搜索结果：The lancet. Diabetes & endocrinology

Friedreich's ataxia is a rare, chronic, progressive, neurodegenerative condition affecting multiple organ systems, including neurological, musculoskeletal, cardiac, and endocrine systems, and is marked by low cardiopulmonary fitness. We tested the effect of exercise and NAD+ precursor supplementation with nicotinamide riboside, which have each shown benefits in animal and early clinical studies, on cardiopulmonary fitness in individuals with Friedreich's ataxia. This 12-week, outpatient, phase 2, single-site (Children's Hospital of Philadelphia, Philadelphia, PA, USA), randomised, 2&#x2008;&#xd7;&#x2008;2 factorial clinical trial recruited individuals aged 10-40 years with an ejection fraction of 45% or greater who were able to exercise. A computer-generated randomisation sequence was developed by the trial statistician. Random allocation was age-stratified (<18 years vs &#x2265;18 years) to one of four groups: placebo and no exercise with attention control (weekly phone calls; henceforth placebo only), nicotinamide riboside and no exercise with attention control (henceforth nicotinamide riboside only), placebo and exercise (exercise only), and nicotinamide riboside and exercise (combination therapy). Individualised exercise plans were developed by the exercise physiologist (three aerobic and two resistance training sessions weekly), performed at the individual's home, and overseen remotely (telephone check-ins by the physiologist). Weight-based dosing of nicotinamide riboside or placebo was 300 mg (1 capsule) for weights of 24 kg up to 48 kg, 600 mg (2 capsules) for weight 48 kg up to 72 kg, and 900 mg (3 capsules) for weights of over 72 kg. The primary outcome was change in peak VO2 (L/min) during cardiopulmonary exercise testing at 12 weeks versus baseline, and the effect of treatment group was assessed in a statistical model accounting for age (stratification variable), sex, and baseline peak VO2. Stage 1 analysis tested the difference between each active treatment versus the control group, and stage 2 analysis (if combination therapy was effective) tested the difference between combination treatment and exercise alone; family-wise type 1 error was maintained <0&#xb7;05. Analyses were by intention-to-treat. Adverse events were recorded systematically. This trial is registered with ClinicalTrials.gov (NCT04192136) and is complete. Between Sept 3, 2020, and April 23, 2025, we enrolled 74 individuals, of whom 66 met the eligibility criteria and were randomly allocated to the four study groups. All participants completed the study. 33 (50%) were children (aged 10-17 years) and 33 (50%) were adults (aged &#x2265;18 years); 37 (56%) were male and 29 (44%) were female. Least mean squares for the change in peak VO2 in L/min were -0&#xb7;05 (95% CI -0&#xb7;16 to 0&#xb7;06) for the 17 participants in the control group; 0&#xb7;06 (-0&#xb7;05 to 0&#xb7;17) for the 17 participants in the nicotinamide riboside and no exercise group; 0&#xb7;11 (0&#xb7;00 to 0&#xb7;22) for the 16 participants in the placebo and exercise group; and 0&#xb7;16 (0&#xb7;05 to 0&#xb7;27) for the 16 participants in the nicotinamide riboside and exercise group. Differences between active treatment and the control group were 0&#xb7;10 (95% CI -0&#xb7;05 to 0&#xb7;26; padjusted=0&#xb7;188) for nicotinamide riboside and no exercise; 0&#xb7;16 (0&#xb7;00 to 0&#xb7;31; padjusted=0&#xb7;103) for placebo and exercise; and 0&#xb7;21 (0&#xb7;05 to 0&#xb7;36; padjusted=0&#xb7;0299) for nicotinamide riboside and exercise in combination. Combination therapy was not statistically different from exercise alone (difference -0&#xb7;05 ([95% CI -0&#xb7;10 to 0&#xb7;21]; p=0&#xb7;49). Adverse events were all mild or moderate, and included gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes. At least one moderate adverse event of interest in these categories was reported by seven (41%) participants in the control group; six (35%) in the nicotinamide riboside and no exercise group; three (19%) in the placebo and exercise group; and four (25%) in the nicotinamide plus exercise group. The combination of nicotinamide riboside plus exercise for 12 weeks was safe and increased cardiopulmonary fitness in children and adults with Friedreich's ataxia. Longer studies are needed to establish whether adding nicotinamide riboside to exercise could be considered as part of a long-term, comprehensive treatment approach. US National Institutes of Health and Friedreich's Ataxia Research Alliance.

Better evaluation of the contribution of the main diseases, injuries, and risk factors for mortality and life expectancy is crucial for more efficient policy making at the national and subnational levels in Iran. The aim of this study is to assess the effect of emerging causes of mortality on health, specifically COVID-19, which can help policy makers implement preventive measures in similar situations. In this systematic analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we present estimates of cause-specific mortality at the national and subnational levels in Iran from 1990 to 2023. New to this iteration of GBD, we present a decomposition analysis of the contribution of specific causes of death to net gain or loss in life expectancy across 31 provinces of Iran. We used an array of data sources including censuses, vital registration, and surveys for national and subnational estimates. The two leading causes of death in Iran were ischaemic heart disease and stroke in both 1990 and 2019. However, in 2020 and 2021, the COVID-19 pandemic displaced the leading causes of death, ranking first with age-standardised mortality rates of 286&#xb7;2 deaths (95% uncertainty interval 267&#xb7;9-310&#xb7;5) per 100&#x2008;000 in 2020 and 250&#xb7;0 deaths (233&#xb7;2-272&#xb7;5) per 100&#x2008;000 in 2021. COVID-19 ranked second and tenth in 2022 and 2023, respectively. Life expectancy at birth for both sexes combined declined from 78&#xb7;0 years (77&#xb7;7-78&#xb7;1) in 2019 to 74&#xb7;3 years (74&#xb7;0-74&#xb7;4) in 2020. It steadily recovered to 78&#xb7;8 years (78&#xb7;5-79&#xb7;2) in 2023. COVID-19 was the main cause of loss in life expectancy, by 4&#xb7;19 years, between 2019 and 2020. There was a net gain of 12&#xb7;4 years in life expectancy in Iran from 1990 to 2023. The net gain at the national level can be mostly attributed to reduced mortality from ischaemic heart disease (2&#xb7;61 years), stroke (1&#xb7;63 years), neonatal disorders (1&#xb7;26 years), transport injuries (0&#xb7;88 years), and neoplasms (0&#xb7;64 years). The decline in mortality rates of major causes continued to 2023 despite the pandemic. An exception was Alzheimer's disease, which showed a 4&#xb7;0% increase in rate between 2019 and 2023 and led to a net loss of 0&#xb7;04 years in life expectancy since 1990. Diabetes led to a net loss of 0&#xb7;09 years since 1990. There were variations between provinces in terms of age-standardised rates and the net change in life expectancy before and after the COVID-19 pandemic. The COVID-19 pandemic disrupted the rising trend of life expectancy in Iran, varying across provinces. Findings show that the health-care infrastructure and policies in Iran were not efficient in controlling the pandemic in 2020 and 2021, mainly due to inadequate vaccination coverage and timeliness, specifically for vulnerable subgroups. Sanctions may have aggravated the effect of COVID-19 on loss in life expectancy of Iranians. Despite the pandemic, the declining trend in age-standardised rates for top causes of mortality has continued to 2023, leading to a full recovery of life expectancy and underscoring the ultimate resilience of Iran's health system. Gates Foundation.

