BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy.
METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete.
FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group.
INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy.
FUNDING: National Health and Medical Research Council, Australia.
CardiovascularKidneySafetyLong-term Outcomes+1 more
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.).
Background & objectives
While obesity usually produces cardio-metabolic dysfunction, some obese individuals are metabolically healthy, and conversely, some nonobese individuals have significant metabolic dysfunction. This study aims to assess the national prevalence of various obesity subtypes and their association with type 2 diabetes (T2D), coronary artery disease (CAD), and chronic kidney disease (CKD) in the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study.
Methods
The ICMR-INDIAB study is a nationally representative cross-sectional survey of 1,13,043 individuals aged ≥20 yr from urban and rural areas across 31 Indian States and Union Territories. In every fifth individual (n=19,370), venous blood glucose and lipids were measured. A body mass index (BMI) ≥25 kg/m2 was defined as being obese, and metabolic obesity was diagnosed if two risk factors, out of the following: high waist circumference, high blood pressure, elevated blood glucose, raised serum triglycerides, or low HDL cholesterol, were present. Four subgroups were identified: Metabolically Healthy Non-Obese (MHNO), Metabolically Healthy Obese (MHO), Metabolically Obese Non-Obese (MONO), and Metabolically Obese Obese (MOO).
Results
The prevalence of various obesity subtypes was as follows: MONO: 43.3 per cent [95% confidence interval (CI): 42.6-44%], MOO: 28.3 per cent (27.7-28.9%), MHNO: 26.6 per cent (26-27.2%), and MHO: 1.8 per cent (1.6-2%). MONO was more prevalent in rural areas [Rural vs. Urban: MONO: 46 per cent (45-46.9%) vs. 39.6 per cent (37.8-41.3%), P<0.001]. MOO showed the highest risk for T2D and CAD, while MONO showed the highest risk of CKD, especially among females.
Interpretation & conclusions
Individuals with MONO have a distinct phenotype with adverse metabolic consequences, highlighting the need to shift from body weight-focused approaches to broader strategies to identify and tackle non-communicable diseases (NCDs) in India.
Keywords: Asian Indians, coronary artery disease, chronic kidney disease, diabetes, dyslipidaemia, hypertension, obesity, South Asians
Obesity, characterised by an elevated body mass index (BMI), has numerous adverse metabolic consequences on overall health. Worldwide, it is estimated that there are five million deaths every year from noncommunicable diseases (NCDs) attributable to high BMI, type 2 diabetes (T2D), cardiovascular disease (CVD), cancer, neurological disorders, chronic respiratory diseases, and chronic kidney disease (CKD)1. As per the World Health Organization (WHO)2 there are 2.5 billion overweight adults and 890 million with obesity worldwide (representing 43% and 16%, respectively, of the global adult population). Generalised obesity is defined based on BMI cut points, while abdominal obesity is defined based on waist circumference (WC) or various waist-related indices like waist to hip ratio (WHR) or waist to height ratio (WHtR). Compared to other ethnicities, Asian Indians have a distinct susceptibility to develop T2D and other obesity-related metabolic disorders at a lower BMI. The ‘Asian Indian Phenotype’, marked by high levels of abdominal fat, insulin resistance, and dyslipidaemia with low HDL cholesterol and high serum triglycerides even with normal BMI, is believed to be a primary factor underlying this heightened risk3-5. The substantial burden of obesity in India was confirmed by a recent publication from the Indian Council of Medical Research (ICMR)-India Diabetes (INDIAB) study6, which documented that there are an alarming 254 million and 351 million adults with generalised and abdominal obesity, respectively, in India6.
