Diabetes Therapy最新文献

The incidence of youth-onset type 2 diabetes (Y-T2D) has been increasing over the last two decades in line with the growing rate of childhood obesity. Prior to 2019, the only United States Food and Drug Administration (FDA)-approved therapies for Y-T2D were metformin and insulin, and the current consensus guidelines recommend these therapies as first-line treatment. While metformin has a known safety profile and early efficacy for glycemic control, it has not been shown to prevent β-cell dysfunction or exogenous insulin requirements. Insulin is effective in treating hyperglycemia, but can result in hypoglycemia and further weight gain, worsening insulin resistance in Y-T2D. Furthermore, longitudinal data from participants treated early in their disease course with metformin and insulin demonstrate a cumulative incidence of at least one diabetes complication in most participants within 13 years of diagnosis. Over the last five years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) have been added to the management toolbox for Y-T2D. However, further research is needed to determine the best timing and use for these medications for Y-T2D. The goal of this narrative review is to describe the current evidence for treatment with SGLT-2is and GLP-1RAs for Y-T2D within the first 1-2 years of the disease process.

Introduction: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are established for cardiorenal benefits in type 2 diabetes mellitus (T2DM), prior meta-analyses have not fully integrated cross-class comparisons or net benefit analyses with updated cardiovascular outcome trials (CVOTs).

Methods: We conducted a systematic review and meta-analysis of 17 CVOTs (N = 132,038; GLP-1RA: N = 73,263; SGLT-2i: N = 58,775) using PubMed and Cochrane CENTRAL. We uniquely synthesized major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), renal composites, and safety outcomes (e.g., retinopathy, genitourinary infections) with random-effects models for hazard ratios (HRs) and relative risks (RRs). Innovative graphical syntheses (tornado/scatter plots, risk curves) and net benefit calculations (absolute risk reductions [ARRs] minus absolute excess risks [AERs]) were employed. Risk of bias (RoB 2) and GRADE certainty were assessed.

Results: Both classes reduced MACE (HR 0.87, 95% CI 0.84-0.90; p = 0.73 for class difference). SGLT-2is were superior for hHF (HR 0.69 vs. 0.88, p < 0.0001) and renal outcomes (HR 0.68 vs. 0.79, p = 0.026). GLP-1RAs increased retinopathy (RR 1.18, AER + 6.5/1000); SGLT-2is increased genitourinary infections (RR 3.34, AER + 19.9/1000) and DKA (RR 2.67, AER + 1.2/1000). Amputation signals attenuated post-sensitivity analysis. Net benefits favored GLP-1RAs for MACE (+ 2.5/1000). For SGLT-2is, base-case estimates using genital-mycotic infections as the sentinel harm were marginal (hHF: - 4.9/1000; renal: - 1.9/1000), whereas sensitivity scenarios with alternative harms (e.g., volume depletion, amputation, DKA) yielded positive net benefits. GRADE certainty was high for efficacy, moderate for harms.

Conclusions: Our innovative integration of updated CVOTs, cross-class comparisons, and graphical risk-benefit tools refines therapeutic decision-making, highlighting tailored T2DM management based on patient-specific cardiorenal risks.

Trial registration: PROSPERO (CRD420251146788).

Cardiac arrest continues to be a predominant cause of mortality worldwide, necessitating its rapid identification, and intervention by reversible aetiologies to optimise successful outcomes. The established 4H 4T framework has served as a foundational guide for advanced life support (ALS) protocols since its formal introduction in the 2000 International Guidelines on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC), effectively targeting critical conditions such as hypoxia, hypothermia, hypo-/hyperkalaemia, hypovolaemia, tension pneumothorax, cardiac tamponade, thrombosis, and exposure to toxins. However, this framework inadequately addresses other significant factors: specifically hypoglycaemia and tachy- and bradyarrhythmias. Hypoglycaemia, a reversible and treatable metabolic state, poses substantial threats to cardiovascular stability, particularly in people with diabetes and in association with sepsis. It disrupts myocardial repolarisation, prolongs the QT interval, and may instigate the R-on-T phenomenon, which can precipitate life-threatening arrhythmias. Likewise, tachyarrhythmias and bradyarrhythmias often precipitate cardiac arrest, thereby warrant dedicated attention within ALS protocols. This paper advocates expanding the current 4H 4T framework to include hypoglycaemia and tachy- and bradyarrhythmias as critical and reversible causes of cardiac arrest (5H 5T). The rationale for such a paradigm shift is supported by evidence from clinical studies, case reports, and experimental models that demonstrate the adverse effect of these conditions on cardiovascular integrity and alert clinicians to look for these reversible factors. The inclusion of these factors into ALS protocols will necessitate revising resuscitation guidelines, modifying training for healthcare practitioners, and including systematic monitoring of blood glucose alongside routine assessment of cardiac rhythm during resuscitation procedures. Future research should focus on elucidating the pathophysiological mechanisms underlying these conditions, to establish operational thresholds for intervention, and validate their integration into resuscitation frameworks. By expanding the conceptualisation of reversible causes, the proposed 5H/5T framework would offer a more rational and practical approach to the management of cardiac arrest, to improve the survival and recovery of these critically ill patients.

