Nitric oxide donor-based FFA1 agonists: Design,synthesis and biological evaluation as potential anti-diabetic and anti-thrombotic agents

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM.     

Potential Place of SGLT2 Inhibitors in Treatment Paradigms for type 2 Diabetes Mellitus

Objective: Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms.Methods: The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin.Results: Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time.Conclusion: The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.Abbreviations: AE = adverse event A1C = glycated hemoglobin CI = confidence interval CKD = chronic kidney disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol HR = hazard ratio LADA = late-onset autoimmune diabetes of adulthood LDL-C = low-density lipoprotein cholesterol MACE = major adverse cardiovascular events SGLT1 = sodium glucose cotransporter 1 SGLT2 = sodium glucose cotransporter 2 T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus UACR = urine albumin to creatinine ratio     

Maximizing Patient Safety with Newly Approved Therapies: Focus on SGLT2 Inhibitors

Abbreviations: CV = cardiovascular DPP4 = dipeptidyl peptidase 4 euDKA = euglycemic diabetic ketoacidosis FDA = Food & Drug Administration SGLT2 = sodium glucose cotransporter 2 T2DM = type 2 diabetes mellitus     

Synthesis,nitric oxide release,and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC₅₀ value of 0.060?μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.     

Inhibition of Renal Glucose Reabsorption: A Novel Strategy for Achieving Glucose Control in Type 2 Diabetes Mellitus

ObjectiveTo review the renal handling of glucose and the role of inhibition of a sodium-glucose transporter (SGLT2) in the treatment of type 2 diabetes mellitus (T2DM).MethodsWe review the published data about (1) the filtration and reabsorption of glucose by the kidneys in normal subjects and patients with diabetes; (2) the deleterious effects of long-term elevation of plasma glucose levels on muscle and hepatic insulin sensitivity and beta cell function (that is, glucotoxicity); (3) the effect of inhibiting the SGLT2 transporter on the induction of glycosuria, glycemic control, insulin resistance, and beta cell dysfunction in animals and humans with diabetes; and (4) the safety of SGLT2 inhibition as a therapeutic modality to treat human T2DM.ResultsStudies in animal models of diabetes document the efficacy of the SGLT2 inhibitors in inducing glycosuria, decreasing both fasting and postprandial glucose levels, augmenting beta cell function, and enhancing hepatic and muscle insulin sensitivity. In human T2DM, short-term studies with dapagliflozin (12 weeks) and sergliflozin (2 weeks) have confirmed the efficacy of these agents in improving glycemic control. Excessive urinary electrolyte or water loss, plasma electrolyte disturbances, and hypoglycemia were not observed.ConclusionSGLT2 inhibitors represent a promising approach to the treatment of T2DM. They have the potential to be used as monotherapy, as well as in combination with all approved antidiabetic agents. Because their mechanism of action is independent of the severity of beta cell dysfunction or insulin resistance, efficacy should not decline with progressive beta cell failure or in the presence of severe insulin resistance. (Endocr Pract. 2008;14:782-790)     

Design,synthesis and evaluation of phenylfuroxan nitric oxide-donor phenols as potential anti-diabetic agents

Both nitric oxide (NO) dysfunction and oxidative stress have been regarded as the important factors in the development and progression of diabetes and its complications. Multifunctional compounds with hypoglycemic, NO supplementation and anti-oxidation will be the promising agents for treatment of diabetes. In this study, six phenylfuroxan nitric oxide (NO) donor phenols were synthesized, which were designed via a combination approach with phenylfuroxan NO-donor and natural phenols. These novel synthetic compounds were screened in vitro for α-glucosidase inhibition, NO releasing, anti-oxidation, anti-glycation and anti-platelet aggregation activity as well as vasodilatation effects. The results exhibited that compound T5 displayed more excellent activity than other compounds. Moreover, T5 demonstrated significant hypoglycemic activity in diabetic mice and oral glucose tolerance test (OGTT) mice. T5 also showed NO releasing and anti-oxidation in diabetic mice. Based on these results, compound T5 deserves further study as potential new multifunctional anti-diabetic agent with antioxidant, NO releasing, anti-platelet aggregation and vasodilatation properties.     

Synthesis and evaluation of nitric oxide-releasing derivatives of 3-n-butylphthalide as anti-platelet agents

Most ischemic stroke results from brain blood vessel blockage by platelet-mediated thrombus, and anti-platelet therapy has been demonstrated clinical benefits in the treatment of this disease. In the present work, novel nitric oxide (NO)-releasing derivatives of an anti-ischemic stroke drug 3-n-butylphthalide (NBP) were synthesized. Compounds 7a and 7c exhibited more potent anti-platelet activity than NBP and aspirin, and released a moderate amount of NO, which is beneficial in improving cardiovascular and cerebral circulation. These findings provide an alternative approach to the development of drugs more potent than NBP for the intervention of ischemic stroke.     