Metabolic dysfunction is often linked with obesity, but some individuals with obesity have no cardiometabolic risk factors. A recent Lancet Commission on Clinical Obesity has distinguished between individuals with excess body fat who have evidence of obesity-associated illness (termed ‘clinical obesity’) and those who do not (termed ‘preclinical obesity’)7. Conversely, some normal-weight or lean individuals may have significant cardiometabolic risks. In the 1980s, Ruderman8,9 introduced the concept of Metabolically Unhealthy Normal Weight (MUHNW) or Metabolically Obese Normal Weight (MONW) to describe individuals who are not obese based on BMI but show traits like hyperinsulinemia, insulin resistance, high triglycerides, and increased risk of coronary artery disease (CAD) and T2D. Another group of individuals who do not exhibit high-risk metabolic profiles yet meet conventional BMI criteria for obesity are classified as ‘metabolically healthy obese (MHO)’10,11. As cardiometabolic risk varies in each of these subtypes, it is important to assess their prevalence to plan preventive or treatment strategies. This is particularly relevant in the Asian Indian context, where individuals tend to develop obesity-related comorbidities even in the non-obese ranges of BMI, leading to a delay of medical interventions when screening is based solely on BMI. There is no national data on the various obesity subtypes in India. We used data from the large, nationally representative, ICMR-INDIAB study to report on the prevalence of various obesity subtypes and evaluate the risk of each subtype for T2D, CAD, and CKD among adults in India.
Materials & Methods
This cross-sectional survey was undertaken by the department of Epidemiology and Research Operations and Diabetes Complications, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India. The study was approved by the Institutional Ethics Committee of the coordinating centres and individual States. Written informed consent was obtained from all study participants. The study was registered with the Clinical Trials Registry of India (CTRI/2019/03/018095).
Sampling and study population
Adults aged ≥20 yr were recruited from the ICMR-INDIAB study12-19, a cross-sectional, population-based survey in India. The study methodology, including sampling strategies, sample size, and phases, have been described previously12 and provided in the supplementary material. Of the total 1,19,022 individuals from 31 States studied, 1,13,043 individuals participated in the study, yielding a response rate of 95 per cent.
Supplementary material
IJMR-161-5-461-SM.pdf (273.2KB, pdf)
Assessments
Data on medical history, family history of diabetes, physical activity, and socioeconomic status were collected using a standardised and structured questionnaire in all participants. Self-reported data included alcohol and smoking (current or in the prior six months). Physical activity was measured using a validated Physical Activity Questionnaire18. Individuals were classified into two categories based on their physical activity level (PAL), which was determined by dividing their total energy expenditure for 24 h by their basal metabolic rate: 1.4-1.69 for inactive individuals and 1.7-2.4 for active individuals. Dietary information was obtained using the MDRF-Food Frequency Questionnaire (M-FFQ)20, a validated, interviewer-administered tool. This meal-based questionnaire lists 222 common food items from urban and rural areas. Daily intake of calories, macronutrients, dietary fibre, and fatty acids was calculated using ‘EpiNu’ Software (Version 2.0). The nutrient densities expressed as the percentage of energy derived from carbohydrates, proteins, and fats were estimated and used in the analysis.
Standardised methods were used to determine blood pressure (BP) and anthropometric measurements, including weight, height, and waist circumference21. Height (in centimetres) was measured using a stadiometer (SECA Model 214, Seca Gmbh Co, Hamburg, Germany). Body weight (in kilograms) was measured using an electronic weighing scale (SECA Model 807, Seca Gmbh Co, Hamburg, Germany) placed on a flat horizontal surface. BMI was calculated using the formula: weight (kg)/height (m)2. Waist circumference (centimetres) was measured using a non-stretchable measuring tape at the smallest horizontal girth between the costal margins and the iliac crest at the end of expiration. Using an electronic sphygmomanometer (Omron HEM-7101; Omron Corporation, Tokyo, Japan), BP was recorded to the nearest 1 mm Hg. The final reading was recorded as the average of two measurements taken five minutes apart. Inter-observer and intra-observer coefficients of variation between the field technicians were documented and were less than 5 per cent. Equipment with the same specifications was used during the investigations as a quality control measure.
