Therapeutic Effect of Canagliflozin on Nephrotic Syndrome and Its Ultrasonic Evaluation / 中山大学学报(医学科学版)

ObjectiveTo investigate the therapeutic effect of antidiabetic drug canagliflozin （CGLZ） on adriamycin-induced nephrotic syndrome （NS） in rats， and the evaluation of contrast-enhanced ultrasound （CEUS） combined with color Doppler flow imaging （CDFI） during the treatment. MethodsA total of 56 male SD rats were randomly divided into normal group （NG）， model group （MG）， prednisone （PAT） group （PG）， low-dose single CGLZ group （LSCG）， high-dose single CGLZ group （HSCG）， low-dose CGLZ + PAT group （LUCG） and high-dose CGLZ + PAT group （HUCG）， with 8 rats in each group. The NS model in rats was induced by injecting adriamycin twice into the tail vein， and then the NS rats were treated by intragastric administration daily for 6 weeks with reference of PAT. Twenty-four hour urine total protein （24 h-UTP） was assessed one day before the start of oral administration and at the end of 2， 4 and 6 weeks after oral administration， respectively. CDFI and CEUS were performed on the right renal artery at the end of 6 weeks after oral administration， and the blood of abdominal aorta was taken for serological test the next day. ResultsCompared with those detection index of NG rats， the 24-hour UTP of MG rats increased （P＜0.01）， the serum ALB decreased and TG， TC， LDL increased （P＜0.01）， and CDFI shows that RRCT was thinner （P＜0.01） and the renal artery blood flow indicators RA-PI， RA-RI， RA-S/D all increased （P＜0.05）， and CEUS image shows that the TIC curve parameters TTP， AT， AUC all increased and DPI decrease in MG rats （P＜0.01）. After drug treatment， compared with those detection index of MG rats， 24 h-UTP decrease in LSCG after 2 weeks （P＜0.01）， and decrease significantly in all drug groups after 6 weeks （P＜0.01）； the serological test results show that the serum ALB in all CGLZ groups increased （P＜0.05）， TG decrease in LSCG （P＜0.01）， TC and LDL also decrease in LUCG after 6 weeks （P＜0.05）； CDFI shows that the RRCT thinning degree in all CGLZ is reduced （P＜0.01）， and the RA-PI in LSCG， RA-RI in PG， and RA-S/D in PG， LSCG， HSCG and LUCG rats all decreased （P＜0.05）； CEUS shows that the TTP， AT and AUC of renal TIC curve in drug treatment groups all decreased （P＜0.01）， and the DPI in PG， HSCG， LUCG and HUCG rats increased （P＜0.01）. ConclusionsCGLZ has the effect of treating NS， and the small dose is the best. CEUS combined with CDFI can be used to evaluate the renal morphology and hemodynamic changes of NS model rats before and after drug treatment， which is helpful to guide clinical application.

Research results and mechanism of sodium glucose cotransporter 2 inhibitors in the treatment of heart failure / 中国医师杂志

Sodium glucose cotransporter 2 inhibitor (SGLT2i) emerged as a new hypoglycemic agent, which can inhibit glucose reabsorption and thus play a hypoglycemic role. Recent studies have shown that SGLT2i not only lowers blood glucose, but also has a protective effect on the cardiovascular system, which may benefit patients with heart failure.The specific mechanism of action is still not fully elucidated. This paper aims to summarize the latest research results of SGLT2i in the treatment of heart failure, and analyze the possible mechanisms for clinical guidance.

Sodium-Glucose Cotransporter 2 Inhibitors for People with Type 1 Diabetes / 임상당뇨병

Althowgh intensive insulin regimen is the main treatment in people with type 1 diabetes, glucose variability and weight gain remain as challenges for this treatment. Sodium-glucose cotransporter (SGLT) inhibitors (including the SGLT1/2 inhibitors) have emerged as an add-on therapy for insulin treatment in peoples with type 1 diabetes due to their insulin-independent mechanism. Recent clinical trials have consistently reported that SGLT inhibition provides additive benefits in glycemic control, including lower insulin dose and weight loss. However, there is concern that an increase in ketone-related adverse events such as diabetic ketoacidosis is higher in SGLT1/2, as well as SGLT2 inhibitors. Despite safety issues that require further evaluation, SGLT2 inhibitors used with caution may provide an adjunctive therapy in people with type 1 diabetes.