Introduction: FreeStyle Libre (FSL) systems are effective and user-friendly glucose monitoring devices. This cost-effectiveness analysis compared FSL vs. self-blood glucose monitoring (SBGM) in patients with poorly controlled [hemoglobin A1c (HbA1c) > 8%] type 2 diabetes (T2DM) on basal insulin, from the Spanish National Health System perspective.

Methods: The DEDUCE model, which simulated 10,000 patients with T2DM over a 50 years' time horizon (annual discount rate = 3.00%), was adapted to the Spanish setting. The population characteristics, frequency of acute and chronic diabetic complications, costs (€, 2025) and utilities/disutilities proceeded from scientific literature and were validated by national multidisciplinary experts. The annual probabilities of acute events associated with SBGM were 17.02% for non-severe hypoglycemia (SHE) (€3.92; disutility = - 0.0016), 2.50% for SHE (€1031.69; disutility = - 0.0470) and 0.25% for ketoacidosis (DKA) (€2523.93; disutility = - 0.0470). The RECODe risk engine was used to model chronic diabetic complications (myocardial infarction [€1248.44-€31,013.22; disutility = - 0.0550]; heart failure [€1523.14-6505.08; disutility = - 0.1080]; stroke [€3187.92-7849.48; disutility = - 0.1640]; blindness [€2943.37; disutility = - 0.0740]; renal failure [€4057.05-42,757.39; disutility = - 0.2040]). According to the Spanish recommendations, a patient with SBGM required 2.5 reactive strips/day and 2.5 lancets/day (€0.57/strip; €0.14/lancet; VAT included). FSL (26 sensors/year; €3.00/day; VAT included) was associated with reductions of 58% in hypoglycemia, 68% in DKA, 83% in the use of strips/lancets, and an absolute decrease of 1.1% in HbA1c. Deterministic and probabilistic sensitivity analyses (SAs) were conducted.

Results: While SBGM yielded 9.18 quality-adjusted life years (QALYs) and total costs of €77,092 (glucose monitoring = €17,080; diabetic complications = €68,272), FSL yielded 9.98 QALYs and total costs of €61,447 (glucose monitoring = €8820; diabetic complications = €44,367). Compared with SBGM, FSL produced total cost savings of €15,645 and 0.80 additional QALYs per patient, being a dominant alternative compared to SBGM. FSL was found to be dominant in all SAs.

Conclusions: This analysis suggests that FSL, which provides better clinical outcomes at a lower overall cost, is a preferable alternative to SBGM among people with poorly controlled T2DM on basal insulin.

Tirzepatide is the first dual long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist indicated for the treatment of type 2 diabetes in adults, for reducing excess body weight and maintaining long-term weight reduction in adults with obesity or overweight and at least one weight-related comorbid condition, and for treating obstructive sleep apnea in adults with obesity. Recent studies found beneficial effects on heart failure with preserved ejection fraction and on metabolic dysfunction-associated steatohepatitis; its effects on cardiovascular outcomes in people with type 2 diabetes, as well as on reducing morbidity and mortality in people with obesity/overweight, remain under investigation. Here, we review the mechanistic activity of tirzepatide and its effect on glycemic control, body weight, the cardiorenal system, and lipid metabolism.

Introduction: Ipragliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor approved in Japan as an adjunct to insulin therapy for the management of type 1 diabetes (T1D). Diabetic ketoacidosis (DKA) and severe hypoglycemia (SH) have been specified as important identified risks for ipragliflozin; however, real-world data on the incidences of these events are limited. We compared the incidences of initial DKA and SH in patients with T1D newly treated with ipragliflozin in combination with insulin versus those treated with insulin.

