Consistent glycaemic efficacy and safety of concomitant use of iGlarLixi and sodium-glucose co-transporter-2 inhibitor therapy for type 2 diabetes: A patient-level pooled analysis of three randomised clinical trials.

AIMS: Sodium glucose co-transporter 2 inhibitors (SGLT2is) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardio- and reno-protective benefits are recommended in people with type 2 diabetes (T2D) at high risk of cardiovascular disease, chronic kidney disease, and/or heart failure. This pooled analysis compared efficacy and safety outcomes of iGlarLixi with or without SGLT2is in people with T2D. METHODS: This post hoc analysis evaluated outcomes in participants who were receiving an SGLT2i when initiating iGlarLixi (SGLT2i users) and those who were not (SGLT2i non-users) in a pooled dataset from three trials: LixiLan-G (advancing from a GLP-1 RA), SoliMix and LixiLan ONE CAN (advancing from basal insulin). RESULTS: Baseline characteristics were generally similar between 219 users and 746 non-users. Least squares mean changes in HbA1c from baseline to Week 26 were similar for users (-1.2 % [95 % confidence intervals: -1.4 %, -1.1 %]) and non-users (-1.2 % [-1.2 %, -1.1 %]). Changes in body weight, fasting glucose and post-prandial glucose were similar between groups, as were hypoglycaemic events. CONCLUSIONS: Pooled results from three studies of adults with T2D demonstrated that iGlarLixi provided similar clinically meaningful improvements in glycaemic control without increased hypoglycaemia risk, regardless of concomitant use of SGLT2is.

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post-hoc analysis of the PROCEED trial.

AIMS: To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS: This was a post-hoc analysis of the PROCEED trial, which evaluated the effect of 24-week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post-treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium-glucose co-transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. RESULTS: The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3-0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3-3.1; p < .001) and erythropoietin (estimated log-transformed group difference, 0.1; 95% CI, 0.01-0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (ß = 0.253, p < .001) or haematocrit (ß = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, -7.94%; 95% CI, -11.6 to -4.26%; p < .001) and estimated extracellular volume (estimated group difference, -181.6 ml; 95% CI, -275.7 to -87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group. CONCLUSIONS: Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. CLINICAL TRIAL: PROCEED trial (registration number: jRCTs071190054).

Sodium-glucose co-transporter 2 inhibitor therapy reduces the administration frequency of anti-vascular endothelial growth factor agents in patients with diabetic macular oedema with a history of anti-vascular endothelial growth factor agent use: A cohort study using the Japanese health insurance claims database.

AIM: We assessed the effectiveness of sodium-glucose co-transporter 2 inhibitors (SGLT2is) in reducing the administration frequency of anti-vascular endothelial growth factor (VEGF) agents in patients with diabetic macular oedema (DMO) using a health insurance claims database. MATERIALS AND METHODS: This retrospective cohort study analysed health insurance claims data covering 11 million Japanese patients between 2005 and 2019. We analysed the frequency and duration of intravitreal injection of anti-VEGF agents after initiating SGLT2is or other antidiabetic drugs. RESULTS: Among 2412 matched patients with DMO, the incidence rates of anti-VEGF agent injections were 230.1 per 1000 person-year in SGLT2i users and 228.4 times per 1000 person-year in non-users, respectively, and the risk ratio for events was unchanged in both groups. Sub-analysis of each baseline characteristic of the patients showed that SGLT2is were particularly effective in patients with a history of anti-VEGF agent use [p = .027, hazard ratio (HR): 0.44, 95% confidence interval (CI): 0.22-0.91]. SGLT2is reduced the risk for the first (p = .023, HR: 0.45, 95% CI: 0.22-0.91) and second (p = .021, HR: 0.39, 95% CI: 0.17-0.89) anti-VEGF agent injections. CONCLUSIONS: There was no difference in the risk ratio for the addition of anti-VEGF therapy between the two treatment groups. However, the use of SGLT2is reduced the frequency of anti-VEGF agent administration in patients with DMO requiring anti-VEGF therapy. Therefore, SGLT2i therapy may be a novel, non-invasive, low-cost adjunctive therapy for DMO requiring anti-VEGF therapy.

