To estimate the proportion of older patients with type 2 diabetes (T2D) and HbA1c above or below goal at provider level and explore factors associated with patients being above or below goal.
We used 2023 Cleveland Clinic electronic health records, including patients ≥ 65 years old with T2D, ≥ 1 diabetes medication and ≥ 1 HbA1c measurement. Patients were assigned to their listed primary care provider or the one they saw most frequently and stratified into good, intermediate, or poor health. Outcomes were patients being above, at, and below goal, defined as HbA1c greater than, 0%–1.5% lower than, and ≥ 1.5% lower than goal, respectively. HbA1c goals were < 7.5% for patients with good, < 8% intermediate and < 9% poor health.
We included 406 providers and 15 865 patients. Across providers, 52.1% (range: 10%–87.9%) of patients were below goal (13.4% in those with good, 42.0% intermediate, 76.0% poor health); 11.3% (range: 0.0%–36.4%) were above goal (25.1% in those with good, 13.7% intermediate, 6.7% poor health). There was significant variation across providers (p < 0.001). In a multivariable model, having endocrinology providers (vs. internal medicine) decreased the adjusted relative risk ratio (aRRR) of being below goal (aRRR = 0.69; 95% CI: 0.57–0.82) and increased the probability of being above goal (aRRR = 1.65; 95% CI: 1.33–2.05).
Substantial provider-level variation suggests that individualised glycemic management for older adults remains difficult to operationalise in routine care. Clinical decision support tools that automate assessment of health status and recommend glycemic goals may help clinicians better align glycemic management with patient needs.
]]>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GLP-1/GIP receptor agonists have transformed the pharmacological management of type 2 diabetes (T2D) and obesity, yet substantial interindividual variability in treatment response remains a defining clinical challenge.
Narrative review. PubMed was searched to 25 May 2026 (English language, human studies, 2005–2026) for biological, genetic, metabolic, hormonal, behavioural and psychosocial predictors of differential response. Evidence is organised across three clinically distinct contexts: glycaemic control in T2D; weight loss in people with overweight or obesity without T2D; and dual metabolic benefit in those with both conditions.
Response heterogeneity is most pronounced in obesity without diabetes, where non-response—commonly defined as less than 5% total body weight loss—affects approximately 10% of participants in controlled trials, with real-world cohorts suggesting a higher frequency in routine practice; glycaemic non-response in T2D is less common but clinically significant. Across all three contexts, early on-treatment response is the most readily actionable predictor currently available. A recent large genome-wide association study reported associations between variation in the GLP1R drug-target gene and both weight-loss efficacy and gastrointestinal tolerability, and between agent-specific GIPR variants and nausea and vomiting with tirzepatide; these self-reported, single-cohort and as-yet unreplicated findings remain hypothesis-generating rather than a basis for individual-level genotyping. Metabolic, microbiome and neuroendocrine predictors are at a comparably preliminary stage.
No single baseline characteristic reliably predicts response. Structured assessment of early on-treatment response is currently the most defensible basis for individualising therapy; genetic, metabolic and microbiome markers require prospective replication before clinical application.
]]>The Risk Assessment and Management Programme—Diabetes Mellitus (RAMP-DM) is a multidisciplinary, protocol-driven, risk-stratified care model integrated into public primary care in Hong Kong for patients with type 2 diabetes mellitus (T2DM). This study evaluated the real-world 10-year cost-effectiveness of RAMP-DM from the public healthcare provider perspective.
Programme costs from 2009 to 2019 were estimated using costing questionnaires and reported in 2019 US dollars. Direct medical costs were compared between patients enrolled in RAMP-DM and a propensity-score matched cohort receiving usual care only. Effectiveness was based on previously published 10-year estimates of absolute risk reduction in complications and all-cause mortality. The primary outcome was the incremental total direct medical cost per diabetes-related complication avoided over 10 years. Secondary outcomes included incremental cost per all-cause mortality avoided and programme cost per complication avoided. Sensitivity analyses examined the effects of parameter uncertainty and discounting.
A total of 36 746 patients (18 373 in each group) were included. RAMP-DM was associated with absolute risk reductions of 12.1% for any complications and 16.2% for all-cause mortality. Accounting for the programme cost of US$329 per participant, total undiscounted direct medical costs over 10 years was US$10 543 lower per person among RAMP-DM participants (RAMP-DM: $23 430; usual care: US$33 973). RAMP-DM was a cost-saving strategy relative to usual care.
RAMP-DM was associated with better 10-year clinical outcomes and lower direct medical costs. These findings support the economic value of structured multidisciplinary diabetes management programmes in publicly funded primary care settings, although residual confounding and uncertainty in cost estimates should be considered.