In the SURPASS-CVOT trial, tirzepatide, a dual incretin agonist that targets the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, was shown to be non-inferior to dulaglutide for the primary composite cardiovascular outcome in people with type 2 diabetes and atherosclerotic cardiovascular disease. Here, we report the results of a pre-specified exploratory analysis of SURPASS-CVOT that aimed to assess major kidney events in the overall population, low-to-moderate-risk chronic kidney disease population, and high-risk chronic kidney disease population. SURPASS-CVOT was a randomised, active comparator-controlled, double-blind trial that enrolled people with type 2 diabetes and atherosclerotic cardiovascular disease at 640 sites in 30 countries. Participants aged 40 years or older with type 2 diabetes and atherosclerotic cardiovascular disease, HbA1c between 7% and 10&#xb7;5%, and a BMI of 25 kg/m2 or greater were randomly assigned 1:1 to once-weekly blinded subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1&#xb7;5 mg. Annual visits included assessment of serum creatinine, cystatin C, and urine albumin-to-creatinine ratio (UACR). High-risk chronic kidney disease was defined by an estimated glomerular filtration rate (eGFR) of 60 mL/min per 1&#xb7;73 m2 or greater and UACR greater than 300 mg/g; eGFR 45 mL/min per 1&#xb7;73 m2 to less than 60 mL/min per 1&#xb7;73 m2 and UACR greater than 30 mg/g; or eGFR less than 45 mL/min per 1&#xb7;73 m2, with eGFR calculated with the CKD-Epidemiology Collaboration serum creatinine-cystatin C equation. The primary composite kidney outcome was time to first occurrence of persistent macroalbuminuria, persistent reduction in eGFR of 50% or greater, end-stage kidney disease (eGFR <15 mL/min per 1&#xb7;73 m2 or initiation of chronic kidney replacement therapy), or death from kidney disease. Between May 29, 2020, and June 27, 2022, 16 979 participants were screened and 13 299 (2948 with high-risk chronic kidney disease) were randomly assigned. After excluding 134 participants randomly assigned in error, 6586 were assigned to tirzepatide and 6579 were assigned to dulaglutide. At baseline, 4142 (32&#xb7;0%) of 12&#x2008;954 participants had microalbuminuria and 1491 (11&#xb7;5%) of 12&#x2008;954 had macroalbuminuria, and 2928 (22&#xb7;5%) of 13&#x2008;004 had an eGFR less than 60 mL/min per 1&#xb7;73 m2. After a median follow-up of 4&#xb7;0 (IQR 3&#xb7;7-4&#xb7;4) years, the risk of the primary composite kidney outcome in the overall population was 23% lower with tirzepatide than with dulaglutide (396 [6&#xb7;0%] vs 498 [7&#xb7;6%] events, hazard ratio 0&#xb7;77 [95% CI 0&#xb7;68 to 0&#xb7;88], p=0&#xb7;0002) and was similarly reduced in those with low-to-moderate-risk chronic kidney disease (195 [4&#xb7;0%] vs 283 [5&#xb7;6%], 0&#xb7;70 [0&#xb7;58 to 0&#xb7;84], p=0&#xb7;0001) and those with high-risk chronic kidney disease (185 [12&#xb7;2%] vs 203 [14&#xb7;5%], 0&#xb7;79 [95% CI 0&#xb7;64 to 0&#xb7;96], p=0&#xb7;018). This was primarily driven by a lower rate of new-onset persistent macroalbuminuria in those with low-to-moderate-risk chronic kidney disease and a lower rate of eGFR decline in those with high-risk chronic kidney disease. Observations were consistent in all other subgroups examined. The annual rate of decline in eGFR was lower with tirzepatide than with dulaglutide in the overall population (between-group difference 0&#xb7;29 mL/min per 1&#xb7;73&#x2008;m2 [95% CI 0&#xb7;17 to 0&#xb7;41]; p<0&#xb7;0001) and in those with high-risk chronic kidney disease (0&#xb7;93 mL/min per 1&#xb7;73&#x2008;m2 [0&#xb7;65 to 1&#xb7;22], p<0&#xb7;0001). Nausea, vomiting, and diarrhoea were all more common in those receiving tirzepatide than in those receiving dulaglutide. Among people with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was associated with a reduced risk of major kidney events compared with dulaglutide, primarily driven by a reduction in new-onset macroalbuminuria in people with low-to-moderate-risk chronic kidney disease, and slowed decline in kidney function in people with high-risk chronic kidney disease. Eli Lilly and Company.

The amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide have complementary effects on glycaemic control and bodyweight. We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity. REIMAGINE 2 was a randomised, double-blind, placebo-controlled and active-controlled, parallel-group study conducted in 30 countries (trial sites included university hospitals, health-care centres, research centres, and other centres). Participants aged 18 years or older with inadequately controlled type 2 diabetes (HbA1c 7&#xb7;0-10&#xb7;5% [53-91 mmol/mol]) receiving metformin with or without an SGLT2 inhibitor, and a BMI of 25 kg/m2 or more, were randomly assigned (8:8:2:8:8:1:1) to receive once-weekly subcutaneous cagrilintide 2&#xb7;4 mg plus semaglutide 2&#xb7;4 mg (hereafter cagrilintide-semaglutide [2&#xb7;4 mg each]), semaglutide 2&#xb7;4 mg, cagrilintide 2&#xb7;4 mg, cagrilintide 1&#xb7;0 mg plus semaglutide 1&#xb7;0 mg (hereafter cagrilintide-semaglutide [1&#xb7;0 mg each]), semaglutide 1&#xb7;0 mg, or corresponding placebo for 68 weeks. Randomisation was done using a web-based system with blocked randomisation (block size 36) and stratification according to inclusion in the continuous glucose monitoring subgroup, HbA1c less than 8&#xb7;5% at screening (yes or no), and country of participation (Japan; yes or no). The study participants, investigators, and study sponsor staff were masked to treatment allocation within dose level throughout the study. The primary endpoint was change in HbA1c from baseline to week 68 with cagrilintide-semaglutide (2&#xb7;4 mg each) versus semaglutide 2&#xb7;4 mg in the full analysis set; safety was assessed in all participants who received at least one dose of study product. This study is registered with ClinicalTrials.gov (NCT06065540) and is complete. From Oct 10, 2023, to July 29, 2024, 3593 people were screened for eligibility, 2713 of whom were randomly assigned to cagrilintide-semaglutide (2&#xb7;4 mg each; n=603), semaglutide 2&#xb7;4 mg (n=605), cagrilintide 2&#xb7;4 mg (n=152), cagrilintide-semaglutide (1&#xb7;0 mg each; n=595), semaglutide 1&#xb7;0 mg (n=609), or placebo (pooled 2&#xb7;4 mg and 1&#xb7;0 mg; n=149). 1164 (42&#xb7;9%) of 2713 were female, 1549 (57&#xb7;1%) were male, and 2207 (81&#xb7;3%) were White. Of the randomly assigned participants, 2595 (95&#xb7;7%) completed the study and 2376 (87&#xb7;6%) were on treatment at week 68. Mean baseline HbA1c was 8&#xb7;2% (SD 0&#xb7;9). For the primary endpoint using the efficacy estimand, mean HbA1c change was significantly greater with cagrilintide-semaglutide (2&#xb7;4 mg each) versus semaglutide 2&#xb7;4 mg (-1&#xb7;91 percentage points [SE 0&#xb7;04] vs -1&#xb7;75 percentage points [0&#xb7;04]; estimated treatment difference -0&#xb7;16 percentage points [95% CI -0&#xb7;27 to -0&#xb7;05]; p=0&#xb7;0035). Adverse events were reported in 524 (86&#xb7;9%) of 603 participants in the cagrilintide-semaglutide (2&#xb7;4 mg each) group, 491 (81&#xb7;2%) of 605 in the semaglutide 2&#xb7;4 mg group, 125 (82&#xb7;2%) of 152 in the cagrilintide 2&#xb7;4 mg group, 485 (81&#xb7;6%) of 594 in the cagrilintide-semaglutide (1&#xb7;0 mg each) group, 477 (78&#xb7;5%) of 608 in the semaglutide 1&#xb7;0 mg group, and 105 (70&#xb7;5%) of 149 in the placebo group. The most common adverse events in the active treatment groups were gastrointestinal disorders. Cagrilintide-semaglutide (2&#xb7;4 mg each) was superior to semaglutide 2&#xb7;4 mg in reducing HbA1c in participants with type 2 diabetes receiving metformin with or without an SGLT2 inhibitor. The safety profile of cagrilintide-semaglutide was consistent with the GLP-1 receptor agonist class and previous safety data for cagrilintide. These findings support the added benefit of cagrilintide-semaglutide (2&#xb7;4 mg each) versus semaglutide 2&#xb7;4 mg for glycaemic control. Novo Nordisk.

Human insulins including intermediate-acting human insulin (ie, isophane insulin) remain widely used for children and young people with type 1 diabetes, especially in low-resource settings. We aimed to assess whether insulin glargine reduces the risk of serious hypoglycaemia or improves time in range when compared against human isophane insulin among children and young people with type 1 diabetes in low-income and middle-income countries. HumAn-1 was a randomised, open label, parallel-group trial conducted at one site in Bangladesh and two sites in Tanzania. Participants aged 7-25 years with a clinical diagnosis of type 1 diabetes were randomly assigned (1:1) to receive insulin glargine (Basaglar, Eli Lilly, Indianapolis, IN, USA) or to continue usual care (ie, isophane insulin or premixed 70/30) for basal insulin coverage. Insulin glargine was administered subcutaneously, usually before bedtime. Isophane insulin or premixed 70/30 was administered once or twice per day, at the discretion of the treating clinician. Doses varied by participant. Randomisation was performed centrally and stratified by site. The coprimary outcomes, measured using blinded continuous glucose monitors at 6 months, were time in very low range (<3 mmol/L or 54 mg/dL) and time in target range (3&#xb7;9 mmol/L to 10&#xb7;0 mmol/L or 70 mg/dL to 180 mg/dL). The primary analysis was done for the overall intention-to-treat (ITT) population. The safety population included all participants who received at least one dose of study treatment and was analysed according to the treatment actually received. In this study, all participants received at least one dose of their randomly assigned intervention (ie, the ITT population is the same as the safety population). This trial is registered with ClinicalTrials.gov (NCT05614089). Between March 1 and Dec 19, 2023, we assessed 426 children and young people for eligibility. Of these, 400 (94%) were randomly assigned to receive either glargine (n=199) or usual care (n=201). At 6 months, the mean time in very low range was 3&#xb7;6% (SD 5&#xb7;6) in the glargine group and 3&#xb7;4% (4&#xb7;3) in the usual care group. After adjustment for prespecified baseline covariates, the adjusted mean difference was 0&#xb7;22% (97&#xb7;5% CI -0&#xb7;83 to 1&#xb7;27, p=0&#xb7;63). The mean time in target range was 40&#xb7;5% (SD 18&#xb7;4) for glargine and 38&#xb7;1% (18&#xb7;1) for usual care. The adjusted mean difference was 0&#xb7;55% (97&#xb7;5% CI -2&#xb7;78 to 3&#xb7;89, p=0&#xb7;71). Serious adverse events (SAEs) were uncommon, with a total of six SAEs among five (3%) of 199 participants in the glargine group and 14 SAEs among 13 (6%) of 201 participants in the usual care group. At 6 months, children and young people with type 1 diabetes living in low-resource settings randomly assigned to glargine had no evidence of effects on time in very low range and time in target range compared with those assigned to usual care. The Leona M. and Harry B. Helmsley Charitable Trust.

