Selective Sodium-glucose Cotransporter 2 Research Articles

465-P: Thrombin Induces SGLT1 and SGLT2 Expression to Promote the AT1R/NADPH Oxidase-Mediated Pro-oxidant Response Inducing Senescence in Atrial Endothelial Cells

Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular (CV) disease independently of glycemic control. Although blood-derived coagulation factors are major contributors of CV diseases, their impact on the expression of SGLT1 and 2 in endothelial cells (ECs) has not been studied. This study investigated whether thrombin affects the expression of SGLT1 and 2 and examined their role in the induction of endothelial senescence. ECs were isolated from porcine atrial tissue (AECs) and used at first passage. Endothelial senescence was assessed by determining senescence-associated beta-galactosidase (SA-beta-gal) activity, oxidative stress using dihydroethidium, and protein level by Western blot analysis and immunofluorescence staining. Exposure of AECs to thrombin (1 or 3 U/ml) for 24 h induced an upregulation of the low protein expression level of SGLT1 and SGLT2. Thrombin induced a sustained pro-oxidant response and increased the level of SA-beta-gal activity that were both inhibited by antioxidants, an angiotensin-converting enzyme inhibitor and an AT1 receptor antagonist and also by sotagliflozin (a dual SGLT1 and SGLT2 inhibitor) and by empagliflozin (a selective SGLT2 inhibitor). In addition, thrombin upregulated the expression level of angiotensin-converting enzyme and AT1 receptors, VCAM-1 and down-regulated that of endothelial NO synthase. In conclusion, thrombin up-regulates both SGLT1 and SGLT2 expression in AECs to sustain oxidative stress leading to endothelial senescence and dysfunction. The fact that the AT1R/NADPH oxidase/SGLT1 and 2 pathway acts in a feedforward manner suggests that inhibition of SGLT1 and/or SGLT2 appears as an attractive strategy to perpetuate the protective endothelial function on the cardiovascular system. Disclosure H. Hasan: None. S. Park: None. E. Belcastro: None. C. Auger: None. H. Lee: None. V. Schini-Kerth: Research Support; Self; Boehringer Ingelheim International GmbH.

1117-P: Cardiovascular and Glycemic Benefits of Bexagliflozin as an Adjunct to Metformin for the Treatment of Type 2 Diabetes in Adults: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Bexagliflozin is a potent and selective sodium glucose co-transporter 2 inhibitor. To evaluate the safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus, participants (317) were randomized to receive bexagliflozin or placebo in addition to ongoing treatment with metformin. The primary endpoint was the placebo-adjusted change in HbA1c from baseline to week 24. Changes in systolic blood pressure (SBP), fasting plasma glucose (FPG) and body mass were secondary endpoints. The study also enrolled an open label arm of participants with elevated HbA1c. Including post-rescue observations, the mean change in HbA1c was 1.09% (95% CI 1.24%, 0.94%) in the bexagliflozin arm and 0.56% ( 0.71%, 0.41%) in the placebo arm, for a difference of -0.53% ( 0.74%, 0.32%; p < 0.0001). By the last-observation-carried-forward method, the intergroup difference was -0.70% ( 0.92, 0.48; p < 0.0001). The open label cohort experienced a mean change in HbA1c of 2.82% ( 3.23%, -2.41%). The placebo-adjusted changes from baseline SBP, FPG and body mass and SBP were 7.07 mm Hg ( 9.83, -4.32; p < 0.0001), -1.35 mmol L-1 (-1.83, -0.86; p < 0.0001) and 2.51 kg (-3.45, -1.57; p < 0.0001). Adverse events were experienced by 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively, and fewer subjects in the bexagliflozin arm experienced serious adverse events. Bexagliflozin produced clinically meaningful and statistically significant improvement in measures of cardiovascular health and glycemic control in a population of diabetic adults inadequately controlled by metformin alone. ClinicalTrials.gov Identifier: NCT03259789. Disclosure Y.C. Halvorsen: Research Support; Self; Theracos, Inc. J.P. Lock: None. M.W. Freeman: Research Support; Self; Theracos, Inc.

