Concomitant inhibition of TLR-4 and SGLT2 by phloretin and empagliflozin prevents diabetes-associated ischemic acute kidney injury.

Toll-like receptor-4 (TLR4) and sodium-glucose co-transporter 2 (SGLT2) signaling is involved in the pathogenesis of diabetes-associated kidney diseases. The purpose of this study was to explore the role and effect of phloretin, a TLR4 inhibitor, as an adjuvant therapy to empagliflozin, an SGLT2 inhibitor, in ischemic acute kidney injury (AKI) under diabetic conditions. To achieve this, firstly we induced type 1 diabetes using streptozotocin (55 mg per kg per intraperitoneally (i.p.)) followed by performing bilateral ischemia-reperfusion kidney injury to induce AKI in male Wistar rats. Treatment with phloretin (50 and 100 mg per kg per orally) and empagliflozin (10 mgper kg per orally) alone or in combination was administered to the diabetic rats for 4 days and 1 h before surgery. Moreover, a hypoxia-reperfusion injury was induced using sodium azide in NRK52E cells under a hyperglycemic environment to mimic the in vivo model. The cells were treated with phloretin (50 µM) and empagliflozin (100 nM) for 24 h. For biochemical analysis, plasma and urine samples were used. The kidney tissues were used to perform immunoblotting, histopathology, and immunohistochemistry. Other experiments like immunofluorescence, cell viability assay, and flow cytometry analysis were performed using the in vitro samples. The study outcomes revealed that compared to monotherapy, combination therapy of phloretin and empagliflozin was significantly effective. Phloretin and empagliflozin target the HMGB1/TLR4/MyD88/IK-ß/α/NF-κB pathway to reduce inflammation and apoptosis, in addition to their antihyperglycemic effect. Thus, phloretin, a natural dietary supplement, as an adjuvant therapy to empagliflozin can be helpful to reduce empagliflozin-associated side effects, by reducing its clinical dose and increasing its therapeutic efficacy in AKI-diabetes comorbidity.

Morroniside ameliorates glucocorticoid-induced osteoporosis and promotes osteoblastogenesis by interacting with sodium-glucose cotransporter 2.

CONTEXT: Morroniside (MOR) possesses antiosteoporosis (OP) effects, but its molecular target and relevant mechanisms remain unknown. OBJECTIVE: We investigated the effects of MOR on glucocorticoid-induced OP and osteoblastogenesis and its underlying mechanisms. MATERIALS AND METHODS: The effects of MOR (10-100 µM) on the proliferation and differentiation of MC3T3-E1 cells were studied in vitro. The glucocorticoid-induced zebrafish OP model was treated with 10, 20 and 40 µM MOR for five days to evaluate its effects on vertebral bone density and related osteogenic markers. In addition, molecular targets prediction and molecular docking analysis were carried out to explore the binding interactions of MOR with the target proteins. RESULTS: In cultured MC3T3-E1 cells, 20 µM MOR significantly increased cell viability (1.64 ± 0.12 vs. 0.95 ± 0.16; p < 0.01) and cell differentiation (1.57 ± 0.01 vs. 1.00 ± 0.04; p < 0.01) compared to the control group. MOR treatment significantly ameliorated vertebral bone loss in the glucocorticoid-induced OP zebrafish model (0.86 ± 0.02 vs. 0.40 ± 0.03; p < 0.01) and restored the expression of osteoblast-specific markers, including ALP, Runx2 and Col-І. Ligand-based target prediction and molecular docking revealed the binding interaction between MOR and the glucose pockets in sodium-glucose cotransporter 2 (SGLT2). DISCUSSION AND CONCLUSIONS: These findings demonstrated that MOR treatment promoted osteoblastogenesis and ameliorated glucocorticoid-induced OP by targeting SGLT2, which may provide therapeutic potential in managing glucocorticoid-induced OP.

A case of anti-HMGCR myopathy triggered by sodium/glucose co-transporter 2 (SGLT2) inhibitors.

