To compare 1-year psychiatric outcomes after GLP-1 receptor agonist (GLP-1 RA) versus sodium-glucose cotransporter-2 inhibitor (SGLT2i) initiation in patients with type 2 diabetes and treated depression.
We conducted a retrospective active-comparator, new-user cohort study using electronic health records from the TriNetX network. Patients with type 2 diabetes, depression and antidepressant treatment within 6 months before index were included. After 1:1 propensity score matching, outcomes were compared using Cox proportional hazards models. Primary outcomes were suicidality and antipsychotic use. All-cause mortality was a secondary outcome.
After propensity score matching, 34 761 patients were included in each group. GLP-1 RA initiation was not associated with a higher risk of suicidality than SGLT2i initiation (hazard ratio [HR] 0.88, 95% CI 0.74–1.05). GLP-1 RA initiation was associated with a lower risk of antipsychotic use (HR 0.86, 95% CI 0.82–0.90; absolute risk difference −1.4%) and lower all-cause mortality (HR 0.64, 95% CI 0.58–0.71). Findings were consistent across sensitivity analyses.
In patients with type 2 diabetes and treated depression, we did not detect increased short-term documented suicidality after GLP-1 RA initiation compared with SGLT2i initiation and observed less subsequent treatment intensification. These observational findings suggest that treated depression alone should not lead to routine avoidance of GLP-1 RAs in this population.
]]>In Ontario, publicly funded insulin pump therapy has been available to children with Type 1 diabetes since 2006. Before 31 March 2022, eligibility required three Haemoglobin A1c (A1C) measurements in the preceding year, with the two most recent < 10%. On 1 April 2022, this criterion was removed. We assessed whether this policy change reduced socioeconomic disparities in pump access among new applicants.
We conducted a population-based retrospective cohort study including all children in Ontario who applied for insulin pump funding from program inception to 31 March 2024. The primary exposure was the time period (pre- vs. post-policy change). The outcome was social disadvantage, measured using a five-level neighbourhood index. Ordinal logistic regression with generalised estimating equations (accounting for neighbourhood clustering) estimated the odds of greater disadvantage post-policy, adjusting for age, sex and diabetes duration. Segmented regression assessed changes over time in differences in application proportions between the most and least disadvantaged quintiles.
A total of 7540 children applied pre-policy and 1311 post-policy. The mean A1C at application was similar between time periods (8.5% vs. 8.3%, p = 0.0002). Adjusted odds of greater disadvantage were higher post-policy (OR: 1.32, 95% CI: 1.18–1.47). The difference in applications between the most versus least disadvantaged quintile decreased by 0.13%/quarter (95% CI: −0.22 to −0.05) pre-policy and by 1.64%/quarter (95% CI: −8.3 to 5.0) post-policy, though the pre versus post-policy difference was not statistically significant (p = 0.1).
Removal of A1C-based eligibility may improve equity in paediatric insulin pump access, though longer follow-up is needed.
]]>To examine the independent and joint associations of metabolic status, obesity, and physical activity with all-cause and cardiovascular disease (CVD) mortality across metabolic–obesity phenotypes.
We analysed 442 666 adults from the Korean National Health Insurance Service health screening cohort (2009–2012). Metabolic status was defined using modified NCEP-ATP III criteria (elevated triglycerides, low HDL-C, elevated blood pressure or antihypertensive use, and elevated fasting glucose or antidiabetic use); ≥ 2 abnormalities indicated metabolically unhealthy. Obesity was defined as BMI ≥ 25 kg/m2 (WHO Asia-Pacific), yielding four phenotypes: metabolically healthy lean (MHL), metabolically unhealthy lean (MUHL), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUHO). Physical activity was assessed by self-report and categorised by total MET-min/week (0, 1–499, 500–999, 1000–1499, ≥ 1500). Multivariable Cox proportional hazards models estimated hazard ratios (HRs) for all-cause and CVD mortality.
In the primary multivariable model (Model 2a), compared with MHL, MUHL had the highest all-cause mortality (HR 1.23, 95% CI 1.19–1.26), whereas MUHO was not significantly associated with all-cause mortality (HR 0.97, 95% CI 0.94–1.01), and MHO showed lower risk (HR 0.85, 95% CI 0.81–0.89). Higher physical activity was consistently associated with lower all-cause and CVD mortality in a dose–response manner, and joint analyses showed progressively lower mortality across all metabolic–obesity phenotypes with increasing activity levels.
Metabolic–obesity phenotypes were associated with differential mortality risk, and higher physical activity was associated with lower all-cause and CVD mortality across phenotypes.