Enteric infectious diseases claim more than 1 million lives annually and are among the top ten causes of death in children younger than 5 years. Remarkable global investment has been dedicated to enteric infectious disease prevention and control; however, the shifting global health landscape is testing the continuance of progress. To evaluate the current status and guide future interventions, we present the latest epidemiological estimates of enteric infectious diseases from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 and assess progress towards the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) mortality target of fewer than 20 deaths per 100&#x2008;000 children younger than 5 years by 2025. We quantified the incidence, mortality, and disability-adjusted life-years (DALYs) of enteric infectious diseases by age, sex, and year across 204 countries and territories from 1990 to 2023. In GBD 2023, the following were considered under the category of enteric infectious diseases: diarrhoeal diseases, enteric fever (typhoid and paratyphoid), invasive non-typhoidal Salmonella spp (iNTS) infections, and other intestinal infectious diseases. We also examined 15 aetiologies contributing to diarrhoeal diseases. Incidence and prevalence were estimated with DisMod-MR (version 2.1), a Bayesian meta-regression tool, drawing on data from systematic reviews, population-based surveys, claims data, and hospital sources. Cause-specific mortality was modelled with Cause of Death Ensemble Modelling based on data from sources including vital registration, mortality surveillance, verbal autopsy, and minimally invasive tissue sampling. Years of life lost and years lived with disability were computed and combined to derive DALYs. For aetiology-specific estimation, population-attributable fractions (PAFs) for 15 pathogens were derived with a counterfactual framework. Point estimates and 95% uncertainty intervals (UIs) were generated from 250 draws from the posterior distribution. In 2023, enteric infectious diseases resulted in an estimated 1&#xb7;27 million (95% UI 0&#xb7;963-1&#xb7;68) deaths globally, declining from 3&#xb7;69 million (3&#xb7;04-4&#xb7;56) in 1990. The global age-standardised mortality rate (ASMR) decreased from 74&#xb7;1 (62&#xb7;0-92&#xb7;9) per 100&#x2008;000 population to 16&#xb7;4 (12&#xb7;6-21&#xb7;3) per 100&#x2008;000 population during the same period. Diarrhoeal diseases accounted for most deaths in 2023 (1&#xb7;11 million [0&#xb7;811-1&#xb7;54]), followed by enteric fever and iNTS. South Asia and sub-Saharan Africa remained the most affected regions in 2023, with 599&#x2008;000 (441&#x2008;000-882&#x2008;000) and 501&#x2008;000 (373&#x2008;000-648&#x2008;000) deaths due to enteric infectious diseases, respectively, predominantly from diarrhoeal disease. Rotavirus was the leading cause of all-age diarrhoeal disease deaths (PAF 16&#xb7;3% [12&#xb7;0-21&#xb7;5]), followed by norovirus (10&#xb7;2% [2&#xb7;4-17&#xb7;0]) and Shigella spp (9&#xb7;3% [5&#xb7;4-15&#xb7;2]). Among children younger than 5 years, PAFs of deaths due to diarrhoeal diseases were 40&#xb7;2% (32&#xb7;5-48&#xb7;5) for rotavirus, 24&#xb7;0% (15&#xb7;1-36&#xb7;7) for Shigella spp, and 23&#xb7;4% (13&#xb7;7-34&#xb7;3) for adenovirus. Across 204 countries and territories, 141 met the GAPPD mortality target in 2023. The driving aetiologies among countries that did not meet the target in 2023 varied slightly by GBD super-region, but the highest or second-highest number of deaths in children younger than 5 years were consistently attributed to rotavirus. Astrovirus and sapovirus, newly included in GBD 2023, were responsible for 24&#x2008;600 (6290-49&#x2008;000) and 18&#x2008;800 (4650-44&#x2008;400) deaths, respectively, in 2023, mainly in children younger than 5 years. Our findings show that mortality and ASMRs of enteric infectious diseases declined substantially between 1990 and 2023. This decline is consistent with the expansion of public health measures and broader socioeconomic development. However, the burden in 2023 remains considerably high, with the highest mortality concentrated in sub-Saharan Africa and south Asia. Considering that more than a quarter of all countries had yet to meet the GAPPD mortality target in 2023, sustained efforts are needed to address the persistent burden in affected countries and to adapt to the changing global health landscape. Gates Foundation.

The combination of cagrilintide and semaglutide has been shown in global studies to induce reductions in bodyweight. We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2&#xb7;4 mg and semaglutide 2&#xb7;4 mg versus semaglutide 2&#xb7;4 mg for weight management in an east Asian population. This double-blind, parallel-group, phase 3a trial (REDEFINE 5) was conducted across 21 sites (community, hospital) in Japan and one site in Taiwan. We included participants aged at least 18 years with a BMI of at least 27 kg/m2 and at least two obesity-related complications, or with a BMI of at least 35 kg/m2 and at least one obesity-related complication (per the Japan Society for the Study of Obesity guidelines), with or without type 2 diabetes. Participants were randomly assigned (1:1) to once-weekly subcutaneous injections of cagrilintide-semaglutide or semaglutide (both escalated to 2&#xb7;4 mg), plus lifestyle intervention, for 68 weeks. Randomisation was done centrally using an interactive web response system and stratified according to planned CT scan, BMI of at least 35 kg/m2, and type 2 diabetes status. Participants, site staff, investigators, and study funder were all masked to active study treatments. The primary endpoint was relative change in bodyweight from baseline to week 68. Efficacy analyses were done in all participants who underwent randomisation, using the trial product estimand (ie, assuming the treatment was taken as intended, regardless of dose) as the primary estimand. Missing data at week 68 were imputed. Safety analyses were done in all participants who underwent randomisation and received at least one dose of trial product. This trial is registered with ClinicalTrials.gov (NCT05813925) and is complete. Between April 3, 2023, and Sept 15, 2023, we screened 355 individuals; 331 were randomly assigned to cagrilintide-semaglutide (n=164) or semaglutide (n=167). 226 (68%) participants were male and 105 (32%) were female; 80 (24%) had type 2 diabetes. 17 (10%) participants discontinued cagrilintide-semaglutide and ten (6%) discontinued semaglutide. The estimated mean change in bodyweight from baseline to week 68 was -18&#xb7;4% (SE 0&#xb7;7) in the cagrilintide-semaglutide group versus -11&#xb7;9% (0&#xb7;7) in the semaglutide group (estimated treatment difference [ETD] -6&#xb7;5 percentage points [95% CI -8&#xb7;4 to -4&#xb7;6]; p<0&#xb7;0001). Adverse events were reported by 143 (87%) of 164 participants in the cagrilintide-semaglutide group and 141 (84%) of 167 in the semaglutide group, the most common of which were gastrointestinal disorders (87 [53%] of 164 participants in the cagrilintide-semaglutide group vs 85 [51%] of 167 in the semaglutide group). One death was reported in the semaglutide 2&#xb7;4 mg group, which was not judged to be treatment related by the investigator. These findings support the efficacy and safety of cagrilintide-semaglutide for weight management in individuals from east Asia with overweight or obesity, with or without type 2 diabetes. Novo Nordisk. For the Japanese and Mandarin translations of the abstract see Supplementary Materials section.

Intermittent fasting is now the third most commonly practiced diet in the USA. Yet, despite more than 225 clinical trials-including nearly 40 in patients with diabetes or prediabetes-intermittent fasting has not yet been recommended as part of the American Diabetes Association (ADA) Standards of Care or the International Diabetes Federation (IDF) Global Clinical Practice Recommendations. In this Personal View, we start by synthesising evidence from trials in patients with type 2 diabetes, type 1 diabetes, prediabetes, and gestational diabetes. In adults with type 2 diabetes, diverse types of intermittent fasting, such as time-restricted eating, the 5:2 diet, and the fasting mimicking diet, reduce HbA1c (typically by 0&#xb7;3-1&#xb7;2%), fasting glucose, 24-h glucose, and bodyweight relative to usual eating patterns. Moreover, intermittent fasting is as effective as calorie restriction for improving glycaemic control and does not increase the risk of hypoglycaemia when medications are adjusted using simple rules. Intermittent fasting might also reduce glycaemia in adults with prediabetes, whereas there are insufficient data to recommend its use in people with type 1 or gestational diabetes. Therefore, we argue that the evidence base has sufficiently matured to warrant including intermittent fasting in clinical practice guidelines as one of several evidence-based lifestyle options for type 2 diabetes. We also provide practical guidance for clinicians on prescribing intermittent fasting and safely managing people with diabetes.