Methods: This post-marketing surveillance study used data from the JMDC Claims Database between June 2018 and December 2021. Using propensity score matching, patients with T1D were matched 1:10 to the ipragliflozin/insulin group and insulin group. For each treatment group, incidence rates (IRs) of DKA and SH were plotted on a Kaplan-Meier curve, and IRs per 1000 patient-years (PY) were calculated. The risks of DKA and SH were compared between the treatment groups by calculating the hazard ratios (HRs) and 95% confidence intervals (CIs) using a Cox proportional-hazards model.

Results: The incidence of DKA was not significantly different between the ipragliflozin/insulin and the insulin groups (log-rank p = 0.793); the IRs of DKA were 8.3 and 8.5 per 1000 PY, respectively (HR 0.902, 95% CI 0.418‒1.945; p = 0.792). The incidence of SH was significantly lower in the ipragliflozin/insulin group versus the insulin group (log-rank p = 0.001). The IRs of SH per 1000 PY were 6.6 and 21.7, respectively (HR 0.284, 95% CI 0.126‒0.637; p = 0.002).

Conclusions: Ipragliflozin/insulin combination therapy showed no difference in the incidence of DKA, but a lower incidence of SH, versus insulin therapy in patients with T1D in Japan. These results suggest that ipragliflozin treatment is not associated with increased incidences of initial DKA or SH; however, its use should be accompanied by appropriate monitoring, education, and risk mitigation strategies to minimize the occurrence of these events.

Introduction: Tirzepatide is recommended as a first-line injectable for people with type 2 diabetes (T2D), but there is a paucity of data on the use of basal insulin after tirzepatide in this population. This study aimed to evaluate glycemic control in people with T2D newly intensified with insulin glargine 300 U/ml (Gla-300) who had suboptimal HbA1c after treatment with tirzepatide.

Methods: DELIVER-T was a retrospective analysis of the US Optum's Clinformatics^® Data Mart from January 1, 2022 to August 31, 2024. People with T2D were included if they were insulin naïve and were previously treated with tirzepatide and then intensified with Gla-300. The primary analysis (Gla-300 switch/add-on group) included all those with a HbA1c > 7.0% at baseline who either switched from tirzepatide to Gla-300 or who added Gla-300 to tirzepatide. The primary endpoint was the change in HbA1c levels from baseline to 6 months. Secondary endpoints included reaching HbA1c target < 7.0% and any hypoglycemia.

Results: In total, 82 people had a HbA1c > 7.0% at baseline and were included in the primary analysis (Gla-300 switch/add-on group). The mean (SD) change in HbA1c from baseline to 6 months was - 1.3% (2.0; p = 0.0027) for the primary analysis (Gla-300 switch/add-on group). The proportion of participants reaching the target of HbA1c < 7.0% at 6 months was 26.8% (n = 22) for the primary analysis (Gla-300 switch/add-on group). No hypoglycemic events were captured in the database during the 6-month follow-up period.

Conclusions: In insulin-naïve people with T2D who had suboptimal HbA1c with tirzepatide, significant reductions in HbA1c and improvements in the percentage of people reaching HbA1c target of < 7.0% were observed with Gla-300. Infographic and video abstract available for this article. Please follow the digital features link under the abstract. A video abstract of the Deliver-T study, which evaluated glycaemic control in people with T2D previously treated with tirzepatide and newly intensified with insulin glargine 300 U/mL (Gla-300).

Introduction: Metformin is widely recommended as a first-line therapy for patients with type 2 diabetes; however, evidence supporting its effects on cardiovascular outcomes is limited and derived from older studies. Furthermore, there is little direct evidence that demonstrates the protective effect of metformin on renal events. By contrast, sodium-glucose cotransporter 2 (SGLT2) inhibitors have consistently shown benefits in reducing cardiovascular and renal events. This study aims to directly compare the effects of an SGLT2 inhibitor and metformin on the urinary albumin-to-creatinine ratio (UACR), which is a marker of diabetic nephropathy and endothelial dysfunction.