P1050THE EFFICACY AND RENAL SAFETY OF SWITCHING FROM DAPAGLIFLOZIN TO EMPAGLIFLOZIN IN PATIENTS WITH TYPE 2 DIABETES

Abstract Background and Aims Both dapagliflozin (DPG) and empagliflozin (EPG) are highly selective sodium-glucose cotransporter-2 (SGLT-2) inhibitors that inhibit glucose reabsorption and increase its excretion in urine. Previously, DPG was limited to patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2, while EPG can be used for those with an eGFR ≥ 45 mL/min/1.73 m2. Therefore DPG was switched to EPG in many patients when eGFR decreased. However, the clinical efficacy and safety of these switches are not clear. In this study, we compared the efficacy and renal safety between patients switching from DPG to EPG and those continuing DPG in patients with type 2 diabetes mellitus (T2DM). Method This retrospective observational study included patients with T2DM who were treated with DPG for more than 6 months. This study included patients who switched to EPG and those who continued using DPG. All other hypoglycemic drugs were maintained at the same dosage before and after the study period. The primary outcome measure was the change in hemoglobin A1c (HbA1c) level after 6 months. The EPG group was evaluated for whether the hypoglycemic effect remain effective after drug switching. Patients with HbA1c levels at or lower than the baseline value after 6 months were defined as effective and patients with levels higher than the baseline were defined as invalid. Safety was evaluated by comparing the difference of eGFR between the baseline value and six months after treatment. Results This study included 169 patients. Among them, 72 patients continued DPG and 97 patients switched to EPG. HbA1c level decreased significantly only in EPG group. In EPG group, 59 patients belong to the effective group (60.8%) and 38 patients were invalid (39.2%). There was no significant change in eGFR after treatment in both groups. Ten patients in DPG group develop adverse reactions (three patients felt uncomfortable and seven patients had urinary tract symptoms), but all continued treatment. In EPG group, five patients lacked follow-up records during the study period and it was difficult to determine whether the patient’s willingness to continue treatment was affected by adverse reactions. Conclusion Our study showed that switching from DPG to EPG in patients with T2DM was effective for blood glucose maintenance and caused no significant changes in renal function. In addition, no severe drug-related adverse reactions were found.

1711-P: Dapagliflozin Promotes Adipose Beiging and Lipolysis and Reduces Adipocyte Size in the Obese Prediabetic Dog

Selective sodium glucose cotransporter-2 inhibition promotes urinary glucose excretion, thus reducing blood glucose. Previously we showed that 6 weeks of Dapagliflozin (Dapa) treatment improved insulin sensitivity and prevented weight gain in a canine model of mild type 2 diabetes. Little is known about the effects of Dapa on adipose tissue (AT) function. Eleven dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were then exposed to Dapa (n=5, 1.25mg/kg) or placebo (n=6) once per day for 6 weeks, while remaining on the high fat diet. At the end of the study, subcutaneous (SC) and visceral (VIS) fat depots were obtained for adipocytes isolation and molecular studies and fasting plasma parameters were measured. Fasting plasma glucose and insulin levels were unaffected by Dapa treatment. Finite mixture modeling linear regression was used for adipocyte distributions. Dapa decreased adipocyte size and bimodal distributions in both SC and VIS by 10% (P<0.001). Dapa increased UCP1, PGC1α and Prdm16 gene expression by 2.68, 2.34 and 2.16 folds (<0.05) in SC and 2.5, 3.6 and 1.6 folds (<0.05) in VIS depots respectively. Immunostaining of UCP1 in SC and VIS tissues confirmed beiging process. Primary adipocytes were cultured for 4 and 24h. Lipolysis, indicated by glycerol release into the media increased by 40% in SC and 43% in vis after 24h (P<0.05). Adiponectin levels increased only in the SC adipocytes by 80% (P<0.05) after 4 and 24h cultures. Leptin levels increased in SC (by 3 folds P<0.05) and VIS by 2.6 P<0.05) after 24h adipocyte cultures. In conclusion, Dapa promotes AT beiging, lipolysis, adiponectin and leptin release by adipocytes and decreased adipocyte size and distributions. These changes were independent of glucose and insulin. Thus, for the first time we are beginning to identify mechanisms by which Dapa enhances AT function and improves energy homeostasis in mild type 2 diabetes canine model. Disclosure M. Kabir: None. R.N. Bergman: None. F. Piccinini: Employee; Self; Medtronic. D. Stefanovski: None. V. Gopaul: None. H. Yang: Employee; Self; AstraZeneca. C.M. Kolka: Research Support; Self; AstraZeneca. Funding AstraZeneca (D1690L00045-CSR212966)