A One Touch Ultra glucose meter (LifeScan Johnson & Johnson, Milpitas, California) was used to assess each individual’s capillary blood glucose (CBG) after confirming an overnight fast of 8-12 h. Participants were administered 82.5 g of glucose (75 g of anhydrous glucose) for an oral glucose tolerance test, and the 2-h post-load CBG was measured. For individuals with self-reported diabetes, only fasting CBG was measured. In every fifth participant and individuals with diabetes, a venous sample was taken for the measurement of lipids, glycated haemoglobin (HbA1c), and creatinine. The VariantTM II Turbo machine (Bio-Rad, Hercules, CA) was utilised for high-pressure liquid chromatography to estimate HbA1c. An autoanalyzer [model 2700/480; Beckman Coulter AU (Olympus, County Clare, Ireland)] was used to measure serum cholesterol (cholesterol esterase oxidase-peroxidase-amidopyrine method), serum triglycerides (glycerol phosphate oxidase-peroxidase-amidopyrine method), and high-density lipoprotein cholesterol (direct method; polyethylene glycol-pre-treated enzymes). Serum creatinine was measured using the Jaffe Kinetic method. For biochemical assays conducted at the central laboratory, the intra-assay and inter-assay coefficients of variation ranged between 3.1 per cent and 7.6 per cent. A resting 12-lead electrocardiogram (ECG) was recorded in every fifth individual, and those with diabetes, and were graded using Minnesota coding. For the present analysis, the sample size (n) was 19,370, as lipids, creatinine, and ECG (needed to categorise individuals for metabolic obesity and assess complications) were performed only on every fifth participant.
Definitions
Metabolic obesity was defined as having ≥2 components of metabolic syndrome: (i) waist circumference ≥90 cm in males and ≥80 cm, in females, (ii) fasting blood glucose (FBG) ≥100 mg/dl, (iii) BP ≥130/85 mmHg or on anti-hypertensive medications, (iv) serum triglyceride levels ≥150 mg/dl or (v) HDL cholesterol <40 mg/dl for males and <50 mg/dl for females. Four obesity subtypes were defined as below: Metabolically Healthy Non-Obese (MHNO): absence of metabolic obesity and BMI <25 kg/m2, MHO: absence of metabolic obesity and BMI ≥25 kg/m2, Metabolically Obese Non-Obese (MONO): presence of metabolic obesity and BMI <25 kg/m2, Metabolically Obese Obese (MOO): presence of metabolic obesity and BMI ≥25 kg/m2.
Diabetes was defined as fasting CBG ≥126 mg/dl (7.0 mmol/l), or 2-h post-oral glucose load CBG ≥200 mg/dl (11.1 mmol/l), or a physician diagnosis of diabetes22.
CAD was diagnosed based on a recorded history of myocardial infarction (MI) or drug treatment for CAD and/or Minnesota codes: Q wave changes (1-1-1 to 1-1-7), ST segment depression (4-1 to 4-2) T-wave abnormalities (5-1 to 5-3) on the resting ECG23.
CKD was diagnosed if the estimated glomerular filtration rate (eGFR) was <60 ml/min/1.73m2 at the time of study. eGFR24 was derived using the following formula:
GFR=141*min (Scr/𝜅,1)𝛼*max(Scr/𝜅, 1)−1.209*0.993Age*1.018 (if female)
[κ=0.7 if female, κ=0.9 if male; α=-0.329 if female, α=-0.411 if male; min=the minimum of Scr/κ or 1, max=the maximum of Scr/κ or 1; Scr=serum creatinine (mg/dl)]
Statistical analysis
The proc survey (frequency/mean) procedure was used to analyse the data collected from complex survey designs, ensuring that the statistical analyses and inferences drawn were accurate and representative of the target population. These procedures are used when dealing with survey data that involves stratification, clustering, and survey weights. Supplementary material (page 9) provides the sampling weights calculation to adjust for sampling at different levels within each State.
Survey-adjusted linear regression was used to compute the mean, and the Wald χ2 test was applied to compare the proportions of variables between subtypes (MHNO vs. MHO, MONO, and MOO; urban vs. rural within each subtype of obesity). Univariate logistic regression was used to estimate risk for T2D, CAD, and CKD for individuals with different subtypes using MHNO as a reference group. The variables that were clinically relevant and/or significant in the univariate logistic regression, such as, sex, age, education, smoking, income, family history of diabetes, physical activity, and dietary nutrient densities (Carbohydrates %E, Fat %E and Protein %E) were adjusted in multiple logistic regression. A P <0·05 was considered statistically significant. To analyse data, we used Statistical Data Analysis Software (version 9.4; SAS Institute, Cary, NC, USA).
