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
SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity, Lincoff et al., NEJM 2023) was the landmark cardiovascular outcomes trial establishing that semaglutide directly reduces major adverse cardiovascular events (MACE) in obesity without diabetes — the first weight-loss medication to demonstrate this outcome.
Trial design. A multinational, double-blind, placebo-controlled, phase 3 cardiovascular outcomes RCT (NCT03574597). Participants were randomized 1:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, in addition to standard cardiovascular care.
Population. 17,604 adults with established cardiovascular disease (prior myocardial infarction, prior stroke, or symptomatic peripheral artery disease) and overweight or obesity (BMI ≥27 kg/m²), but without diabetes. Mean age 62 years; 72% men. Mean follow-up approximately 39.8 months (median ~3.3 years).
Primary endpoint. Time to first MACE — defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Key results. MACE occurred in 6.5% of semaglutide-treated participants vs 8.0% on placebo (hazard ratio 0.80, 95% CI 0.72-0.90, p<0.001) — a 20% relative risk reduction. Mean weight change was -9.4% on semaglutide vs -0.9% on placebo. Improvements were also observed in cardiometabolic risk factors and inflammation markers.
Adverse events. Gastrointestinal events were most common; semaglutide had more adverse-event-related discontinuations than placebo, but no excess of serious adverse events.
Indian context. Cardiovascular disease is the leading cause of death in India and disproportionately affects South Asians at younger ages and lower body weights than Western populations. SELECT establishes a clinically meaningful CV benefit at the same 2.4 mg dose now available across multiple Indian generic brands. For Indian patients with prior cardiovascular events and overweight or obesity, semaglutide provides not only weight management but also direct cardiovascular protection.
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.
STEP 1 (Semaglutide Treatment Effect in People with Obesity Trial 1) was the foundational randomized controlled trial establishing semaglutide 2.4 mg as an effective treatment for chronic weight management in adults without diabetes.
Trial design. A 68-week, double-blind, placebo-controlled, phase 3 RCT (NCT03548935). Participants were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, both with lifestyle intervention (reduced-calorie diet and increased physical activity). Conducted across approximately 16 countries.
Population. 1,961 adults aged ≥18 with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity, but without type 2 diabetes. Mean baseline BMI was 37.9 kg/m²; mean age 46 years; 74% women.
Primary endpoints. Percentage change in body weight from baseline at week 68, and the proportion achieving ≥5% weight loss.
Key results. Mean body-weight loss was 15.3% on semaglutide versus 2.6% on placebo — an estimated treatment difference of approximately −12.7 percentage points. 86% of semaglutide recipients lost ≥5% of body weight (versus 32% on placebo); 69% lost ≥10%; 50% lost ≥15%; about 1 in 3 (32%) lost ≥20%. Improvements were also observed in cardiometabolic risk factors — waist circumference, systolic blood pressure, HbA1c, and lipid profile.
Adverse events. Gastrointestinal events were the most common: nausea ~44%, diarrhea ~32%, vomiting ~24%, constipation ~24% on semaglutide. Most were mild-to-moderate and concentrated during dose escalation. 4.5% of semaglutide participants discontinued due to adverse events versus 0.8% on placebo.
Indian context. South Asian subgroup data are limited in STEP 1. Indian regulators (CDSCO/ESI) recognise lower BMI thresholds for intervention — ≥27.5 kg/m², or ≥25 with comorbidity — reflecting higher visceral adiposity and metabolic risk at lower body weights. Clinical benefit in Indian patients is expected at body weights below the trial's average baseline.
STEP 2 (Davies et al., Lancet 2021) was the pivotal randomized controlled trial establishing semaglutide 2.4 mg for chronic weight management in adults with type 2 diabetes — extending the STEP 1 obesity finding into the dual-indication population.
Trial design. A 68-week, double-blind, placebo-controlled, phase 3 RCT (NCT03552757). Participants were randomized 1:1:1 to once-weekly subcutaneous semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo, all with lifestyle intervention (reduced-calorie diet and increased physical activity). Conducted across 12 countries, 149 sites.
Population. 1,210 adults with type 2 diabetes (HbA1c 7-10%) and overweight or obesity (BMI ≥27 kg/m²). Mean baseline BMI 35.7 kg/m²; mean age 55 years; 51% women.
Primary endpoints. Percentage change in body weight at week 68, and the proportion achieving ≥5% weight loss.
Key results. Mean body-weight loss was 9.6% on semaglutide 2.4 mg, 7.0% on semaglutide 1.0 mg, and 3.4% on placebo. 68.8% of patients on semaglutide 2.4 mg achieved ≥5% weight loss (vs 57.1% on 1.0 mg vs 28.5% on placebo). HbA1c reductions were comparable across both semaglutide arms (~1.6% reduction) and substantially larger than placebo (-0.4%).
Adverse events. Gastrointestinal events (nausea, diarrhea, vomiting, constipation) were the most common, similar to STEP 1, mostly mild-to-moderate and concentrated during dose escalation.
