Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m-2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 .

Effects of an oral biodegradable device used for 12 weeks on weight reduction, cardiovascular risk factors, satiety, snacking, and meal size.

Background: The Epitomee Capsule (EC) is an, oral, self-use, bio-degradable device for weight management, composed of absorbent polymers that self-expands in the stomach (pH-sensitive) and creates a triangular shape, space-occupying super-absorbent gel structure. A recent study reported that 42 % of study completers obtained >5 % weight reduction at 12 weeks. We performed exploratory analyses of this study to evaluate its effect on cardiovascular risk factors and on self-reported satiety, between-meal snacking and meal-size. Methods: This single-center observational study (Israel) enrolled 78 volunteers, with mean age 41 years, BMI 32.5 kg/m2, systolic/diastolic blood pressure (SBP/DBP) 124/77 mmHg. The EC was given in addition to diet and physical activity counseling. Assessments included anthropometrics, BP, lipids, and three questions (translated from Hebrew) scored 1 (not at all) to 5 (very much) for "Do you feel the EC - Q1:helps you to consume less snacks in between meals? Q2:helps you to eat less in the meal?; Q3:is causing an early sense of satiety?". Changes from baseline were assessed using a mixed model and included all patients with at least one measure. Correlation-analysis between weight-change and PROs used Kendall's tau. Result: Compared to baseline, at 12 weeks, SBP/DBP were reduced (ΔSBP: -5.5 mmHg, p = 0.0003/ΔDBP: -1.9 mmHg, p = 0.1341), with a larger effect in people with hypertension at baseline (ΔSBP: -13.2 mmHg, p < 0.00001/ΔDBP: -6.1, p = 0.008). Triglyceride-level was also significantly reduced, but not other lipids. Mean scores to Q1-3 were high throughout, with slight decreases (Q1 at W2 3.9 ± 1.1/W12 3.0 ± 1.6; Q2 at W2 3.7 ± 1.1/W12 3.1 ± 1.6; Q3 at W2 3.8 ± 1.2/W12 2.9 ± 1.6). There was a moderate correlation between PROs and weight reduction, although significance was not observed for all weeks. Conclusions: Exploratory analyses of 12 weeks treatment with EC demonstrated significant reductions in SBP, DBP, and triglycerides. The weight reduction correlated with satiety, less snacking, and reduced meal size.

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).

Lifestyle-Based Obesity Care.

Lifestyle intervention is an alluring concept. Changing behaviors to reduce food intake and increase energy expenditure will reduce body weight and body fat. Large randomized clinical trials in academic settings demonstrate lifestyle intervention can produce weight loss and significant health benefits. However, they also demonstrate the problems-not all participants are able to lose even 5%, and weight regain is common. Studies conducted in real-world settings achieve modest weight loss, but no reimbursement model supports it. Health care providers need to understand the benefits and limitations of lifestyle intervention delivery in the medical office setting.

Prioritizing obesity treatment: expanding the role of cardiologists to improve cardiovascular health and outcomes.

Obesity is a major risk factor for cardiovascular disease, yet management remains poor. Cardiologists and healthcare professionals treating people with high cardiovascular risk are in a position to address overweight and obesity to improve cardiovascular health. There are several treatment options for obesity, which are associated with numerous health benefits. Modest weight reductions of 5-10% improve cardiovascular risk factors, with greater weight loss bringing about greater benefits. Anti-obesity medications can support weight reduction when lifestyle modifications alone are insufficient. The weight loss induced by these treatments can improve cardiovascular risk, and some therapies - such as glucagon-like-peptide-1 analogues - may promote these benefits independently of weight loss. Bariatric surgery can induce greater weight losses than other treatment modalities and is associated with numerous health benefits, but newer medications such as semaglutide and those in development, such as tirzepatide, produce robust weight loss efficacy that is approaching that of bariatric surgery. Healthcare professionals must approach this disease with compassion and collaborate with patients to develop sustainable plans that improve health and maintain weight loss over the long term.

Trends in obesity prevalence and cardiometabolic risk factor control in US adults with diabetes, 1999-2020.