Results
Figure 1 presents the prevalence of different subtypes of obesity in the study population. The most prevalent obesity subtype was MONO, accounting for 43.3 per cent [95% confidence interval (CI): 42.6-44.%], followed by MOO (28.3%; 95% CI: 27.7-28.9%), MHNO (26.6%; 95% CI: 26.0-27.2%) and MHO (1.8%; 95% CI: 1.6-2.0%). The obese subtypes (MHO and MOO) were more common in the urban areas (urban vs. rural: MHO: 2%; 95% CI: 1.5-2.4% vs. 1.7%; 95% CI: 1.5-2%; P=0.304; MOO: 39%; 95% CI: 37.2-40.8% vs. 22.8%; 95% CI: 22-23.7%; P<0.001). MOO was more common among females (male vs. female: 23.2%; 95% CI: 22.2-24.3% vs. 32.9%; 95% CI: 31.7-34.2%; P<0.001), whereas MHO was more common in males (male vs. female: 2.1%; 95% CI: 1.8-2.4% vs. 1.5%; 95% CI: 1.3-1.8%; P=0.011).
Obesity is a chronic, relapsing disease associated with multiple complications and a substantial morbidity, mortality and health care burden. Pharmacological treatments for obesity provide a valuable adjunct to lifestyle intervention, which often achieves only limited weight loss that is difficult to maintain. The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial programme is evaluating once-weekly subcutaneous semaglutide 2.4 mg (a glucagon-like peptide-1 analogue) in people with overweight or obesity. Across STEP 1, 3, 4 and 8, semaglutide 2.4 mg was associated with mean weight losses of 14.9%-17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68; 69%-79% of participants achieved ≥10% weight loss with semaglutide 2.4 mg (vs. 12%-27% with placebo) and 51%-64% achieved ≥15% weight loss (vs. 5%-13% with placebo). In STEP 5, mean weight loss was -15.2% with semaglutide 2.4 mg versus -2.6% with placebo from baseline to week 104. In STEP 2 (individuals with overweight or obesity, and type 2 diabetes), mean weight loss was -9.6% with semaglutide 2.4 mg versus -3.4% with placebo from baseline to week 68. Improvements in cardiometabolic risk factors, including high blood pressure, atherogenic lipids and benefits on physical function and quality of life were seen with semaglutide 2.4 mg. The safety profile of semaglutide 2.4 mg was consistent across trials, primarily gastrointestinal adverse events. The magnitude of weight loss reported in the STEP trials offers the potential for clinically relevant improvement for individuals with obesity-related diseases.
BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.
METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.
RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).
CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).
BACKGROUND: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes.
METHODS: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants.
FINDINGS: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo.
INTERPRETATION: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo.
FUNDING: Novo Nordisk.
BACKGROUND: Obesity-related asthma, a specific type of asthma, tends to have more severe symptoms and more frequent exacerbations, and it is insensitive to standard medications. Plumbagin (PLB) has many positive effects on human health. However, it remains unclear whether PLB protects against obesity-related asthma. The study investigated the effect of PLB on obesity-related asthma.
METHODS: Four-week-old male C57BL6/J mice were fed either standard-chow diet or high-fat diet (HFD). The mice were sensitized to 100 μg ovalbumin (OVA) once a week and intraperitoneally injected with 1 mg/kg PLB once daily from Week 10 to 11 and then challenged with 10 μg OVA twice a day on Week 12. The lung tissue and bronchoalveolar lavage fluid (BALF) were collected 48 h after the first OVA challenge.
RESULTS: HFD enhanced inflammatory cell infiltration within the airways and increased total inflammatory cell and eosinophil counts, levels of eosinophil-related inflammatory cytokines, including interleukin-4 (IL-4), IL-5, and eotaxin in BALF, and oxidative stress in the lung tissues of asthmatic mice. PLB reduced inflammatory cell infiltration in the airway walls, levels of eosinophil-related inflammatory cytokines in BALF, and oxidative stress in lung tissues of obese asthmatic mice. In addition, PLB restored HFD-induced decreases in adenosine monophosphate-activated protein kinase (AMPK) phosphorylation.
