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.

Canagliflozin reduces the contractile response of isolated heart of normal adult rats / Canagliflozin reduce la respuesta contráctil del corazón aislado de ratas adultas normales

SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.

RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.

Excavation and Evaluation of ADR Signals of SGLT 2 Inhibitors / 中国药房

OBJECTIVE：To excavate and evaluate ADR signals of SGLT 2 inhibitors as canagliflozin ，dapagliflozin and empagliflozin，and to provide reference for rational drug use in the clinic. METHODS ：The proportional reporting ratio （PRR）and reporting odds ratio （ROR）were used to find the adverse drug reactions （ADR）signal of SGLT 2 inhibitors as canagliflozin ， dapagliflozin and empagliflozin from the second quarter of 2013 to the third quarter of 2020 in the US FDA Adverse Event Reporting System （FAERS）. The basic information （including gender ，age，reporting year ，reporting country ，severe ADR ）and safety warning signals of corresponding patients in ADR report were analyzed. RESULTS ：Among 6 029 375 ADR reports ，SGLT2 inhibitors of 43 807 ADR reports were concomitant and suspected drugs ；there were 19 301 ADR reports of canagliflozin ，10 960 ADR reports of dapagliflozin ，13 546 ADR reports of empagliflozin. Except for the ADR patients with unknown gender and missing age ，the gender distribution of the included reports was balanced ，mainly in the range of 50-75 years old. The reporting year was mainly in 2018，and the main reporting country was the United States ，with“hospitalization or prolonged hospitalization ” as the main serious ADR. A total of 573 ADR signals were obtained ，involving 26 systems，mainly focusing on metabolic and nutritional diseases ，endocrine disorders ，kidney and urinary system disease ，infection and invasion diseases ，etc. The results showed that there were 14 main ADR signals in the top 10 ADR of canagliflozin ，dapagliflozin and empagliflozin. The strongest ADR signals of dapagliflozin and empagliflozin were ketoacidosis （PRR＝119.64/140.11，95％CI lower limit of ROR ＝148.28/ 178.78）and fungal infection （PRR＝47.76/34.77，95％ CI lower limit of ROR ＝50.69/36.28）；except above signals in addition ， toe amputation （PRR＝489.79，95％CI lower limit of ROR ＝520.15）and osteomyelitis （PRR＝61.42，95％CI lower limit of ROR＝65.38）were strong in the ADR signals of canagliflozin. CONCLUSIONS ：SGLT2 inhibitors have a higher security risk in metabolic and nutritional diseases ，endocrine disorders ，kidney and urinary system ，and infection and intrusion diseases. Dapagliflozin，canagliflozin and empag liflozin are prone to cause ADR such as ketoacidosis and fungal infection ，while canagliflozin is easy to cause ADRs such as toe amputation and osteomyelitis.

Rp-Hplc And Chemometric Methods For The Determination Of Two Anti-Diabetic Mixtures; Metformin Hydrochloride-Canagliflozin And Metformin Hydrochloride-Gliclazide In Their Pharmaceutical Formulation

Objective: To develop and validate novel more sensitive analytical methods for the concurrent quantification of metformin-canagliflozin and metformin-gliclazide in their bulk forms and in their pharmaceutical preparations. Methods: Two methods were developed based on several chemometric assisted spectrophotometric methods and a Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC). The first method applies different spectrophotometric chemometric assisted methods, including ratio difference, derivative ratio and extended ratio subtraction method, while the second method describes a RP-HPLC separation of metformin hydrochloride-canagliflozin and metformin hydrochloride-gliclazide binary mixtures using a C18 column with a mobile phase consisting of acetonitrile: potassium dihydrogen phosphate (adjusted to pH 3) with sodium lauryl sulphate as additive in the ratio of 30:70 (%v/v) in isocratic elution mode at 1 ml/min. Results: The proposed methods were able to quantify each of the studied drugs in their binary mixtures with high percentage recoveries in both methods. The spectrophotometric methods were able to quantify each of metformin, canagliflozin and gliclazide in the ranges of 2.0-20.0 μg/ml, 1.5-40.0 μg/ml and 2.0-30.0 μg/ml, respectively. The RP-HPLC method produced well-resolved peaks at a retention time of 3.92, 6.92 and 9.10 min in the concentration ranges of 50.0-300.0 μg/ml, 5.0-50.0 μg/ml and 10.0-100.0 μg/ml for metformin, canagliflozin and gliclazide, respectively. The proposed methods were optimized and validated in accordance to the International Conference of Harmonisation (ICH) guidelines in terms of linearity, LOD, LOQ, precision and accuracy. Conclusion: The developed methods were found to be sensitive and reproducible methods for the simultaneous determination of anti-diabetic binary mixtures; metformin hydrochloride-canagliflozin and metformin hydrochloride-gliclazide. And thus were successfully employed for the quality control analysis of the pharmaceutical formulations of the studied binary mixtures.