Inflammatory myopathies, including immune-mediated necrotizing myopathy (IMNM), are a rare and heterogeneous group of autoimmune diseases which can even involve extramuscular districts and seriously impact patients' quality of life. We report the case of a 76-year-old woman who developed muscle weakness, fatigue, and increased CK, following treatment with dapagliflozin, a sodium/glucose co-transporter 2 (SGLT2) inhibitor, and metformin. Neurophysiology, muscle biopsy, and antibody dosage confirmed the diagnosis of IMNM. The temporal correlation between the onset of clinical manifestations and the increase in the dosage of antidiabetic drugs, the improvement of symptoms with the dechallenge of dapagliflozin, and the exclusion of other possible causes triggering myopathy suggests that this may be the first case of dapagliflozin-induced myopathy, different from the former one associated with the use of SGLT2 inhibitors.

Tubulointerstitial Nephritis after Using a Sodium-glucose Cotransporter 2 Inhibitor.

We herein report a case of acute kidney injury (AKI) due to tubulointerstitial nephritis (TIN) after starting empagliflozin in a diabetic patient. The patient developed stage 1 AKI with proteinuria and elevated tubulointerstitial markers. A renal biopsy showed acute TIN with lymphocytic infiltration into the interstitium. The patient's renal function improved after discontinuation of empagliflozin and steroid administration. Sodium-glucose cotransporter 2 (SGLT2) inhibitor-induced AKI has been reported, but the underlying mechanism remains unclear, potentially because few patients with SGLT2-inhibitor-induced AKI have undergone a renal biopsy. We report the present case in the hope that it will help clarify the mechanism.

Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment.

PURPOSE: The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway controls insulin sensitivity and glucose metabolism. Hyperglycemia is one of the most common on-target adverse effects (AEs) of PI3K/AKT inhibitors. As several PI3K and AKT inhibitors are approved by the United States Food and Drug Administration or are being studied in clinical trials, characterizing this AE and developing a management strategy is essential. METHODS: Patients with hematologic or solid malignancies treated at Memorial Sloan Kettering Cancer Center with a PI3K or AKT inhibitor were included in this retrospective analysis. A search for patients experiencing hyperglycemia was performed. The frequency, management interventions and outcomes were characterized. RESULTS: Four hundred and ninety-one patients with 10 unique cancer types who received a PI3K or AKT inhibitor were included. Twelve percent of patients required a dose interruption, 6% of patients required a dose reduction and 2% of patients were hospitalized to manage hyperglycemia. No events occurred among patients receiving ß-, γ-, or δ- specific PI3K inhibitor. There was one case where the PI3K or AKT inhibitor was permanently discontinued due to hyperglycemia. Metformin was the most commonly used antidiabetic medication, followed by insulin, sodium-glucose transport protein 2 (SGLT2) inhibitors, and sulfonylurea. SGLT2 inhibitors were associated with the greatest reductions in blood sugar, followed by metformin. At least one case of euglycemic diabetic ketoacidosis (DKA) occurred in a patient on PI3K inhibitor and SGLT2 inhibitor. Body mass index ≥ 25 and HbA1c  ≥ 5.7 are were independently significant predictors of developing hyperglycemia. CONCLUSION: Hyperglycemia is one of the major on-target side effects of PI3K and AKT inhibitors. It is manageable with antidiabetic medications, treatment interruption and/or dose modification. We summarize pharmacological interventions that may be considered for PI3K/AKT inhibitor induced hyperglycemia. SGLT2-inhibitor may be a particularly effective second-line option after metformin but there is a low risk of euglycemic DKA, which can be deadly. To our knowledge, our report is the largest study of hyperglycemia in patients receiving PI3K/AKT inhibitors.

Euglycaemic diabetic ketoacidosis in a 43-year-old woman with type 2 diabetes mellitus on SGLT-2 inhibitor (empagliflozin).

