The Effect of Semaglutide on Mortality and COVID-19-Related Deaths: An Analysis From the SELECT Trial.

BACKGROUND: Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk. OBJECTIVES: This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19). METHODS: The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants ≥45 years of age with a body mass index ≥27 kg/m2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively. RESULTS: Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19-related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death. CONCLUSIONS: Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597).

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial.

BACKGROUND: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. METHODS: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. FINDINGS: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. INTERPRETATION: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. FUNDING: Novo Nordisk.

Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial.

OBJECTIVE: To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes. RESEARCH DESIGN AND METHODS: In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m2, and with preexisting cardiovascular disease but without diabetes (HbA1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA1c and proportions achieving biochemical normoglycemia (HbA1c <5.7%) and progressing to biochemical diabetes (HbA1c ≥6.5%). RESULTS: Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference of -0.32 percentage points (95% CI -0.33 to -0.30; -3.49 mmol/mol [-3.66 to -3.32]) and with the difference favoring semaglutide throughout the study (P < 0.0001). Body weight plateaued at 65 weeks and was 8.9% lower with semaglutide. At week 156, a greater proportion treated with semaglutide were normoglycemic (69.5% vs. 35.8%; P < 0.0001) and a smaller proportion had biochemical diabetes by week 156 (1.5% vs. 6.9%; P < 0.0001). The number needed to treat was 18.5 to prevent a case of diabetes. Both regression and progression were dependent on glycemia at baseline, with the magnitude of weight reduction important in mediating 24.5% of progression and 27.1% of regression. CONCLUSIONS: In people with preexisting cardiovascular disease and overweight or obesity but without diabetes, long-term semaglutide increases regression to biochemical normoglycemia and reduces progression to biochemical diabetes but does not slow glycemic progression over time.

Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT.

OBJECTIVE: To evaluate the cardiovascular effects of semaglutide by baseline glycated hemoglobin (HbA1c) and change in HbA1c in a prespecified analysis of Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT). RESEARCH DESIGN AND METHODS: In SELECT, people with overweight or obesity and atherosclerotic cardiovascular disease without diabetes were randomized to weekly semaglutide 2.4 mg or placebo. The primary end point of first major adverse cardiovascular event (MACE) (cardiovascular mortality, nonfatal myocardial infarction, or stroke) was reduced by 20% with semaglutide versus placebo. Analysis of outcomes included first MACE, its individual components, expanded MACE (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failure composite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality by baseline HbA1c subgroup and categories of HbA1c change (<-0.3, -0.3 to 0.3, and >0.3 percentage points) from baseline to 20 weeks using the intention-to-treat principle with Cox proportional hazards. RESULTS: Among 17,604 participants (mean age 61.6 years, 72.3% male), baseline HbA1c was <5.7% for 33.5%, 5.7% to <6.0% for 34.6%, and 6.0% to <6.5% for 31.9%. Cardiovascular risk reduction with semaglutide versus placebo was not shown to be different across baseline HbA1c groups and was consistent with that of the overall study for all end points, except all-cause mortality. Cardiovascular outcomes were also consistent across subgroups of HbA1c change. CONCLUSIONS: In people with overweight or obesity and established atherosclerotic cardiovascular disease but not diabetes, semaglutide reduced cardiovascular events irrespective of baseline HbA1c or change in HbA1c. Thus, semaglutide is expected to confer cardiovascular benefits in people with established atherosclerotic cardiovascular disease who are normoglycemic at baseline and/or in those without HbA1c improvements.

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.

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.

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.).

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.

Improving Quality Outcomes: The Value of Diabetes Care and Education Specialists.

Given the growing prevalence and accelerating cost of diabetes, there is an urgent need to expand strategies in health care that improve access and outcomes and reduce the financial and human burden of the disease. Diabetes care and education specialists (DCESs) are well positioned to assist health care systems with delivery models that enhance diabetes care through evidence-based standards and quality improvement strategies. DCESs have increased opportunities to apply their competencies in primary, specialty, hospital, and acute care settings; accountable care organizations; community settings; research; and academia. Two national certification programs provide an evidence-based foundation for quality in the specialty, with updated competencies guiding practice. This article serves as a call to action for health care systems to integrate specialists in diabetes care and education into diabetes care delivery models and raise awareness of the positive impact these professionals have on the lives of people with diabetes.

Current and Emerging Trends in Diabetes Care and Education: 2021 National Practice and Workforce Survey.

PURPOSE: The purpose of the National Practice Survey is to understand current trends related to the diabetes care and education specialist's integration into the full care team beyond formal diabetes self-management education and support services. METHODS: The 2021 National Practice Survey (NPS2021) contained 61 questions for all respondents with an additional 56 questions pertaining to specific diabetes care and education segments. An anonymous survey was administered online to respondents who are diabetes care and education specialists or a part of the diabetes care team. Email lists were obtained from the Association of Diabetes Care & Education Specialists (ADCES) and the Certification Board for Diabetes Care and Education (CBDCE). Approximately 39,258 emails were sent, and 3357 were undeliverable, with 3797 surveys completed between February 9 to April 6, 2021, resulting in an 11% response rate. The response rate may have been affected by the COVID-19 public health emergency. RESULTS: Diabetes care and education specialists represent an interprofessional specialty of nurses, dietitians, physicians, pharmacists, health educators, and others. Many respondents reported holding either certification as a Certified Diabetes Care and Education Specialist (CDCES) or being Board Certified in Advanced Diabetes Management (BC-ADM). In addition, there appears to be a slight increase in those trained as a Lifestyle Coach to provide the National Diabetes Prevention Program (CDC Recognized National DPP) compared to NPS2017. Most respondents reported being Caucasian/White (84%), followed by Hispanic or Latinx (7%) and African American/Black and Asian/Asian American (at 4% each), like in previous surveys. Respondents reported diverse care delivery models, including traditional and nontraditional services, and expanded models of care such as population health/risk stratification models, the Chronic Care Model, Accountable Care Organizations, managed care, and others. CONCLUSION: The NPS2021 describes DCES workforce opportunities and challenges. Identifying and addressing those that impact the specialty's sustainability, diversity, and growth will guide strategies for the future workforce and their practice settings. Opportunities identified include embracing diabetes community care coordinators for person-centered delivery of care and education services and supporting frontline health care team members to increase competence and expertise in the prevention of type 2 diabetes, diabetes care, and education/support for related chronic diseases. In addition, as health care evolves, it creates opportunities for the DCESs to demonstrate a broader, key role as part of the diabetes care team.

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.