Effects of Safety and Other Related Indexes of Canagliflozin in the Treatment of Type 2 Diabetes Complicated with High Risk of Cardiovascular Disease / 中国药房

OBJECTIVE：To observe the safety and other related indexes of canagliflozin in the treatment of type 2 diabetes complicated with high risk of cardiovascular disease. METHODS ：Totally 306 patients，admitted to Hainan Provincial People ’s Hospital and Haikou People ’s Hospital ，with type 2 diabetes complicated with high risk of cardiovascular disease were selected from Dec. 2018 to Apr. 2019. They were divided into observation group （153 cases）and control group （153 cases）according to random number table . The control group was treated with in sulin，metformin or sulfonylureas conventional hypoglycemic therapy ， and the observation group was treated with Canagliflozin tablets 100 mg，once a day ，po，on the basis of control group. The course of treatment was 1 year in both groups. The levels of HbA 1c，BMI，SBP，DBP and eGFR before and after treatment were observed in 2 groups，and the incidence of safety （including death from cardiovascular causes ，myocardial infarction ，ischemic stroke ， hospitalization for heart failure and death from any cause etc. ） after treatment and serious ADR/ADE （including hypogly- cemia，diabetic ketoacidosis ，fracture，acute kidney injury 68622942。E-mail：zhaixin0123@126.com etc.）during the treatment were recorded. RESULTS ：A total of 5 patients in the control group were not followed up ， in which 3 quited and 2 were lost ；and 4 patients in the observation group were not followed up ，in which 1 quited and 3 were lost . Before treatment ，there were no statistical significance in the levels of HbA 1c，BMI，SBP，DBP and eGFR between 2 groups（P＞0.05）. After treatment ，HbA1c levels of 2 groups，BMI and SBP of observation group were all significantly lower than those before treatment with the same group ；HbA1c level and SBP of observation group were significantly lower than those of control group （P＜0.05）. eGFR levels of 2 groups after treatment were significantly higher than before treatment with the same group ，while the observation group was significantly higher than that of contrl group. The incidence of death from cardiovascular causes and death from any cause in observation group were significantly lower than control group （P＜0.05）. There were no statistically significant differences in other safety indexes and the incidence of serious ADR/ADE between 2 groups（P＞0.05）. CONCLUSIONS ：Canagliflozin can significantly reduce the incidence of death from cardiovascular causes and death from any cause in type 2 diabetes patients complicated with high risk of cardiovascular disease，ameliorate blood glucose and blood pressure ，and do not increase the occurrence of serious ADR/ADE.

