Icodec is the first once-weekly basal insulin for type 2 diabetes (T2D), potentially improving quality of life through a reduced administration burden versus once-daily basal insulins. This study assessed the long-term cost-effectiveness of icodec versus glargine U100, degludec and a mix of once-daily basal insulins (degludec, glargine U100 and glargine U300) in insulin-naïve adults with T2D in Italy.
Outcomes were projected over patient lifetimes (up to 60 years) using the PRIME T2D Model, discounted annually at 3.0%. Baseline characteristics and treatment effects were taken from ONWARDS 1, 3 and 5. Modelled patients received basal insulins for 4 years, before intensifying with the addition of bolus insulin. Treatment effects applied in the first year of the analysis and a utility benefit relating to once-weekly versus once-daily injection were maintained until intensification. Costs were expressed in 2024 euros (EUR) from the perspective of the Italian National Health Service.
Icodec was associated with improved quality-adjusted life expectancy of 0.16 quality-adjusted life years (QALYs) versus glargine U100 and degludec, and 0.26 QALYs versus the once-daily insulin mix. Benefits primarily resulted from the reduced injection frequency with icodec. Higher acquisition costs with icodec were partially offset by reduced use of consumables and modelled reductions in diabetes-related complications. Icodec was associated with incremental cost-effectiveness ratios of EUR 25 623, EUR 5438 and EUR 3940 per QALY gained versus glargine U100, degludec and the once-daily insulin mix, respectively.
Icodec was projected to be cost-effective versus once-daily insulins for insulin-naïve people with T2D in Italy.
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]]>To provide a practical guide on when to suspect endogenous hypercortisolism, how to use the overnight 1-mg dexamethasone suppression test (DST) for targeted case-finding, and which patients are most likely to benefit from treatment.
This narrative review synthesizes evidence from clinical practice guidelines, prospective prevalence studies, randomized controlled trials, systematic reviews, and meta-analyses addressing the recognition, diagnosis, and management of endogenous hypercortisolism in patients with treatment-resistant type 2 diabetes (T2D), resistant hypertension, and adrenal incidentalomas.
Confirmed endogenous hypercortisolism is found in 0.6%-3.4% of broader T2D cohorts after stepwise biochemical evaluation, but recent prospective studies—including CATALYST and MOMENTUM—report abnormal cortisol suppression in approximately one in four patients within selected high-risk groups. Mild autonomous cortisol secretion (MACS), defined as ACTH-independent cortisol production with post-dexamethasone serum cortisol > 50 nmol/L (> 1.8 μg/dL) in the absence of classic Cushingoid features, is associated with clinically meaningful increases in hypertension, T2D, visceral adiposity, and all-cause mortality. Routine screening of all patients with diabetes or hypertension is not recommended; testing should be reserved for those with multiple, progressive, or atypical cardiometabolic features, or with adrenal incidentalomas. Attention to test timing, drug interactions, and physiologic non-neoplastic hypercortisolism is essential for accurate interpretation. When etiology and laterality permit, surgical resection offers the best chance for durable remission. When surgery is not feasible, not curative, or declined, medical alternatives—including glucocorticoid-receptor antagonists (e.g., mifepristone) and steroidogenesis inhibitors (e.g., osilodrostat, ketoconazole)—can reduce cortisol activity or lower cortisol production, each with specific efficacy, tolerability, and safety considerations warranting endocrinologist involvement.
As cortisol activity falls, glucose- and blood-pressure medications often require down-titration. Monitoring for adrenal insufficiency, cortisol withdrawal syndrome, and drug-specific adverse effects requires coordinated multidisciplinary follow-up. Through careful evaluation and targeted treatment, hypercortisolism can be recognized and managed as a modifiable contributor to cardiometabolic risk.
]]>Type 2 diabetes (T2D) is a complex and highly heterogeneous disease driven in part by genetic predisposition and can be stratified into clinical subgroups to aid disease management. We recently grouped T2D subjects in the Qatar Biobank (QBB) cohort into Severe Insulin-Deficient Diabetes (SIDD), Severe Insulin-Resistant Diabetes (SIRD), Mild Obesity-Related Diabetes (MOD) and Mild Age-Related Diabetes (MARD) subtypes. Herein, we focused on the genetic makeup of these subtypes.
