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Many people who have tried to lose weight by cutting calories are familiar with this frustrating reality: At some point, the body stops shedding pounds. It senses the reduced calorie intake and responds by slowing down metabolism, causing it to burn fewer calories than before the diet.

Diabetes, Obesity and Metabolism, EarlyView.

Diabetes, Obesity and Metabolism, EarlyView.

Abstract
Aims
To characterize trends in obesity and prescriptions for glucagon-like peptide-1 receptor agonists (GLP-1RAs) across body mass index (BMI) categories among US youth and adults with type 1 diabetes (T1D) from 2008 to 2023.
Materials and Methods
Patients with T1D were identified using a validated algorithm using de-identified electronic health record (EHRs) data from 33 US health systems. BMI categories were based on age- and sex-specific percentiles for youth (2–19 years) and World Health Organization cut points for adults (≥20 years). Trends in obesity and GLP1-RA prescriptions were characterized by BMI categories among youth and adults with T1D from 2008–2011 to 2020–2023.
Results
From 2008–2011 to 2020–2023, the prevalence of obesity among youth with T1D increased from 18.1% (95% confidence interval [CI], 17.3%–18.9%) to 26.0% (25.2%–26.8%) (p-for-trend < 0.001). Among adults with T1D, the prevalence of obesity rose from 30.5% (30.0%–31.0%) in 2008–2011 to 38.1% (37.8%–38.5%) in 2020–2023 (p-for-trend < 0.001). Obesity was highest in Black and Hispanic youth and adults, and racial and ethnic disparities persisted over time. Over the last 15-year period, GLP-1RA prescriptions significantly increased across all BMI categories in a dose–response manner among both youth and adults with T1D (all p-for-trend < 0.001).
Conclusions
Over the last 15-year period, obesity has reached epidemic levels in US youth and adults with T1D, with significant disparities among racial and ethnic minoritized populations. These findings, coupled with the increase in GLP-1RA prescriptions, underscore the urgent need for data on GLP-1RAs’ safety and effectiveness and guidance for obesity management in T1D.

Abstract
Aim
To understand the existing literature on the epidemiology and clinical, humanistic, and economic burden of diabetic ketoacidosis (DKA) in people living with type 2 diabetes mellitus (T2DM).
Materials and Methods
MEDLINE, Embase and the Cochrane library were systematically searched for studies published between 1 January 2014 and 14 December 2023. Clinical trials and observational studies, conducted in people living with T2DM, were included if they provided data on DKA epidemiology, morbidity, mortality, hospitalizations or patient-reported outcomes. Studies of DKA-associated costs in T2DM were also included. Data were summarized descriptively.
Results
Overall, 197 publications were included. We found wide variations in DKA prevalence (0.0%–50.0%; 5th–95th percentile: 0.02%–26%; 126 publications) and incidence (0.0–24.5 events per 1000 patient years; 5th–95th percentile: 0.004–7.6 events per 1000 patient years; 37 publications). Populations at increased risk of DKA included patients using sodium–glucose cotransporter-2 inhibitors, those using insulin and those with poor glycaemic control. The most common precipitating factors were infection and non-adherence to treatment. There was limited evidence on the humanistic burden of DKA, but the results highlighted a high burden of complications including acute kidney injury or failure. The length of hospital stay ranged from days to several weeks.
Conclusions
DKA is associated with a high clinical burden in people living with T2DM. Resources to screen for and potentially prevent DKA may reduce the burden of DKA for patients with T2DM and the healthcare system.

Abstract
Aims
GZR18, a novel long-acting GLP-1 receptor agonist, has demonstrated substantial metabolic improvements in diabetic and obese animal models. The present studies aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the ascending dose of GZR18 in healthy American and Chinese subjects.
Materials and Methods
In these phases 1, randomized, double-blind, placebo-controlled, sequential, dose-escalation US and Chinese studies, healthy American and Chinese adults with similar age were enrolled to once-weekly subcutaneous injection of GZR18 or placebo. The studies included three cohorts of male American subjects (cohorts US-1–3) and six cohorts of Chinese subjects (cohorts CN-1–6, male and female), each with a specified target dose of GZR18 ranging from 1 to 50 μg/kg (1–10 μg/kg for US study and 5–50 μg/kg for Chinese study). The primary endpoints were the safety and tolerability of GZR18. Blood samples were collected for PK and PD analysis of GZR18 before and after dosing. A population PK analysis of GZR18 was conducted to ascertain whether there are ethnic PK differences between American and Chinese adults.
Results
The exposure of GZR18 was comparable between healthy American and Chinese subjects, with the geometric mean ratio between the two populations for AUC0-t and C
max close to 1. A dose-dependent increase in AUC0–t and C
max occurred in both populations. The median time to maximum plasma concentrations (T
max) in American subjects ranged from 72 to 96 h, and the mean T
max ranged from 60 to 72 h in Chinese subjects. The half-life of GZR18 was approximately 7 days in both American and Chinese subjects. Evident body weight reduction was observed in GZR18 treatment groups in Chinese subjects (cohorts CN-3–6 on Day 15, −1.25 to −1.86 kg; −1.88% to −3.11%). No deaths, serious adverse events or hypoglycaemia were reported. Decreased appetite and nausea were the most frequently reported treatment-emergent adverse events, observed in Chinese study and mild in severity. The safety profile of GZR18 was generally consistent with the same class of drugs.
Conclusions
GZR18 demonstrates good tolerability in healthy American and Chinese subjects. No ethnic differences were observed between healthy American and Chinese subjects. The safety, PK and PD profiles of GZR18 support its further clinical evaluation for glycaemic and body weight control.