Análise crítica dos estudos que mudaram a prática clínica recente: diabetes mellitus e doenças cardiovasculares / Critical analysis of studies that changed recent clinical practice: diabetes mellitus and cardiovascular disease

Já é bem conhecida a importância da terapêutica para os pacientes com diabetes mellitus (DM) no que diz respeito à redução dos eventos cardiovasculares e, por isso, existe interesse em comprovar a segurança cardiovascular das diferentes terapias anti-hiperglicêmicas disponíveis no mercado. O objetivo desta revisão consiste em discutir três grandes estudos publicados recentemente, LEADER, CANVAS e DECLARE ­ TIME 58, que avaliaram o efeito sobre morbidade e mortalidade cardiovascular das medicações em questão em comparação com placebo

The importance of therapy for patients with diabetes mellitus (DM) in reducing cardiovascular events is well-known and, therefore, there is interest in confirming the cardiovascular safety of the different antihyperglycemic therapies available on the market. The objective of this review is to discuss three large recently-published studies, LEADER, CANVAS and DECLARE ­ TIME 58, which evaluated the effect of the medications in question on morbidity and cardiovascular mortality as compared to a placebo

Evaluation and comparison of anti-cancer activity of dapagliflozin and canagliflozin in oral cancer cell line: an in vitro study

Background: Cancer is rapidly evolving life-threatening ailment in the mankind due to changes in daily food intake and lifestyle changes. Oral carcinoma is 6th major cause of cancer death in the world and it is third major reason of cancer mortality in India. Every cell in the human body requires glucose for its metabolic energy. Besides normal cell, cancer cells also require the glucose for its endurance and multiplication. SGLT2 inhibitors which are aimed at diabetes therapy exhibited anticancer properties also in colon and pancreatic cancer lines. Present study aim is to evaluate the anticancer activity of SGLT2 inhibitors against oral cancer cell by MTT Assay.Methods: To evaluate the anticancer activity of SGLT2 inhibitors MTT Cytotoxic assay is performed as per standard protocols. Cancer cells were plated in 24-well plates and incubated at 370C with 5% CO2 condition. After convergence, samples are added to the plates in various concentrations and allowed to incubate then they are detached from the plates and cleansed with the reagents. The wells are coated with the dye and incubated. Later samples are analysed in UV-spectrophotometer.Results: Cytotoxic assay showed decrease in cell viability with increasing dose of SGLT2 inhibitors. IC50 values were determined graphically. The IC50 value of dapagliflozin is 400礸/ml and canagliflozin is 250礸/ml respectively after 24 hours of Assessment.Conclusions: The results of the current study give us an evidence that SGLT2 inhibitors dapagliflozin and canagliflozin exhibits anticancer property in Oral Cancer cell line.

Prevention of Major Adverse Cardiovascular and Renal Outcomes with Sodium-Glucose Cotransporter 2 Inhibitors / 임상당뇨병

Management of hyperglycemia limits progression of microvascular complications in type 2 diabetes mellitus (T2DM). According to large-scale randomized control studies to demonstrate the cardiovascular safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors, SGLT2 inhibitors showed not only cardiovascular safety, but also cardiovascular benefits. Heart failure is adequately prevented by SGLT2 inhibitors regardless of history of heart failure. Additionally, SGLT inhibitors also showed renal protective benefits in slowing the decline of glomerular filtration rate and reducing proteinuria. SGLT2 inhibitors are beneficial to T2DM patients with established cardiovascular disease, high risk of heart failure, and renal impairment. As oral hypoglycemic agents, SGLT2 inhibitors not only control the serum glucose level, but also reduce the macrovascular complications of T2DM.

Short-term outcomes of patients with Type 2 diabetes mellitus treated with canagliflozin compared with sitagliptin in a real-world setting