We used the QBB cohort (n = 13,808), of whom 2687 were with T2D, and comprehensively assessed polygenic risk scores (PGS) across T2D subtypes, investigated genetic loci associated with each subtype by leveraging the most recent and largest GWAS for T2D, evaluated SNP associations across T2D genetic clusters, and identified protein interaction pathways associated with these distinct T2D subtypes.
MOD showed consistently lower PGS compared with other T2D subtypes across all tested scores. SIDD showed more associations with SNPs mapping to residual glycemic cluster compared with other T2D subtypes. The incremental analysis of PGS004838 demonstrated a high ΔAUC of 0.101 for SIDD and a moderate ΔAUC of 0.068 for SIRD, but not for MOD and MARD. Protein interaction analyses identified candidate subtype-associated gene networks linked to pathways related to glucose homeostasis in SIDD, insulin signalling and hepatic metabolism in SIRD, body fat distribution in MOD and vascular-related processes in MARD.
We found heterogeneous genetic architectures across clinically defined T2D subtypes in a Middle Eastern population. Our findings provide evidence supporting differential polygenic burden, subtype genetic associations and subtype-associated biological pathways across T2D subtypes. These observations support the utility of subtype-based genetic analyses for improving biological understanding of T2D heterogeneity.
]]>Although finerenone has shown efficacy in randomized trials, evidence from routine clinical practice remains limited. We aimed to assess the real-world effectiveness and safety of finerenone in people with type 2 diabetes (PWT2D) and chronic kidney disease (CKD), with a particular focus on residual cardiorenal risk as reflected by changes in urinary albumin-to-creatinine ratio (UACR).
MEDFINE-RWD was a multicentre, retrospective study across eight Spanish centres, enrolling patients initiating finerenone (June 2024–December 2025). The primary endpoint was a ≥ 30% reduction in UACR. Multivariable logistic regression identified response predictors. Secondary outcomes included safety (hyperkalaemia ≥ 5.5 mmol/L, major kidney [MAKE] and cardiovascular events [MACE]).
Among 844 participants (median age 72 years; median follow-up 184 days; 76.8% male; baseline eGFR 49 mL/min/1.73 m2; UACR 285 mg/g; 77.8% were at high/very high KDIGO risk), finerenone was associated with a 34.5% median UACR reduction at 6 months (p < 0.001), despite intensive SGLT2 inhibitors (88.4%) and GLP-1 receptor agonists (35.7%) use. The primary endpoint was achieved by 52.7%, consistently across background renoprotection or baseline KDIGO risk strata. Predictors of response were age ≥ 70 (aOR 2.12), baseline UACR > 245 mg/g (aOR 1.94), and BMI > 27 kg/m2 (aOR 1.84), while insulin use was associated with lower response odds. Treatment persistence was 89.5%, with low incidences of hyperkalaemia (4.8%), MAKE (0.9%), and MACE (1.1%).
In real-world practice, finerenone was associated with a substantial reduction in albuminuria. Finerenone demonstrated high persistence and a favourable safety profile, irrespective of baseline renoprotective regimens or KDIGO risk.
]]>Evidence on psychological, cognitive and functional outcomes of advanced diabetes technologies in older adults with long-standing type 1 diabetes (T1D) remains limited. We evaluated whether initiation of advanced hybrid closed-loop (AHCL) therapy was associated with changes in fear of hypoglycaemia, diabetes distress, psychological well-being, cognition, frailty-related measures and mobility-related function in adults aged ≥ 65 years with T1D.
This prespecified, exploratory secondary analysis was conducted within a single-centre, open-label, randomised, controlled, parallel-group trial including adults aged ≥ 65 years with long-standing T1D. Participants were randomly assigned (1:1) to initiate AHCL therapy using the MiniMed 780G system or to continue standard diabetes treatment. The secondary outcomes included WHO-5, the 17-item Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey-II (HFS-II), Montreal Cognitive Assessment, Digit Symbol Substitution Test, Fried frailty phenotype and performance-based functional measures. No formal sample-size calculation was performed for these secondary outcomes.