To assess the prevalence of obesity and related health conditions among children and adolescents aged 7-17 in the Xinjiang Uygur Autonomous Region from 2016 to 2017. The data were sourced from the 2016-2017 China Children and Lactating Mothers Nutrition and Health Surveillance Program. A total of 1112 individuals were surveyed in this study, with 754 from urban schools and 358 from rural schools. Among them, boys accounted for 49.01% and girls for 50.99%; students aged 7-11 years comprised 49.01%, and those aged 12-17 years comprised 50.99%. Obesity, central obesity, hypertension, diabetes, and dyslipidemia were defined according to the following criteria: "Screening for Overweight and Obesity Among School-Age Children and Adolescents(WS/T 586-2018)", "Threshold for High Waist Circumference Screening in Children and Adolescents Aged 7-18 Years(WS/T 611-2018)", "Blood Pressure Reference for Hypertension Screening in Chinese Children and Adolescents Aged 7-18 Years", "Guidelines for the Diagnosis and Treatment of Type 2 Diabetes in Children(2025)", and "Chinese Guidelines for Lipid Management(2023)". Referring to the clinical obesity definition and diagnostic criteria framework proposed by the Lancet Diabetes &amp; Endocrinology Commission, and considering the availability of indicators in this study, criteria for defining subclinical obesity and clinical obesity in children and adolescents were established. The general obesity rate was 3.96%, and the central obesity rate was 9.44%. According to the clinical obesity criteria, the subclinical obesity rate was 2.34%, and the clinical obesity rate was 0.45%. The general obesity rate, central obesity rate, and clinical obesity rate were higher among urban school students compared to rural school students, with all differences being statistically significant(P<0.05). The general obesity rate was higher in boys than in girls(P<0.05), while no statistically significant difference was observed in central obesity rate between genders. The obesity rate was higher in the 7-11-year-old group than in the 12-17-year-old group, whereas the central obesity rate was lower in the 7-11-year-old group compared to the 12-17-year-old group; both differences were statistically significant(P<0.05). In both boys and girls, a trend of increasing cental obesity rate and dyslipidemia rate was observed with increasing BMI(P<0.05). No association was found between BMI and hypertension. The prevalence of obesity among children and adolescents in the Xinjiang Uygur Autonomous Region shows population-specific differences and is associated with increased health risks.

Road injuries are a leading cause of mortality and morbidity worldwide. Years of international efforts have aimed to strengthen policy engagement, including the 2020 UN General Assembly's proclamation of the Second Decade of Action for Road Safety (2021-30), targeting a 50% reduction in road traffic deaths and serious injuries by 2030. The aim of this study is to provide estimates to monitor progress and identify intervention gaps. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2023, we estimated incidence, mortality, and morbidity of road injuries for 204 countries and territories from 1990 to 2023. Four road injury types and 47 nature-of-injury categories were examined. Morbidity and mortality data from clinical records, vital registration, and police reports were harmonised using meta-analytic techniques to ensure consistency and correct for systematic bias. Incidence was modelled with the meta-regression tool Disease Modelling-Meta-Regression version 2.1 and cause-specific mortality with the Cause of Death Ensemble model, both incorporating location-specific covariates to support interpolation. Years of life lived with disability (YLDs) were estimated from the prevalence and severity of the nature of road injury, and years of life lost (YLLs) from the number of cause-specific deaths multiplied by the standard life expectancy at the age of death. Disability-adjusted life-years (DALYs) were the sum of YLLs and YLDs. All metrics were calculated with 95% uncertainty intervals (UIs). In 2023, there were 50&#xb7;9 million (95% UI 46&#xb7;1-56&#xb7;1) road injury incident cases, 1&#xb7;34 million (1&#xb7;04-1&#xb7;58) deaths, and 75&#xb7;3 million (59&#xb7;8-89&#xb7;2) DALYs globally. Road injuries were the leading global cause of death among males aged 10-39 years. Between 1990 and 2023, age-standardised incidence decreased by 38&#xb7;3% (95% UI 36&#xb7;9-39&#xb7;7) and mortality decreased by 32&#xb7;3% (6&#xb7;1-49&#xb7;0), but progress varied widely by World Bank income group. Mortality in low-income countries (43&#xb7;8 [95% UI 31&#xb7;7-56&#xb7;0] deaths per 100&#x2008;000 population) was approximately six times higher than in high-income countries (7&#xb7;5 [7&#xb7;1-7&#xb7;9] deaths per 100&#x2008;000), despite the high-income countries showing the highest age-standardised incidence rates (858&#xb7;1 [95% UI 781&#xb7;9-947&#xb7;1] cases per 100&#x2008;000). In the past decade, many countries achieved notable reductions in road injuries, but others, including Ghana and the USA, saw increases. More severe injuries tended to occur in low-income and middle-income countries. Although global incidence, mortality, and DALY rates from road injuries have declined, progress remains uneven, with pronounced disparities across income groups reflecting systemic inadequacies in infrastructure, vehicle standards, enforcement, and post-crash care. Strengthening emergency response, improving road design, enforcing safety measures, and adapting policies to the evolving demographics remain essential. Gates Foundation.

Cagrilintide-semaglutide (CagriSema) is a novel, once-weekly combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide. We aimed to assess the efficacy and safety of cagrilintide-semaglutide for people with type 2 diabetes inadequately controlled with diet and exercise. REIMAGINE 1 was a randomised, double-blind, parallel-group, phase 3a study carried out at 42 sites (study sites included university hospitals, health-care centres, research centres, and other centres) in six countries. Adults aged 18 years or older with type 2 diabetes inadequately controlled with diet and exercise were randomly assigned (2:1:2:1) to receive once-weekly subcutaneous cagrilintide 2&#xb7;4 mg plus semaglutide 2&#xb7;4 mg (cagrilintide-semaglutide [2&#xb7;4 mg each]), placebo 2&#xb7;4 mg plus 2&#xb7;4 mg, cagrilintide 1&#xb7;0 mg plus semaglutide 1&#xb7;0 mg (cagrilintide-semaglutide [1&#xb7;0 mg each]), or placebo 1&#xb7;0 mg plus 1&#xb7;0 mg for 40 weeks. Randomisation was done using a web-based system with a block size of six and stratified according to HbA1c less than 8&#xb7;5% at screening and participation in the MRI substudy. Participants, care providers, investigators, and outcome assessors were masked within dose level and all participants received visually identical injections to maintain masking throughout the study. The primary endpoint was change in HbA1c from baseline to week 40 in the full analysis set; safety was assessed in all participants who received at least one dose of the trial product. Change in bodyweight from baseline to week 40 was a prespecified secondary endpoint. This study is registered with ClinicalTrials.gov, NCT06323174, and is complete. Between March 19 and Dec 5, 2024, 294 people were screened for eligibility, 189 of whom were enrolled and randomly assigned to cagrilintide-semaglutide (2&#xb7;4 mg each; n=62), cagrilintide-semaglutide (1&#xb7;0 mg each; n=63), or placebo (n=64). 103 (54%) of 189 were male, 86 (46%) were female, 147 (78%) were White, and 26 (14%) were Asian. Baseline mean HbA1c was 7&#xb7;8% (SD 0&#xb7;7) and BMI was 35&#xb7;2 kg/m2 (7&#xb7;4). Using the efficacy estimand, the estimated mean change in HbA1c after 40 weeks was -1&#xb7;8 percentage points (SE 0&#xb7;1) with cagrilintide-semaglutide (2&#xb7;4 mg each), -1&#xb7;5 percentage points (0&#xb7;1) with cagrilintide-semaglutide (1&#xb7;0 mg each), and -0&#xb7;1 percentage points (0&#xb7;2) with placebo. This corresponded to an estimated treatment difference of -1&#xb7;7 percentage points (95% CI -2&#xb7;0 to -1&#xb7;3; p<0&#xb7;0001) for cagrilintide-semaglutide (2&#xb7;4 mg each) versus placebo and -1&#xb7;3 percentage points (-1&#xb7;8 to -0&#xb7;9; p<0&#xb7;0001) for cagrilintide-semaglutide (1&#xb7;0 mg each) versus placebo. Cagrilintide-semaglutide was superior to placebo with respect to estimated mean relative change in bodyweight from baseline to week 40 for cagrilintide-semaglutide (2&#xb7;4 mg each; -13&#xb7;8% [SE 1&#xb7;0]) versus placebo (-1&#xb7;4% [0&#xb7;7]; estimated treatment difference -12&#xb7;4 percentage points [95% CI -14&#xb7;7 to -10&#xb7;1]; p<0&#xb7;0001) and cagrilintide-semaglutide (1&#xb7;0 mg each; -11&#xb7;8% [1&#xb7;0]) versus placebo (-1&#xb7;4% [0&#xb7;7]; estimated treatment difference -10&#xb7;4 percentage points [-12&#xb7;9 to -8&#xb7;0]; p<0&#xb7;0001). Adverse events were reported by 49 (79%) of 62 participants in the cagrilintide-semaglutide (2&#xb7;4 mg each) group, 47 (75%) of 63 in the cagrilintide-semaglutide (1&#xb7;0 mg each) group, and 42 (66%) of 64 in the placebo group. Most adverse events were mild or moderate and gastrointestinal related. In a population of people with early-stage type 2 diabetes inadequately controlled with diet and exercise, cagrilintide-semaglutide (2&#xb7;4 mg each and 1&#xb7;0 mg each) was superior to placebo in reducing HbA1c. The safety profile was consistent with the GLP-1 receptor agonist class and previous safety data for cagrilintide. These findings support cagrilintide-semaglutide as a potential novel and effective therapeutic intervention for people with early-stage type 2 diabetes. Novo Nordisk.