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC₅₀?=?45?nM), and excellent potency at SGLT2 (IC₅₀?=?1?nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F?=?78–107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24?h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.     

The Emerging Role Of Adjunctive Noninsulin Antihyperglycemic Therapy In The Management Of Type 1 Diabetes

Objective: Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents.Methods: Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term “type 1 diabetes” and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin.Results: The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia.Conclusion: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.Abbreviations:A1C = glycated hemoglobinBMI = body mass indexCI = confidence intervalDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase 4GLP-1 = glucagonlike peptide 1PYY = polypeptide tyrosine tyrosineSGLT = sodium-glucose cotransporterSGLT1 = sodium-glucose cotransporter 1SGLT2 = sodium-glucose cotransporter 2T1D = type 1 diabetesT2D = type 2 diabetesTDD = total daily dosage     

Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.     

Angiotensin II‐induced redox‐sensitive SGLT1 and 2 expression promotes high glucose‐induced endothelial cell senescence

High glucose (HG)‐induced endothelial senescence and dysfunction contribute to the increased cardiovascular risk in diabetes. Empagliflozin, a selective sodium glucose co‐transporter2 (SGLT2) inhibitor, reduced the risk of cardiovascular mortality in type 2 diabetic patients but the protective mechanism remains unclear. This study examines the role of SGLT2 in HG‐induced endothelial senescence and dysfunction. Porcine coronary artery cultured endothelial cells (ECs) or segments were exposed to HG (25 mmol/L) before determination of senescence‐associated beta‐galactosidase activity, protein level by Western blot and immunofluorescence staining, mRNA by RT‐PCR, nitric oxide (NO) by electron paramagnetic resonance, oxidative stress using dihydroethidium and glucose uptake using 2‐NBD‐glucose. HG increased ECs senescence markers and oxidative stress, down‐regulated eNOS expression and NO formation, and induced the expression of VCAM‐1, tissue factor, and the local angiotensin system, all these effects were prevented by empagliflozin. Empagliflozin and LX‐4211 (dual SGLT1/2 inhibitor) reduced glucose uptake stimulated by HG and H₂O₂ in ECs. HG increased SGLT1 and 2 protein levels in cultured ECs and native endothelium. Inhibition of the angiotensin system prevented HG‐induced ECs senescence and SGLT1 and 2 expression. Thus, HG‐induced ECs ageing is driven by the local angiotensin system via the redox‐sensitive up‐regulation of SGLT1 and 2, and, in turn, enhanced glucotoxicity.     

Synthesis of novel l-rhamnose derived acyclic C-nucleosides with substituted 1,2,3-triazole core as potent sodium-glucose co-transporter (SGLT) inhibitors

Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes by preventing renal glucose reabsorption. In our efforts to identify novel inhibitors of SGLT, we synthesized a series of l-rhamnose derived acyclic C-nucleosides with 1,2,3-triazole core. The key β-ketoester building block 4 prepared from l-rhamnose in five steps, was reacted with various aryl azides to produce the respective 1,2,3-triazole derivatives in excellent yields. Deprotection of acetonide group gave the desired acyclic C-nucleosides 7a–o. All the new compounds were screened for their sodium-glucose co-transporters (SGLT1 and SGLT2) inhibition activity using recently developed cell-based nonradioactive fluorescence glucose uptake assay. Among them, 7m with IC₅₀: 125.9 nM emerged as the most potent SGLT2 inhibitor. On the other hand compound 7d exhibited best selectivity for inhibition of SGLT2 (IC₅₀: 149.1 nM) over SGLT1 (IC₅₀: 693.2 nM). The results presented here demonstrated the utility of acyclic C-nucleosides as novel SGLT inhibitors for future investigations.     