CONCLUSION: The study suggested that HFD exacerbated inflammation and oxidative stress, while PLB probably alleviated inflammation and oxidative stress and activated AMPK pathway to attenuate obesity-associated asthma. Thus, PLB likely had the potential to treat obesity-related asthma.
The World Health Organization (WHO) recognizes obesity as a chronic, progressive and relapsing disease. As per the International
Classification of Disease 11, it is “a chronic complex disease defined by excessive adiposity that can impair health. It is in most cases a
multifactorial disease due to obesogenic environments, psycho-social factors and genetic variants. In a subgroup of patients, single major
etiological factors can be identified (medications, diseases, immobilization, iatrogenic procedures, monogenic disease/genetic syndrome).
Body mass index (BMI) is a surrogate marker of adiposity calculated as weight (kg)/height2 (m2). For adults, obesity is defined by a BMI
greater than or equal to 30 kg/m2” (4). Hence, obesity is not merely a risk factor or lifestyle condition, but a disease itself, shaped by a
complex interplay of biological, social, commercial and environmental determinants. With far-reaching health, economic and social
consequences, obesity is now one of the most pressing global health challenges of the 21st century.
As of 2022, over 1 billion people are living with obesity globally, and prevalence is rising in nearly every country (5). In 2021 alone, obesity
was estimated to contributed to 3.7 million deaths from linked noncommunicable diseases (NCDs) (6). The economic toll is staggering –
projected to reach US$ 3 trillion annually by 2030, with high-prevalence countries potentially spending up to 18% of total health
expenditure on obesity-related care (7).
Despite the growing burden, the global response to obesity remains fragmented and under-resourced. Most health systems are not yet
equipped to treat obesity as a chronic disease. Clinical pathways are often absent or disconnected, while provider training is limited and
access to effective interventions is constrained – especially in low-resource and marginalized settings. These challenges are compounded
by widespread stigma, misinformation and a lack of demand for care, all of which prevent many people living with obesity from receiving
the services they need and deserve (8)(9)(10).
Moreover, obesity continues to be treated in many public health strategies as a behavioural or modifiable risk factor – leading to delayed
diagnosis, inadequate treatment and missed opportunities for comprehensive care. Until recently, pharmacological options for obesity
management showed limited and often unsustainable impact. However, recent therapeutic advances, particularly glucagon-like peptide-1
receptor agonists (GLP-1 receptor agonists) and glucose-dependent insulinotropic polypeptides (GIP)/GLP-1 dual agonists, have
transformed the treatment landscape (11)(12)(13)(14)(15)(16)(17).
Originally developed for treatment of type 2 diabetes, these agents have demonstrated clinically significant and lasting reductions in body
weight (5-16%) in clinical trials, along with an array of health benefits (18)(19)(20). As of early 2025, 10 GLP-1–based therapies had
received regulatory approval for obesity and/or diabetes treatment, with more than 40 compounds in development, including novel multireceptor agonists.
These innovative medical therapies are making it possible to incorporate effective pharmacotherapy as one component of an integrated
intervention into chronic obesity care models. Yet the expansion of access must be guided by robust evidence, health system alignment,
public health priorities and principles of equity. There is an urgent need for global guidance that ensures the appropriate, safe and
inclusive use of these therapies across diverse health systems.
This WHO guideline is grounded in the recognition that obesity is a chronic disease requiring long-term care that goes far beyond weight
reduction alone. Effective obesity care must address the full spectrum of health, social and economic impacts of the disease, across the
life course. It must be embedded in multimodal clinical algorithms that integrate behaviour change and lifestyle support, pharmacotherapy,
long-term follow-up, social protection and supportive environments. Critically, this care must also reflect the lived experiences of people
living with obesity, who play an essential role in the design, delivery and evaluation of effective and stigma-free services and policies.
Aroda VR, Jørgensen NB, Kumar B, Lingvay I, Laulund AS, Buse JB, et al.
OBJECTIVE: Studies have demonstrated dose-dependent efficacy of glucagon-like peptide 1 receptor agonists for glycemic control and body weight. The aim of this trial was to characterize the dose-dependent effects of semaglutide (up to 16 mg/week) in people with type 2 diabetes and overweight or obesity.