]]>Gestational diabetes (GDM) is the strongest known risk factor for maternal type 2 diabetes. However, little is known about type 2 diabetes risk in women with normal glucose challenge test (GCT) results during pregnancy. We investigated the association between GCT results in the normal range and type 2 diabetes risk, both overall and across pre-pregnancy BMI categories.
This retrospective cohort study identified pregnant women aged 20–50 who had normal (< 140 mg/dL) GCT results between 2004 and 2022. Follow-up for type 2 diabetes extended from the date of the last documented GCT until 31 September 2024. Survival analyses examine GCT and combine BMI-GCT exposures.
Among 249 190 eligible women (mean age 32.7 years), 1354 developed type 2 diabetes during a median follow-up of 7 years. GCT results within the normal range were associated with the risk of type 2 diabetes, in a graded manner, without a clear threshold. Compared to women with normal pre-pregnancy BMI and GCT of 70–89 mg/dL, women with a GCT of 130–140 mg/dL had adjusted hazard ratios for type 2 diabetes ranging from 14.7 (95% CI: 6.2–33.3) among women with normal BMI to 145 (95% CI: 67.7–309) among women with obesity.
Pre-pregnancy BMI and GCT values within the normal range can be used for further type 2 diabetes risk stratification, ranging from minimal risk among women with a GCT < 90 mg/dL and normal weight to substantially increased risk among women with pre-pregnancy overweight or obesity.
]]>Methods
Results
Conclusions/interpretation
Graphical Abstract
]]>The social drivers of diabetic foot disease (SDDFD) impact ulcer incidence and outcomes, but how is relatively unknown. We aimed to build a conceptual model positing how three SDDFD—poverty, insurance, and government assistance—influence outcomes for patients with diabetic foot ulcers.
To inform the model, we conducted a scoping review of studies linking poverty, insurance, and/or government assistance with diabetic foot ulcer outcomes using Levac and colleagues’ 6-stage framework, the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, and the SPIDER tool. We searched PubMed, CINAHL, and Embase for original research articles set in the United States and published between 1 January 2005 and 7 November 2025. We excluded those published in a language other than English, case reports, abstracts, and studies of other SDDFD.
Data from 35 included studies informed our conceptual model, depicting a complex causal pathway between SDDFD and outcomes, often mediated by healthcare system factors and moderated by patients’ abilities to adhere to healthcare recommendations. Multidisciplinary teams might ameliorate the risk of amputations associated with poverty, lack of insurance, or qualifying for government assistance. Additionally, the model highlights reinforcing feedback loops, both positive and negative.
Our model can be used to inform mediation and moderation analyses and help avoid collider-conditioning bias during statistical analyses. It can help identify potential points of intervention within the healthcare system for those working to dampen the negative effects of SDDFD on outcomes.
]]>Gestational diabetes (GDM) and preeclampsia (PE) are major complications of pregnancy. The ratio of soluble Fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF) may predict the short-term absence of PE in pregnant women with clinically suspected PE. The aim of this study was to determine the role of placental angiogenic factors in predicting PE risk in women with pregnancies complicated by GDM.
In this prospective observational study, pregnant women were enrolled at the time of screening for GDM. sFlt-1 and PlGF were measured at 24–28, 28–32 and 35–37 weeks of gestation. Univariate and multivariate analysis were used to investigate risk factors for PE.
Of 398 women, 213 (53.5%) had GDM and 18 (5%) developed PE (67% with GDM). GDM women developing PE had significantly lower levels of PlGF at 24–28, 28–32 and 35–37 gestational weeks, and higher sFlt1 and sFlt1/PlGF at 28–32 and 35–37 gestational weeks compared with GDM women without PE. On a multivariate analysis, PlGF and sFlt1/PlGF were associated with PE, regardless of other clinical data. A sFlt1/PlGF ratio > 38 at 28–32 gestational weeks identified GDM women at risk of developing PE within the ensuing 4 weeks, with 100% sensitivity and good specificity.
In women with GDM, the sFlt1/PlGF ratio can identify those at higher risk of PE.
NCT04877119: 2021-04-29
]]>Diabetes therapeutics can lower glycated haemoglobin (HbA1c) by several percentage points within weeks. While long-term microvascular risk is reduced by improved glycaemia, abrupt metabolic transitions may destabilise tissues adapted to chronic hyperglycemia. We review treatment-induced neuropathy of diabetes (TIND) and active Charcot neuro-osteoarthropathy (CNO) as two neurovascular complications reported after rapid glycaemic correction, and we propose a unifying ‘metabolic tempo’ framework for prevention and early detection.
