted as a cure for diabetes (4). Several procedures are now available (Figure 1). Bariatric procedures were initially classified as restrictive, malabsorptive, or combined, reflecting the purported mechanism of weight loss (1). Restrictive procedures, such as laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG), greatly reduce the volume of the stomach to decrease food intake and induce early satiety. Malabsorptive procedures, such as biliopancreatic diversion (BPD), shorten the small intestine to decrease nutrient absorption. Combined procedures, such as the Roux-en-Y gastric bypass (RYGB), incorporate both restrictive and malabsorptive elements. Roux-en-Y gastric bypass surgery is the current gold standard treatment for severe obesity. Both BPD and RYGB alter the secretion of orexigenic and anorexigenic gut peptides, which interact with appetitive centers in the arcuate nucleus of the hypothalamus to decrease appetite (5). Because both BPD and RYGB bypass similar segments of the small bowel, we use the term intestinal bypass procedure to refer to either. Figure 1. Surgical procedures. Reprinted with permission of the American Society for Metabolic and Bariatric Surgery, copyright 2008, all rights reserved. Weight Loss Two recent meta-analyses (6, 7) reported weight loss; operative mortality; and obesity-related comorbid conditions, including diabetes, after bariatric surgery. Buchwald and colleagues (7) reported mean excess weight loss (see Glossary) (710) of 61% across all procedures in 22094 patients; weight loss rates associated with each procedure varied (Table 1). On average, bariatric surgery reduces body mass index by 10 to 15 kg/m2 and weight by 30 to 50 kg (11). Table 1. Results of Different Types of Bariatric Surgery Several relatively poor-quality randomized, controlled trials that compared different bariatric surgery procedures (12) showed that weight loss was greater with gastric bypass than with VBG or LAGB. The SOS (Swedish Obese Subjects) study (13), a landmark observational study that followed more than 4000 obese participants, matched those who selected medical management with those undergoing various bariatric procedures, including RYGB, VBG, or LAGB. At 10 years, RYGB was associated with a 25% reduction in total body weight, whereas VBG and LAGB were associated with 16% and 14% weight loss, respectively. Diabetes Resolution and Improvement Observational evidence suggests that bariatric surgery is associated with a 60% to 80% rate of diabetes resolution (14). In 1 meta-analysis (7), approximately 15% of the patients were diabetic. In studies reporting complete resolution of diabetes (defined as normoglycemia with no diabetes medications), 1417 of 1846 patients (76.8%) met the criteria for resolution. Among studies reporting resolution or improvement of diabetes, 414 of 485 patients (mean, 86.0%) experienced either outcome. Table 1 shows rates of diabetes resolution for individual bariatric procedures. Conclusions about bariatric surgery and diabetes resolution come with an important qualifier: The studies had serious methodological weaknesses. Few are randomized, controlled trials; most surgical outcome studies are uncontrolled case series with considerable missing data (6, 10). In 1 meta-analysis (6), one quarter of the studies did not report enrolling consecutive patients and fewer than 50% reported how many enrolled patients provided follow-up data. Table 2 (4, 1422) includes selected studies that met the minimum GRADE criteria quality standards and reported follow-up rates of at least 80% (3). Paired comparisons of surgical procedures typically favored RYGB or BPD over the restrictive procedures (23). Table 2. Efficacy for Resolution of Diabetes Predictors of Diabetes Resolution Identifying preoperative predictors of diabetes resolution is critical for determining which diabetic patients will obtain the greatest benefit from surgery. In earlier studies of RYGB, longer duration of diabetes (>10 years), poor preoperative glycemic control, and preoperative insulin use reduced the probability of diabetes resolution (18, 19); however, these studies did not adjust for the effects of known confounding factors. More recently, Torquati and colleagues (24) adjusted for body mass index, sex, and preoperative hemoglobin A1c level and found that preoperative treatment with oral antidiabetic agents (as opposed to insulin) and smaller preoperative waist circumference predicted diabetes resolution (18). Shorter duration of diabetes was a weaker, statistically nonsignificant predictor, which supports earlier studies of RYGB (18). The same factors predict diabetes resolution after gastric banding. Dixon and colleagues (25) reported that diabetes for less than 3 years predicted diabetes resolution, after they controlled for age and excess weight loss. Less deterioration in -cell function at the time of surgery may maximize the effect of the surgery-altered secretion of gut peptides that enhance -cell insulin secretion. The Enteroinsular Axis Bayliss and Starling first described the connection between the gut and the pancreas in 1902, when they demonstrated that intestinal mucosa extracts contained a factor, which they called secretin, that acted through the bloodstream to stimulate exocrine secretion by the pancreas (26). Sixty-five years later, Perley and Kipnis (27) demonstrated that ingested nutrients stimulated greater insulin release than intravenously administered glucose. In 1979, Creutzfeldt (28) defined incretins as gastrointestinal hormones that stimulate insulin release after enteral nutrition. This connection between the gut and pancreatic islet cells is called the enteroinsular axis, a term first used by Unger and Eisentraut (29). The Incretins: GLP-1 and GIP By potentiating glucose-dependent insulin secretion, GLP-1 and GIP account for 50% to 60% of nutrient-stimulated insulin release (2). In animal models of diabetes, GLP-1 also increases -cell mass through regulation of proliferation, neogenesis, and apoptosis (30). Glucagon-like peptide-1 is a potent insulin secretatogue that is secreted by the L cells of the distal ileum in response to ingested nutrients and is inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV) (31). By activating adenylate cyclase, GLP-1 acts on pancreatic islets to augment glucose-dependent insulin secretion. The subsequent increase in insulin levels within islets inhibits glucagon secretion, possibly through direct activation of GLP-1 receptors on cells (31). Glucagon-like peptide-1 also slows gastric emptying, which delays digestion and blunts postprandial glycemia (32), and acts on the central nervou

