Methods
Results
Conclusions/interpretation
Trial registration
Graphical Abstract
]]>Methods
Results
Conclusions/interpretation
Data availability
Graphical Abstract
]]>Population-based surveillance is essential for quantifying the burden of diabetes and monitoring temporal changes. In Denmark, nationwide health registers enable long-term surveillance of type 1 diabetes (T1D) and type 2 diabetes (T2D). We aimed to estimate trends in prevalence, incidence, mortality and years of life lost to diabetes in Denmark from 1996 to 2024.
Research design and methods
We conducted a nationwide register-based cohort study from 1996 to 2024. We used an updated national diabetes register integrating hospital, prescription, clinical, and laboratory data to identify diabetes type and date of onset. Prevalence was estimated annually using a binomial model. Incidence, mortality and standardized mortality ratios (SMR) were analyzed using age-period-cohort models. Analyses were stratified by sex and diabetes type. A multistate model was used to assess the lifetime risk and years of life lost to diabetes.
Results
As of January 1, 2025, a total of 366 174 individuals (6.1% of the population) had diabetes identified through national healthcare registers; of these, 8.2% had T1D and 91.8% had T2D. Since 1996, diabetes prevalence more than tripled, largely driven by an overall annual increase in T2D of ~4.1%. T1D prevalence remained stable, with increases in individuals aged <40 years and decreases in older age groups. From 1996 to 2024, a total of 567 510 incident diabetes cases were recorded, of which 4.6% were T1D. T1D incidence declined on average by 1.1% annually, with increasing rates at younger ages and declining rates at older ages. T2D incidence showed a non-linear pattern, with a decline from 2010 to 2015 followed by an increase in recent years, resulting in an overall upward trend from 1996 to 2024. Men had higher T2D incidence than women across age and calendar years. Mortality declined for T1D after 2008 and for T2D until 2012, then stabilized. SMRs decreased for T1D after 2008 but increased for T2D, converging by 2025.
Conclusions
In Denmark, diabetes prevalence and incidence increased markedly since 1996, largely driven by T2D. Although mortality declined, particularly for T1D, excess mortality remains, emphasizing the need for continued surveillance and prevention efforts.
]]>To assess whether self-reported leisure-time physical activity, moderate-to-vigorous leisure-time physical activity, and genetically determined cardiorespiratory fitness are associated with age-related BMI trajectories and incident obesity.
We pooled 14 993 adults (30–90 years; 52.7% women; cohorts: REGICOR-ACRISC, ILERVAS, ARTPER) with estimated LTPA (moderate-to-vigorous LTPA [MVLTPA] in REGICOR-ACRISC), genotype, and 120 352 repeated BMI measurements from electronic health records (1990–2024). LTPA was categorised into cohort-specific quartiles; MVLTPA in 0, < 100, < 200, and ≥ 200 METs-min/day. In one-sample Mendelian randomisation analyses, we categorised participants in quartiles of a cardiorespiratory fitness polygenic risk score derived from a large GWAS in UK Biobank. Group-dependent BMI trajectories were modelled using spline mixed-effects models. Obesity onset (first BMI ≥ 30 kg/m2) was analysed with IPW-weighted Kaplan–Meier curves and Cox models.
Higher LTPA was associated with slower BMI increases in ages 30–60 (Q1: +0.120 vs. Q4: +0.075 kg/m2·year), slower declines in ages 70–90 (Q1: −0.143 vs. Q4: −0.123 kg/m2·year), and lower obesity risk (Q4 vs. Q1: HR 0.83, 95% CI 0.72–0.96). Similar trends were observed for MVLTPA. Higher genetically determined cardiorespiratory fitness showed parallel gradients (ages 30–60, Q1: +0.109 vs. Q4: +0.101 kg/m2·year; ages 70–90, Q1: −0.130 vs. Q4: −0.102 kg/m2·year) and lower obesity risk (Q4 vs. Q1: HR 0.66, 0.56–0.78). Associations were present for women and men separately, but were stronger in men.
Higher LTPA and MVLTPA were associated with more favourable lifelong BMI trajectories, delayed obesity risk, and convergent support from Mendelian randomisation analyses, supporting a causal protective role of physical activity (in both sexes but stronger in men).
]]>The effects of individual sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) on ventricular arrhythmias (VAs) remain uncertain. This study aimed to comprehensively compare their effects on VAs and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) and/or heart failure (HF).
Four databases were systematically searched from inception through May 16, 2026, to identify randomised controlled trials. Nine outcomes were evaluated, including VAs, cardiovascular mortality, all-cause mortality and hospitalization for heart failure (HHF).