Sodium-glucose co-transporter 2 inhibitors in acute heart failure: real-world prescription trends and outcomes analysis.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown potential therapeutic benefits in heart failure (HF). However, data on their real-world usage and benefits in acute decompensated heart failure (ADHF) are limited. METHODS AND RESULTS: We conducted a post hoc analysis of real-world data from 1108 patients with ADHF admitted to Nihon University Itabashi Hospital (Tokyo, Japan) between 2018 and 2022. Patients were divided into two groups based on the prescription of SGLT2 inhibitors during hospitalization: an SGLT2 inhibitor group (SGLT2i group) (n = 289) and a non-SGLT2i group (n = 819). The primary endpoints were death and rehospitalization for HF after discharge. The median age was 76 [interquartile range (IQR): 66, 83] years, and 732 patients (66%) were male. Data showed an increasing trend in the prescription of SGLT2 inhibitors since 2021. During a median follow-up period of 366 days (IQR: 116, 614), 458 (41.3%) patients reached the primary endpoint. The Kaplan-Meier analysis showed that the SGLT2i group had a significantly lower rate of composite events than the non-SGLT2i group, both overall (log-rank test, P < 0.001) and in the following left ventricular ejection fraction (LVEF) subgroups: HF with reduced ejection fraction (EF) (n = 413), HF with mildly reduced EF (n = 226), and HF with preserved EF (n = 466) (log-rank test; P = 0.044, P = 0.013, and P = 0.001, respectively). Furthermore, patients starting SGLT2 inhibitors during hospitalization had a significantly lower rate of composite events than those not using SGLT2 inhibitors (log-rank test, P < 0.001). This association was also significant in the LVEF subgroups (P = 0.005, P = 0.032, and P = 0.004, respectively). CONCLUSIONS: The prescription and initiation of SGLT2 inhibitors during hospitalization are associated with improved post-discharge outcomes in patients with ADHF, irrespective of LVEF.

Impact of Early Intervention with Triiodothyroacetic Acid on Peripheral and Neurodevelopmental Findings in a Boy with MCT8 Deficiency

Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disorder characterized by peripheral thyrotoxicosis and severe cognitive and motor disability due to cerebral hypothyroidism. 3,3',5-triiodothyroacetic acid (Triac) was shown to improve peripheral thyrotoxicosis but data on neurodevelopmental outcome are scarce. We present a case of MCT8 deficiency and the experience with Triac focusing on change in neurodevelopmental and peripheral features. A five-month-old boy was referred because of feeding difficulty, central hypotonia and global developmental delay. Despite six months of physiotherapy, physical developmental milestones did not improve, and distal muscle tone was increased. A hemizygous pathogenic variant in SLC16A2 was found and MCT8 deficiency was confirmed at 19-months. Thyroid stimulating hormone was 2.83 mIU/mL, free thyroxine 6.24 pmol/L (N=12-22) and free triiodothyronine (FT3) 15.65pmol/L (N=3.1-6.8). He had tachycardia, blood pressure and transaminases were elevated. Triac was started at 21-months. Two weeks after treatment, FT3 dramatically decreased, steady normal serum FT3 was achieved at 28-months. Assessment of neurodevelopmental milestones and signs of hyperthyroidism were evaluated at baseline, 6 months and 12 months after treatment. Signs of hyperthyroidism were improved by 6 months. Developmental composite scores of Bayley Scales of Infant Developmental 3rd Edition remained the same but important developmental milestones (head control, recognition of caregiver, response to his name) were attained, regression in the attained milestones were not observed. Initial dose, management protocol for Triac and research into its efficacy on neurodevelopmental signs in MCT8 deficiency are progressing. This case presents evidence that Triac may resolve peripheral thyrotoxicosis successfully and may slow neurodevelopmental regression, while some developmental milestones were achieved after one year of treatment.

SGLT2 Inhibitors to Slow Chronic Kidney Disease Progression: A Review.

PURPOSE: One in seven Americans is at risk for chronic kidney disease (CKD). For decades, the only treatment proven to slow progression of CKD was the use of renin-angiotensin-aldosterone system inhibitors. Based on promising secondary kidney outcomes in the cardiovascular outcome trials with sodium-glucose co-transporter-2 inhibitors, kidney outcome trials in patients with CKD were published for canagliflozin, dapagliflozin, and empagliflozin. METHODS: A literature search was conducted of PubMed using the MeSH terms "Sodium-Glucose Transporter 2 Inhibitors" and "Renal Insufficiency, Chronic" and looking for clinical trials, meta-analyses, or randomized controlled trials in humans between 2015 and 2023. FINDINGS: Primary and secondary outcomes from CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), and EMPA-KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease) are described along with complete descriptions of the patient populations studied. IMPLICATIONS: This review describes the role of sodium-glucose co-transporter-2 inhibitors in slowing the progression of CKD, describes guideline changes that have occurred because of these data, and provides information on how these agents may be used clinically.