RESEARCH DESIGN AND METHODS: In this parallel-group, participant- and investigator-blinded, phase 2 trial, 245 individuals with type 2 diabetes and BMI ≥27 kg/m2 on metformin were randomized to weekly semaglutide (2, 8, or 16 mg s.c.) or placebo for 40 weeks. Doses were escalated every 4 weeks, followed by a maintenance period. Dose modifications were not allowed. Primary and secondary efficacy end points included change from baseline to week 40 in HbA1c and body weight, respectively.
RESULTS: Estimated treatment difference between 16 and 2 mg was -0.3 percentage points (%-points) (95% CI -0.7 to 0.2; P = 0.245) for HbA1c change and -3.4 kg (-6.0 to -0.8; P = 0.011) for weight change for the treatment policy estimand and -0.5%-points (-1.0 to -0.1; P = 0.015) and -4.5 kg (-7.6 to -1.4; P = 0.004), respectively, for the hypothetical estimand. Dose-response modeling confirmed these findings. Treatment-emergent adverse events (AEs) and treatment discontinuations due to AEs, primarily gastrointestinal, were more frequent in the semaglutide 8 and 16 mg groups than in the 2 mg group. No severe hypoglycemic episodes were reported.
CONCLUSIONS: Higher semaglutide doses for type 2 diabetes and overweight or obesity provide modest additional glucose-lowering effect, with additional weight loss, at the expense of more AEs and treatment discontinuations. A study for evaluating high-dose semaglutide in obesity is currently underway.
Wharton S, Lingvay I, Bogdanski P, Duque do Vale R, Jacob S, Karlsson T, et al.
BACKGROUND: Oral semaglutide at a dose of 25 mg may provide an alternative treatment option to injectable semaglutide (2.4 mg) and higher-dose oral semaglutide (50 mg) for persons with overweight or obesity.
METHODS: In a 71-week, double-blind, randomized, placebo-controlled trial conducted at 22 sites in four countries, we enrolled persons without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. The participants were randomly assigned in a 2:1 ratio to receive oral semaglutide (25 mg) or placebo once daily, plus lifestyle interventions. The coprimary end points at week 64 were the percent change in body weight and a reduction of 5% or more in body weight; confirmatory secondary end points included reductions in body weight of 10% or more, 15% or more, and 20% or more and the change in the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score.
RESULTS: A total of 205 participants were randomly assigned to receive oral semaglutide, and 102 to receive placebo. The estimated mean change in body weight from baseline to week 64 was -13.6% in the oral semaglutide group and -2.2% in the placebo group (estimated difference, -11.4 percentage points; 95% confidence interval, -13.9 to -9.0; P<0.001). Participants in the oral semaglutide group were significantly more likely than those in the placebo group to have body-weight reductions of 5% or more, 10% or more, 15% or more, and 20% or more (P<0.001 for all comparisons) and to have an improved IWQOL-Lite-CT Physical Function score (P<0.001). Gastrointestinal adverse events were more common with oral semaglutide than with placebo (74.0% vs. 42.2%).
CONCLUSIONS: Oral semaglutide at a dose of 25 mg once daily resulted in a greater mean reduction in body weight than placebo in participants with overweight or obesity. (Funded by Novo Nordisk; OASIS 4 ClinicalTrials.gov number, NCT05564117.).
Solomon SD, Ostrominski JW, Wang X, Shah SJ, Borlaug BA, Butler J, et al.
BACKGROUND: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown.
OBJECTIVES: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function.
METHODS: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values.
RESULTS: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm2; 95% CI: -3.60 to -0.38 cm2; P = 0.016; EMD in RV end-systolic area: -1.41 cm2; 95% CI: -2.42 to -0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area.
CONCLUSIONS: In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).
McGowan BM, Bruun JM, Capehorn M, Pedersen SD, Pietiläinen KH, Muniraju HAK, et al.
BACKGROUND: There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes.
METHODS: STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete.
FINDINGS: Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m2 (6·9), waist circumference 120·1 cm (14·7), HbA1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported.
INTERPRETATION: Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia.
FUNDING: Novo Nordisk.
TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.
BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.
METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.
CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).
Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al.
BACKGROUND: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction.