Thirty-seven publications, corresponding to 32 independent RCTs and 140 156 participants, were included. Most SGLT2 inhibitors and GLP-1 receptor agonists did not significantly increase VA risk; empagliflozin showed a statistically significant but exploratory signal for lower VA risk in the T2DM network (OR 0.31, 95% CI 0.11–0.86). Dapagliflozin in the HF network and empagliflozin and liraglutide in the T2DM network, were associated with lower cardiovascular and all-cause mortality. SGLT2 inhibitors consistently reduced HHF across both networks. Dapagliflozin was associated with lower AKI risk, while albiglutide and liraglutide were associated with lower hypoglycemia risk; however, these safety findings should be interpreted cautiously because adverse-event reporting was not uniform across trials. Several safety outcomes were based on sparse events and non-uniform adverse-event reporting; no statistically significant increase in diabetic ketoacidosis risk was detected for empagliflozin and the semaglutide fracture signal should be interpreted cautiously. Because the evidence networks were largely placebo-centered and lacked closed loops, treatment rankings and between-drug comparisons depend heavily on the transitivity assumption. These rankings, including P-score rankings, should be regarded as exploratory and should not be interpreted as head-to-head comparative evidence.
SGLT2 inhibitors consistently reduced HHF risk across the HF and T2DM networks and selected agents showed mortality benefits in clinically relevant populations. Empagliflozin showed an exploratory signal for lower VA risk in the T2DM network; however, this finding requires confirmation in trials with prespecified and adjudicated arrhythmia endpoints. Safety signals, including DKA and fracture, should be interpreted cautiously because adverse-event ascertainment was not uniform across trials.
]]>Achieving glucose targets without hypoglycaemia is the treatment goal in type 1 diabetes. Structured education, intensified insulin injection regimens, continuous glucose monitoring, automated insulin delivery, and ongoing support from a multidisciplinary team all support people with type 1 diabetes to achieve this goal. Despite these advances, significant barriers to achieving optimal management remain. Continuous intraperitoneal insulin infusion has comparable or better glucose outcomes to continuous subcutaneous insulin infusion and may reduce the frequency of hypoglycaemia, including severe episodes. Intraperitoneal insulin may be considered as a treatment modality for children and adults with type 1 diabetes using optimised intensive insulin therapy for whom subcutaneous insulin has failed due to lipoatrophy, -dystrophy or -hypertrophy, local allergy, subcutaneous insulin resistance or co-existing skin conditions. Failure of subcutaneous insulin may result in recurrent or unexplained severe hypoglycaemia or hyperglycaemia. Intraperitoneal insulin may also be considered as a treatment modality for people with type 1 diabetes with severe needle-phobia, and for those being considered for islet cell or pancreatic transplantation, or where transplantation is not available. This paper summarises current intraperitoneal insulin delivery technology, its potential risks and benefits, and an expert position statement. It is intended for use by diabetes specialist healthcare professionals, and as a reference for other healthcare professionals, commissioners, payors, people with diabetes, their carers, and advocates.
]]>This systematic review and meta-analysis aimed to evaluate the efficacy and safety of anti-obesity medications (AOMs) for long-term weight maintenance following initial weight loss in adults with overweight or obesity.
We searched PubMed, Embase, Web of Science and the Cochrane Library from inception to 31 October 2025. Eligible studies were randomised controlled trials (RCTs) comparing AOMs with placebo during the weight-maintenance phase in adults with overweight or obesity after initial weight loss achieved through lifestyle, dietary, surgical or pharmacological interventions. Outcomes included anthropometric indices, cardiometabolic measures, safety endpoints, quality of life and neuropsychiatric adverse events. Weighted mean differences (WMDs) and odds ratios (ORs), each with 95% confidence intervals (CIs), were pooled for continuous and categorical outcomes, respectively, using fixed-effect or random-effects models as appropriate. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated using the GRADE framework. The protocol was registered with PROSPERO (CRD420261293040).
A total of 12 RCTs comprising 4915 participants met the inclusion criteria. Compared with placebo, AOM therapy during the weight-maintenance phase was associated with prevention of weight regain and additional improvements in anthropometric and cardiometabolic outcomes. AOMs led to further reductions in body weight (BW, WMD: −8.68 kg, 95% CI: −13.25 to −4.11), waist circumference (WC, WMD: −7.16 cm, 95% CI: −10.34 to −3.98) and body mass index (BMI, WMD: −3.58 kg/m2, 95% CI: −5.69 to −1.46). Additional benefits were observed for triglycerides, total cholesterol, low-density lipoprotein cholesterol, systolic blood pressure and diastolic blood pressure. Gastrointestinal adverse events were more common with AOMs, whereas serious adverse events were not significantly increased. Neuropsychiatric adverse events were generally comparable between groups, and available quality-of-life measures favoured AOM treatment.