Thirty-one participants were randomised and 29 completed 12 months of follow-up and were included in the treatment-effect analyses. In the baseline-adjusted primary analysis, AHCL therapy was associated with a lower HFS-II score than standard treatment (adjusted mean difference −18.9; 95% CI: −32.4 to −5.4; nominal p = 0.008), although this finding did not remain statistically significant after Holm correction (adjusted p = 0.104) or in an exploratory model additionally adjusted for sex (difference −13.6; 95% CI: −32.2 to 5.0; p = 0.145). Diabetes distress, psychological well-being, global cognition and processing speed did not differ between groups. In sex-adjusted sensitivity analyses, the between-group differences remained statistically significant for 6-min walk distance (92.6 m; 95% CI: 36.8 to 148.3; p = 0.002) and Timed Up and Go performance (−2.27 s; 95% CI: −4.28 to −0.27; p = 0.028), but not for gait speed (0.27 m/s; 95% CI: −0.05 to 0.59; p = 0.099). At 12 months, 12 of 14 AHCL participants were robust and 2 were pre-frail; in the control group, 11 of 15 were robust and 4 were pre-frail. No participant was classified as frail at follow-up.
In this small, selected cohort, AHCL therapy was associated with a nominally lower fear-of-hypoglycaemia score and better performance on selected mobility-related tests over 12 months. The fear-of-hypoglycaemia finding did not remain statistically significant after correction for multiple comparisons or additional adjustment for sex. Six-minute walk distance and Timed Up and Go remained statistically significant in the exploratory sex-adjusted sensitivity analyses, whereas the gait-speed difference did not. No measurable between-group deterioration in global cognition or processing speed was observed. These exploratory findings require confirmation in larger studies with balanced representation by sex and direct measurement of physical activity. These findings also support a person-centred clinical message: older age alone should not be regarded as a barrier to AHCL when treatment is introduced with individualised education and appropriate ongoing support.
]]>To estimate the societal costs of Type 1 diabetes (T1D) in France, including direct and indirect costs.
We conducted a descriptive retrospective cross-sectional study on all adult patients (aged 18 and over) with T1D identified in the SFDT1 cohort and compared them to a matched cohort of patients without diabetes considering age, gender, deprivation status and geographical area. An Insurance claim data analysis was conducted for the year 2023 individually and then extrapolated to all of France. Costs were broken down by expense categories and insulin delivery devices.
The average individual societal cost of T1D in France in 2023 compared with the absence of diabetes was estimated at €9940 (€9340 when considering direct costs only). Nearly half of the identified costs were attributable to the use of medical devices. An analysis stratifying patients by treatment modality (closed-loop, pump or multiple daily injections) highlighted the significant costs associated with the use of the most advanced technologies for delivering insulin (average costs were respectively €13 557, €11 062, and €7004, respectively). The total cost of T1D in France was estimated at between €1.59 and €1.79 billion in 2023 excluding undiagnosed cases and premature mortality associated with the disease.
Our results suggest that the most advanced insulin delivery devices have a significant short-term economic impact. Although this paper does not cover the research, model-based studies do suggest that there are some advantages to using such devices, including potential future savings due to lower complication rates.
]]>Type 5 Diabetes Mellitus (T5DM) is an emerging diabetes phenotype linked to chronic undernutrition. It predominantly affects young, lean individuals in low- and middle-income countries. After its formal recognition by the International Diabetes Federation in 2025, T5DM resurfaced as a clinically relevant insulin-deficient phenotype. It is now viewed as distinct from classical autoimmune and insulin-resistant forms of diabetes. This review synthesises recent evidence on the epidemiology, pathophysiology, clinical characteristics, and management of T5DM. Recent studies show that T5DM is influenced by early-life nutritional deprivation. This fits within the Developmental Origins of Health and Disease (DOHaD) framework. Undernutrition during key developmental periods harms pancreatic morphogenesis. It creates a permanent reduction of functional beta-cell mass through epigenetic programming. Clinically, T5DM often appears before age 30. Patients have low body mass index, sarcopenia, marked insulinopenia, absence of diabetes-associated autoantibodies, and resistance to ketosis, despite significant hyperglycemia. Diagnostic challenges remain, as patients are frequently misclassified as type 1 or type 2 diabetes. Relying only on body mass index is insufficient. Accurate diagnosis requires a multidimensional assessment including nutritional history, metabolic features, and exclusion of monogenic diabetes. T5DM is a distinct insulin-deficient phenotype caused by chronic undernutrition. Effective management requires more than glycaemic control. Nutritional rehabilitation is key, with a focus on adequate energy intake, high–biological–value protein supplementation, and correction of key micronutrient deficiencies. Given preserved insulin sensitivity, low-dose insulin should be used cautiously to avoid iatrogenic hypoglycemia. Better recognition and tailored management strategies are needed for optimal clinical outcomes.
]]>To assess the feasibility of a decentralised response-guided trial and to characterise urinary albumin-to-creatinine ratio (UACR) responses to empagliflozin and finerenone in type 2 diabetes and chronic kidney disease (CKD).