Methods: This article presents the study protocol for a multicenter, randomized, open-label, controlled trial that evaluates the efficacy of the SGLT2 inhibitor tofogliflozin versus metformin on UACR in patients with type 2 diabetes and diabetic kidney disease (DKD). A total of 120 participants with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m² and UACR between 30 and 2000 mg/gCr will be enrolled. Participants will be randomized (1:1) to receive either tofogliflozin or metformin and will be stratified using baseline UACR (< 300 or ≥ 300 mg/gCr), eGFR (< 60 or ≥ 60 mL/min/1.73 m²), and age (< 65 or ≥ 65 years).

Planned outcomes: The primary endpoint is the change in UACR from baseline at 52 weeks. The secondary endpoints include changes in UACR at 26 and 104 weeks (absolute and percentage changes); slope of eGFR decline; and changes in hemoglobin A1c, body weight, and blood pressure. If tofogliflozin demonstrates a superior reduction in albuminuria, SGLT2 inhibitors may be considered an alternative first-line therapy in selected patients with type 2 diabetes and DKD.

Trial registration: jRCTs031210339; Clinicaltrials.gov (NCT05469659).

Introduction: Once-weekly semaglutide has proven to be a safe and effective treatment for type 2 diabetes; however, clinical trial data on Asian populations are limited, warranting real-world data (RWD). In this study we assessed the effectiveness and safety of semaglutide in Japanese patients with type 2 diabetes using RWD.

Methods: A retrospective analysis was conducted at five diabetes centers in Japan between December 2019 and June 2022. Changes in hemoglobin A1C (HbA1c), body weight (BW), lipid parameters, liver/kidney function, and adverse events were assessed over 52 weeks. Subgroup analyses were stratified by glucagon-like peptide-1 receptor agonist (GLP-1RA)-naïve users versus prior GLP-1RA users (GLP-1RA switch group), baseline body mass index (BMI) (< 30 or ≥ 30 kg/m²), and alanine aminotransferase (ALT) level (≤ 30 or > 30 U/L).

Results: Of the 503 patients included in the study, 270 (mean age 53 years; 61.8% men; mean duration of diabetes 10.7 years) were included in the per-protocol analysis. Mean (± standard deviation) baseline HbA1c and BMI were 8.1 ± 1.5% and 31.7 ± 6.2 kg/m², respectively; 52% patients were prior GLP-1RA users. HbA1c level had fallen by approximately 0.9% at both 26 and 52 weeks after treatment initiation (p < 0.001), with BW reductions of - 3.2 kg at 26 weeks and - 4.3 kg at 52 weeks (p < 0.001). Lipid profiles and liver function improved significantly (p < 0.001). Compared to prior GLP-1RA users, GLP-1RA-naïve patients showed greater reductions in HbA1c level (- 1.2% vs. - 0.8%, p = 0.009) and BMI (- 1.6 vs. - 1.2 kg/m², p = 0.03). Patients with BMI ≥ 30 kg/m² had a larger reduction in BMI than those with BMI < 30  kg/m² (- 1.7 vs. - 1.1 kg/m², p = 0.002), and those with ALT > 30 U/L showed greater HbA1c reduction (- 1.2% vs. - 0.8%, p = 0.04) and improved liver function than those with ALT ≤ 30 U/L. Gastrointestinal adverse events occurred in 53.7% of patients, leading to discontinuation of treatment in 7.6%.

Conclusions: Once-weekly semaglutide improved glycemic control, BW, lipid profiles, and liver function in Japanese patients with type 2 diabetes in RWD and subgroup analyses, supporting a broad effectiveness range. The rate of gastrointestinal adverse events in the RWD was comparable to that in prospective clinical studies.

Registration: University hospital Medical Information Network Clinical Trial Registry No.: UMIN000050499).

Early gestational diabetes mellitus (eGDM) is a condition identified during early pregnancy, characterized by glucose levels that are neither normal nor high enough to meet the criteria for overt diabetes. eGDM is associated with adverse pregnancy and postpartum outcomes, but owing to its heterogeneity, management remains challenging. Women with eGDM can be categorized into distinct phenotypes: mild, moderate, and severe, based on glycemic levels, response to behavioral interventions, and associated risk factors. Additionally, some women with eGDM regress to normoglycemia, while others with early normoglycemia may develop gestational diabetes later ("potential GDM"). Precision medicine offers a tailored approach to managing eGDM, emphasizing individualized treatment plans to optimize outcomes and minimize harm. Future research should focus on refining diagnostic criteria, identifying phenotypes early, and implementing personalized management strategies. This commentary highlights the need for a nuanced understanding of eGDM to improve maternal and neonatal health.