AOM therapy during the weight-maintenance phase can help prevent weight regain, provide further reductions in body weight and improve cardiometabolic risk factors in adults with overweight or obesity. Gastrointestinal adverse events were more common with AOMs, whereas serious adverse events were not significantly increased. Further long-term trials are needed to clarify optimal treatment strategies and safety.
]]>Chronic hepatitis B virus (HBV) infection is associated with an increased risk of diabetes; however, early detection of diabetes remains challenging due to silent progression in early stages. Given that 30%–50% of diabetic patients develop severe complications such as cardiovascular disease, renal failure, and neuropathy, timely risk assessment is critical for prevention.
We developed a machine learning model using data from 14,287 HBV-positive adults across eight NHANES cycles (2003–2018) to identify diabetes. Eleven inflammation-immune composite indicators were integrated with demographic and biochemical parameters. Following LASSO variable selection and a 7:3 train-test split, seven algorithms were compared. Model performance was evaluated using the area under the ROC curve (AUC), calibration curve, and decision curve analysis (DCA).
The Artificial Neural Network (ANN) emerged as the optimal model for diabetes risk assessment. It achieved an AUC of 0.83 (95% CI: 0.80–0.85) and an accuracy of 82% (95% CI: 0.79–0.85). SHAP analysis identified age and UHR as the most influential predictors, while HRR showed significant protective effects.
This study presents a robust, interpretable model for diabetes risk assessment in HBV patients that integrates novel inflammation-immune composite indicators. These findings highlight the model’s utility as a potential clinical tool for screening individuals with undiagnosed diabetes.
]]>Hypoglycaemia is a frequent complication during diabetic ketoacidosis (DKA) treatment. Continuous glucose monitoring (CGM) provides real-time glucose trend information; however, its clinical utility during paediatric DKA management in the intensive care unit (ICU) remains uncertain. We investigated whether CGM insertion during DKA treatment in the paediatric ICU (PICU) is associated with reduced hypoglycaemia and a lower burden of point-of-care (POC) glucose measurements.
We conducted a retrospective single-centre cohort study of paediatric patients (< 20 years) admitted to the PICU with DKA between December 2013 and December 2025 who received continuous intravenous insulin infusion. Patients were categorised based on CGM insertion during their PICU stay. The primary outcome was hypoglycaemia. Secondary outcomes included frequency of POC glucose measurements, ICU length of stay and time to DKA resolution.
Seventy-three patients were included; 31 (42.5%) underwent CGM insertion. The incidence of hypoglycaemia was significantly lower in the CGM group (glucose < 70 mg/dL: 6.5% vs. 47.6%, p < 0.001; < 60 mg/dL: 0% vs. 21.4%, p = 0.008). In multivariable analysis, CGM insertion was independently associated with lower hypoglycaemia risk (adjusted OR 0.059, 95% CI 0.011–0.323; p = 0.001). The CGM group also had a significantly lower frequency of POC glucose measurements than the control group.
Amongst paediatric patients with DKA treated in the PICU, CGM insertion was independently associated with reduced hypoglycaemia and a lower POC testing burden. Prospective studies are warranted to determine whether CGM-guided DKA management improves clinical outcomes in critically ill children.
]]>Neuropsychiatric safety concerns, including depression and suicidal ideation, have emerged during the expanding clinical use of incretin-based therapies for type 2 diabetes mellitus (T2DM) and obesity. However, whether risks differ across successive generations of incretin-based therapies remains uncertain.
This retrospective cohort study used the TriNetX Global Federated Network (> 192 million patients). Adults with T2DM, obesity, or both initiating tirzepatide, semaglutide, or other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) between July 2022 and June 2025 were identified using a new-user design with a 12-month washout. Propensity score matching balanced demographic, clinical, and metabolic variables. Two comparisons were conducted: tirzepatide versus semaglutide and semaglutide versus other GLP-1 RAs. Follow-up included Year 1 (day 31–365) and Year 2 landmark analysis (day 366–730). Hazard ratios (HRs) for incident depression, anxiety, and suicidal ideation were estimated using Cox models.