]]>To provide a comprehensive overview of the cardiovascular and renal effects of glucose-dependent insulinotropic polypeptide (GIP) by integrating its physiological role with recent human trial data on tirzepatide, the first dual GIP and glucagon-like peptide-1 (GLP-1) receptor agonist.
This narrative review synthesizes key physiological data of native GIP across tissues—especially the heart, vessels, kidney, and adipose tissue—and summarizes clinical evidence from the SUMMIT and the SURPASS programmes. Central to this review is the analysis of the SURPASS-CVOT trial, which compared the cardiovascular protective effects of tirzepatide versus dulaglutide in individuals with type 2 diabetes and established atherosclerotic CV disease.
Preclinical data regarding GIP receptor modulation in the cardiorenal district remains controversial, a contention partially reflected in recent clinical evidence. Within the innovative framework of SURPASS-CVOT, tirzepatide established non-inferiority to dulaglutide for 3-point MACE while slowing eGFR decline in participants with high-risk chronic kidney disease. Furthermore, the SUMMIT trial demonstrated that in individuals with obesity and heart failure (HF) with preserved ejection fraction, tirzepatide reduced the composite endpoint of CV death or worsening HF events, regardless of baseline kidney function. Despite these advancements, knowledge gaps persist regarding the potential synergistic cardiorenal benefits of combining dual incretin agonism with sodium-glucose cotransporter-2 inhibitors.
While adding GIP receptor agonism to GLP-1 receptor agonism clearly improves cardiometabolic risk factors, its precise and independent contribution to long-term CV and renal protection remains to be fully elucidated. Ongoing outcome trials, such as SURMOUNT-MMO and TREASURE-CKD, will provide additional insights into these effects. Furthermore, emerging strategies—including combining GIP receptor antagonism with GLP-1 receptor agonism or moving toward triple agonism—represent promising alternatives to favorably modify the multiple determinants of cardiometabolic risk.
]]>To compare the effects of individual glucagon-like peptide-1 receptor agonists (GLP-1RAs) on direct body composition among adults with overweight or obesity, with or without type 2 diabetes (T2D).
We systematically searched six electronic databases and grey literature from inception to 3 November 2025, to identify all randomised controlled trials (RCTs) that investigated individual GLP-1RAs on change in body composition from baseline among adults with overweight or obesity with or without T2D, without language restrictions. The main outcomes included total body fat (%), fat mass (kg), visceral adipose tissue (VAT) area (cm2), subcutaneous adipose tissue (SAT) area (cm2), liver fat content (%), total lean tissue (%) and lean mass (kg). A frequentist network meta-analysis was employed using a random-effects model and reported as standardised mean differences (SMDs). Certainty of evidence was appraised using the Confidence in Network Meta-Analysis.
We identified 43 unique RCTs with 3379 participants that compared 17 different interventions or dosages with a control group. Regarding variations in treatment benefits on body composition, GLP-1RAs subcutaneously were more efficacious than the control group in decreasing total body fat, fat mass, VAT, SAT and liver fat from baseline. No significant differences for change in total lean tissue were observed. However, subcutaneously, liraglutide 1.8 mg/day, semaglutide 1.0 mg—weekly and tirzepatide 15 mg—weekly (SMDs ranged from −1.09 to −0.50) significantly decreased lean mass from baseline.
GLP-1RAs substantially improve body composition-related excess adiposity, but unfavourable effects on lean mass were observed, particularly at high doses.
]]>To examine the dose–response relationship between diabetes self-management education (DSME) attendance and psychological outcomes in type 2 diabetes, assessing whether minimal attendance (10%) produces clinically meaningful improvements and comparing outcomes at the internationally adopted 60% completion benchmark with full (100%) completion.
This randomised feasibility trial enrolled 120 adults (≥ 18 years) due to attend a UK DSME programme. Participants were randomised to receive 100% (routine DSME), 60%, 10% or 0% (delayed DSME). Primary outcomes were changes in self-management skills; secondary outcomes included health-related quality of life (HRQoL) and diabetes distress.
Participants had a mean age of 61 years, mean HbA1c of 8.4% (68 mmol/mol) and median diabetes duration of 8 years. Significant between-group differences were observed in change scores for self-management skills (F[3,109] = 6.914, p < 0.001) and diabetes distress (F[3,108] = 7.369, p < 0.001). Education dose explained 16%–17% of the variance demonstrating a dose–response relationship (ηp
2 = 0.16–0.17) with a moderate effect size (n
2 = 0.16, 95% CI [0.04, 0.27]). Within-group statistical improvements were observed for both 100% and 60% completion, but clinically meaningful improvements across all psychological domains occurred only with full (100%) completion. No significant between-group differences were observed for HRQoL.
