BACKGROUND: Bone fragility is a critical issue in the treatment of elderly people with type 2 diabetes (T2D). In the Canagliflozin Cardiovascular Assessment Study, the subjects with T2D who were treated with canagliflozin showed a significant increase in fracture events compared to a placebo group as early as 12 weeks post-initiation. In addition, it has been unclear whether sodium-glucose co-transporter 2 (SGLT2) inhibitors promote bone fragility. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to prospectively evaluate the short-term effect of the SGLT2 inhibitor luseogliflozin on bone strength and microarchitecture in elderly people with T2D.
METHODS: This was a single-center, randomized, open-label, active-controlled pilot trial for ≥ 60-year-old Japanese individuals with T2D without osteoporosis. A total of 22 subjects (seven women and 15 men) were randomly assigned to a Lusefi group (added luseogliflozin 2.5 mg) or a control group (added metformin 500 mg) and treated for 48 weeks. We used the second-generation HR-pQCT (Xtreme CT II®, Scanco Medical, Brüttisellen, Switzerland) before and 48 weeks after the treatment to evaluate the subjects\' bone microarchitecture and estimate their bone strength.
RESULTS: Twenty subjects (Lusefi group, n = 9; control group, n = 11) completed the study, with no fracture events. As the primary outcome, the 48-week changes in the bone strength (stiffness and failure load) estimated by micro-finite element analysis were not significantly different between the groups. As the secondary outcome, the changes in all of the cortical/trabecular microarchitectural parameters at the radius and tibia from baseline to 48 weeks were not significantly different between the groups.
CONCLUSIONS: In the pilot trial, we observed no negative effect of 48-week luseogliflozin treatment on bone microarchitecture or bone strength in elderly people with T2D.
BACKGROUND: UMIN-CTR no. 000036202 and jRCT 071180061.

UNASSIGNED: There remains an unmet need to reduce kidney and cardiovascular risk in patients with chronic kidney disease (CKD). This report is therefore intended to provide real-world clinical guidance to primary care providers on sodium-glucose co-transporter-2 (SGLT2) inhibitor use in patients with CKD, focusing on practical considerations. Initially developed as glucose-lowering drugs, SGLT2 inhibitors preserve kidney function and reduce risks of cardiovascular events and mortality. Clinical benefits of SGLT2 inhibitors in CKD have been demonstrated in multiple clinical trials, yet utilization in practice remains relatively low, likely due to the complexity of labeled indications (past and present) and misconceptions about SGLT2 inhibitors as a class.
UNASSIGNED: A panel of 8 US-based nephrologists convened in August 2022 to develop consensus guidance for the primary care community surrounding risk assessment as well as initiation and implementation of SGLT2 inhibitors in patients with CKD. Here, we provide an adapted version of the Kidney Disease: Improving Global Outcomes (KDIGO) heatmap and a treatment-decision algorithm.
UNASSIGNED: We advocate SGLT2 inhibitors as co-first-line therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors, where RAAS inhibitor dose titration need not be completed before initiation of an SGLT2 inhibitor. In fact, SGLT2 inhibitor therapy may facilitate up-titration or maintenance of optimal RAAS inhibitor dosing. We describe potential strategies to aid implementation of an SGLT2 inhibitor in clinical practice, including improving education and awareness among care providers and patients and dispelling misconceptions about the safety of SGLT2 inhibitors. In summary, we support the use of SGLT2 inhibitors with RAAS inhibitors as co-first-line therapy in most patients with CKD.

OBJECTIVE: To investigate safety and effectiveness of velagliflozin oral solution as sole therapy in naïve and previously insulin-treated diabetic cats.
METHODS: 252 client-owned cats receiving ≥ 2 doses of velagliflozin; 214 (85%) naïve diabetics and 38 (15%) insulin-treated diabetics.
METHODS: Prospective, baseline-controlled, open-label clinical field trial. Cats received velagliflozin orally, once daily. Physical examinations and blood collections were performed days 0, 3, 7, 30, 60, 120, and 180.
RESULTS: Data are median (range). Screening blood glucose (BG) was 436 mg/dL (272 to 676 mg/dL). On days 30, 60, 120, and 180, single BG after receiving velagliflozin was 153 mg/dL (62 to 480 mg/dL), 134 mg/dL (64 to 414 mg/dL), 128 mg/dL (55 to 461 mg/dL), and 125 mg/dL (77 to 384 mg/dL), respectively. Screening fructosamine was 538 µmol/L (375 to 794 µmol/L). On the same recheck days, fructosamine was 310 µmol/L (204 to 609 µmol/L), 286 µmol/L (175 to 531 µmol/L), 269 µmol/L (189 to 575 µmol/L), and 263 µmol/L (203 to 620 µmol/L). At day 180, 81% of 158 cats remaining had BG and/or fructosamine within reference ranges; 88.6% (124 of 140) and 87.7% (121 of 138) showed improvement in polyuria and polydipsia, respectively. Ketonuria developed in 35 cats (13.9%), including 18 (7.1%) that had ketoacidosis. Ketoacidosis was less common in naïve diabetic cats (11 of 214 [5.1%]) compared to insulin-treated diabetic cats (7 of 38 [18.4%]). At ketoacidosis diagnosis, 14 of 18 cats (77.8%) were euglycemic (ie, BG < 250 mg/dL). Most episodes of ketosis or ketoacidosis (30 of 35 [85.7%]) occurred within the first 14 days of treatment. Insulin-treated diabetic cats were less likely to complete the trial. No clinical hypoglycemia occurred.
CONCLUSIONS: Velagliflozin improved glycemic parameters and clinical signs in diabetic cats. Velagliflozin provides an alternative to insulin as a stand-alone treatment of diabetic cats.