After matching, 85 546 pairs were included for tirzepatide versus semaglutide and 80 115 pairs for semaglutide versus other GLP-1 RAs. Tirzepatide and semaglutide showed similar risks for the composite psychiatric outcome (Year 1 HR 0.984 [95% CI 0.950–1.019]; Year 2 HR 1.002 [0.960–1.046]); a nominally higher anxiety hazard was observed with tirzepatide during Year 2 (HR 1.052 [1.001–1.106]), which should be interpreted cautiously given multiple comparisons. Compared with other GLP-1 RAs, semaglutide was associated with lower risks of depression (HR 0.811 [0.770–0.855]), anxiety (HR 0.915 [0.871–0.961]), suicidal ideation (HR 0.488 [0.339–0.702]), and the composite psychiatric outcome (HR 0.866 [0.832–0.901]) during Year 1.
In real-world practice, tirzepatide and semaglutide demonstrated comparable neuropsychiatric risk profiles over 2 years. Semaglutide was associated with lower psychiatric event rates compared with earlier-generation GLP-1 receptor agonists.
]]>In December 2022, semaglutide injections for weight management were marketed in Denmark. Pre-marketing trials documented high efficacy when adherence to the treatment and the recommended dose titration schedule was followed. This study aimed to describe real-world use of semaglutide, including dose titration, discontinuation patterns and effectiveness on body weight in adults with overweight or obesity treated in primary care.
This retrospective, observational study included adults prescribed semaglutide for weight management between December 2022 and May 2024 in one general practise in Denmark. The primary outcome was the relative mean change in body weight from baseline to 12-months follow-up in individuals who had not discontinued treatment and who had a baseline and a follow-up weight.
A total of 206 individuals were included (76% women; mean age 48 years, standard deviation (SD) 13). Mean baseline body weight was 105 kg (SD 23.8). Twelve months after treatment initiation, 38% (n = 78) had permanently discontinued semaglutide, whilst 15% (n = 30) had temporarily discontinued (paused) semaglutide. Approximately 48% (n = 98) remained on treatment. Amongst these, 40% were treated with ≤ 1.0 mg/week, 30% with 1.7 mg/week and 30% with 2.4 mg/week. Relative mean body weight change after 12 months was −13.6 (95% CI −15.0 to −12.2)%.
Based on the experience from utilisation in a single general practise, semaglutide for weight management is frequently discontinued and titrated slower and to lower maintenance doses in real-world clinical practise than in the approved labelling. Despite this, the observed mean weight loss for individuals who had not discontinued treatment was substantial.
]]>Hybrid closed-loop (HCL) systems achieve rapid, algorithm-driven improvements in glycaemia in type 1 diabetes (T1D). Paradoxically, rapid improvement in glycaemic control is associated with early worsening of diabetic retinopathy (EWDR), a phenomenon established in the intensive insulin therapy era. Whether HCL initiation carries a clinically meaningful EWDR risk is unknown. No systematic review has previously addressed this question.
A systematic review and structured quantitative synthesis was performed using study-level estimates only (PROSPERO CRD:420261391951). MEDLINE, SCOPUS and Web of Science were searched to 14th May 2026. Studies reporting retinal outcomes in people with T1D initiating any HCL system were eligible. Two reviewers independently screened studies and extracted data. Risk of bias was assessed using ROBINS-I and certainty of evidence using the GRADE framework. EWDR incidence was summarised using study-level proportions, and comparative studies were summarised using study-specific risk ratios for HCL versus control therapy. Given substantial heterogeneity in EWDR definitions, retinal assessment timing, follow-up duration, and comparator groups, no pooled or meta-analytic estimates were derived.
Eight studies (n = 1487 participants; 860 HCL users) were included; all were observational and six were retrospective. EWDR varied markedly with the timing of retinal assessment. In studies assessing the retina within ≤ 12 months of HCL initiation, EWDR rates ranged from 8.9% to 26.5%. Studies with longer follow-up reported lower rates of retinal worsening or incident DR, 6.7% at 24 months and 6.1% over a mean follow-up of 4.9 years, suggesting that these studies may capture background DR progression rather than true early worsening. Three comparative studies included 177 HCL users and 315 controls; EWDR study-specific risk ratios were directionally inconsistent, ranging from 0.32 to 1.51, and were therefore not pooled. The most consistently identified risk factors were higher baseline HbA1c and older age. The magnitude of HbA1c reduction was not a consistent predictor of EWDR in the HCL context, in contrast to pre-HCL era evidence. Risk of bias ranged from moderate to critical and certainty of evidence was very low for all outcomes.
Study-defined retinal worsening was reported in a minority of participants. The current evidence base is dominated by retrospective studies, variable retinal assessment timing, and inconsistent EWDR definitions. Well-designed prospective studies with protocol-specified retinal surveillance anchored to HCL initiation are required to generate reliable incidence estimates, identify risk factors, determine visual consequences, and inform standardised screening guidance.
]]>