OBJECTIVE: Trends in obesity prevalence and trends in control of cardiometabolic risk factors among National Health and Nutrition Examination Survey participants with diabetes from 1999 through 2020 were analyzed. METHODS: Adults who were 20 years or older and who reported having received a diagnosis of diabetes from a physician were included. RESULTS: The prevalence of overall obesity, obesity class II, and obesity class III increased from 46.9%, 14.1%, and 10.3% in 1999 to 2002 to 58.1%, 16.6%, and 14.8% in 2015 to 2020, respectively. The prevalence of participants who achieved glycemic control (HbA1c <7%) increased from 42.5% in 1999 to 2002 to 51.8% in 2007 to 2010, then decreased to 48.0% in 2015 to 2020. The prevalence of participants who achieved blood pressure control (<140/90 mmHg) or achieved non-high-density lipoprotein cholesterol control (<130 mg/dL) increased throughout the study periods. The prevalence of participants who met all three risk factor goals increased from 8.3% in 1999 to 2002 to 21.2% in 2011 to 2014 and then decreased to 18.5 in 2015 to 2020. Participants with obesity showed worsening glycemic control and lipid control than participants with normal weight. CONCLUSIONS: There were increasing trends in prevalence of obesity, blood pressure control, and lipid control from 1999 to 2002 to 2015 to 2020. Participants with obesity showed worsening glycemic control and lipid control than normal-weight participants.

Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics.

OBJECTIVE: This paper describes the baseline characteristics of the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) study, one of the largest cardiovascular (CV) outcome studies in the field of obesity, which evaluates the effect of semaglutide versus placebo on major CV events. METHODS: SELECT enrolled individuals with overweight or obesity without diabetes, with prior myocardial infarction, stroke, and/or peripheral artery disease. This study reports participants' baseline characteristics in the full study population and subgroups defined by baseline glycated hemoglobin (HbA1c ; <5.7%, ≥5.7 to <6.0%, ≥6.0 to <6.5%), baseline waist to height ratio tertile, and qualifying prior CV event or condition. RESULTS: The study enrolled 17,605 participants (72.5% male) with an average (SD) age of 61.6 (8.9) years and BMI of 33.34 (5.04) kg/m2 . The most common prior CV event was myocardial infarction (76.3% of participants), followed by stroke (23.3%) and peripheral artery disease (8.6%). Furthermore, 24.3% had a heart failure diagnosis. Two-thirds of participants (66%) had HbA1c in the prediabetes range (5.7%-6.4%). Across groups of increasing HbA1c , prevalence of all CV risk factors increased. CONCLUSIONS: The enrolled population in SELECT includes participants across a broad range of relevant risk categories. This will allow the study to garner information about the CV benefits of semaglutide across these relevant clinical subgroups.

Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss.

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight-loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight-loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long-lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

The energy balance model of obesity: beyond calories in, calories out.

A recent Perspective article described the "carbohydrate-insulin model (CIM)" of obesity, asserting that it "better reflects knowledge on the biology of weight control" as compared with what was described as the "dominant energy balance model (EBM)," which fails to consider "biological mechanisms that promote weight gain." Unfortunately, the Perspective conflated and confused the principle of energy balance, a law of physics that is agnostic as to obesity mechanisms, with the EBM as a theoretical model of obesity that is firmly based on biology. In doing so, the authors presented a false choice between the CIM and a caricature of the EBM that does not reflect modern obesity science. Here, we present a more accurate description of the EBM where the brain is the primary organ responsible for body weight regulation operating mainly below our conscious awareness via complex endocrine, metabolic, and nervous system signals to control food intake in response to the body's dynamic energy needs as well as environmental influences. We also describe the recent history of the CIM and show how the latest "most comprehensive formulation" abandons a formerly central feature that required fat accumulation in adipose tissue to be the primary driver of positive energy balance. As such, the new CIM can be considered a special case of the more comprehensive EBM but with a narrower focus on diets high in glycemic load as the primary factor responsible for common obesity. We review data from a wide variety of studies that address the validity of each model and demonstrate that the EBM is a more robust theory of obesity than the CIM.

Drugs for Treating Obesity.

Older medications approved for chronic weight management (orlistat, naltrexone/bupropion, liraglutide 3 mg and, in the USA, phentermine/topiramate) have not been widely adopted by health care providers. Those medications produce only modest additional weight loss when used to augment lifestyle intervention. However, semaglutide 2.4 mg weekly has recently emerged and produces much more weight loss - on average 15% weight loss at 1 year. Semaglutide's enhanced efficacy and that its class (GLP-1 receptor analogs) is well-known may result in more clinicians adopting pharmacotherapy. Furthermore, the first dedicated cardiovascular outcome trial powered for superiority testing an anti-obesity medication (SELECT) is underway with semaglutide 2.4 mg. A positive outcome will further promote the concept that weight management should be a primary target for cardiometabolic disease control. In phase 3, tirzepatide and cagrilintide/semaglutide combination are showing promise for even greater weight loss efficacy. Another recently approved medication takes a personalized medicine approach; setmelanotide is approved as a therapy for those with some of the ultra-rare genetic diseases characterized by severe, early onset obesity. This chapter reviews the currently available and anticipated medications for chronic weight management as well as those approved for the genetic and syndromic obesities.

Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?

There is a new generation of antiobesity drugs in development or just arriving on the scene. First, setmelanotide has been approved for three of the ultrarare genetic conditions that cause obesity-pro-opiomelanocortin deficiency, proprotein convertase subtilisin and kexin type 1 (an important enzyme in the melanocortin pathway) and leptin receptor deficiency. Setmelanotide marks the first in a personalized medicine approach to obesity. Second, semaglutide 2.4 mg once weekly has been submitted to regulators in the United States and the European Union for approval for patients with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one weight related comorbidity. This drug has been studied in five phase 3 clinical trials, four discussed herein: semaglutide produces roughly twice as much weight loss as we have seen in older antiobesity medications. Semaglutide is already in use for treatment of diabetes and, as a glucagon-like peptide 1 (GLP-1) receptor analog, is part of a class of drugs used widely in diabetes. Tirzepatide, a glucose-insulin peptide and GLP-1 dual agonist is in phase 3 study for obesity management, and bimagrumab is a new agent in phase 2 with a unique mechanism of action; they are generating much interest. The purpose of this narrative review is lay the groundwork for a discussion of the clinical impact of these new medications on the clinical practice of obesity. Further, these developments shall be used to launch a speculation of what is likely to be their impact on the future of obesity pharmacotherapy.

Return on Investment: Medical Savings of an Employer-Sponsored Digital Intensive Lifestyle Intervention, Weight Loss.

OBJECTIVE: This study aimed to determine the medical cost impact and return on investment (ROI) of a large, commercial, digital, weight-management intensive lifestyle intervention (ILI) program (Real Appeal). METHODS: Participants in this program were compared with a control group matched by age, sex, geographic region, health risk, baseline medical costs, and chronic conditions. Medical costs were defined as the total amount paid for all medical expenses, inclusive of both the insurers' and the study participants' responsibility. RESULTS: In the 3 years following program registration, the intent-to-treat (ITT) cohort had significantly lower medical expenditures than the matched controls, with an average of -$771 or 12% lower costs (P = 0.002). Among 4,790 ITT participants, a total savings of $3,693,090 compared with total program costs of $1,639,961 translated into a 2.3:1 ROI. Program completers (n = 3,990), who attended more sessions than the overall ITT group, had greater mean weight loss (-4.4%), greater cost savings (-$956 or 14%), and an ROI of 2.0:1 over the 3-year time frame compared with matched controls. CONCLUSIONS: The findings demonstrated that the digital weight-management ILI was associated with a significantly positive ROI. Employers and payers willing to cover the cost of an ILI that produces both weight loss and demonstrated cost benefits can improve health and save money for their population with overweight or obesity.

Evidence-based weight loss interventions: Individualized treatment options to maximize patient outcomes.

Against the backdrop of obesity as a major public health problem, we examined three questions: How much weight loss is needed to benefit patients with obesity? How well do current therapies do in producing weight loss? What strategies can be used to improve patient outcomes using evidence-based studies. This paper reviews literature on the outcomes of lifestyle, diet, medications and surgical treatments for obesity using literature searches for obesity treatments. Current treatments, including lifestyle, diet and exercise, produce a weight loss of 5% to 7% on average. Despite continued attempts to identify superior dietary approaches, most careful comparisons find that low carbohydrate diets are not significantly better than low fat diets for weight loss. The four medications currently approved by the US Food and Drug Administration for long-term management of obesity are not as effective as surgery, adding about 5% on average to lifestyle approaches to weight loss. Two new medications that are under investigation, semaglutide and tirzepatide, significantly improve on this. For all treatments for weight loss, including lifestyle, medications and surgery, there is enormous variability in the amount of weight lost. Examination of this literature has yielded evidence supporting baseline and process predictors, but the effect sizes associated with these predictors are small and there are no prospective studies showing that a personalized approach based on genotype or phenotype will yield uniform success. Because obesity is a chronic disease it requires a 'continuous treatment model' across the lifespan.