We report a case of euglycaemic diabetic ketoacidosis (EDKA) in a 43-year-old woman with type 2 diabetes mellitus who presented to the emergency department with problems of vomiting, cough, shortness of breath and generalised weakness after following a ketogenic diet for 2 weeks. Therapy with sodium glucose transport protein-2 empagliflozin had been started 2 months prior. Initial evaluation revealed high anion gap metabolic acidosis with blood glucose level of 169 mg/dL. Treatment for EDKA with fluid resuscitation, intravenous insulin and dextrose resolved her acidosis and symptoms in less than 24 hours. Empaglifozin was discontinued on discharge. This entity represents a diagnostic challenge since the differential diagnosis is broad with a potentially misleading clinical presentation that can result in delayed diagnosis and adverse outcomes including acute kidney injury, multiple electrolyte abnormalities, cerebral oedema, acute respiratory distress syndrome, shock and death.

Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin.

OBJECTIVE: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. MATERIALS AND METHODS: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. RESULTS: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: -0.32% [-0.54, -0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, -0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, -1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, -1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. CONCLUSION: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.

Seguridad de los iSGLT-2. Revisión de las reacciones adversas notificadas a nivel nacional / Safety of SGLT2 inhibitors. A review of the adverse drug reactions registered in a national database

Objetivo. Conocer las reacciones adversas medicamentosas (RAM) producidas por los inhibidores del co-transportador sodio-glucosa tipo 2 (iSGLT-2) notificadas en España desde su comercialización. Material y métodos. Estudio de todas las notificaciones existentes en la base de datos del Sistema Español de Farmacovigilancia de medicamentos de uso humano derivadas del uso de iSGLT-2. Resultados. Se recopilaron 311 notificaciones: 169 relacionadas con dapagliflozina (54,34%), 81 con empagliflozina (26,05%) y 61 con canagliflozina (19,61%). El 52,1% de los pacientes fueron mujeres y el 47,6%, hombres. La edad media fue de 62,07±12,176años. Un total de 167 notificaciones (53,7%) fueron clasificadas como no-graves y 144 (46,3%), como graves. Se notificaron 534 RAM, siendo las más frecuentes las infecciones del tracto urinario (37 casos; 6,9%), cetoacidosis diabética (30; 5,6%), balanopostitis (24; 4,5%), cetoacidosis (16; 3%), candidiasis vulvovaginal (16; 3%), mareo (11; 2,1%) y disuria, balanitis candidiásica y prurito vulvovaginal (10; 1,9%). El desenlace de las 534 RAM fue: recuperado sin secuelas, 55,6%; todavía no recuperado, 14%; no recuperado, 4,9%; mortal, 1,1%, y desconocido, 24,3%. Conclusiones. La mayoría de las RAM notificadas son infecciones del tracto urogenital, cetoacidosis y daño renal, y aunque las primeras en su mayoría no fueron graves, la cetoacidosis y el daño renal sí lo fueron, generando ingresos y haciendo peligrar la vida de los pacientes, por lo que creemos que ello nos obliga a hacer una prescripción cuidadosa, a consultar las advertencias publicadas por las autoridades sanitarias y notificar cualquier RAM que se sospeche de esta familia terapéutica para su mejor y más completo conocimiento (AU)

Objective. To analyse the adverse drug reactions (ADRs) caused by Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) notified in Spain since they have been on the market. Material and methods. An analysis was made of all the notifications registered in the Spanish Pharmacovigilance System of drugs for human use, arising from the use of SGLT2i. Results. A total of 311 notifications were recorded, of which 169 (54.34%) were related to dapagliflozin, 81 (26.05%) to empagliflozin, and 61 (19.61%) to canagliflozin. There was a ratio of 52.1% women to 47.9% men. The mean age was 62.07±12.17years. There were 167 (53.7%) notifications were classified as non-serious and 144 (46.3%) as serious. A total of 534 ADRs were notified, with the most common being urinary tract infections in 37 (6.9%) cases, diabetic ketoacidosis in 30 (5.6%), balanoposthitis in 24 (4.5%), ketoacidosis in 16 (3%), vulvovaginal candidiasis in 16 (3%), dizzy spells in 11 (2.1%), and 10 (1.9%) with dysuria, Candida balanitis, and vulvovaginal pruritus. As regards the outcomes of the 534 ADRs, 55.6% recovered with no sequelae, with 14% still recovering, 4.9% not recovered, fatal in 1.1%, and unknown in 24.3%. Conclusions. The majority of the ADRs notified are infections of the urogenital tract, ketoacidosis, and kidney damage. Although the majority of the former were not serious, the ketoacidosis and kidney damage were, leading to hospital admission and being life threatening in some patients. For these reasons, it is recommended that they are, prescribed with caution, the warnings published by the health authorities consulted, as well as notify any ADR that is suspected in this therapeutic group, in order to improve and provide us with further knowledge (AU)