In this randomised feasibility trial, clinically significant psychological benefits from DSME required full (100%) programme completion. Attendance thresholds of ≤ 10% or partial completion (≥ 60%) did not yield meaningful improvements in diabetes distress or HRQoL. These findings suggest that existing performance indicators based on partial attendance may not reflect meaningful benefits and support 100% DSME attendance as the gold standard.
Clinicaltrials.gov identifier: NCT06419907
]]>Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing pancreatic β-cells. Preserving remaining β-cells at the time of diagnosis may improve long-term outcomes. Frexalimab is a humanised monoclonal antibody specific for CD40L undergoing evaluation for treatment of various immune-mediated conditions.
This is a double-blind, Phase 2 trial to assess the efficacy and safety of frexalimab for preservation of pancreatic β-cell function in adolescents and young adults (12–35 years) with recently diagnosed Stage 3 T1D on insulin therapy. Participants who meet all inclusion criteria will be randomly assigned to receive frexalimab or a matching placebo in a 2:1 ratio in all cohorts for 104 weeks. A total of 192 participants will be recruited sequentially into two parts. Part A (n = 30) is exploratory and designed to establish the safety of the highest dose of frexalimab compared with placebo in adults (18–35 years). In Part B, 162 adolescents and young adults (12–21 years) are randomised sequentially to three age-adjusted dose-levels of frexalimab or placebo. The primary endpoint is the change from baseline to 52 weeks in mean 2-h mixed meal tolerance test stimulated C-peptide concentration, calculated from the area under the curve. Secondary endpoints include time in range by intermittent continuous glucose monitoring measures, glycated haemoglobin (HbA1c), daily insulin dose, number of hypoglycaemic events and insulin dose adjusted HbA1c measurements.
This trial received ethical approval in October 2023 and began screening in December 2023 with first participant randomised in January 2024. The results will be submitted to a peer-reviewed medical journal and presented at conferences.
Trial registration: EU trial number: 2022-500531-36-00 and ClinicalTrials.gov: NCT06111586
]]>Chronic kidney disease (CKD) is a global health and economic burden, particularly among individuals with type 2 diabetes (T2D). According to Kidney Disease: Improving Global Outcomes guidelines, key CKD indicators include urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Although independent genetic loci for these traits have been reported, their shared genetic architecture remains insufficiently understood. We hypothesized that there are shared genetic markers of kidney function (eGFR) and albuminuria generally, but also specific to the T2D population.
Methods
We conducted a cross-sectional observational study including 432 451 UK Biobank participants of primarily European descent (94%), with a subgroup of 16 265 with T2D after data quality control. We examined whether 423 single-nucleotide polymorphisms previously associated with eGFR in a large genome-wide association study meta-analysis were associated with (a) eGFR estimated using the 2021 race-free CKD-Epidemiology Collaboration creatinine equation (eGFR2021) and (b) UACR. Multiple linear regression models were adjusted for systolic blood pressure, age, sex, and the first 10 genetic principal components to account for population stratification. Analyses were performed using Python and R. Bonferroni correction (BC) was performed. For the T2D subgroup, the models were additionally adjusted for body mass index and glycated hemoglobin.
Results
In the overall population, 422 loci were nominally associated with eGFR2021, of which 75 were nominally associated with UACR (p≤0.05); 12 remained significant after BC (Pb ≤ ). In the T2D subgroup, 76 loci nominally associated with eGFR2021, six also associated nominally with UACR (p≤0.05), and one remained significant after BC (Pb ≤ ). Two pleiotropic loci (GSTA2, USP2-AS1) suggested diabetes-specific effects.
Conclusion
This study identifies several shared genetic loci underlying eGFR and UACR in both general and T2D European populations. These findings highlight common pathobiological pathways between albuminuria and reduced kidney function and provide a genetic map that may inform future CKD risk stratification and towards the development of therapeutic targets.
]]>To evaluate the 12-month effectiveness and patient persistence of a semaglutide-supported digital weight-loss service (DWLS) in a real-world German cohort.
This retrospective study analysed 4535 patients who initiated the Juniper Germany DWLS. Primary endpoints included 12-month medication and data submission adherence (receiving ≥ 10 orders) and mean weight-loss percentage. Effectiveness was assessed via a per-protocol (PP) analysis of an adherent sub-cohort (n = 546) and an intention-to-treat (ITT) analysis of the full cohort using Last Observation Carried Forward (LOCF) and a Worst-Case Scenario (WCS) sensitivity model. Binary logistic and multiple linear regressions identified predictors of attrition (churn) and efficacy.