METHODS: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
RESULTS: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group.
CONCLUSIONS: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).
Deshpande NR, Kapoor N, Dalal JJ, Palshetkar N, Shah S, Makkar BM, et al.
Objectives: The objective of this consensus article was to form a list of expert recommendations and an easily adaptable algorithm for obesity management in India by primary care physicians (PCPs). Methods: A Delphi-based model was followed to form a list of the consensus recommendations. Consensus statements were created from the results of a literature review that were graded as per the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. After being evaluated by an expert panel comprising diabetologists, endocrinologists, cardiologists, bariatric surgeons, and gynecologists, the statements were revised and reevaluated by a larger group of practitioners, including PCPs and diabetologists, to arrive at a consensus. Results: The panel opined that obesity is increasing in prevalence in India and is projected to rise in the coming years. Body mass index and waist circumference were both recommended for better identification of people at risk of obesity-related comorbidities than either of them alone. The Edmonton Obesity Staging System (EOSS) was suggested as being most suitable for the assessment (staging) of obesity. A multidisciplinary team was considered invaluable for assessing and managing patients with obesity. The use of once-a-week semaglutide (2.4 mg) via the subcutaneous route was suggested as the first-choice anti-obesity treatment when pharmacotherapy is deemed necessary. An algorithm considering all these aspects was proposed. Conclusion: Obesity needs to be recognized as a significant contributor to other comorbidities. The diagnosis and management of obesity should be comprehensive and consider patient psychology, the presence or absence of comorbidities, available pharmacologic agents, and long-term outcomes. The proposed algorithm could help clinicians in this aspect and improve the overall outcomes. How to cite this article: Deshpande NR, Kapoor N, Dalal JJ, et al. Consensus on Current Landscape and Treatment Trends of Obesity in India for Primary Care Physicians. J Assoc Physicians India 2023;71(10):69-77.
Anjana RM, Unnikrishnan R, Deepa M, Pradeepa R, Tandon N, Das AK, et al.
BACKGROUND: Non-communicable disease (NCD) rates are rapidly increasing in India with wide regional variations. We aimed to quantify the prevalence of metabolic NCDs in India and analyse interstate and inter-regional variations.
METHODS: The Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study, a cross-sectional population-based survey, assessed a representative sample of individuals aged 20 years and older drawn from urban and rural areas of 31 states, union territories, and the National Capital Territory of India. We conducted the survey in multiple phases with a stratified multistage sampling design, using three-level stratification based on geography, population size, and socioeconomic status of each state. Diabetes and prediabetes were diagnosed using the WHO criteria, hypertension using the Eighth Joint National Committee guidelines, obesity (generalised and abdominal) using the WHO Asia Pacific guidelines, and dyslipidaemia using the National Cholesterol Education Program-Adult Treatment Panel III guidelines.
FINDINGS: A total of 113 043 individuals (79 506 from rural areas and 33 537 from urban areas) participated in the ICMR-INDIAB study between Oct 18, 2008 and Dec 17, 2020. The overall weighted prevalence of diabetes was 11·4% (95% CI 10·2-12·5; 10 151 of 107 119 individuals), prediabetes 15·3% (13·9-16·6; 15 496 of 107 119 individuals), hypertension 35·5% (33·8-37·3; 35 172 of 111 439 individuals), generalised obesity 28·6% (26·9-30·3; 29 861 of 110 368 individuals), abdominal obesity 39·5% (37·7-41·4; 40 121 of 108 665 individuals), and dyslipidaemia 81·2% (77·9-84·5; 14 895 of 18 492 of 25 647). All metabolic NCDs except prediabetes were more frequent in urban than rural areas. In many states with a lower human development index, the ratio of diabetes to prediabetes was less than 1.
INTERPRETATION: The prevalence of diabetes and other metabolic NCDs in India is considerably higher than previously estimated. While the diabetes epidemic is stabilising in the more developed states of the country, it is still increasing in most other states. Thus, there are serious implications for the nation, warranting urgent state-specific policies and interventions to arrest the rapidly rising epidemic of metabolic NCDs in India.
FUNDING: Indian Council of Medical Research and Department of Health Research, Ministry of Health and Family Welfare, Government of India.