Indian context. Type 2 diabetes is highly prevalent in India (~10% of adults), and the Indian phenotype shows higher visceral adiposity and earlier metabolic complications at lower BMIs than Western populations. STEP 2 confirms that semaglutide 2.4 mg delivers both weight loss and glycemic control in patients with both indications — relevant given that several Indian generic brands (Noveltreat, Semaglyn, SUNDAE, Semasize) are now DCGI-approved for both type 2 diabetes and obesity.
The Executive Committee of the Endocrine Society of India appointed a writing committee for framing the guidelines. The members of the committee were chosen from endocrinologists involved in research as well as clinical care of obesity and related disorders. The writing committee was chaired by the Editor-in-Chief, Indian Journal of Endocrinology and Metabolism. The writing committee met on several occasions and came up with 14 sub-sections under which the guidelines would be formulated. Each member was then allotted one or more subsections in order to search the literature, including all existing literature, and suggest recommendations for that subsection. Each recommendation had two options: (a) Recommended care as the primary recommendation and (b) limited care recommendation for resource-limited settings. The recommendations are numbered as 1.1, 1.2, etc., where the first number indicates the subsection while the second denotes the serial number of the recommendation. The limited care recommendations are denoted by (L) after the recommendation number (such as 1.1 (L)). An abridged version of the document for primary care providers was also made. Once the members had completed the literature search and formulated the recommendations, all the subsections were compiled together and circulated amongst the committee members for their comments. Any corrections or suggestions by the other committee members were incorporated into the document. The chairman of the writing committee approved this draft and forwarded it to the Executive Committee of the ESI. The members of the Executive Committee, consisting of national experts in the field of endocrinology, vetted the document and gave their inputs. After incorporation of these inputs, the draft was uploaded on the official website of ESI and inputs or suggestions were sought from all members of the ESI or any other stakeholder. The inputs were considered for inclusion as per their merit and relevance; the draft was then finalized for publication in the Indian Journal of Endocrinology and Metabolism.
STEP 4 (Rubino et al., JAMA 2021) was the pivotal weight-maintenance trial demonstrating that continued semaglutide is required to sustain weight loss. Stopping semaglutide leads to substantial weight regain — establishing obesity as a chronic condition requiring ongoing treatment.
Trial design. A 68-week phase 3 RCT with a withdrawal design (NCT03548987). All participants received once-weekly subcutaneous semaglutide 2.4 mg + lifestyle intervention during a 20-week open-label run-in. At week 20, those who had reached the maintenance dose and tolerated it (803 of 902 enrolled) were re-randomized 2:1 to continue semaglutide 2.4 mg or switch to placebo for the remaining 48 weeks (week 20 to 68).
Population. 803 adults (post-run-in cohort) with overweight or obesity (BMI ≥27 kg/m²) without type 2 diabetes. Mean baseline BMI ~38; mean age 46; 79% women.
Primary endpoint. Percentage change in body weight from week 20 (re-randomization) to week 68.
Key results. From week 20 to week 68: participants who continued semaglutide lost an additional 7.9% of body weight; those switched to placebo regained 6.9%. Cumulative weight change over the full 68 weeks: −17.4% on continued semaglutide vs −5.0% on those switched to placebo. The estimated treatment difference at week 68 was −14.8 percentage points. Cardiometabolic risk factors deteriorated in the placebo-switched group consistent with weight regain.
Adverse events. Gastrointestinal events were the most common, similar to STEP 1 and STEP 2, mostly mild-to-moderate.
Indian context. STEP 4 establishes obesity as a chronic disease requiring ongoing pharmacotherapy — analogous to hypertension or dyslipidemia. For Indian patients considering semaglutide, this means treatment is not short-course: discontinuing typically leads to weight regain. The decision to start semaglutide should account for long-term cost (₹220/shot to ₹4,500/month across DCGI-approved Indian generics) and adherence over years.
EfficacyWeight LossObesityLong-term Outcomes+1 more
**Abstract**
The prevalence of overweight and obesity has more than doubled since 1980, and it is predicted that around two-thirds of the global burden of the disease will be attributed to chronic non-communicable diseases. Developing countries are experiencing a more dramatic rise in the prevalence of obesity in recent years. As per National Family Health Survey-5 (NFHS-5), one in every four Indians is now having obesity. It has been reported that being overweight and obese is a significant problem among different socioeconomic spectrums of men and women in India, especially among the elderly, people residing in urban regions, and diverse socioeconomic strata. There is an urgent need to identify obesity as a chronic disease requiring immediate attention, mandating timely screening, timely treatment, and economical ways of achieving and managing weight loss across the country. In this review, the authors have discussed various aspects of overweight and obesity and critically appraised the current status of obesity in India, its public health implications, the significance of screening, the role of BMI and other parameters in diagnosing obesity, and the need for treatment and cost-effective prescriptions.
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.
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).
Background
The cardiovascular safety of oral semaglutide, a glucagon-like peptide 1 receptor agonist, has been established in persons with type 2 diabetes and high cardiovascular risk. An assessment of the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both is needed.
Methods
In this double-blind, placebo-controlled, event-driven, superiority trial, we randomly assigned participants who were 50 years of age or older, had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and had known atherosclerotic cardiovascular disease, chronic kidney disease, or both to receive either once-daily oral semaglutide (maximal dose, 14 mg) or placebo, in addition to standard care. The primary outcome was major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis. The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome).
Results
Among the 9650 participants who had undergone randomization, the mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months. A primary-outcome event occurred in 579 of the 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P=0.006). The results for the confirmatory secondary outcomes did not differ significantly between the two groups. The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group; the incidence of gastrointestinal disorders was 5.0% and 4.4%, respectively.
Conclusions
Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events. (Funded by Novo Nordisk; SOUL ClinicalTrials.gov number, NCT03914326.)
West S, Scragg J, Aveyard P, et al. — University of Oxford
## Abstract
**Objectives** To quantify and compare the rate of weight regain after cessation of weight management medications (WMMs) in adults with overweight or obesity.
**Design** Systematic review and meta-analysis.
**Study selection** Trial registries and databases (Medline, Embase, PsycINFO, CINAHL, Cochrane, Web of Science, and trial registries) were searched from inception until February 2025 for randomised controlled trials (RCTs), non-randomised trials, and observational studies that included WMM (≥8 weeks) with follow-up for ≥4 weeks after cessation of treatment in adults with overweight or obesity. Comparators were any non-drug weight loss intervention or placebo.
**Data extraction and synthesis** The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Two independent reviewers screened titles, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias 2 tool for RCTs and the ROBINS-I tool for non-randomised trials. Data were analysed using mixed effect, meta-regression, and time-to-event models. Weight regain after cessation of WMM was compared with that reported after cessation of behavioural weight management programmes (BWMPs).
**Main outcome measures** The primary outcome was rate of weight regain from end of treatment, with associated changes in cardiometabolic markers as a secondary outcome.
**Results** Of the 9288 titles screened, 37 studies (63 intervention arms, 9341 participants) were included. Average treatment duration was 39 (range 11-176) weeks, with average follow-up of 32 (4-104) weeks. The average monthly rate of weight regain was 0.4 kg (95% confidence interval (CI) 0.3 to 0.5) (mixed model 0.3 kg (0.2 to 0.4) monthly v control in RCTs). All cardiometabolic markers were projected to return to baseline within 1.4 years after the cessation of WMM. Weight regain was faster after WMM than after BWMP (by 0.3 kg (0.22 to 0.34) monthly), independent of initial weight loss. Estimates and precision were robust in sensitivity analyses.
**Conclusions** This review found that cessation of WMM is followed by rapid weight regain and reversal of beneficial effects on cardiometabolic markers. Regain after WMM was faster than after BWMP. These findings suggest caution in short term use of these drugs without a more comprehensive approach to weight management.
**Systematic review registration** PROSPERO CRD42024532069.
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.).
**Background:** Semaglutide, a GLP-1 receptor agonist, has demonstrated significant efficacy in glycemic control and weight reduction in Type 2 Diabetes Mellitus (T2DM). However, gastrointestinal (GI) side effects remain a common barrier to long-term adherence in real-world clinical practice. This study aimed to evaluate the prevalence, severity, and impact of gastrointestinal (GI) adverse events on discontinuation rates among patients initiated on semaglutide therapy.
**Methods:** A prospective observational study was conducted on 100 adult T2DM patients prescribed semaglutide in a routine outpatient setting. Data on demographics, GI side effects (nausea, vomiting, diarrhea, constipation), severity grading (mild, moderate, severe), dose adjustments, and discontinuation rates were collected over a 12-week follow-up period. Descriptive statistics were applied to analyze frequency distributions.
**Results:** The mean age of participants was 54.6 ± 10.8 years, with 52% being male. GI side effects were reported in 43% of patients. Nausea (28%) was the most common symptom, followed by vomiting (12%), diarrhea (10%), and constipation (6%). Multiple GI symptoms occurred in 14% of patients. Among affected individuals, 58.1% experienced mild symptoms, 27.9% required dose reduction for moderate symptoms, while 14% discontinued due to severe intolerance. The overall discontinuation rate was 9%, with GI side effects accounting for 6% of treatment cessations. Dose reductions were performed in 18% of patients, with 66.7% of them successfully continuing therapy post-titration.
**Conclusion:** Gastrointestinal side effects are common but generally mild to moderate with semaglutide therapy. Proactive management, including gradual dose escalation and patient education, can mitigate side effects and improve adherence. Despite initial intolerance, most patients can continue therapy with appropriate interventions.
**Recommendations:** Routine counseling, slow titration schedules, and early side-effect management strategies are crucial to optimize semaglutide adherence in clinical practice.
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.
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.).
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).
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.).