Comparison of the efficacy of anti-diabetic medications as add-on to metformin in type 2 diabetes mellitus from a real-world database.

BACKGROUND: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. METHODS: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. RESULTS: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). CONCLUSIONS: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c.

Neurovascular unit disruption and blood-brain barrier leakage in MCT8 deficiency.

BACKGROUND: The monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease. METHODS: Neurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls. RESULTS: Ultrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density. CONCLUSIONS: These findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease.

Sodium-glucose co-transporter 2 inhibitors & glucagon-like peptide-1 receptor agonists, efficacy & safety in diabetic kidney transplant recipients.

INTRODUCTION: Cardiovascular and renal complications define the outcomes of diabetic kidney transplant recipients (KTRs). The new diabetes medications have changed the management of diabetes. However, transplant physicians are still reluctant to use sodium-glucose cotransporter 2 inhibitors (SGLT2i) and Glucagon-like peptide-1 receptor agonists (GLP-1RA) post kidney transplantation due to fear of drug related complications and lack of established guidelines. PATIENTS AND METHODS: We collected 1-year follow-up data from records of 98 diabetic KTRs on SGLT2I, 41 on GLP- 1RA and 70 on standard-of-care medicines. Patients were more than 3 months post-transplant with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73 m2 . Demographic data were similar except for a slightly lower HbA1c in the control group and higher albuminuria in SGLT2i group. RESULTS: HbA1c dropped significantly by .4% in both SGLT2i and GLP-1RA compared to .05% in the control group. A significant decrease in BMI by .32 in SGLT2i and .34 in GLP-1RA was observed compared to an increase by .015 in control group. A tendency for better eGFR in study groups was observed but was non-significant except for the SGLT2i group with an eGFR above 90 (p = .0135). The usual dip in eGFR was observed in the SGLT2i group at 1-3 months. Albuminuria was significantly reduced in both study groups. Adverse events were minimal with comparable safety in all groups. CONCLUSION: The use of SGLT2i and GLP-1RA appears to be effective and safe in diabetic KTRs with good outcomes. Randomized control trials are required to confirm these findings and establish guidelines.

Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis.

AIM: To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease. METHODS: We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs). RESULTS: We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate. CONCLUSIONS: The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.

Role of novel sodium glucose co-transporter-2 inhibitor enavogliflozin in type-2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Enavogliflozin is a novel sodium glucose co-transporter-2 inhibitor (SGLT2i) developed in South Korea. This meta-analysis was done as no meta-analysis has analysed the efficacy and safety of enavogliflozin in type-2 diabetes (T2DM). METHODS: Electronic databases were systematically reviewed for randomized controlled trials having patients with T2DM receiving enavogliflozin in treatment-arm, and placebo/any other medicine in control-arm. Primary outcome was to evaluate changes in glycosylated haemoglobin (HbA1C). Secondary outcomes were to evaluate alterations in fasting glucose (FPG), 2-h post prandial glucose (2-h PPG), blood pressure (BP), weight, lipids, and adverse events. RESULTS: Data from 4 trials (684 patients) was analysed for clinical outcomes over 12-24 weeks clinical use. Compared to placebo, patients receiving enavogliflozin had significantly lower HbA1c [MD -0.76%(95% CI: 0.93 to -0.60); P < 0.00001; I2 = 97%], FPG [MD -2.12 mmol/l(95%CI: 2.47 to -1.77); P < 0.00001; I2 = 91%], body-weight [MD-1.37 kgs (95% CI: 1.73-1.00); P < 0.00001; I2 = 89%], systolic BP [MD-4.99 mm Hg (95%CI: 7.83 to -2.16); P = 0.0006; I2 = 47%], diastolic BP [MD-3.09 mm Hg(95%CI: 3.38 to -2.81); P < 0.00001; I2 = 0%]. Treatment emergent adverse-events [OR1.16(95%CI:0.64-2.09); P = 0.63; I2 = 0%], serious adverse events [OR1.81(95%CI:0.37-8.83); P = 0.46; I2 = 0%], urinary infections [OR1.37(95%CI:0.09-20.61); P = 0.82; I2 = 33%] and genital infections [OR 3.07(95%CI:0.31-29.88); P = 0.33; I2 = 0%] were comparable. Compared to dapagliflozin, patients receiving enavogliflozin had significantly lower HbA1c [MD-0.06%(95%CI: 0.07-0.05); P < 0.00001; I2 = 0%], FPG [MD-0.19 mmol/l(95%CI: 0.21 to -0.17); P < 0.00001; I2 = 0%], body-weight [MD-0.20 kgs(95%CI: 0.24 to -0.15); P < 0.00001; I2 = 0%], diastolic BP [MD -0.92 mm Hg (95%CI: 1.36 to -0.48); P < 0.0001; I2 = 91%] and significantly higher urine glucose creatinine ratio [MD 16.69 g/g (95%CI:16.11-17.26); P < 0.00001; I2 = 0%]. CONCLUSION: Enavogliflozin is a well tolerated and effective SGLT2i for T2DM and may be superior to dapagliflozin with regard to certain clinical aspects over 6 months clinical use.