Adults with type 2 diabetes, estimated glomerular filtration rate (eGFR) ≥ 25 mL/min/1.73 m2, and UACR > 4.5 mg/mmol (> 40 mg/g) were enrolled in a decentralised response-guided trial. Participants completed study procedures remotely and received empagliflozin 10 mg once daily for 3 weeks. Based on predefined UACR response thresholds during empagliflozin treatment, participants entered a 4-week second treatment phase with continuation of empagliflozin, add-on finerenone or substitution with finerenone. Primary outcomes were feasibility measures, including participant-reported acceptability, sample delivery and completion of home measurements. Exploratory outcomes included changes in UACR.
Eleven participants completed the study (mean [SD] age 69.6 [6.1] years; mean eGFR 61.1 [24.8] mL/min/1.73 m2; median [IQR] UACR 246.9 mg/g [102.8–457.7]). All predefined feasibility criteria were met: urine and capillary blood sample delivery rates were 100% and 98.8%, respectively; home blood pressure and body weight completion rates were 91.3% and 98.6%. During empagliflozin monotherapy, UACR changed by −18.7% overall, after which nine participants (81.8%) initiated empagliflozin–finerenone combination therapy and 2 (18.2%) switched to finerenone monotherapy. UACR was further reduced by 40.1% after finerenone addition and by 34.0% after finerenone substitution, relative to the end of empagliflozin monotherapy. No serious adverse events or hyperkalaemia events were observed during treatment with empagliflozin, finerenone, or their combination.
A decentralised response-guided trial was feasible and safe, supporting further evaluation of this approach for individualised optimisation of kidney-protective therapy in type 2 diabetes and CKD.
Trial Registration:
ClinicalTrials.gov Identifier: NCT06094920.
To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 [500 U/mL]; AT278-U500) compared with standard concentration insulin aspart (InsAsp [100 U/mL]; InsAsp-U100) and U500 human regular insulin (HumIns [500 IU/mL]; HumIns-U500).
This single-centre, randomised, double-blind crossover 12-h euglycaemic clamp study was conducted in 41 overweight and obese people with type 2 diabetes (BMI 25.0–38.7 kg/m2) receiving a single subcutaneous dose (0.5 U/kg) of AT278-U500 and InsAsp-U100. HumIns-U500 was consecutively studied open label in a 24-h clamp.
AT278-U500 exhibited a significantly faster insulin absorption than InsAsp-U100 and HumIns-U500 (t
Early50%Cmax: 9 min vs. 35 min vs. 55 min), leading to a significantly higher glucose-lowering effect within the first hour (AUCGIR,0-60min) compared with both InsAsp-U100 (treatment ratio 2.02 [95% CI 1.64; 2.50]) and HumIns-U500 (3.91 [2.89; 5.27]). When divided by median BMI (29.7 kg/m2), AUCGIR,0-60min was significantly higher with AT278-U500 in both the low-BMI and high-BMI subgroup compared to InsAsp-U100. Linear regression showed a significant inverse relationship between BMI and AUCGIR,0-60min for InsAsp-U100 (slope −0.142, p < 0.0001), whereas AT278-U500 showed no such relationship. Overall insulin exposure was similar for AT278-U500 and InsAsp-U100, while overall glucose-lowering effect was comparable across all three treatments.
AT278-U500 maintains its ultra-rapid onset characteristics independent of BMI, representing the first ultra-rapid U500 option for prandial dosing in insulin-resistant people with type 2 diabetes requiring high-dose therapy.
Trial Registration: ClinicalTrials.gov identifier: NCT05754424
]]>To assess the effect of all the approved classes of medications for type 2 diabetes on Major Adverse Cardiovascular events (MACE) and all-cause mortality.
We performed a pairwise and network meta-analysis, including randomised controlled trials with a duration of at least 40 weeks, comparing medications versus placebo or an active comparator, in which MACE and deaths were adjudicated.