Effect of Dapagliflozin on Alanine Aminotransferase Improvement in Type 2 Diabetes Mellitus with Non-alcoholic Fatty Liver Disease

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are expected to improve the liver function of patients with non-alcoholic fatty liver disease (NAFLD) combined type 2 diabetes mellitus (T2DM) by its characteristic mechanism. This study was designed to investigate the effect of dapagliflozin, one of the SGLT2i, on the liver function of T2DM with NAFLD when combined with metformin. METHODS: Among patients who received dual oral hypoglycemic agents within the 3 months of diagnosing NAFLD, patients who had abnormal alanine aminotransferase (ALT) level (>40 IU/L) were included. Patients were divided into two groups: metformin+dapagliflozin group and metformin+dipeptidyl peptidase-4 inhibitors (DPP4i) group. Demographic data, biochemical data and the clinical and treatment histories of all patients were reviewed. RESULTS: A total of 102 patients were included (dapagliflozin group, n=50; DPP4i group, n=52). Dapagliflozin group showed more weight loss and more ALT decline than DPP4i group (−2.9 kg vs. −0.4 kg, P=0.005; −21.1 U/L vs. −9.5 U/L, P=0.008, respectively) and the proportion of patients with ALT normalization after treatment was also significantly higher in the dapagliflozin group (80.0% vs. 61.5%, P=0.041). The effect of dapagliflozin with metformin on ALT normalization remained significant after adjustment for confounding variables including body weight loss (odds ratio, 3.489; P=0.046). CONCLUSION: ALT improvement was statistically significant in the dapagliflozin than the DPP4i when combined with metformin and the result was consistent after adjustment for confounding variables including body weight loss.

Potential benefit of the combination therapy of dipeptidyl peptidase-4 inhibitor with sodium-glucose cotransporter-2 inhibitor in patients with type 2 diabetes mellitus: From the standpoint of renoprotection / 中华内分泌代谢杂志

Both dipeptidyl peptidase-4(DPP-4)inhibitor and sodium-glucose cotransporter-2(SGLT-2) inhibitor have been approved for the treatment of type 2 diabetes mellitus(T2DM). In preclinical or clinical studies, DPP-4 inhibitor shows a potential beneficial effect on renal architecture damage,whereas SGLT-2 inhibitor has a role in renoprotection by improving renal hemodynamics. Therefore,the combination therapies with DPP-4 inhibitor and SGLT-2 inhibitor not only improve metabolic control, but also may have a synergistic or complementary effect in protecting renal structure and function in patients with T2DM. This combination therapy provides a novel option for raising the comprehensive management level in patients with T2DM.

Addition of Ipragliflozin to Metformin Treatment in Korean Patients with Type 2 Diabetes Mellitus: Subgroup Analysis of a Phase 3 Trial

BACKGROUND: This is a subgroup analysis of Korean patients from a phase 3 clinical trial investigating the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin. METHODS: This multicenter, placebo-controlled, double-blind, parallel-group study was carried out between November 2011 and January 2013. Patients entered a 2-week placebo pretreatment period, followed by a 24-week treatment period with either ipragliflozin (50 mg/day) or placebo, while continuing metformin. Efficacy outcomes (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], and body weight) and safety outcomes (treatment-emergent adverse events [TEAEs]) were measured and compared between the two treatment groups for patients enrolled in all 18 study sites in Korea. RESULTS: Eighty-two Korean patients received ipragliflozin (n=43) or placebo (n=39) during the study period. Mean changes in HbA1c levels from baseline to the end of treatment were –0.97% in the ipragliflozin group and –0.31% in the placebo group, with an adjusted between-group difference of –0.60% (P<0.001). Compared to placebo, FPG and body weight also decreased significantly (both P<0.001) from baseline after treatment in the ipragliflozin group, with between-group differences of –21.4 mg/dL and –1.53 kg, respectively. Decreased weight was the most common TEAE in the ipragliflozin group (7.0%); there were no reports of genital and urinary tract infection. CONCLUSION: Ipragliflozin treatment in addition to metformin led to significant improvement in glycemic outcomes and reduction in body weight in Korean patients with type 2 diabetes mellitus, compared with metformin treatment alone; the safety profile was comparable in both groups.