Of the total cohort (n = 4535), mean 12-month weight loss was 9.47% (LOCF). However, sensitivity analysis using a WCS model—assuming 0% weight loss for all dropouts—yielded a mean of 2.40%. Among the 12% of patients (n = 546) who remained adherent to both medication and data submission protocols, mean weight loss was 15.13% (±7.1). Program persistence was significantly bolstered by achieving a healthy BMI milestone (OR = 0.29, p < 0.001), encountering a weight-loss plateau (OR = 0.41, p < 0.001), and higher baseline obesity severity (Obesity Class I–III: p < 0.023). Conversely, high clinical complexity (≥ 3 comorbidities) more than doubled the risk of churn (OR = 2.12, p = 0.002), while previous GLP-1 RA use also significantly increased churn risk (OR = 1.57, p = 0.001). While moderate early engagement (2–10 logs) was a strong predictor of persistence (p < 0.001), intensive tracking (> 10 logs) did not significantly reduce churn risk (p = 0.393).
The population-level impact of this DWLS is fundamentally limited by high attrition (88%) in an unsubsidised environment. While significant weight loss is possible for a non-representative adherent minority, the mean effectiveness for the total initiating population (2.40% WCS) highlights that real-world success is strictly conditional upon long-term persistence. The study found that both clinical success and setbacks were associated with program adherence. It also observed that patients of high clinical complexity were at greater risk of attrition. Finally, it found that high-friction manual weight logging serves as a marker of commitment rather than anxiety as had been reported in app-based DWLSs where tracking has significantly lower friction. These findings suggest that the predictive value of digital engagement is fundamentally shaped by DWLS delivery mode and the behavioural cost of engagement.
]]>Cushing’s disease (CD) is a rare endocrine disorder caused by the overproduction of adrenocorticotrophin hormone (ACTH) from a pituitary tumour, leading to excessive secretion of cortisol. The chronic exposure to cortisol leads to endocrine and cardiovascular complications that persist even after remission of hypercortisolism. CD is associated with a significant clinical burden characterised by insulin resistance, renal dysfunction and cardiovascular complications. In addition, patients frequently experience impaired health-related quality of life (HRQoL) and have an increased risk of mortality. There are currently no approved therapies targeting these complications. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycaemic agents that target SGLT2 transporters in the renal proximal convoluted tubules, thus leading to glycosuria and reduction of glycaemia. Initially approved as anti-diabetic agents, SGLT2i have subsequently revealed to exert a wide range of beneficial effects, namely cardiorenal protection; therefore having been recently approved as a first-line treatment for chronic kidney disease and heart failure, regardless of the presence of diabetes. While the clinical and metabolic efficacy of SGLT2i has been extensively documented in type 2 diabetes, heart failure and chronic kidney disease, their systemic effects may also be relevant in patients with CD, who exhibit cardiovascular, renal and metabolic alterations even after biochemical remission. The myriad benefits of SGLT2i align closely with the unmet clinical needs for new medical treatment for patients with CD, supporting their potential therapeutic relevance in this disease. Accordingly, we herein review the pathophysiology, clinical presentation and treatment of CD, and explore the potential therapeutic benefit of SGLT2i in this disorder.
]]>To compare the efficacy and safety of the fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin degludec plus insulin aspart (IDegAsp) according to the injection time of IDegAsp.
The 24-week, multicentre, randomised, open-label Soli-D study enrolled Chinese adults with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drugs (OADs). This exploratory analysis evaluated glycaemic efficacy, body weight, basal insulin daily dose and hypoglycaemia outcomes with once-daily iGlarLixi (injected before breakfast) versus IDegAsp (injected before breakfast, lunch or dinner).
Of 582 participants, 291 received iGlarLixi, with injections self-administered before breakfast, and 291 received IDegAsp, with injections self-administered before breakfast (n = 139), lunch (n = 54) or dinner (n = 98). Glycated haemoglobin (HbA1c) reductions from baseline to Week 24 were greater with iGlarLixi than IDegAsp injected before lunch (least squares mean difference −0.24% [−2.3 mmol/mol]) or dinner (−0.29% [−3.2 mmol/mol]), and slightly greater than IDegAsp injected before breakfast (−0.12% [−1.3 mmol/mol]). Average 2-h postprandial glucose (2-h PPG) reductions were also greater with iGlarLixi than IDegAsp, regardless of injection time. iGlarLixi provided additional benefits, including reduced body weight, lower total insulin doses and less hypoglycaemia risk compared with IDegAsp in all injection-time subgroups.
Once-daily iGlarLixi, injected before breakfast, was associated with improved HbA1c control and greater average 2-h PPG reductions compared with IDegAsp, regardless of injection time, in Chinese adults with T2D suboptimally controlled with OADs.
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