Naloxone could limit morphine hypersensitivity: Considering the molecular mechanisms.

BACKGROUND: Naloxone has been used as an opioid antagonist to prevent multiple adverse side effects of opioid-like tolerance and hyperalgesia. This study has investigated naloxone combined with morphine to limit pain hypersensitivity. In addition, the expression of brain-derived neurotrophic factor (BDNF) and K+ Cl- cotransporter2 (KCC2) were also studied. METHODS: Forty-eight adult male Wistar rats (180-220 g) were divided into eight groups, with six rats in each group. Rats were divided into two tolerance and hyperalgesia groups; the sham group, the morphine group, the treatment group (naloxone along with morphine), and the sham group (naloxone along with saline) for eight consecutive days. Tail-flick test was performed on days 1, 5, and 8, and the plantar test on days 1 and 10. On days 8 and 10, the lumbar segments of the spinal cord were collected, and BDNF and KCC2 expression were analyzed using western blotting and immunohistochemistry, respectively. RESULTS: Results showed that tolerance and hyperalgesia developed following eight days of repeated morphine injection. BDNF expression significantly increased, but KCC2 was downregulated. Co-administration of naloxone and morphine decreased tolerance and hyperalgesia by decreasing BDNF and increasing KCC2 expression, respectively. CONCLUSION: This study suggests that BDNF and KCC2 may be candidate molecules for decreased morphine tolerance and hyperalgesia.

A review of current key guidelines for managing high-risk patients with diabetes and heart failure and future prospects.

We reviewed recent guidelines on the management of heart failure (HF) in patients with diabetes. Major recommendations in European and US society guidelines were scrutinized. First, sodium-glucose co-transporter 2 inhibitors are now recommended treatments for all patients with symptomatic HF (stage C and D; New York Heart Association class II-IV), irrespective of the presence of type 2 diabetes and left ventricular ejection fraction (LVEF). Second, patients with HF and reduced EF (LVEF ≤40%) should have foundational therapies from four drug classes (sodium-glucose co-transporter 2 inhibitor, angiotensin-receptor neprilysin inhibitor, beta-blocker and mineralocorticoid receptor antagonist). Third, patients with HF with mildly reduced (41%-49%) and preserved (≥50%) LVEF may also benefit from angiotensin-receptor neprilysin inhibitor, beta-blocker and mineralocorticoid receptor antagonist therapy, although evidence for these is less robust. Fourth, selected patients should be considered for other therapies such as diuretics (if congestion), anticoagulation (if atrial fibrillation) and cardiac device therapy. Fifth, glucose-lowering therapies such as thiazolidinediones and certain dipeptidyl peptidase-4 inhibitors (such as saxagliptin and alogliptin) should be avoided in patients with HF. Sixth, guidelines recommend enrolment of patients with HF into exercise rehabilitation and multidisciplinary HF management programmes. Particular attention should be paid to important comorbidities such as obesity, alongside pharmacological therapies. As diabetes and obesity are major risk factors for HF, earlier consideration of, and diagnosis of HF, followed by guideline-directed medical therapy can meaningfully improve patients' lives. Diabetes doctors would do well to understand the basics of such guidelines to help improve all aspects of HF diagnosis and care.

Sotagliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, reduces the risk of cardiovascular and kidney disease, as assessed by the Steno T1 Risk Engine in adults with type 1 diabetes.

AIMS: Sotagliflozin (SOTA) as adjunct to insulin therapy improves glycemic control, reduces body weight and blood pressure, and increases time in range in adults with type 1 diabetes (T1D). SOTA demonstrated CV and kidney benefits in high-risk adults with type 2 diabetes. These potential benefits using SOTA for T1D may collectively outweigh the risk of diabetic ketoacidosis. The present analysis estimated the risk of CVD and kidney failure in adults with T1D treated with SOTA. MATERIALS AND METHODS: Participant-level data were used from the inTandem trials evaluating 2980 adults with T1D randomized to once-daily placebo, SOTA 200 mg, or SOTA 400 mg for 24 weeks. For each participant, the cumulative risks of developing CVD and kidney failure were estimated using the Steno T1 Risk Engine. A subgroup analysis was performed in participants with BMI ≥ 27 kg/m2 . RESULTS: SOTA significantly reduced the predicted 5- and 10-year CVD risk in the SOTA 200 and 400 mg pooled group with a relative change in the SOTA group compared to the relative change in the placebo group of (mean [95%-confidence interval (CI)]) -6.6 (-7.9, -5.3) % and -6.4 (-7.6, -5.1) % (p < 0.0001 for both) respectively. For the 5-year ESKD risk there was a significant reduction with a relative change of -5.0 (-7.6, -2.3) % (p = 0.0003). Similar results were observed with the individual doses and in participants with BMI ≥ 27 kg/m2 . CONCLUSION: This analysis provides additional clinical results that may positively balance the benefit/risk assessment of SGLT inhibition use in T1D.

A model-based meta analysis study of sodium glucose co-transporter-2 inhibitors.

Type 2 diabetes mellitus (T2DM) agent sodium-glucose co-transporter 2 (SGLT2) inhibitors show special benefits in reducing body weight and heart failure risks. To accelerate clinical development for novel SGLT2 inhibitors, a quantitative relationship among pharmacokinetics, pharmacodynamics, and disease end points (PK/PD/end points) in healthy subjects and patients with T2DM was developed. PK/PD/end point data in published clinical studies for three globally marketed SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) were collected according to pre-set criteria. Overall, 80 papers with 880 PK, 27 PD, 848 fasting plasma glucose (FPG), and 1219 hemoglobin A1c (HbA1c) data were collected. A two-compartmental model with Hill's equation was utilized to capture PK/PD profiles. A novel translational biomarker, the change of urine glucose excretion (UGE) from baseline normalized by FPG (ΔUGEc ) was identified to bridge healthy subjects and patients with T2DM with different disease statuses. ΔUGEc was found to have a similar maximum increase with different half-maximal effective concentration values of 56.6, 2310, and 841 mg/mL·h for dapagliflozin, canagliflozin, and empagliflozin respectively. ΔUGEc will change FPG based on linear function. HbA1c profiles were captured by indirect response model. Additional placebo effect was also considered for both end points. The PK/ΔUGEc /FPG/HbA1c relationship was validated internally using diagnostic plots and visual assessment and further validated externally using the fourth globally approved same-in-class drug (ertugliflozin). This validated quantitative PK/PD/end point relationship offers novel insight into long-term efficacy prediction for SGLT2 inhibitors. The novelty identified ΔUGEc could make the comparison of different SGLT2 inhibitors' efficacy characteristics easier, and achieve early prediction from healthy subjects to patients.

The sodium glucose co-transporter 2 inhibitor ertugliflozin for Alzheimer's disease: Inhibition of brain insulin signaling disruption-induced tau hyperphosphorylation.

An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7-8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1Ser307/Total.IRS-1 ratio and increased Phospho.AktSer473/Total.Akt and Phospho.GSK3ßSer9/Total.GSK3ß ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.

Comparative efficacy of sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists in chronic kidney disease and type 2 diabetes: A systematic review and network meta-analysis.