Dapagliflozin's Effects on Glycemia and Cardiovascular Risk Factors and Incidence of Adverse Events in Patients with Type 2 Diabetes

BACKGROUND: Dapagliflozin is an oral selective inhibitor of sodium-glucose cotransporter 2(SGLT2), the kidney transporter chiefly responsible for glucose reabsorption from the glomerular filtrate. Because this mechanism does not require the action of insulin, dapagliflozin rarely causes hypoglycemia. Dapagliflozin may affect blood glucose control as well as blood pressure and the body weight which are one of the cardiovascular disease risk factors. However, dehydration and ketoacidosis are reported as the side effects of the dapagliflozin treatment and the safety issues have been occurred. The aim of this study is to analyze the effectiveness and adverse events of dapagliflozin in Korean patients. METHODS: From December 2014 to August 2015, we retrospectively reviewed the electronic medical records of type 2 diabetes patients who were prescribed dapagliflozin at Severance Hospital. RESULTS: A total of 202 Korean patients were enrolled in this study. The effectiveness in the reduction of blood glucose was statistically significant(p < 0.001). Dapagliflozin decreased 0.74% of HbA1c after 24 weeks. Significantly more participants achieved the target HbA1c level(HbA1c < 7%) after 24 weeks(n=42, 35.3%) than before taking dapagliflozin(n=21, 17.6%). Blood pressure decreased 5.7 mmHg s ystolic b lood p ressure(SBP), 1.9 mmHg d iastolic b lood p ressure(DBP) a fter 24 weeks. M ore than o ne q uarter of participants(n=35, 29.4%) experienced weight loss. Most common adverse event was genitourinary symptoms. CONCLUSION: In this study, the effectiveness of dapagliflozin in improving glycemic control, blood pressure control, and weight loss was statistically significant. However, elderly and female patients, who have higher incidence of adverse events, should use dapagliflozin cautiously.

Emerging Safety Issues of Dipeptidyl Peptidase-4 Inhibitors and Sodium Glucose Cotransporter 2 Inhibitors: How to Interpret and Apply in Clinical Practice / 임상당뇨병

Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are newer classes of glucose-lowering agents that are currently widely used in clinical practice. Their glycemic efficacy and cardiovascular safety have been well proven, and recent large clinical trials even have shown cardiovascular benefits of SGLT2 inhibitors. However, data regarding drug-related long-term safety remain inconclusive. Recently, several safety issues related to DPP-4 inhibitors and SGLT2 inhibitors have been raised by cardiovascular outcome trials or post-marketing pharmacoepidemiological studies. In this review, we summarize emerging safety issues regarding the use of DPP-4 inhibitors and SGLT2 inhibitors in type 2 diabetes and suggest how to interpret and apply these results to clinical practice.

Dapagliflozin: a new adjunct in the treatment of Type 2 diabetes mellitus.

Diabetes mellitus (DM) Type 2 is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. The classic symptoms are excess thirst, frequent urination, and constant hunger. Management of Type 2 diabetes focuses on lifestyle interventions, lowering other cardiovascular risk factors, and maintaining blood glucose levels in the normal range. There are several classes of anti-diabetic medications available and these include sulfonylureas, nonsulfonylurea secretagogues, alpha glucosidase inhibitors, thiazolidinediones, glucagon-like peptide-1 analog, and dipeptidyl peptidase-4 inhibitors. Recently, dapagliflozin (Farxiga™), a sodium-glucose cotransporter 2 inhibitor has been approved by Food and Drug Administration as an adjunct to diet and exercises to improve glycemic control in adults with Type 2 DM.

Progress in Pharmacological and Clinical Research of Dapagliflozin / 中国药师

Pharmacology, pharmacokinetics, clinical study and safety of dapagliflozin in the treatment of type 2 diabetes mellitus were reviewed in the paper. As a sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin can reduce HbA1c, FPG and body weight of patients with type 2 diabetes mellitus. The main adverse reaction is genital infection. The antihypertensive effect of dapagliflo-zin is still under study at present.