Behavior therapy for obesity: where are we now?

Purpose of reviewTo describe the short-term and long-term results of lifestyle modification for obesity. Recent findingsRandomized controlled trials, which compared different diet and activity interventions were reviewed. Studies that investigated the efficacy of new technologies to provide lifestyle modification, such as web-based delivery, also were examined. SummaryIn general, comprehensive lifestyle modification programs delivered in person induce a loss of approximately 10% of initial weight in 16–26 weeks of treatment. The use of portion-controlled diets, which typically involve the use of meal replacement products, was associated with significantly larger weight losses in the short term. In contrast, interventions delivered via the Internet induced a loss of approximately 5%. However, web-based programs appear to have potential in facilitating the continuation on patient-provider contact, which along with high levels of physical activity, appear to be key strategies for successful long-term weight control. Recent studies also have suggested that the combination of lifestyle modification with long-term use of pharmacotherapy holds promise for maximizing initial weight losses and promoting long-term maintenance.

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.

Effects of a low-intensity intervention that prescribed a low-carbohydrate vs. a low-fat diet in obese, diabetic participants.

Low‐carbohydrate diets have been associated with significant reductions in weight and HbA1c in obese, diabetic participants who received high‐intensity lifestyle modification for 6 or 12 months. This investigation sought to determine whether comparable results to those of short‐term, intensive interventions could be achieved over a 24‐month study period using a low‐intensity intervention that approximates what is feasible in outpatient practice. A total of 144 obese, diabetic participants were randomly assigned to a low‐carbohydrate diet (<30 g/day) or to a low fat diet (≤30% of calories from fat with a deficit of 500 kcal/day). Participants were provided weekly group nutrition education sessions for the first month, and monthly sessions thereafter through the end of 24 months. Weight, HbA1c, glucose, and lipids were measured at baseline and 6, 12, and 24 months. Of the 144 enrolled participants, 68 returned for the month 24 assessment visit. Weights were retrieved from electronic medical records for an additional 57 participants (total, 125 participants) at month 24. All participants with a baseline measurement and at least one of the three other measurements were included in the mixed‐model analyses (n = 138). The low‐intensity intervention resulted in modest weight loss in both groups at month 24. At this time, participants in the low‐carbohydrate group lost 1.5 kg, compared to 0.2 kg in the low‐fat group (P = 0.147). Lipids, glycemic indexes, and dietary intake did not differ between groups at month 24 (or at months 6 or 12) (ClinicalTrials.gov number, NCT00108459).

Relation of Health-Related Quality of Life to Metabolic Syndrome, Obesity, Depression, and Comorbid Illnesses

Background:Metabolic syndrome has been associated with impaired health-related quality of life (HRQoL) in several studies. Many studies used only one HRQoL measure and failed to adjust for important confounding variables, including obesity, depression and comorbid conditions.Objective:To investigate the relationship between metabolic syndrome and HRQoL using multiple measures. We also sought to determine whether increasing body mass index or diabetes status further modified this relationship.Methods:This cross-sectional study included 390 obese participants with elevated waist circumference and at least one other criterion for metabolic syndrome. Of these 390 participants, 269 had metabolic syndrome (that is, they met 3 out of the 5 criteria specified by the NCEP (National Cholesterol Education Program)) and 121 did not. Participants were enrolled in a primary care-based weight-reduction trial. HRQoL was assessed using two generic instruments, the Medical Outcomes Study Short-Form 12 and the EuroQol-5D, as well as an obesity-specific measure, the Impact of Weight on Quality of Life. Differences in HRQoL were compared among participants with and without metabolic syndrome. Multivariable linear regression was used to determine how HRQoL varied according to metabolic syndrome status, and whether factors including weight, depression and burden of comorbid disease modified this relationship.Results:Metabolic syndrome was not associated with HRQoL as assessed by any of the measures. In univariable analysis, depression, disease burden and employment status were significantly associated with worse HRQoL on all instruments. In multivariable models, only depression remained significantly associated with reduced HRQoL on all measures. Increasing obesity and diabetes status did not modify the relationship between metabolic syndrome and HRQoL.Conclusion:In contrast to previous studies, metabolic syndrome was not associated with impaired HRQoL as assessed by multiple measures. This suggests that metabolic syndrome in itself is not associated with decreased HRQoL, but other factors such as obesity, depression and greater disease burden may significantly influence the quality of life in this population.

Managing obesity in primary care practice: an overview with perspective from the POWER-UP study

Primary care practitioners (PCPs) have been encouraged to screen all adults for obesity and to offer behavioral weight loss counseling to the affected individuals. However, there is limited research and guidance on how to provide such intervention in primary care settings. This led the National Heart, Lung and Blood Institute in 2005 to issue a request for applications to investigate the management of obesity in routine clinical care. Three institutions were funded under a cooperative agreement to undertake the practice-based opportunities for weight reduction (POWER) trials. The present article reviews selected randomized controlled trials, published before the initiation of POWER, and then provides a detailed overview of the rationale, methods and results of the POWER trial conducted at the University of Pennsylvania (POWER-UP). POWER-UP’s findings are briefly compared with those from the two other POWER trials, conducted at Johns Hopkins University and Harvard University/Washington University. The methods of delivering behavioral weight loss counseling differed markedly across the three trials, as captured by an algorithm presented in the article. Delivery methods ranged from having medical assistants and PCPs from the practices provide counseling to using a commercially available call center, coordinated with an interactive website. Evaluation of the efficacy of primary care-based weight loss interventions must be considered in light of costs, as discussed in relation to the recent treatment model proposed by the Centers for Medicare and Medicaid Services.

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.

A randomized comparison of a commercially available portion-controlled weight-loss intervention with a diabetes self-management education program

Objective:This study examined the efficacy of a commercially available, portion-controlled diet (PCD) on body weight and HbA1c over 6 months in obese patients with type 2 diabetes.Research Design and Methods:One-hundred participants with a mean±s.d. age of 55.6±10.6 year, body weight of 102.9±18.4 kg and HbA1c of 7.7±1.3% were randomly assigned to a 9-session group lifestyle intervention that included a PCD or to a 9-session group program of diabetes self-management education (DSME). Participants in the two groups were prescribed the same goals for energy intake (1250–1550 kcal per day) and physical activity (200 min per week).Results:While both groups produced significant improvements in weight and HbA1c after 6 months of treatment, PCD participants lost 7.3 kg [95% confidence interval (CI): −5.8 to −8.8 kg], compared with 2.2 kg (95% CI: −0.7 to −3.7 kg) in the DSME group (P<0.0001). Significantly more PCD than DSME participants lost ⩾5% of initial weight (54.0% vs 14.0%, P<0.0001) and ⩾10% (26.0% vs 6.0%, P<0.0001). HbA1c declined by 0.7% (95% CI: −0.4 to −1.0%) in the PCD group, compared with 0.4% (95% CI: −0.1 to −0.7%) in DSME (P<0.026). Across both groups, larger weight losses were associated with greater reductions in HbA1c (r=0.52, P<0.0001).Conclusions:These findings demonstrate that a commercially available portion-controlled meal plan can induce clinically meaningful improvements in weight and glycemic control in obese individuals with type 2 diabetes. These data have implications for the management of obesity in primary care, as now provided by the Centers for Medicare and Medicaid Services.

The impact of a primary care-based weight loss intervention on the quality of life.

Objective:This study investigated changes in the quality of life of men and women who participated in a primary care-based weight loss intervention program.Methods:Participants were enrolled in a 2-year randomized clinical trial (POWER-UP) conducted at the University of Pennsylvania and in six affiliated primary care practices. Inclusion criteria included the presence of obesity (body mass index of 30–50 kg m−2) and at least two components of the metabolic syndrome.Main Outcome Measures:Quality of life was assessed by three measures: the Short Form Health Survey (SF-12); the Impact of Weight on Quality of Life-Lite; and the EuroQol-5D.Results:Six months after the onset of treatment, and with a mean weight loss of 3.9±0.3 kg, participants reported significant improvements on all measures of interest with the exception of the Mental Component Score of the SF-12. These changes remained significantly improved from baseline to month 24, with the exception of the EuroQol-5D. Many of these improvements were correlated with the magnitude of weight loss and, for the most part, were consistent across gender and ethnic group.Conclusions:Individuals with obesity and components of the metabolic syndrome reported significant improvements in most domains of the quality of life with a modest weight loss of 3.7% of initial weight, which was achieved within the first 6 months of treatment. The majority of these improvements were maintained at month 24, when participants had lost 3.0% of their weight.