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.

The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are filtered and secreted to their primary site of action in the proximal tubule of the kidney. At this site, SGLT2 inhibitors also reduce renal elimination of ketone bodies, a finding implicated in their propensity to cause ketoacidosis. Many commonly used medications have potential to diminish renal elimination of SGLT2 inhibitors and to compound the effects of SGLT2 inhibitors on renal elimination of ketone bodies by inhibiting tubular secretion of the SGLT2 inhibitor itself and/or ketone bodies. We present a case of severe diabetic ketoacidosis (DKA) in a patient with type 2 diabetes occurring several days after co-prescription of empagliflozin and probenecid. Other than the recent introduction of empagliflozin, no cause for the DKA episode was apparent. A pharmacokinetic interaction between probenecid and empagliflozin, involving organic anion transporter 3 (OAT3), reduces proximal tubular secretion of empagliflozin and increases patient exposure to the drug. Whether or not this phenomenon is sufficient to cause severe DKA is discussed. An alternative explanation as to the DKA aetiology is proposed, wherein probenecid may compound effects of empagliflozin on renal elimination of ketone bodies. We suggest that clinicians exercise caution when prescribing SGLT2 inhibitors alongside pharmacologic inhibitors of, or competitors for, proximal tubular organic anion transporters in patients with diabetes mellitus due to the risk of severe DKA.

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor that has shown promising results as a drug for the treatment of insulin dysregulation in horses. Even though CFZ is used clinically, no pharmacokinetic data has previously been published. In this study, the pharmacokinetics of CFZ after administration of a single oral dose of 1.8 mg/kg in eight healthy Icelandic horses was examined. Additionally, the effect of treatment on glucose and insulin levels in response to a graded glucose infusion was investigated. Plasma samples for CFZ quantification were taken at 0, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 5, 6, 8, 12, 24, 32, and 48 h post administration. CFZ was quantified using UHPLC coupled to tandem quadrupole mass spectrometry (UHPLC-MS/MS). A non-compartmental analysis revealed key pharmacokinetic parameters, including a median Tmax of 7 h, a Cmax of 2350 ng/mL, and a t1/2Z of 28.5 h. CFZ treatment reduced glucose (AUCGLU, p = 0.001) and insulin (AUCINS, p = 0.04) response to a graded glucose infusion administered 5 h after treatment. This indicates a rapid onset of action following a single dose in healthy Icelandic horses. No obvious adverse effects related to the treatment were observed.

OBJECTIVE: The role of lower hemoglobin A1c (HbA1c) variability in the effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on acute kidney injury (AKI) remains unclear. We compared AKI risk between SGLT2i and dipeptidyl peptidase 4 inhibitors (DPP4i) initiators. Additionally, we aimed to explore the extent to which SGLT2i\'s influence on AKI risk is mediated by reducing long-term HbA1c variability.
METHODS: Using 2018-2022 year data in Yinzhou Regional Health Care Database, we included adult, type 2 diabetes patients who were new users of SGLT2i or DPP4i. The effect of SGLT2i versus DPP4i on AKI, HbA1c variability, and AKI through HbA1c variability was compared using inverse probability of treatment weighted Cox proportional hazards models, median regression models, and causal mediation analysis.
RESULTS: With a median follow-up of 1.76 years, 19 717 adults (for SGLT2i, n = 6008; for DPP4i, n = 13 709) with type 2 diabetes were included. The adjusted hazard ratio for SGLT2i versus DPP4i was 0.79 (95% confidence interval [CI] 0.64-0.98) for AKI. The adjusted differences in median HbA1c variability score (HVS) and HbA1c reduction were -16.67% (95% CI: -27.71% to -5.62%) and -1.98% (95% CI: -14.34% to 10.38%), respectively. Furthermore, lower AKI risk associated with SGLT2i was moderately mediated (22.77%) through HVS. The results remained consistent across various subgroups and sensitivity analyses.
CONCLUSIONS: Compared to DPP4i, lower AKI risk associated with SGLT2i is moderately mediated through HbA1c variability. These findings enhance our understanding of the effect of SGLT2i on AKI and underscore the importance of considering HbA1c variability in diabetes treatment and management.

BACKGROUND: Patients with type 2 diabetes often face early tubular injury, necessitating effective treatment strategies. This study aimed to evaluate the impact of the SGLT2 inhibitor empagliflozin on early tubular injury biomarkers in type 2 diabetes patients with normoalbuminuria.
METHODS: A randomized controlled clinical study comprising 54 patients selected based on specific criteria was conducted. Patients were divided into an intervention group (empagliflozin, n = 27) and a control group (n = 27) and treated for 6 weeks. Tubular injury biomarkers KIM-1 and NGAL were assessed pre- and post-treatment.
RESULTS: Both groups demonstrated comparable baseline characteristics. Post-treatment, fasting and postprandial blood glucose levels decreased similarly in both groups. The intervention group exhibited better improvements in total cholesterol, low-density lipoprotein, and blood uric acid levels. Renal function indicators, including UACR and eGFR, showed greater enhancements in the intervention group. Significant reductions in KIM-1 and NGAL were observed in the intervention group.
CONCLUSIONS: Treatment with empagliflozin in type 2 diabetes patients with normoalbuminuria led to a notable decrease in tubular injury biomarkers KIM-1 and NGAL. These findings highlight the potential of SGLT2 inhibitors in early tubular protection, offering a new therapeutic approach.