Effects of Dapagliflozin on Epicardial Fat Thickness in Patients with Type 2 Diabetes and Obesity.

Epicardial adipose tissue (EAT) thickness is a marker of visceral fat and an emerging therapeutic target. Dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, improves glucose control and induces moderate weight loss in patients with type 2 diabetes mellitus. Dapagliflozin has recently been shown to reduce cardiovascular risk. Nevertheless, whether dapagliflozin could reduce EAT thickness is unknown. This hypothesis was tested in a 24-week, randomized, double-blind, placebo-controlled clinical trial in 100 patients with type 2 diabetes mellitus with BMI ≥ 27 kg/m2 and a hemoglobin A1c level ≤ 8% on metformin monotherapy. Individuals were randomly assigned to 2 groups to receive additional dapagliflozin up to 10 mg once daily or to remain on metformin up to 1,000 mg twice daily. Ultrasound-measured EAT thickness was measured at baseline, 12 weeks, and 24 weeks. In the dapagliflozin group, EAT decreased by 20% from baseline to 24 weeks, by 15% after 12 weeks, and by 7% between 12 and 24 weeks, respectively (P < 0.01 for all), whereas in the metformin group, there was a significant but smaller EAT reduction. There was no statistically significant correlation between EAT and body weight changes. Dapagliflozin causes a rapid and significant EAT reduction that could be independent of weight loss.

Safety and effectiveness of tofogliflozin in Japanese patients with type2 diabetes mellitus: Results of 24-month interim analysis of a long-term post-marketing study (J-STEP/LT).

Aims/IntroductionTofogliflozin is a potent and highly selective sodium–glucose cotransporter 2 inhibitor, and is currently used to treat patients with type 2 diabetes mellitus. We designed a 3‐year study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3‐ and 12‐month interim analysis showed tofogliflozin was well‐tolerated, safe and clinically effective. Here, we report the results of the 24‐month interim analysis.Materials and MethodsThis is a 3‐year prospective, observational and multicenter post‐marketing study (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term).ResultsOf the 6,897 patients enrolled, 6,712 and 6,461 patients were analyzed for the safety and effectiveness of tofogliflozin, respectively. During the 24‐month observation period, the incidence rates of adverse drug reactions (ADRs) and serious adverse drug reactions were 11.25 and 1.21%, respectively. As to adverse drug reactions of special interest, the incidence rates of hypoglycemia, polyuria/pollakiuria, volume depletion‐related events, urinary tract infections and genital infection were 0.83, 1.28, 1.46, 1.18 and 1.62%, respectively. Renal disorders, and cardiovascular and cerebrovascular disorders occurred in 0.63 and 0.76% of the patients, respectively. Glycated hemoglobin A1c and bodyweight decreased significantly by −0.70% (P < 0.0001) and −2.95 kg (P < 0.0001), respectively, from baseline to week 104 (last observation carried forward).ConclusionsSignificant safety concerns have not been observed, and clinical benefit including a long‐term reduction in glycated hemoglobin A1c over a 104‐week (24 months) observation period with weight loss was suggested in this 24‐month interim analysis of the 3‐year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term in routine clinical practice.

Model-based Prediction of the Long-term Glucose-Lowering Effects of Ipragliflozin, a Selective Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor, in Patients with Type 2 Diabetes Mellitus.