ABSTRACT
Background
The prevalence of obesity and related co-morbidities has reached epidemic proportions. Effective evidence-based treatment approaches are therefore important. Lifestyle intervention remains the mainstay of the treatment strategy to manage obesity. Increased evidence has also emerged regarding the efficacy of metabolic bariatric surgery (MBS) to induce significant and sustained weight loss while also reducing the progression of obesity-related co-morbidities for people living with obesity.
Aims & Methods
This article aims to bring together current evidence, guidance and best practice for the prevention and management of people living with overweight or obesity by means of lifestyle and behavioural intervention, as well as by MBS.
Result
Lifestyle intervention encompasses dietary strategies, physical activity and behavioural intervention. Discussion on MBS will focus on current indications, comparison between different MBS procedures, novel endoscopic techniques, potential complications and pre-operative management.
Plain Language Summary
The number of people living with excess weight and complications associated with being overweight is alarmingly quite high. Effective treatment approaches that are supported by clinical studies are therefore important. Lifestyle changes remain very important to manage excess weight. Increased evidence has also shown the benefits of weight loss surgery to produce significant weight loss which could be sustained, while also reducing the risk of developing medical conditions associated with excess weight. This article aims to bring together current evidence, guidance and best practice for the prevention and management of people living with excess weight by means of lifestyle and behavioural changes, as well as by weight loss surgery. Lifestyle intervention encompasses dietary strategies, physical activity and behavioural intervention. Discussion on weight loss surgery will focus on current criteria for suitability, comparison between different weight loss surgery procedures, new techniques, possible complications and appropriate management prior to weight loss surgery.

Abstract
Aims
Heart failure is a leading cause of mortality in the United States, with significant disparities in its burden, particularly among underserved populations. A similar pattern exists for diabetes, but less is known about the mortality impact of these two comorbid conditions. This study aims to examine the risk of death from heart failure among people with diabetes, focusing on socio-demographic disparities.
Materials and Methods
We analysed data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death Database, examining patterns of heart failure deaths in which diabetes was a contributing cause. Our analysis was stratified by socio-demographic variables, including race, ethnicity and geography, and we also explored trends over time.
Results
Between 1999 and 2020, there were 82 617 deaths from heart failure in which diabetes was a contributing cause, with an age-adjusted mortality rate of 32.04 deaths per 1 000 000 individuals. The death rate increased by 2.18% during the study period. Death rates were higher among Black Americans compared with White Americans (age-adjusted mortality rate ratio = 1.51, 95% confidence interval: 1.49–1.53), with disparities growing over time (a 10.75% increase for Black Americans vs. a 1.11% increase for White Americans).
Conclusions
Deaths from comorbid heart failure and diabetes are increasing in the United States, with significant and worsening disparities, particularly among minorities. Urgent action is needed to reduce heart failure mortality among people with diabetes, especially in underserved populations.

Abstract
Aims
The aims of the study were to develop and validate WHOLISTIIC, a data-driven cluster analysis for identifying anthropometric metabolic subtypes.
Materials and Methods
K-means cluster analysis was performed in 397 424 UK Biobank participants based on five domains, that is, central obesity (waist-to-height ratio), general obesity (body mass index [BMI]), limb strength (handgrip strength), insulin resistance (triglyceride to high-density lipoprotein cholesterol [HDLc] ratio) and inflammatory condition (neutrophil-to-lymphocyte ratio). Replication was done in the NHANES. Cox proportional hazards regression models were used to estimate the associations of clusters with incident adverse health outcomes.
Results
Six replicable clusters were identified. Compared with individuals in cluster 1 (lowest BMI with preserved handgrip strength), individuals in cluster 2 (highest handgrip strength) were not at increased risk of all-cause mortality despite higher BMI, but had small yet significant increased risks of cardiovascular mortality, incident major adverse cardiovascular events (MACE), chronic renal failure and decreased risks of mortality due to respiratory disease, as well as incident dementia; individuals in cluster 3 (lowest handgrip strength and borderline elevated BMI), cluster 4 (highest triglyceride-to-HDLc ratio and moderately elevated BMI), cluster 5 (highest neutrophil-to-lymphocyte ratio and borderline elevated BMI) and cluster 6 (highest BMI) had substantially increased risks of all-cause, cardiovascular, and cancer mortality, incident MACE and chronic renal failure. The associations of anthropometric clusters with the risk of mortality were replicated in the NHANES cohort.
Conclusions
Anthropometric metabolic subtypes identified with easily accessible parameters reflecting multifaceted pathology of overweight and obesity were associated with distinct risks of long-term adverse health outcomes.

Diabetes, Obesity and Metabolism, EarlyView.