Reducing oxidative stress in patients with type 2 diabetes mellitus: A primary care call to action

Background: Oxidative stress is believed to be the primary cause of the microvascular and macrovascular complications of type 2 diabetes mellitus (DM).Objective: This paper examines the evidence linking oxidative stress with long-term complications of type 2 DM and explores methods to minimize its effect.Methods: A literature search was performed to identify relevant studies for this review. Articles published in English from 2000 to 2008 were identified through searches of PubMed, Diabetes Care, and Google using the search terms oxidative stress, postprandial hyperglycemia, ACCORD Trial, and endothelial cell dysfunction.Results: The literature search identified 423 articles. Although chronic hyperglycemia can be effectively monitored and targeted using glycosylated hemoglobin concentrations, postprandial glucose levels are also important. Postprandial glucose excursions are exhibited by almost all patients with type 2 DM and are independent risk factors for cardiovascular morbidity and mortality. Furthermore, glucose fluctuations during the postprandial period elicit more oxidative stress than chronic, sustained hyperglycemia and can lead to endothelial dysfunction, vascular inflammation, and microvascular complications. In turn, endothelial dysfunction has been implicated in the development of vascular pathologies such as atherosclerosis. Pharmacologic interventions (eg, rapid-acting insulin analogues that target post-prandial glucose excursions) reduce oxidative stress and vascular inflammation and improve endothelial dysfunction.Conclusions: Given the important role of oxidative stress in the development of complications of type 2 DM, physi-cians should consider methods to reduce oxidative stress that may occur during both acute (postprandial) and chronic hyperglycemia. One critical aspect is to reduce postprandial glucose levels to <180 mg/dL while lowering fasting glucose levels to <110 mg/dL. By coaching patients to reach these goals, physicians and other health care professionals can minimize the risk of long-term complications of type 2 DM.     

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: Discovery of YM543

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.     

Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2

Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4′-substituted benzyl group to a β-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.     

Weight Gain and Management Concerns in Patients on Insulin Therapy

Background: The benefits of tight glycemic control in preventing the onset and progression of microvascular complications in patients with type 2 diabetes mellitus (DM) are unarguable. The majority of patients with type 2 DM will eventually require insulin to achieve adequate glycemic control. Using insulin earlier rather than later in the course of type 2 DM may diminish the deleterious effects of hyperglycemia on β-cell function and therefore help prolong good glycemic control and prevent the occurrence of microvascular complications. However, weight gain is a potential adverse effect of insulin therapy.Objective: The goal of this article was to describe the benefit of insulin therapy early in the course of type 2 DM, review the association of weight gain with insulin therapy, and examine potential detrimental effects that insulin-associated weight gain could have in patients with type 2 DM.Methods: Materials used for this article were identified through a search of MEDLINE (1966–2006). English-language articles were chosen using the search terms diabetes mellitus type 2, insulin, and obesity.Results: Intensive insulin therapy is often associated with weight gain. Although there is concern that weight gain in patients with type 2 DM may have adverse effects on risk factors for cardiovascular disease, unfavorable changes in blood pressure and lipid levels have not been consistently observed in clinical trials. Furthermore, clinical evidence, including data from the United Kingdom Prospective Diabetes Study, supports the view that intensive insulin therapy does not increase the risk for cardiovascular disease.Conclusions: Early insulin therapy in patients with type 2 DM may be a strategy that will help patients achieve and maintain good glycemic control, thereby reducing the risk of developing microvascular complications. Although weight gain is commonly associated with insulin therapy, it does not appear to put these patients at greater risk for cardiovascular disease.     

Discovery of triazole-based uracil derivatives bearing amide moieties as novel dipeptidyl peptidase-IV inhibitors

Dipeptidyl peptidase-IV (DPP-4) is a validated target for T2DM treatment. We previously reported a novel series of triazole-based uracil derivatives bearing aliphatic carboxylic acids with potent DPP-4 inhibitory activities in vitro, but these compounds showed poor hypoglycemic effects in vivo. Herein we further optimized the triazole moiety by amidation of the carboxylic acid to improve in vivo activities. Two series of compounds 3a-f and 4a-g were designed and synthesized. By screening in DPP-4, compound 4c was identified as a potent DPP-4 inhibitor with the IC₅₀ value of 28.62 nM. Docking study revealed compound 4c has a favorable binding mode and interpreted the SAR of these analogs. DPP-8 and DPP-9 tests indicated compound 4c had excellent selectivity over DPP-8 and DPP-9. Further in vivo evaluations revealed that compound 4c showed more potent hypoglycemic activity than its corresponding carboxylic acid in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice. The overall results have shown that compound 4c could be a promising lead for further development of novel DPP-4 agents treating T2DM.     

Design,synthesis, and structure–activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1)

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.     

Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models

Background

Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM).

Methods

¹⁴C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; ³H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RT_G) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity.

Results

Treatment with canagliflozin 1 mg/kg lowered RT_G from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT_G. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio.

Conclusions

Canagliflozin lowered RT_G and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.