IntroductionSodium-dependent glucose cotransporter 2 (SGLT2) inhibitors inhibit the reabsorption of glucose from the kidneys and increase urinary glucose excretion (UGE), thereby lowering the blood glucose concentration in people suffering from type 1 and type 2 diabetes mellitus (T2DM). In a previous study, we reported a pharmacokinetics/pharmacodynamics model to estimate individual change in UGE (ΔUGE), which is a direct pharmacological effect of SGLT2 inhibitors. In this study, we report our enhancement of the previous model to predict the long-term effects of ipragliflozin on clinical outcomes in patients with T2DM.MethodsThe time course of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) in patients with T2DM following ipragliflozin treatment that had been observed in earlier clinical trials was modeled using empirical models combined with the maximum drug effect (Emax) model and disease progression model. As a predictive factor of drug effect, estimated ΔUGE was introduced into the Emax model, instead of ipragliflozin exposure. The developed models were used to simulate the time course of FPG and HbA1c following once-daily treatment with placebo or ipragliflozin at doses of 12.5, 25, 50 and 100 mg, and the changes at 52 weeks at the approved dose of 50 mg were summarized by renal function category.ResultsThe developed models that included UGE as a dependent variable of response were found to well describe observed time courses in FPG and HbA1c. Baseline blood glucose level and renal function had significant effects on the glucose-lowering effect of ipragliflozin, and these models enabled quantification of these impacts on clinical outcomes. Simulated median changes in HbA1c in T2DM patients with mild and moderate renal impairment were 25 and 63% lower, respectively, than those in T2DM patients with normal renal function. These results are consistent with the observed clinical data from a previous renal impairment study.ConclusionsEmpirical models established based on the effect of UGE well predicted the renal function-dependent long-term glucose-lowering effects of ipragliflozin in patients with T2DM.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00785-2) contains supplementary material, which is available to authorized users.

Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice.

Aim: Recent studies have demonstrated that selective sodium–glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism.Method: Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE−/−) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed.Result: Canagliflozin decreased blood glucose (P < 0.001) and total cholesterol (P < 0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P < 0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P < 0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P < 0.05, both). Methylglyoxal also decreased the phosphorylation of eNOSSer1177 and Akt but increased the phosphorylation of eNOSThr495 and p38 MAPK in HUVECs.Conclusion: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.

Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat

BackgroundEmpagliflozin (empa), a selective sodium–glucose cotransporter (SGLT)2 inhibitor, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk independent of glycemic control. The cardiovascular protective effect of empa was evaluated in an experimental model of metabolic syndrome, the obese ZSF1 rat, and its’ lean control.MethodsLean and obese ZSF1 rats were either non-treated or treated with empa (30 mg/kg/day) for 6 weeks. Vascular reactivity was assessed using mesenteric artery rings, systolic blood pressure by tail-cuff sphygmomanometry, heart function and structural changes by echocardiography, and protein expression levels by Western blot analysis.ResultsEmpa treatment reduced blood glucose levels from 275 to 196 mg/dl in obese ZSF1 rats whereas normoglycemia (134 mg/dl) was present in control lean ZSF1 rats and was unaffected by empa. Obese ZSF1 rats showed increased systolic blood pressure, and blunted endothelium-dependent relaxations associated with the appearance of endothelium-dependent contractile responses (EDCFs) compared to control lean rats. These effects were prevented by the empa treatment. Obese ZSF1 rats showed increased weight of the heart and of the left ventricle volume without the presence of diastolic or systolic dysfunction, which were improved by the empa treatment. An increased expression level of senescence markers (p53, p21, p16), tissue factor, VCAM-1, SGLT1 and SGLT2 and a down-regulation of eNOS were observed in the aortic inner curvature compared to the outer one in the control lean rats, which were prevented by the empa treatment. In the obese ZSF1 rats, no such effects were observed. The empa treatment reduced the increased body weight and weight of lungs, spleen, liver and perirenal fat, hyperglycemia and the increased levels of total cholesterol and triglycerides in obese ZSF1 rats, and increased blood ketone levels and urinary glucose excretion in control lean and obese ZSF1 rats.ConclusionEmpa reduced glucose levels by 28% and improved both endothelial function and cardiac remodeling in the obese ZSF1 rat. Empa also reduced the increased expression level of senescence, and atherothrombotic markers at arterial sites at risk in the control lean, but not obese, ZSF1 rat.