Euglycemic Diabetic Ketoacidosis Secondary to Dapagliflozin Use: A Case Report.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of oral antihyperglycemic agents. They are associated with rare cases of euglycemic diabetic ketoacidosis (DKA), which presents a diagnostic challenge in the emergency department (ED) and potentially severe consequences if missed. CASE REPORT: A 53-year-old man with type 2 diabetes mellitus and a recent Roux-en-Y gastric bypass surgery presented to the ED with nausea, vomiting, and generalized abdominal pain. His medications included dapagliflozin. Work-up revealed anion-gap acidosis, which prompted us to send serum ketone levels despite a blood glucose level of 9.8 mmol/L (162 mg/dL). The patient was ultimately diagnosed with euglycemic DKA. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients on SGLT2 inhibitors may present in DKA despite having normal blood glucose levels. It is important for emergency physicians to be aware of this phenomenon in all SGLT2-inhibitor users, as a delay in the diagnosis of DKA can be life threatening.

National trends in the treatment of diabetic nephropathy in the United States.

WHAT IS KNOWN AND OBJECTIVE: The prevalence of diabetic nephropathy continues to rise and it remains a strong predictor of morbidity and mortality in diabetic patients. Patients diagnosed with diabetic nephropathy are actively excluded from most trials involving diabetic medications and it is important to understand the prescription patterns in this subset of patients with diabetes. METHODS: Using the IMS Health's National Disease and Therapeutic Index, we analysed the medication prescription patterns for six classes of medications from 2010 to 2014 among patients, 35 years or older, with diabetic nephropathy. RESULTS: Annual office visits increased from 772 860 (95% confidence interval (CI), 755, 470-790, 249) in 2010 to 1 868 618 (95% CI, 1 834 422-1 902 814) in 2013 and declined to 830 596 (95% CI, 809 167-852 025) in 2014. Sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were the most frequently used of the four classes of diabetic medications included in this study. DPP-4 inhibitors use increased gradually and was used in 54% (95% CI 49-58) of treatment visits by the last quarter of 2014. Across these years, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEIs and ARBs) were prescribed in the majority of treatment visits with peaks above 90%. However, there were some periods when utilization of these antihypertensives was low. WHAT IS NEW AND CONCLUSIONS: Significant increases occurred in the uptake of new diabetic medications; DPP-4 inhibitors and SGLT-2 inhibitors and in the utilization of ACEIs and ARBs compared to the findings reported in other studies with increased complexity in the treatment of patients with diabetic nephropathy. Improved and continued used of these medications may be beneficial in improving patient outcomes.

Bone effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus.

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM), lowers blood glucose by inhibiting renal glucose reabsorption and increasing urinary glucose excretion. It has been reported that SGLT2 inhibitors may have potential adverse effects on bone, including increased fracture risk and decreased bone mineral density (BMD). Across clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, vitamin D, or parathyroid hormone. Minimal increases in serum phosphate and magnesium that were within normal limits were seen with canagliflozin versus placebo. Canagliflozin was associated with increases in serum collagen type 1 beta-carboxy telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker. Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus placebo after 2 years (-1.7%, -2.1%, -0.8%; differences of -0.9% and -1.2%), but not at other skeletal sites (normal age-related bone loss, ~0.5-1.0%/year). Changes in beta-CTX and total hip BMD were significantly associated with weight loss, which is known to increase bone resorption markers and decrease BMD. Canagliflozin was associated with a higher fracture incidence in an interim analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) in patients with a history or high risk of cardiovascular disease (incidence per 100 patient-years of 1.6, 1.6, and 1.1 with canagliflozin 100 and 300 mg and placebo), but not in other clinical studies of patients with T2DM. Fractures tended to occur as early as 12 weeks after initiating treatment and were primarily located in the distal parts of the upper and lower extremities. The reason for increased fracture risk with canagliflozin treatment is unknown, but is likely not related to a direct effect of canagliflozin on bone-related biomarkers. Data from ongoing canagliflozin studies, including CANVAS, will provide additional information on fracture risk in patients with T2DM.