<p><b>INTRODUCTION</b>We aimed to evaluate the effectiveness and safety of canagliflozin as compared to sitagliptin in a real-world setting among multiethnic patients with Type 2 diabetes mellitus (T2DM) in Singapore.</p><p><b>METHODS</b>This was a new-user, active-comparator, single-centre retrospective cohort study. Patients aged 18-69 years with T2DM and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m were eligible for inclusion if they were initiated and maintained on a steady daily dose of canagliflozin 300 mg or sitagliptin 100 mg between 1 May and 31 December 2014, and followed up for 24 weeks.</p><p><b>RESULTS</b>In total, 57 patients (canagliflozin 300 mg, n = 22; sitagliptin 100 mg, n = 35) were included. The baseline patient characteristics in the two groups were similar, with overall mean glycated haemoglobin (HbA1c) of 9.4% ± 1.4%. The use of canagliflozin 300 mg was associated with greater reductions in HbA1c (least squares [LS] mean change -1.6% vs. -0.4%; p < 0.001), body weight (LS mean change -3.0 kg vs. 0.2 kg; p < 0.001) and systolic blood pressure (LS mean change: -9.7 mmHg vs. 0.4 mmHg; p < 0.001), as compared with sitagliptin 100 mg. About half of the patients on canagliflozin 300 mg reported mild osmotic diuresis-related side effects that did not lead to drug discontinuation.</p><p><b>CONCLUSION</b>Our findings suggest that canagliflozin was more effective than sitagliptin in reducing HbA1c, body weight and systolic blood pressure in patients with T2DM, although its use was associated with an increased incidence of mild osmotic diuresis-related side effects.</p>

Development and Validation of a Stability-Indicating High Performance Thin Layer Chromatography (HPTLC) Method for estimation of Canagliflozin in bulk and Pharmaceutical Dosage Form.

The objective of the study was to develop and validate simple, authentic and stability indicating high performance thin-layer chromatographic method for determination of Canagliflozin in bulk and pharmaceutical formulations as per ICHQ2 R1 Guidelines. HPTLC aluminium plates Precoated with Silica Gel 60F254 using Toluene: Ethyl acetate: Methanol (2:2:1, v/v/v) as mobile phase were used for the chromatographic separation and it was validated with different parameters such as Linearity, Precision, Accuracy, Robustness, Ruggedness, Limit of Detection (LOD) and Limit of Quantification (LOQ). Also, Forced degradation study was carried out in different mediums. The densitometric analysis of the spots was performed at 290 nm. A Linear data over the range of 10-500ng/spot with a good correlation coefficient of 0.9988 unfolds linear relationship between area and concentration in calibration curve. The LOD and LOQ were found to be 0.39 and 1.19 respectively. A recovery of Canagliflozin in tablet formulation was observed in the range of 99.04-99.82%. Percentage assay of Canagliflozin tablets (INVOKANA®) was found to be 99.8%. Forced degradation studies of canagliflozin showed the degradation in acidic, alkaline, photolytic and oxidation but were most stable in thermal degradation. The proposed method is definite, meticulous and reproducible and can be used for routine analysis of Canagliflozin in bulk and pharmaceutical dosage form.

Berberine enhances antidiabetic effects and attenuates untoward effects of canagliflozin in streptozotocin-induced diabetic mice / 中国天然药物

The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFα) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFα in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies.

Efficacy and Safety of Different Doses of Canagliflozin in the Treatment of Type 2 Diabetes:A Meta-analysis / 中国药房

OBJECTIVE:To systematically review the efficacy and safety of different doses of canagliflozin in the treatment of type 2 diabetes,and provide evidence-based reference for the clinical treatment. METHODS:Retrieved from PubMed,Cochrane Library,Clinical Trails.gov,CJFD,Wangfang Database and VIP,randomized controlled trials (RCT) about different doses of canagliflozin in the treatment of type 2 diabetes were collected. Meta-analysis was performed by using Rev Man 5.3 software after data extract and quality evaluation by Cachrane 5.10. RESULTS:Totally 11 RCTs were enrolled,involving 5 399 patients. Results of Meta-analysis showed,canagliflozin 300 mg/d were superior to 100 mg/d in reducing HbA1c[MD=0.14,95%CI(0.09,0.19), P<0.001],FPG[MD=0.40,95%CI(0.20,0.61),P<0.001] and reduction rate of body mass[MD=0.69,95%CI(0.42,0.96),P<0.001],the differences were statistically significant;and there were no significant differences in the incidence of total adverse reac-tions [RR=0.97,95%CI(0.94,1.01),P=0.10],hypoglycemia [RR=1.02,95%CI(0.94,1.10),P=0.67],urinary tract infection[RR=0.96,95%CI (0.78,1.18),P=0.69] in 2 groups;There was significantly different of genital mycotic infection in 2 groups[RR=0.84,95%CI(0.70,1.00),P=0.04]. CONCLUSIONS:Canagliflozin 300 mg/d is better than 100 mg/d in controlling HbA1c,fasting blood glucose and body mass of patients with type 2 diabetes,and the genital mycotic infection should be attentioned.