Effect of Tofogliflozin on Carotid Intima-Media Thickness in Patients with Type 2 Diabetes: Results from the Prospective, Randomized, Open-Label, Parallel-Group Comparative UTOPIA Trial

Effect of Tofogliflozin on Carotid Intima-Media Thickness in Patients with Type 2 Diabetes: Results from the Prospective, Randomized, Open-Label, Parallel-Group Comparative UTOPIA Trial

Effect of dapagliflozin alone and in combination with insulin in a rat model of type 1 diabetes

Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor; it reduces glucose reabsorption via the kidney and increases the glucose excretion in urine. This inhibitor functions through a unique insulin-independent mechanism, and is therefore a potential new approach for the treatment of hyperglycemia in patients with diabetes. In this study, we evaluated the effectiveness of the SGLT2 inhibitor, dapagliflozin, by using a rat model of type 1 diabetes. Type 1 diabetes was induced by a single intraperitoneal injection of 60 mg/kg streptozotocin (STZ). The STZ-induced rats showed marked hyperglycemia and other metabolic abnormalities. We clarified the hypoglycemic effect of the combination treatment of dapagliflozin with a low dose of insulin compared with dapagliflozin alone and insulin alone in 3-week and 8-week studies. Our results showed that dapagliflozin in combination with a low dose of insulin significantly lowered hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. Furthermore, the antioxidant status and body weight were improved. In contrast, treatment with dapagliflozin alone did not improve the blood glucose levels, lipid profile, antioxidant status, or body weight. These findings suggested that in type 1 diabetes, dapagliflozin was effective in combination with a low dose of insulin; however, the administration of dapagliflozin alone did not achieve a significant effect.

The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma.

The aim of the present study is to investigate the effects of canagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, on non-alcoholic steatohepatitis (NASH) and NASH-related hepatocellular carcinoma (HCC) in a mouse model of diabetes and NASH-HCC. First, mice aged five weeks were divided into two groups (vehicle group and canagliflozin group) and were treated for three weeks. Then, mice aged five weeks were divided into three groups of nine animals each: the vehicle group, early canagliflozin group (treated from five to nine weeks), and continuous canagliflozin group (treated from five to 16 weeks). Canagliflozin was administered at a dose of 30 mg/kg in these experiments. In addition, the in vitro effects of canagliflozin were investigated using HepG2 cells, a human HCC cell line. At the age of eight or 16 weeks, the histological non-alcoholic fatty liver disease activity score was lower in the canagliflozin-treated mice than in vehicle-treated mice. There were significantly fewer hepatic tumors in the continuous canagliflozin group than in the vehicle group. Immunohistochemistry showed significantly fewer glutamine synthetase-positive nodules in the continuous canagliflozin group than in the vehicle group. Expression of α-fetoprotein mRNA, a marker of HCC, was downregulated in the continuous canagliflozin group when compared with the vehicle group. At 16 weeks, there was diffuse SGLT1 expression in the hepatic lobules and strong expression by hepatocytes in the vehicle group, while SGLT2 expression was stronger in liver tumors than in the lobules. In the in vitro study, canagliflozin (10 μM) suppressed the proliferation of HepG2 cells. Flow cytometry showed that canagliflozin reduced the percentage of HepG2 cells in the G2/M phase due to arrest in the G1 phase along with decreased expression of cyclin D and Cdk4 proteins, while it increased the percentage of cells in the G0/1 phase. Canagliflozin also induced apoptosis of HepG2 cells via activation of caspase 3. In this mouse model of diabetes and NASH/HCC, canagliflozin showed anti-steatotic and anti-inflammatory effects that attenuated the development of NASH and prevented the progression of NASH to HCC, partly due to the induction of cell cycle arrest and/or apoptosis as well as the reduction of tumor growth through the direct inhibition of SGLT2 in tumor cells.