AIM: To compare the relative efficacy of sodium-glucose co-transporter 2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs) and non-steroidal mineralocorticoid receptor antagonists (nsMRAs) in improving the cardiovascular and renal outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). MATERIALS AND METHODS: We searched PubMed, Embase and Cochrane Library from inception through 25 November 2022. We selected randomized controlled trials that studied patients with CKD and T2D with a follow-up of at least 24 weeks and compared SGLT-2is, GLP-1RAs and nsMRAs with each other and with placebo. Primary outcomes were major adverse cardiovascular events (MACE) and composite renal outcomes (CRO). Secondary outcomes were cardiovascular death, all-cause death, stroke, myocardial infarction and heart failure hospitalization (HFH). A frequentist approach was used to pool risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Twenty-nine studies with 50 938 participants for MACE and 49 965 participants for CRO were included. SGLT-2is did not significantly reduce MACE but were associated with significantly lower risks of CRO compared with GLP-1RAs (RR, 0.77; 95% CI, 0.64-0.91; P = .003) and nsMRAs (RR, 0.78; 95% CI, 0.68-0.90; P = .001). Compared with GLP-1RAs and nsMRAs, SGLT-2is significantly reduced risks of HFH by 31% (RR, 0.69; 95% CI, 0.55-0.88; P = .002) and 22% (RR, 0.78; 95% CI, 0.63-0.95; P = .016), respectively, but did not significantly reduce other secondary outcomes. There were no significant differences between GLP-1RAs and nsMRAs in lowering all outcomes. CONCLUSIONS: SGLT-2is were associated with better cardiorenal protection than GLP-1RAs and nsMRAs in patients with CKD and T2D.

Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma.

BACKGROUND: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed. METHODS: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms. RESULTS: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice. CONCLUSIONS: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.

Sodium-Glucose Co-transporter 2 Inhibitors Versus Metformin as the First-Line Treatment for Type 2 Diabetes: Is It Time for a Revolution?

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a promising therapeutic option for hyperglycemia and its complications. However, metformin remains the first-line pharmacological treatment in most algorithms for type 2 diabetes (T2D). Although metformin is generally believed to exert positive effects on cardiovascular (CV) outcomes, relevant data are mainly observational and potentially overinterpreted. Yet, it exerts numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities. CV outcome trials have demonstrated cardiorenal protection with SGLT2i among people at high CV risk and mostly on concomitant metformin therapy. However, post hoc analyses of these trials suggest that the cardiorenal effects of gliflozins are independent of background treatment and consistent across the full spectrum of CV risk. Considering the importance of addressing hyperglycemia as a means of preventing diabetic complications and significant knowledge gaps, particularly regarding the cost-effectiveness of SGLT2i in drug-naïve populations with T2D, the position of metformin in the management of people with diabetes at low CV risk remains solid for the moment. On the other hand, available evidence-despite its limitations-suggests that specific groups of people with T2D, particularly those with heart failure and kidney disease, could probably benefit more from treatment with SGLT2i. This narrative mini-review aims to discuss whether current evidence justifies the use of SGLT2i as the first-line treatment for T2D.

Early treatment with a sodium-glucose co-transporter 2 inhibitor in high-risk patients with acute heart failure: Rationale for and design of the EMPA-AHF trial.

AIMS: The aim of the EMPA-AHF trial is to clarify whether early initiation of a sodium-glucose co-transporter 2 inhibitor before clinical stabilization is safe and beneficial for patients with acute heart failure (AHF) who are at a high risk of adverse events. METHODS: The EMPA-AHF trial is a randomized, double-blind, placebo-controlled, multicentre trial examining the efficacy and safety of early initiation of empagliflozin (10 mg once daily). In total, 500 patients admitted for AHF will be randomized 1:1 to either empagliflozin 10 mg daily or placebo at 47 sites in Japan. Study entry requires hospitalization for AHF with dyspnoea, signs of volume overload, elevated natriuretic peptide, and at least one of the following criteria: estimated glomerular filtration rate <60 mL/min/1.73 m2; already taking ≥40 mg of furosemide daily before hospitalization; and urine output of <300 mL within 2 hours after an adequate dose of intravenous furosemide. Patients will be randomized within 12 hours of hospital presentation, with treatment continued up to 90 days. The primary outcome is the clinical benefit of empagliflozin on the win ratio for a hierarchical composite endpoint consisting of death within 90 days, heart failure rehospitalization within 90 days, worsening heart failure during hospitalization, and urine output within 48 hours after treatment initiation. CONCLUSION: The EMPA-AHF trial is the first to evaluate the efficacy and safety of early initiation of empagliflozin in patients with AHF considered to be at high risk under conventional treatment.