Systematic Review on Efficacy and Safety of Canagliflozin in the Treatment of Type 2 Diabetes / 中国药房

OBJECTIVE:To make a systematic review on the efficacy and safety of canagliflozin in the treatment of type 2 dia-betes,and to provide evidence-based reference for clinical treatment. METHODS:Retrieved from Cochrane Library,PubMed,EM-Base,CBM and Wanfang database,randomized controlled trials (RCT) of canagliflozin (test group) versus placebo (control group)in the treatment of type 2 diabetes were collected,and Meta-analysis was performed by using Rev Man 5.2 statistical soft-ware after extracting data and evaluating quality. RESULTS:A total of 7 RCTs were included,involving 2 188 patients. The results of Meta analysis indicated that glycosylated hemoglobin levels [WMD=-0.82,95%CI(-0.99,-0.65),P<0.001],the proportion of HbA1c<7%[RR=2.51,95%CI(1.98,3.19),P<0.001],fasting plasma glucose levels [WMD=-32.91,95%CI(-39.65,-26.17), P<0.001] in test group were significantly better than those of control group,the incidence of genital tract infections was significant-ly higher than control group [RR=3.76,95%CI(2.23,6.35),P<0.001];however,compared with control group,there was no sig-nificant difference in the incidence of hypoglycemia [RR=1.13,95%CI(0.40,3.20),P=0.81] and urinary tract infections[RR=1.19,95%CI(0.82,1.73),P=0.36]. CONCLUSIONS:Canagliflozin is safe and effective in the treatment of type 2 diabetes,and it needs to be noticed with genital tract infections during the clinical use. Due to the limitation of methodology,large-scale and poly-centric RCT are required for further validation of the conclusions.

Canagliflozin: a novel ‘glucuretic’ approach for the treatment of type 2 diabetes mellitus.

Canagliflozin is the first in a new class of glucose-lowering drugs, an oral inhibitor of sodium glucose cotransporter 2 (SGLT2). SGLT2, the transporter is responsible for reabsorbing the majority of glucose filtered by the kidney. SGLT2 inhibitors are a new class of oral drugs indicated only for the treatment of type 2 diabetes mellitus in conjunction with exercise and a healthy diet. They inhibit glucose re-absorption in the proximal renal tubules providing an insulin independent mechanism to lower blood glucose. Their use in clinical studies is associated with improved glycemic control, weight loss, and a low risk of hypoglycemia. They have been studied alone and with other medications including sulfonylureas, sitagliptin, and insulin.

A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor

Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.

SGLT-2 inhibitors: The glucosuric antidiabetics.

Despite availability of a number of oral antidiabetics, a sizeable population of diabetics remains uncontrolled. Thus there is growing need of new group of drugs for diabetic control. Understanding renal conservation of glucose by efficient reabsorption through sodium glucose cotransporter-2 (SGLT-2) has paved way for development of an entirely new group of drugs, the SGLT-2 inhibitors. These glucosuric antidiabetic agents have shown promise in early clinical studies. Canagliflozin is recently approved for use in diabetes alone or along with other antidiabetics. Other highly selective inhibitors undergoing various stages of clinical developments are dapagliflozin, sergliflozin, remogliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin and desoxyrhaponticin. KGA-2727 (pyrazole-O-glucoside) is the first selective SGLT-1 inhibitor undergoing intense preclinical testing. There are safety issues associated with this group like urogenital infections (fungal), weight loss, initial osmotic diuresis and increased incidence of cardiovascular events. The long term safety remains to be established. Despite these limitations, SGLT-2 inhibition offers a unique target for achieving adequate control of diabetes in adults.