Safety of Ipragliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Phase II/III/IV Clinical Trials.

IntroductionIpragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials.MethodsSafety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements.ResultsThe overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier’s gangrene in ipragliflozin-treated patients across the 12 studies.ConclusionIn randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed.Trial Registration NumbersNCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094.FundingAstellas Pharma Inc.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-00699-8) contains supplementary material, which is available to authorized users.

Chronopharmacology of dapagliflozin-induced antihyperglycemic effects in C57BL/6J mice

Chronopharmacology is the study of the varying responses of drugs to changes in biological timing and endogenous periodicities. The selective sodium-glucose cotransporter 2 inhibitor, dapagliflozin, is a globally prescribed antihyperglycemic drug. Although dapagliflozin is usually administered once a day, the specific intake time is generally not mentioned. Therefore, this study aimed at investigating the diurnal effects of dapagliflozin on high-fat diet (HFD)-induced obesity in mice. Five-week-old male C57BL/6J mice were fed a normal (control) diet or HFD for 10 weeks. During the last 2 weeks, the mice were administered olive oil/ethanol emulsion or dapagliflozin (1mg/kg, p.o.) in the light or dark phase. At the end of the experiment, the mice were euthanized after an 18h fasting period, and plasma and tissue samples (epididymal white adipose tissues, liver, and kidney) were collected. Dapagliflozin administration in the light phase significantly decreased plasma glucose levels, insulin levels, adipose adipokines, and decreased the size of adipocytes, compared with the HFD group. In contrast, these parameters remained unchanged in the mice treated during the dark phase. Our data therefore suggests that dapagliflozin portrays definite chronopharmacology, which may provide valuable information on the importance of drug administration timing for maximal pharmacological effects.

Ertugliflozin in type 2 diabetes: a profile of its use

Oral ertugliflozin (Steglatro™), a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved in numerous countries as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes (T2D), either as monotherapy or add-on therapy to other antihyperglycaemic agents; specific indications may vary between individual countries. In numerous well-designed VERTIS trials and extension studies in adults with inadequately controlled T2D, ertugliflozin monotherapy, initial combination therapy to sitagliptin and add-on therapy to metformin or to metformin plus sitagliptin consistently provided effective and durable glycaemic control, and reduced bodyweight and blood pressure. Ertugliflozin is generally well tolerated, with a good benefit/risk profile. The availability of ertugliflozin/metformin (Segluromet™) and ertugliflozin/sitagliptin (Steglujan™) fixed-dose combinations (FDCs) may potentially improve compliance/adherence in patients requiring intensification of antihyperglycaemic treatment with combination therapy to achieve adequate glycaemic control. Given the proven benefits of other SGLT2 inhibitors on cardiovascular (CV) and renal outcomes, results from the ongoing VERTIS CV outcome trial are awaited with interest.

Dapagliflozin: A Review in Type 2 Diabetes.

Dapagliflozin (Forxiga®) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. In numerous well-designed clinical studies and their extensions, dapagliflozin as monotherapy and combination therapy with other antihyperglycaemic agents provided effective glycaemic control and reduced bodyweight and blood pressure (BP) across a broad spectrum of patients. Dapagliflozin reduced the rate of cardiovascular (CV) death or hospitalization for heart failure (HHF), did not adversely affect major adverse CV events (MACE) and possibly reduced progression of renal disease relative to placebo in patients with established atherosclerotic CV disease (CVD) or multiple risk factors for CVD. Dapagliflozin was generally well tolerated, with a low risk of hypoglycaemia; diabetic ketoacidosis (DKA), although rare, and genital infections were more common with dapagliflozin than placebo. Given its antihyperglycaemic, cardioprotective and possibly renoprotective properties and generally favourable tolerability profile, dapagliflozin provides an important option for the management of a broad patient population, regardless of the history of CVD.