The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials. Participants with CKD (FLOW) or atherosclerotic cardiovascular disease (SELECT and SOUL) were randomly assigned semaglutide (once-weekly subcutaneous 1&#xb7;0 mg [FLOW], once-weekly subcutaneous 2&#xb7;4 mg [SELECT], or once-daily oral 14 mg [SOUL]) or matching placebo, added to standard of care. The primary outcome in this pooled analysis was time to first occurrence of a kidney composite, defined as onset of persistent 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure (persistent eGFR <15 mL/min per 1&#xb7;73 m2, or initiation of kidney replacement therapy), kidney-related death, or cardiovascular-related death. Safety was also assessed. The pooled participants from the trials (N=30&#x2008;787) had a mean follow-up of 39&#xb7;5-47&#xb7;5 months. Among participants assigned to semaglutide, 973 first events of the primary kidney composite occurred compared with 1134 first events for placebo (hazard ratio [HR] 0&#xb7;84 [95% CI 0&#xb7;77-0&#xb7;91]). First events of a narrower secondary kidney composite (excluding cardiovascular-related death from the primary outcome) were also reduced with semaglutide versus placebo (347 and 416, respectively; 0&#xb7;80 [0&#xb7;69-0&#xb7;92]). Safety outcomes were overall similar between groups, and in line with other GLP-1 receptor agonist trials. Serious adverse events were numberically lower with semaglutide than with placebo. Data pooled from three large phase 3 trials suggest that semaglutide reduces the risk of major kidney outcomes in a broad population with cardio-kidney-metabolic disease while having a favourable risk-benefit profile. In people with cardio-kidney-metabolic disease, with and without diabetes, semaglutide (oral or injected) prevents kidney-related and cardiovascular complications and induces adverse events in line with GLP-1 receptor agonist studies, regardless of baseline characteristics within the cardio-kidney-metabolic spectrum. This was a participant-level analysis conducted in a large database of three randomised controlled trials of similar design and examining the same treatment, but there were some differences in participants' baseline characteristics, and in the dose and route of administration of treatment. This pooled analysis adds evidence for the benefit of GLP-1 receptor agonists in general, and semaglutide in particular, in a broad population of people with cardio-kidney-metabolic disease, suggesting that the benefit of semaglutide might not be explained only by its glycaemic effects, weight-management effects, or both. Novo Nordisk.

Vascular complications of Type 2 diabetes (T2D) significantly contribute to its morbidity and mortality. Identifying robust biomarkers is critical for improving risk prediction, understanding disease mechanisms, and guiding targeted therapies. Fasting plasma samples from a subset of 542 participants in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial were subjected to mass spectrometry. Participants were divided into groups for analysis based on presence of microvascular and/or macrovascular complications, and time of its occurrence (history of at baseline or during trial follow-up). Random Forest algorithm was applied to identify potential novel protein biomarkers. Gene ontology analysis was performed to determine the biological pathways and processes linked to these proteins. Fifty proteins associated with type 2 diabetes vascular complications were identified with 14 uniquely associated with microvascular complications, 13 with macrovascular and 23 common for both. Pathway analysis revealed seven main pathways underlying type 2 diabetes vascular complications including platelet degranulation and extracellular matrix interactions. Gene ontology analysis showed that these proteins functioned predominantly in the extracellular matrix and were involved in biological processes related to blood coagulation and lipoproteins remodelling. This study provides insights into the molecular mechanisms underlying type 2 diabetes vascular complications, highlighting novel protein biomarkers and their key biological pathways. These findings support the development of precision medicine strategies for risk prediction and targeted interventions in type 2 diabetes management. Further clinical validation of these biomarkers is warranted to confirm their potential utility in improving patient outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for managing type 2 diabetes and obesity. As their clinical applications expand, interest in their safety and adverse effects has grown. This study provides a comprehensive bibliometric analysis of global research trends, collaboration patterns, and thematic evolution on GLP-1RA-related adverse effects from 2006 to 2025. This study is a bibliometric analysis. Data were extracted from the Scopus database and analyzed using Bibliometrix (R package) and VOS viewer. Indicators assessed included publication and citation metrics, institutional productivity, and keyword co-occurrence and mapping. Correlations were evaluated using Pearson and Spearman tests, and the Durbin-Watson statistic was applied to assess the independence of residuals. A total of 1075 articles published in 389 journals were identified, authored by 6068 researchers across 85 countries. The annual growth rate was 32.06%, with no single-author papers and 34.23% international co-authorship, indicating strong global collaboration. The United States (30.5%), the United Kingdom (10.6%), and Denmark (7.8%) led in publication output and total citations. Institutional analysis identified Novo Nordisk A/S (60 papers, 11&#x2009;207 citations) and Eli Lilly & Co. (45 papers, 9948 citations) as the most influential contributors. Diabetes, Obesity and Metabolism published the most articles (n&#x2009;=&#x2009;106), followed by Diabetes Care and The Lancet Diabetes & Endocrinology. Significant correlations were found between article count and h-index (r&#x2009;=&#x2009;.677, P&#x2009;<&#x2009;.001) and total citations (r&#x2009;=&#x2009;.779, P&#x2009;<&#x2009;.001). Keyword analysis revealed 2 main thematic clusters-one pharmacological (drug safety, efficacy, liraglutide, semaglutide) and 1 clinical (human, male, female, adult)-with an emerging focus on population-specific safety since 2021. Research on GLP-1RA-related adverse effects has expanded rapidly, shaped by strong international collaboration and industry-academic partnerships. Future efforts should prioritize balanced global participation, real-world safety data, and mechanistic insights to inform clinical practice and pharmacovigilance.