TIND is an acute, painful small-fibre and autonomic neuropathy occurring within 2–8 weeks after large HbA1c reductions, frequently coinciding with early worsening of retinopathy and nephropathy. Human in vivo nerve imaging demonstrates epineurial arteriovenous shunting and proliferative, leaky microvessels, supporting a microvascular dysregulation/ischaemia-reperfusion model. For CNO, causal evidence linking rapid glycaemic improvement to disease onset remains limited and mainly observational; however, multiple case reports (including pregnancy, post-transplantation, and major weight loss contexts) and retrospective cohorts suggest that major glycaemic ‘deceleration’ may cluster in the months preceding active CNO in susceptible patients with long-standing neuropathy.
Rapid glycaemic correction should not be avoided when urgently needed, but ‘tempo-aware’ strategies may be warranted in microvascularly fragile patients (very high baseline HbA1c, established neuropathy/retinopathy, kidney disease, or major weight loss). We outline pragmatic risk stratification, surveillance, and interdisciplinary pathways (neurology-podiatry-ophthalmology-nephrology) to reduce delayed diagnosis and prevent deformity and disability.
]]>To investigate whether artificial intelligence (AI) models trained on standard 12-lead electrocardiograms (ECG) can identify symptom-defined diabetic peripheral neuropathy (DPN) as assessed by the Michigan Neuropathy Screening Instrument Questionnaire (MNSI-Q).
This was an observational study of people with diabetes enrolled in the Silesia-Diabetes Heart Project. DPN was assessed using the MNSI-Q. We used an original questionnaire cut-off score of ≥ 7 and revised cut-off score of ≥ 4 to diagnose DPN and classified DPN as highly symptomatic and moderately symptomatic accordingly. Feature extraction from 10-s raw ECG recordings utilised algorithms to identify recurring signal segments (motifs) and anomalies (discords). These features were used to train XGBoost, Support Vector Machine (SVM) and Ridge classifiers to differentiate between DPN-positive and DPN-negative people.
A total of 640 participants (mean age 54 ± 17; 52% female) were included. Of these, 95 (15%) had highly symptomatic DPN (MNSI-Q ≥ 7) and 281 (44%) had moderately symptomatic DPN (MNSI-Q ≥ 4). For the highly symptomatic DPN, the XGBoost classifier utilizing a combination of motifs and discords demonstrated the highest performance, achieving an area under the receiver-operating characteristic curve (AUC) of 0.89 (95% CI 0.88–0.91), an accuracy of 88.5% and a sensitivity of 93.4%. The model showed substantially lower predictive capability when tested against the broader screening threshold of MNSI ≥ 4 (AUC 0.64).
AI analysis of the standard ECG demonstrated a strong association with the presence of symptom-defined peripheral neuropathy but lacked sensitivity for milder presentation. With further validation, this method could serve as an accessible, supplementary screening aid to help identify high-risk patients during routine cardiovascular assessment.
]]>Diabetic kidney disease (DKD) is a major cause of renal failure and end-stage renal disease. Pyroptosis, a Gasdermin-dependent inflammatory form of programmed cell death, has been implicated in DKD progression. Metformin has shown renoprotective effects in DKD; however, the underlying mechanisms remain unclear.
To investigate whether metformin attenuates high glucose-induced pyroptosis and inflammatory responses in HK-2 cells through SIRT1-mediated regulation of the TXNIP/NLRP3 pathway.
Bioinformatics analyses were performed to identify DKD-related pyroptosis-associated genes and enriched pathways. Serum TXNIP and IL-1β levels were measured in patients with type 2 diabetes mellitus stratified by urinary albumin-to-creatinine ratio (UACR). HK-2 cells were exposed to high glucose (30 mM) to establish an in vitro injury model. Oxidative stress, pyroptosis-related signalling and inflammatory cytokines were evaluated using molecular and immunological assays. SIRT1 modulation and TXNIP silencing were used to investigate pathway regulation. Chromatin immunoprecipitation assays were performed to assess SIRT1 occupancy and histone acetylation status within the TXNIP promoter region.
Pyroptosis-related genes were mainly enriched in inflammatory and NLRP3 inflammasome-associated pathways. Serum TXNIP and IL-1β levels were elevated in DKD patients and positively correlated with UACR. In HK-2 cells, high glucose reduced SIRT1 expression and activated the TXNIP/NLRP3 inflammasome pathway, accompanied by increased GSDMD cleavage and inflammatory cytokine expression. Metformin partially reversed these changes. Altered SIRT1 activity was also associated with changes in H3K56 acetylation enrichment within the TXNIP promoter region.
Metformin may alleviate high glucose-induced pyroptosis and inflammatory responses in HK-2 cells, potentially through modulation of SIRT1-associated TXNIP/NLRP3 signalling and TXNIP-related chromatin acetylation status.
]]>