Bioequivalence of Ertugliflozin/Metformin Fixed‐Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components

A fixed‐dose combination (FDC) of ertugliflozin, a selective sodium‐glucose cotransporter 2 inhibitor, and immediate‐release metformin is approved for the treatment of type 2 diabetes mellitus in the United States and European Union. Four open‐label, randomized, 2‐period, single‐dose, crossover studies were conducted under fasted conditions in healthy subjects to demonstrate bioequivalence of the ertugliflozin/metformin FDC tablets and coadministration of the individual components at respective strengths. In each study, 32 or 34 subjects received an ertugliflozin/metformin FDC tablet (2.5 mg/500 mg, 7.5 mg/850 mg, or 7.5 mg/1000 mg) and the respective doses of individual components (ertugliflozin with US‐ or EU‐sourced metformin [Glucophage]). Plasma samples for ertugliflozin and metformin concentrations were collected for 72 hours in each period. For both ertugliflozin and metformin, the 90% confidence intervals for the adjusted geometric mean ratio (FDC : coadministration) for area under the plasma concentration–time profile from time zero extrapolated to infinity and maximum observed plasma concentration were within acceptance criteria for bioequivalence. The majority of adverse events were mild in intensity. The studies demonstrated that each strength of FDC tablet is bioequivalent to respective doses of coadministered individual components, supporting that safety and efficacy can be bridged to the individual components used in phase 3 studies evaluating ertugliflozin in combination with metformin.

Remogliflozin Etabonate: First Global Approval.

Remogliflozin, a selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor, which is to be administered as remogliflozin etabonate (Remo™, Remozen™), the prodrug for remogliflozin, recently received its first approval as a treatment for type 2 diabetes mellitus (T2DM) in India. This article summarizes the milestones in the development of remogliflozin etabonate leading to this first approval for T2DM.

1222-P: Comparative Efficacy of Ertugliflozin (ERTU) vs. Other Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i): Model-Based Meta-analysis (MBMA) of HbA1c Lowering

Background: ERTU is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of adults with type 2 diabetes mellitus (T2DM). As several SGLT2i are commercially available, MBMA of the HbA1c-lowering effect of these drugs was undertaken to assess their comparative effectiveness. Methods: MBMA quantified the time course of dose vs. HbA1c response of SGLT2i and evaluated the impact of covariates including baseline HbA1c, estimated glomerular filtration rate (eGFR) and background diabetes treatment on HbA1c efficacy. Of the 496 randomized controlled trials (RCTs) in the database, 94 RCTs representing &amp;gt;31,000 T2DM patients were with SGLT2i, including 5 RCTs for ERTU. Results: For SGLT2i, there was a 28.7% (95% CI, 24.5 to 33.1%) greater relative HbA1c efficacy for a 1% absolute increase in baseline HbA1c. Additionally, the HbA1c efficacy was 25.0% (17.0 to 34.0%) greater on a diet background alone relative to a background of metformin (or other oral antidiabetic treatment). For every 10 mL/min/1.73m2 decrease in eGFR, there was a 8.80% (5.90 to 11.6%) decrease in HbA1c efficacy. Conclusion: This MBMA allowed an indirect comparison of SGLT2 inhibitor efficacy across trials (Table). Overall, ERTU doses of 5 and 15 mg were of comparable or numerically greater efficacy to other SGLT2i. Disclosure D. Fediuk: Employee; Self; Pfizer Inc. J. Mandema: Consultant; Self; Merck &amp; Co., Inc., Pfizer Inc., Sanofi. K. Sweeney: Employee; Self; Pfizer Inc. S.G. Terra: Employee; Self; Pfizer Inc. V. Sahasrabudhe: Employee; Self; Pfizer Inc. Funding Pfizer Inc.; Merck Sharp &amp; Dohme Corp.

A novel high-performance liquid chromatographic method combined with fluorescence detection for determination of ertugliflozin in rat plasma: Assessment of pharmacokinetic drug interaction potential of ertugliflozin with mefenamic acid and ketoconazole

Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10 mM potassium phosphate buffer (pH 6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320 nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000 ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs.