Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial.

The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/m2 and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean per cent weight change from randomization to week 72 was met with changes of -18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo (estimated treatment difference -20.8 percentage points (95% confidence interval (CI) -23.2%, -18.5%; P < 0.001). The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; P < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity. Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016 .

Evaluation of weight change and cardiometabolic risk factors in a real-world population of US adults with overweight or obesity.

Whether individuals in real-world settings are able to lose weight and improve cardiometabolic risk factors over time is unclear. We aimed to determine the management of and degree of body weight change over 2 years among individuals with overweight or obesity, and to assess associated changes in cardiometabolic risk factors and clinical outcomes. Using data from 11 large health systems within the Patient-Centered Outcomes Research Network in the U.S., we collected the following data on adults with a recorded BMI ≥25 kg/m2 between January 1, 2016 and December 31, 2016: body-mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), triglycerides and glycated hemoglobin (HbA1c). We found that among 882,712 individuals with BMI ≥25 kg/m2 (median age 59 years; 56% female), 52% maintained stable weight over 2 years and 1.3% utilized weight loss pharmacotherapy. Weight loss of 10% was associated with small but significant lowering of mean SBP (-2.69 mmHg [95% CI -2.88, -2.50]), DBP (-1.26 mmHg [95% CI -1.35, -1.18]), LDL-C (-2.60 mg/dL [95% CI -3.14, -2.05]), and HbA1c (-0.27% [95% CI -0.35, -0.19]) in the same 12 months. However, these changes were not sustained over the following year. In this study of adults with BMI ≥25 kg/m2, the majority had stable weight over 2 years, pharmacotherapies for weight loss were under-used, and small changes in cardiometabolic risk factors with weight loss were not sustained, possibly due to failure to maintain weight loss.

Impact of a Community-Based Weight Management Program in a North Carolina Health Care System.

BACKGROUND AND OBJECTIVES: Current strategies for obesity management in primary care leave many patients inadequately treated or unable to access treatment entirely. We aimed to evaluate a comprehensive, primary care clinic-based weight management program's clinical effectiveness in a community practice setting.  Methods:  This was an 18-month pre/postintervention study. We collected demographic and anthropometric data on patients enrolled in a primary care-based weight management program. The primary outcomes were percent weight loss postintervention and the proportion of patients who achieved a clinically significant total body weight loss (TBWL) of 5% or greater.  Results:  Our program served 550 patients over 1,952 visits from March 2019 through October 2020. A total of 209 patients had adequate program exposure, defined as four or more completed visits. Among these, all received targeted lifestyle counseling and 78% received antiobesity medication. Patients who attended at least four visits had an average TBWL of 5.7% compared to an average gain of 1.5% total body weight for those with only one visit. Fifty-three percent of patients (n=111) achieved greater than 5% TBWL, and 20% (n=43) achieved greater than 10% TBWL. CONCLUSION: We demonstrated that a community-based weight management program delivered by obesity medicine-trained primary care providers effectively produces clinically significant weight loss. Future work will include wider implementation of this model to increase patient access to evidence-based obesity treatments in their communities.

Tirzepatide for the treatment of obesity: Rationale and design of the SURMOUNT clinical development program.

OBJECTIVE: Obesity is a growing global concern compounded by limited availability of effective treatment options. The SURMOUNT development program aims to evaluate the efficacy and safety of tirzepatide as an adjunct to lifestyle intervention compared with placebo on chronic weight management in adults with BMI ≥ 27 kg/m2 with or without type 2 diabetes. METHODS: The SURMOUNT program includes four global phase 3 trials NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3), and NCT04660643 (SURMOUNT-4). Participants are randomized to once-weekly subcutaneous tirzepatide versus placebo in a double-blind manner. The primary end point in all trials is the percentage change in body weight from randomization to end of treatment. Results for the primary end point for SURMOUNT-1 were published recently and results for the other trials are expected in 2023. RESULTS: Across trials, participants have a mean age of 44.9 to 54.2 years, are mostly female (50.7% to 69.7%), and have a mean BMI of 36.1 to 38.9. CONCLUSIONS: The extensive assessment of once-weekly tirzepatide in the global SURMOUNT program will detail the clinical effects of this first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist in chronic weight management.

Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program.

OBJECTIVE: This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes. RESEARCH DESIGN AND METHODS: STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc). RESULTS: Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01). CONCLUSIONS: STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.

Effect of a virtual self-management intervention for atrial fibrillation during the outbreak of COVID-19.

BACKGROUND: As the pandemic continues to unfold, effective, technology-based solutions are needed to help patients with atrial fibrillation (AF) maintain their health and well-being during the outbreak of COVID-19. METHODS: This single-center, pilot study investigated the effects of a 4-week (eight sessions) virtual AF self-management program. Questionnaires were completed at baseline and 1 week after the intervention, and assessed AF knowledge, adherence to self-management behaviors, mental health, physical function, and disease-specific quality of life in patients with AF. Secondary outcomes included knowledge of COVID-19, intervention, acceptability, and satisfaction. RESULTS: Of 68 patients who completed baseline questionnaires, 57 participated in the intervention and were included in the analysis (mean age of 73.4 ± 10.0 years, 60% male). Adherence to AF self-monitoring behaviors, including monitoring their heart rate (p < .001), heart rhythm (p = .003), and blood pressure (p = .013) were significantly improved at the end of the intervention compared with baseline. Symptom identification (p = .007) and management (p < .001) also improved. Reductions in sleep disturbance (p < .001), anxiety (p = .014), and depression (p = .046) were also observed. Misinformation and inaccurate beliefs about COVID-19 were significantly reduced at the end of the intervention compared with baseline. CONCLUSIONS: This pilot study suggests that a virtual patient education program could have beneficial effects on adherence to guideline-recommend self-care of AF, emotional wellbeing, physical function, and knowledge of COVID-19 in patients with AF. Future randomized studies in larger samples are needed to determine the clinical benefits of the intervention.

Refractory Hypocalcemia Following Stomach Intestinal Pylorus-Sparing Bariatric Surgery and Thyroidectomy: Successful Management With Creation of a Proximal Roux-en-Y Gastric Bypass.

Some forms of bariatric surgery make patients susceptible to calcium malabsorption, and the parathyroid hormone (PTH) axis is important for maintaining normocalcemia in these patients. Injury to the parathyroid glands due to anterior neck surgery commonly causes PTH axis disruption and can result in severe hypocalcemia in bariatric surgery patients. Herein, we present a case of a patient with a history of stomach intestinal pylorus-sparing bariatric surgery who developed refractory hypocalcemia requiring daily intravenous (IV) calcium 2 years after thyroidectomy. PTH levels were inappropriately normal during episodes of hypocalcemia, and urinary calcium level was <3.0 mg/dL following large oral doses of calcium, suggesting that both inadequate PTH response and malabsorption contributed to her severe hypocalcemia. In order to enhance calcium absorptive capacity while minimizing the risk of weight regain, she was surgically treated with a Roux-en-Y gastric bypass proximal to the prior operation. The surgery successfully improved blood calcium levels; the patient was successfully weaned from IV calcium and was able to maintain normocalcemia with oral supplements. We discuss the case in the context of available literature and provide our recommendations.

Weight History in Clinical Practice: The State of the Science and Future Directions.

Eliciting a weight history can provide clinically important information to aid in treatment decision-making. This view is consistent with the life course perspective of obesity and the aim of patient-centered care, one of six domains of health care quality. However, thus far, the value and practicality of including a weight history in the clinical assessment and treatment of patients with obesity have not been systematically explored. For these reasons, the Clinical Committee of The Obesity Society established a task force to review and assess the available evidence to address five key questions. It is concluded that weight history is an essential component of the medical history for patients presenting with overweight or obesity, and there are strong and emerging data that demonstrate the importance of life stage, duration of exposure to obesity, maximum BMI, and group-based trajectory modeling in predicting risk for increased morbidity and mortality. Consideration of these and other patient-specific factors may improve risk stratification and clinical decision-making for screening, counseling, and management. Recommendations are provided for the key elements that should be included in a weight history, and several needs for future clinical research are outlined.

Obesity Coverage on Medical Licensing Examinations in the United States. What Is Being Tested?

Phenomenon. As one of the most common chronic disease affecting adults and children, obesity is a major contributor to noncommunicable diseases, both nationally and globally. Obesity adversely affects every organ system, and as such it is imperative that the United States Medical Licensing Examination (USMLE) adequately assesses students' knowledge about the science and practice of obesity management. The purpose of this study was to evaluate the coverage and distribution of obesity-related items on the three USMLE Step examinations. APPROACH: Examination items that included obesity-related keywords were identified by National Board of Medical Examiners (NBME) staff. A panel of 6 content experts evaluated all items and coded obesity-relevant items using the American Board of Obesity Medicine (ABOM) test outline rubric into 4 domains and 107 subdomains. FINDINGS: There were 802 multiple-choice items containing obesity-related keywords identified by NBME, of which 289 (36%) were identified as being relevant to obesity and were coded into appropriate domains and subdomains. Among the individual domains, the Diagnosis & Evaluation domain comprised most of the items (174) for all 3 Step examinations. Fifty-eight percent of items were represented by 4 of 17 organ systems, and 80% of coded items were represented by 6 ABOM subdomains. The majority of obesity-coded items pertained to the diagnosis and management of obesity-related comorbid conditions rather than addressing the prevention, diagnosis, or management of obesity itself. Insights. The most important concepts of obesity prevention and treatment were not represented on the Step exams. Exam items primarily addressed the diagnosis and treatment of obesity-related comorbid conditions instead of obesity itself. The expert review panel identified numerous important obesity-related topics that were insufficiently addressed or entirely absent from the examinations. The reviewers recommend that the areas identified for improvement may promote a more balanced testing of knowledge in obesity.

Weight Loss After RYGB Is Independent of and Complementary to Serotonin 2C Receptor Signaling in Male Mice.

Roux-en-Y gastric bypass (RYGB) typically leads to substantial, long-term weight loss (WL) and diabetes remission, although there is a wide variation in response to RYGB among individual patients. Defining the pathways through which RYGB works should aid in the development of less invasive anti-obesity treatments, whereas identifying weight-regulatory pathways unengaged by RYGB could facilitate the development of therapies that complement the beneficial effects of surgery. Activation of serotonin 2C receptors (5-HT2CR) by serotonergic drugs causes WL in humans and animal models. 5-HT2CR are located on neurons that activate the melanocortin-4 receptors, which are essential for WL after RYGB. We therefore sought to determine whether 5-HT2CR signaling is also essential for metabolic effects of RYGB or whether it is a potentially complementary pathway, the activation of which could extend the benefits of RYGB. Diet-induced obese male mice deficient for the 5-HT2CR and their wild-type littermates underwent RYGB or sham operation. Both groups lost similar amounts of weight after RYGB, demonstrating that the improved metabolic phenotype after RYGB is 5-HT2CR independent. Consistent with this hypothesis, wild-type RYGB-treated mice lost additional weight after the administration of the serotonergic drugs fenfluramine and meta-chlorophenylpiperazine but not the nonserotonergic agent topiramate. The fact that RYGB does not depend on 5-HT2CR signaling suggests that there are important WL mechanisms not fully engaged by surgery that could potentially be harnessed for medical treatment. These results suggest a rational basis for designing medical-surgical combination therapies to optimize clinical outcomes by exploiting complementary physiological mechanisms of action.

Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity.

Roux-en-Y gastric bypass (RYGB) results in rapid weight loss, reduced adiposity, and improved glucose metabolism. These effects are not simply attributable to decreased caloric intake or absorption, but the mechanisms linking rearrangement of the gastrointestinal tract to these metabolic outcomes are largely unknown. Studies in humans and rats have shown that RYGB restructures the gut microbiota, prompting the hypothesis that some of the effects of RYGB are caused by altered host-microbial interactions. To test this hypothesis, we used a mouse model of RYGB that recapitulates many of the metabolic outcomes in humans. 16S ribosomal RNA gene sequencing of murine fecal samples collected after RYGB surgery, sham surgery, or sham surgery coupled to caloric restriction revealed that alterations to the gut microbiota after RYGB are conserved among humans, rats, and mice, resulting in a rapid and sustained increase in the relative abundance of Gammaproteobacteria (Escherichia) and Verrucomicrobia (Akkermansia). These changes were independent of weight change and caloric restriction, were detectable throughout the length of the gastrointestinal tract, and were most evident in the distal gut, downstream of the surgical manipulation site. Transfer of the gut microbiota from RYGB-treated mice to nonoperated, germ-free mice resulted in weight loss and decreased fat mass in the recipient animals relative to recipients of microbiota induced by sham surgery, potentially due to altered microbial production of short-chain fatty acids. These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery.

Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery.

BACKGROUND: The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short- and long-term changes in hormonal determinants of blood glucose. METHODS: Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non-diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C-peptide, proinsulin, amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) levels and the incretin effect on insulin secretion. RESULTS: The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP-1 and GIP) levels, early phase insulin secretion, and other parameters of ß-cell function (amylin, proinsulin/insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year. CONCLUSIONS: The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.

Superior appetite hormone profile after equivalent weight loss by gastric bypass compared to gastric banding.

The goal of this study was to understand the mechanisms of greater weight loss by gastric bypass (GBP) compared to gastric banding (GB) surgery. Obese weight- and age-matched subjects were studied before (T0), after a 12 kg weight loss (T1) by GBP (n = 11) or GB (n = 9), and at 1 year after surgery (T2). peptide YY(3-36) (PYY(3-36)), ghrelin, glucagon-like peptide-1 (GLP-1), leptin, and amylin were measured after an oral glucose challenge. At T1, glucose-stimulated GLP-1 and PYY levels increased significantly after GBP but not GB. Ghrelin levels did not change significantly after either surgery. In spite of equivalent weight loss, leptin and amylin decreased after GBP, but not after GB. At T2, weight loss was greater after GBP than GB (P = 0.003). GLP-1, PYY, and amylin levels did not significantly change from T1 to T2; leptin levels continued to decrease after GBP, but not after GB at T2. Surprisingly, ghrelin area under the curve (AUC) increased 1 year after GBP (P = 0.03). These data show that, at equivalent weight loss, favorable GLP-1 and PYY changes occur after GBP, but not GB, and could explain the difference in weight loss at 1 year. Mechanisms other than weight loss may explain changes of leptin and amylin after GBP.