We included 93 studies. In pairwise meta-analyses, versus all comparators, GLP-1 receptor agonists (GLP1RA), SGLT-2 inhibitors (SGLT2i), metformin and pioglitazone were associated with a significant reduction of MACE and sulfonylureas with increased MACE. Furthermore, tirzepatide, SGLT2i and GLP1RA were associated with a significantly reduced all-cause mortality. In the principal (frequentist) network meta-analysis, metformin (OR 0.69, 95% CI 0.53–0.89), SGLT2i (0.82, 0.75–0.90), GLP1RA (0.87, 0.83–0.92) and tirzepatide (0.82, 0.72–0.93) were associated with a significant reduction of MACE versus placebo; no effect was observed for insulin, DPP4 inhibitors (DPP4i) or sulfonylureas. Tirzepatide (0.72, 0.64–0.82), SGLT2i (0.85, 0.80–0.91) and GLP1RA (0.85, 0.80–0.91) were associated with a significantly reduced mortality versus placebo; no effect was detected for other drugs. The sensitivity (Bayesian) analysis did not confirm the significance of results for pioglitazone on MACE. The certainty of evidence was moderate-to-high for GLP1RA, SGLT2i, Tirzepatide, DPP4i; low for metformin; low-to-moderate for other drugs.
SGLT2i, GLP1RA, tirzepatide and (with lower quality of evidence) pioglitazone and metformin are associated with a reduced incidence of cardiovascular events; tirzepatide, SGLT2i and GLP1RA are also associated with a reduced all-cause mortality.
]]>This study aims to systematically evaluate the efficacy of bimagrumab on body composition and glucose parameters in adults with obesity and metabolic dysfunction and its safety profile.
We searched MEDLINE, PubMed, Embase, and the Cochrane Library on April 20, 2026, for randomized controlled trials (RCTs) assessing bimagrumab treatment in adults with obesity, insulin resistance, or type 2 diabetes mellitus (T2DM). The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2), and meta-analyses of efficacy and safety data were conducted using R software. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system was used to assess the strength of evidence. The study was registered with PROSPERO (CRD420261377110).
Of the 134 retrieved records, 4 RCTs (enrolling 268 participants) were included. The included population represented a broad spectrum of metabolic dysfunction, from obesity and nondiabetic insulin resistance to established T2DM. Compared with placebo, bimagrumab treatment significantly reduced total weight (mean difference [MD] –4.85 kg, 95% confidence interval [CI] –6.82 to −2.88), fat mass (−4.72 kg [−8.05 to −1.40]), and glycated haemoglobin (HbA1c) (−0.13% [−0.23 to −0.03]) and significantly increased total lean mass (1.66 kg [0.81 to 2.51]). However, bimagrumab led to an increase in low-density lipoprotein (LDL) concentrations of 0.47 mmol/L [0.03 to 0.91] and significantly increased incidences of discontinuation (risk ratio [RR] 5.75 [1.61 to 20.46]), muscle spasms (RR 10.44 [4.23 to 25.75]), and diarrhoea (RR 4.91 [2.38 to 10.11]).
Bimagrumab effectively reversed adverse effects on body composition in obese individuals, resulting in significant fat reduction, increased skeletal muscle mass, and improved glycemic control, suggesting that bimagrumab is a promising new target for personalized metabolic therapy.
]]>Islet-resident macrophages (IRMs) have emerged as important regulators of pancreatic islet biology, operating at the intersection of metabolism and immunity. Beyond their classical roles as immune sentinels, accumulating evidence indicates that IRMs dynamically integrate β-cell activity, environmental cues, and metabolic stress, thereby coordinating islet homeostasis, adaptive remodelling, and disease progression. However, their context-dependent functions and therapeutic potential remain incompletely understood.
This review summarizes current evidence regarding IRM origins, phenotype, metabolic plasticity, and bidirectional crosstalk with β cells in health, type 1 diabetes, and type 2 diabetes. We further review emerging therapeutic concepts targeting macrophage metabolism, intercellular communication, and organelle function, while discussing current challenges in translating findings from murine IRMs to human disease.
Under physiological conditions, IRMs maintain islet integrity through surveillance, efferocytosis, trophic signalling, redox control, and maintenance of intercellular communication within the islet niche. In diabetes, chronic glucolipotoxicity, autoimmunity, oxidative stress, and amyloid-associated injury can redirect these homeostatic programs toward maladaptive inflammatory states that impair insulin secretion and accelerate β-cell loss. Collectively, these findings support a unified framework in which IRMs act as immunometabolic hubs integrating local and systemic signals to determine β-cell fate.
IRMs represent central immunometabolic hubs that orchestrate β-cell fate during health and diabetes. Emerging therapeutic strategies targeting macrophage metabolism, intercellular communication, and organelle function may help prioritize future mechanistic studies and guide safer macrophage-centered interventions for diabetes.
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