Obesity is a chronic, adiposity-based disease with increasing global prevalence and multiple, competing definitions. Traditionally, body mass index (BMI) has been the primary tool for diagnosis, although it does not completely reflect adipose tissue mass, distribution or associated organ dysfunction. In the past 2 years, major professional societies (including the European Association for the Study of Obesity (EASO), the Lancet Diabetes & Endocrinology Commission, the American College of Cardiology (ACC) and the American Association of Clinical Endocrinologists (AACE)) have advanced new diagnostic frameworks that move beyond BMI to incorporate multimodal assessment of adiposity and its clinical consequences. By integrating anthropometric precision with standardized complication assessment, these frameworks support earlier identification of risk, improved prognostication and more equitable, patient-centred obesity care. However, the way in which the new guidelines should be integrated into routine clinical care remains unclear. Here we synthesize current evidence across anthropometric measures of obesity and body composition imaging. We clarify the diagnostic performance, limitations and relevance of these measures across diverse populations. We compare areas of convergence and divergence among the new guidelines, particularly the shift towards defining clinical obesity on&#xa0;the basis of both excess adiposity and evidence of organ dysfunction or functional impairment.

Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Recent reductions in global health funding have threatened TB control, making comprehensive assessment of TB, HIV-related TB, and drug-resistant TB burdens before these disruptions essential for shaping effective responses. The WHO End TB Strategy sets targets of a 95% reduction in TB deaths and a 90% reduction in TB incidence between 2015 and 2035. Using results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, this study aims to assess the burden of TB and multidrug-resistant TB (MDR-TB) across 204 countries and territories, and to evaluate progress towards the WHO End TB incidence and mortality targets. We quantified TB mortality using the Cause of Death Ensemble modelling platform with global vital registration, surveillance, verbal autopsy, and minimally invasive tissue sampling data. For TB morbidity estimation, we simultaneously modelled incidence, prevalence, and mortality by age and sex using DisMod-MR 2.1. A population attributable fraction (PAF) approach was applied to stratify morbidity and mortality estimates by HIV and drug-resistance status. We also calculated disability-adjusted life-years (DALYs) as the sum of years of life lost and years lived with disability. For the risk factor analysis, a comparative risk assessment framework was used and PAFs were derived for alcohol use, smoking, and high fasting plasma glucose to determine the proportion of TB burden associated with these risk factors. In 2023, there were an estimated 9&#xb7;11 million (95% uncertainty interval 8&#xb7;04-10&#xb7;3) incident cases of all-form TB, 1&#xb7;22 million (0&#xb7;98-1&#xb7;49) deaths, and 54&#xb7;6 million (43&#xb7;8-65&#xb7;5) DALYs globally. HIV-related TB comprised 781&#x2008;000 (690&#x2008;000-879&#x2008;000) incident cases and 210&#x2008;000 (142&#x2008;000-279&#x2008;000) deaths, contributing 11&#xb7;0 million (7&#xb7;56-14&#xb7;3) DALYs. MDR-TB accounted for 466&#x2008;000 (198&#x2008;000-1&#x2008;080&#x2008;000) incident cases, 102&#x2008;000 (31&#x2008;700-238&#x2008;000) deaths, and 3&#xb7;96 million (1&#xb7;31-9&#xb7;01) DALYs. From 2015 to 2023, global all-form TB incidence rates declined by 19&#xb7;2% (17&#xb7;8-20&#xb7;5) and deaths declined by 22&#xb7;6% (4&#xb7;7-35&#xb7;7); declines were larger for drug-susceptible TB than for MDR-TB. Sub-Saharan Africa and south Asia had the highest mortality burdens in 2023; reductions in all-form TB incidence and mortality were uneven between 2000 and 2023, with limited progress in both measures in Latin America and the Caribbean. Removing smoking, alcohol use, and high fasting plasma glucose would reduce global TB deaths to 768&#x2008;000 (592&#x2008;000-970&#x2008;000) and DALYs to 34&#xb7;9 million (27&#xb7;8-43&#xb7;8) in 2023; MDR-TB deaths would decrease to 77&#x2008;200 (23&#x2008;400-183&#x2008;000) and DALYs to 3&#xb7;12 million (1&#xb7;03-7&#xb7;29). Global progress towards WHO End TB targets is disparate and fragile. Although many regions achieved meaningful gains, others have stagnated in recent years. The complexity of TB prevention is amplified by divergent MDR-TB trends, the persistent burden of HIV, and growing exposure to modifiable risk factors. Recent volatility in global health financing threatens to further destabilise this vulnerable epidemiological landscape; concerted action is urgently needed to temper disruptions and preserve progress. Gates Foundation.

This study examined the association of hypertension and obesity with incident heart failure (HF) and the feasibility of the clinical obesity definition proposed by The Lancet Diabetes & Endocrinology Commission. Data from the UK Biobank (n&#x2009;=&#x2009;444,754) and Tongzhou Cohort (n&#x2009;=&#x2009;10,459) were analyzed. Hypertension was defined as physician-diagnosed hypertension, blood pressure &#x2265;140/90&#x2009;mmHg, or antihypertensive treatment. Obesity was assessed as BMI-defined obesity, central obesity, a combined "BMI+central" anthropometric phenotype, and clinical obesity, defined as excess adiposity with obesity-related organ dysfunction and/or functional limitation. Participants were classified into four groups: neither hypertension nor obesity, obesity only, hypertension only, and coexisting hypertension and obesity. Kaplan-Meier curves and multivariable Cox models were used to estimate HF risk, and joint effects of elevated blood pressure and pre-obesity were evaluated. The two cohorts had similar mean ages: 58.15&#x2009;&#xb1;&#x2009;6.84 years in the UK Biobank and 59.42&#x2009;&#xb1;&#x2009;6.29 years in Tongzhou Cohort. Depending on the obesity definition, the prevalence of coexisting hypertension and obesity ranged from 18.0% to 25.9% in the UK Biobank and 23.1% to 37.3% in Tongzhou Cohort. Across BMI-defined obesity, central obesity, the combined "BMI+central" phenotype, and, in the UK Biobank, clinical obesity, coexistence of hypertension and obesity was consistently associated with the highest HF risk. Among individuals without hypertension or obesity, the combination of elevated blood pressure and pre-obesity was associated with increased risk of HF. Coexisting hypertension and obesity are associated with the highest HF risk across multiple adiposity definitions, and excess risk is evident even at preclinical stages.

The prevalence of type 2 diabetes is rising rapidly across sub-Saharan Africa; however, its epidemiology, clinical phenotypes, and underlying mechanisms remain insufficiently characterised. This first paper in a Series on diabetes in sub-Saharan Africa synthesises current evidence on the burden, distribution, and determinants of diabetes, including emerging phenotypes and the roles of early life adversity, psychosocial stress, and interactions with infectious disease. We also identify major gaps in surveillance systems, research capacity, prevention, and clinical management across the region. Sub-Saharan Africa is experiencing one of the fastest global increases in diabetes, with the highest proportion of undiagnosed cases and a projected steep rise in intermediate hyperglycaemia and diabetes by 2050. Urbanisation, ageing, obesity, and lifestyle transitions are major contributors; however, a substantial proportion of type 2 diabetes occurs in lean individuals (BMI <25 kg/m2), particularly in rural settings, suggesting distinct metabolic and developmental pathways not captured by models derived from high-income countries. Bidirectional interactions between diabetes and malaria, tuberculosis, HIV, or COVID-19 make disease trajectories complex. Persistent gaps in surveillance, a reliance on modelled estimates, low genomic representation, and constrained access to modern diabetes medications hinder progress. Strengthening health system capacity, improving data infrastructure, and investing in regionally driven research are essential to develop effective, context-specific interventions and advance precision medicine tailored to sub-Saharan African populations.

Non-communicable diseases are the leading cause of death globally. Smartphone apps can offer benefits for individuals, health-care professionals, and governments in the prevention and management of such conditions. We aimed to systematically evaluate the effectiveness of app-based interventions in improving the outcomes of non-communicable diseases and in modifying their metabolic and behavioural risk factors. For this umbrella review and meta-analysis, we searched eight databases (Embase, Epistemonikos, IEEE Xplore Digital Library, APA PsycInfo via Ovid, PubMed, Scopus, Web of Science Core Collection, and Cochrane Central Register of Controlled Trials) for systematic reviews with meta-analysis published between Jan 1, 2013, and Jan 10, 2024, with no restrictions by geographical location or language. Additional studies were located through citation chaining and searching of reference lists. Eligible studies reviewed randomised controlled trials or controlled studies focused on adults (aged &#x2265;18 years) with or at risk of non-communicable diseases and the use of app-based interventions for managing or improving the outcomes of these diseases and related health and risk factors, both metabolic and behavioural. Two investigators (EK and MFV) used COVIDENCE software to screen abstracts and full texts and to subsequently extract data from eligible studies. In case of missing data, authors of the relevant articles were contacted for unreported data or additional details. Effect sizes were measured as the standardised mean difference (SMD) and were aggregated through meta-analyses. 95% CIs for each review were synthesised using a random-effects model and prediction intervals were based on a t distribution. When more than ten reviews were available, publication bias was assessed visually through the inspection of funnel plots and by Egger's test; if bias was suspected, a trim-and-fill analysis was applied to estimate a revised effect size. The quality of the included reviews was evaluated with the AMSTAR 2 checklist, the certainty of evidence for each outcome was assessed using the GRADE framework and the Ioannidis criteria, and heterogeneity was measured by calculating I2 values. This study was registered with PROSPERO, CRD42023426735. Of 6951 unique records identified by our searches, 383 underwent full-text review and 78 systematic reviews with meta-analysis, covering 31 outcomes, were included in the study. These reviews covered 496 primary studies and involved a total of 177&#x2009;373 participants. App-based interventions were found to be effective in lowering diastolic blood pressure (SMD -0&#xb7;414 [95% CI -0&#xb7;606 to -0&#xb7;221], I2=93%), systolic blood pressure (-0&#xb7;444 [-0&#xb7;689 to -0&#xb7;199], I2=96%), glycated haemoglobin (-0&#xb7;587 [-0&#xb7;715 to -0&#xb7;460], I2=91%), fasting blood glucose concentration (-1&#xb7;189 [-1&#xb7;605 to -0&#xb7;774], I2=93%), 2 h postprandial glucose concentration (-1&#xb7;229 [-1&#xb7;609 to -0&#xb7;848], I2=95%), anxiety (-0&#xb7;215 [-0&#xb7;407 to -0&#xb7;023], I2=92%), depression (-0&#xb7;097 [-0&#xb7;176 to -0&#xb7;019], I2=77%), stress (-0&#xb7;336 [-0&#xb7;528 to -0&#xb7;143], I2=87%), bodyweight (-0&#xb7;427 [-0&#xb7;594 to -0&#xb7;260], I2=91%), BMI (-0&#xb7;265 [-0&#xb7;522 to -0&#xb7;007], I2=92%), waist circumference (-0&#xb7;310 [-0&#xb7;464 to -0&#xb7;156], I2=75%), and sedentary time (-0&#xb7;600 [-1&#xb7;121 to -0&#xb7;079], I2=22%). Additionally, apps significantly improve diet quality (0&#xb7;551 [0&#xb7;261-0&#xb7;842], I2=91%), exercise capacity (0&#xb7;259 [0&#xb7;119-0&#xb7;398], I2=17%), moderate-to-vigorous physical activity (0&#xb7;240 [0&#xb7;025-0&#xb7;456], I2=75%), number of steps taken daily (0&#xb7;489 [0&#xb7;209-0&#xb7;770], I2=83%), multiple physical activity outcomes (0&#xb7;466 [0&#xb7;243-0&#xb7;689], I2=90%), mindfulness (0&#xb7;293 [0&#xb7;177-0&#xb7;409], I2=77%), wellbeing (0&#xb7;186 [0&#xb7;065-0&#xb7;307], I2=74%), quality of life (0&#xb7;227 [0&#xb7;083-0&#xb7;371], I2=80%), and medication adherence (0&#xb7;688 [0&#xb7;410-0&#xb7;965], I2=88%) when compared with control groups. However, no significant effect was found on cardiovascular mortality; HDL, LDL, total cholesterol, or triglyceride concentrations; body fat; distress; fruit and vegetable intake; hospitalisation; or smoking abstinence. Of the 78 systematic reviews, only one (1%) was rated as being of high quality, with three (4%) of moderate quality, 17 (22%) of low quality, and 57 (73%) of critically low quality. According to Ioannidis criteria, five outcomes were categorised as having highly suggestive (class II) evidence, with eight outcomes having suggestive evidence (class III), eleven outcomes having weak evidence, and seven outcomes categorised as non-significant. Our analyses provide evidence that app-based interventions support significant improvements in multiple outcomes of and risk factors for non-communicable diseases, including cardiovascular diseases, glucose control, mental health outcomes, physical activity, and quality of life. The integration of app-based interventions into health-care systems should be prioritised to enhance patient care and health outcomes. None.