Sodium glucose co-transporter 2 inhibitors: a novel approach to the management of type 2 diabetes mellitus.

PURPOSE: The purpose of this article is to educate nurse practitioners about the newest class of oral medications developed to treat type 2 diabetes mellitus (T2DM). This article will review dapagliflozin and canagliflozin, the two Food and Drug Administration (FDA) approved sodium glucose co-transporter 2 (SGLT2) inhibitors, and discuss their place in therapy. DATA SOURCES: A comprehensive literature search was conducted using MEDLINE with the key terms: dapagliflozin, canagliflozin, SGLT2 inhibitors, and SGLT2 inhibitors. Other resources included the World Health Organization (WHO), U.S. FDA, Centers for Disease Control and Prevention (CDC), clinical guidelines, FDA labeling, briefings, and press releases. CONCLUSIONS: Dapagliflozin and canagliflozin appear to be safe and moderately effective. SGLT2 inhibitors provide an alternative for dual and triple therapy for T2DM or can be used as monotherapy in patients who cannot tolerate other first-line options. IMPLICATIONS FOR PRACTICE: SGLT2 inhibitors have a unique, insulin-independent mechanism of action, targeting the kidneys. They have a low incidence of hypoglycemia and result in a moderate reduction in HbA1C. Improvements in weight, blood pressure, and lipid parameters have been demonstrated. Dosing considerations are required for the elderly, renally impaired, and patients at risk for hypotension.

Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs. PURPOSE: To assess the efficacy and safety of SGLT2 inhibitors in adults with type 2 diabetes. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Library from inception through April 2013 without language restrictions; regulatory authorities' reports; and gray literature. STUDY SELECTION: Randomized trials comparing SGLT2 inhibitors with placebo or other medication for type 2 diabetes. DATA EXTRACTION: Three reviewers extracted or checked data for study characteristics, outcomes of interest, and risk of bias, and 3 reviewers summarized strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Sodium-glucose cotransporter 2 inhibitors were compared with placebo in 45 studies (n = 11 232) and with active comparators in 13 studies (n = 5175). They had a favorable effect on hemoglobin A1c level (mean difference vs. placebo, -0.66% [95% CI, -0.73% to -0.58%]; mean difference vs. active comparators, -0.06% [CI, -0.18% to 0.05%]). Sensitivity analyses incorporating unpublished data showed similar effect estimates. Compared with other agents, SGLT2 inhibitors reduced body weight (mean difference, -1.80 kg [CI, -3.50 to -0.11 kg]) and systolic blood pressure (mean difference, -4.45 mm Hg [CI, -5.73 to -3.18 mm Hg]). Urinary and genital tract infections were more common with SGLT2 inhibitors (odds ratios, 1.42 [CI, 1.06 to 1.90] and 5.06 [CI, 3.44 to 7.45], respectively). Hypoglycemic risk was similar to that of other agents. Results for cardiovascular outcomes and death were inconclusive. An imbalance in incidence of bladder and breast cancer was noted with dapagliflozin compared with control. LIMITATION: Most trials were rated as high risk of bias because of missing data and last-observation-carried-forward methods. CONCLUSION: Sodium-glucose cotransporter 2 inhibitors may improve short-term outcomes in adults with type 2 diabetes, but effects on long-term outcomes and safety are unclear. PRIMARY FUNDING SOURCE: None.