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9/22/2015 Some Newer Non-Insulin Therapies for Type 2 Diabetes:Present and future Faculty/presenter disclosure Speaker’s name: Dr. Robert G. Josse SGLT2 Inhibitors Grants/research support: Astra Zeneca, BMS, Boehringer Dopamine D2 Receptor Agonist Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Roche, Bile acid sequestrant sanofi, Consulting Fees: Astra Zeneca, BMS, Eli Lilly, Janssen, Merck, Dr Robert G Josse Division of Endocrinology & Metabolism Speakers bureau: Janssen, Astra Zeneca, BMS, Merck, St. Michael’s Hospital Professor of Medicine Stocks and Shares:None University of Toronto 100-year History of Objectives Anti-hyperglycemic Therapeutics 14 Discuss the mechanism of action of SGLT2 inhibitors, SGLT-2 inhibitor 12 Bromocriptine-QR dopamine D2 receptor agonists and bile acid sequestrants Bile acid sequestrant in the management of type 2 diabetes Number of 10 DPP-4 inhibitor classes of GLP-1 receptor agonist Amylinomimetic anti- 8 Glinide Basal insulin analogue Identify the benefits and risks of the newer non-insulin hyperglycemic Thiazolidinedione agents 6 Alpha-glucosidase inhibitor treatment options Phenformin Human Rapid-acting insulin analogue 4 Sulphonylurea insulin Metformin Intermediate-acting insulin Phenformin Describe the potential uses of these therapies in the 2 withdrawn Soluble insulin treatment of type 2 diabetes 0 1920 1940 1960 1980 2000 2020 Year UGDP, DCCT and UKPDS studies. Buse, JB © 1 9/22/2015 Renal handling of glucose Collecting (180 L/day) Glomerulus duct (1000 mg/L) Proximal =180 g/day Distal tubule S1 tubule Glucose ~90% filtration SGLT2 Inhibitors ~10% S3 Glucose reabsorption Loop No/minimal of Henle glucose excretion S1 segment of proximal tubule S3 segment of proximal tubule - ~90% glucose reabsorbed - ~10% glucose reabsorbed - Facilitated by SGLT2 - Facilitated by SGLT1 SGLT = Sodium-dependent glucose transporter Adapted from: 1. Bailey CJ. Trends in Pharmacol Sci 2011;32:63-71. 2. Chao EC. Core Evidence 2012;7:21-28. Sodium Glucose Co-Transporter-2 (SGLT-2) inhibitors The roles of the sodium glucose co-transporters1,2 • History of SGLT-2 inhibitors – Sodium Glucose Co-Transporter-2 (SGLT-2) is the most prevalent and functionally important transporter Kidney for glucose reabsorption in the kidney Intestine – The compound phlorizin was first isolated in 1835 from 1 root bark of the apple tree by French chemists SGLT-1 SGLT-2 – The Merck Index of 1887 lists ‘phlorizin’ as a ‘Glycosid aus der Wurzelrinde des Apfelbaumes’ ▪ main uptake mechanism for glucose ▪ almost completely expressed in the (‘glycoside from the bark of apple trees’)1 and galactose in the intestine brush-border membrane of proximal – Animal studies demonstrated that phlorizin induced renal tubular cells in the S1 segment urinary glucose excretion normalised both fasting and ▪ S2 and S3 segments of the proximal post-prandial hyperglycaemia as well as reversing renal tubule is responsible for the ▪ is responsible for 90% of the total renal 2,3 both first and second phase insulin secretory defects remaining 10% of the renal glucose glucose reabsorption – It was found that the mode of action is to selectively and reversibly block the SGLT-2 receptor, which ▪ high-affinity (Km = ~0.5 mM), low- ▪ low-affinity (Km = ~6 mM), high- prevents the reabsorption of glucose at the renal capacity transporter, which transfers capacity transporter, which transfers proximal tubule glucose and sodium with a Na+:glucose glucose and sodium with a Na+:glucose – Therapeutic potential of phlorizin is limited by poor GI coupling ratio of 2 coupling ratio of 1 absorption and inhibition of both SGLT-1 and SGLT-2 transporters3 – SGLT-2 inhibitors have been synthesized similar to Structure of phlorizin phlorizin – such as dapagliflozin, canagliflozin and empagliflozin3 1 Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005 Jan;21(1):31-8. 1 Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers, Arch 2004; 447: 510–518; 2 Rossetti L, Shulman GI, Zawalich W, DeFronzo RA: Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatomized rats. J Clin Invest. 2 Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007; 261: 32–43 1987; 80(4):1037-44 3 White J. Apple Trees to Sodium Glucose Co-Transporter Inhibitors; A Review of SGLT2 Inhibition. Clinical Diabetes. 2010;28(1):5-10. 2 9/22/2015 SGLT2 Inhibitors in Development Familial Renal Glucosuria and SGLT2 Compound Stage of Development • Glucose is excreted in the urine despite normal or low Dapagliflozin blood glucose levels due to a genetic mutation on the Canagliflozin FDA-approved SLC5A2 gene that encodes for SGLT2 Empagliflozin • Patients lose approximately 50 to 100 g per day of glucose Ipragliflozin in urine (60 to 100 g per day with an SGLT2 inhibitor) Luseogliflozin Phase 3 • Accepted to be a benign hereditary condition that, in the Tofogliflozin majority of cases, does not pose serious physical/clinical Remogliflozin consequences to affected individuals. Ertugliflozin LX 4211 - sotagliflozin • In its infrequent severe forms, characterized by complete absence of tubular glucose resorption, clinical EGT0001442 Phase 2 manifestations are rare. TS-071 GW869682 ISIS 388626 Santer R, et al. J Am Soc Nephrol 2003;14:2873‐82; Jabbour SA, et al. Int J ClinPract 2008;62:1279‐84; Santer R, et al. J Am Soc Nephrol 2010;5:133–141. Adapted from: Foote C, et al. Diab Vasc Dis Res. 2012;9(2):117-123. Misra M. J Pharm Pharmacol. 2013;65(3):317-327 Canagliflozin: Dapagliflozin: A1C Change from Baseline in Placebo- A1C Change from Baseline in Placebo-Controlled Studies Controlled Studies Baseline 8.01% 7.94% 8.13% 7.9% 8.27% 8.35% 8.1% 8.1% Add-on A1C (%) to insulin Add-on to Add-on Add-on to Add-on Add-on Add-on Add-on ± other Add-on to Add-on Add-on Add-on Insulin ± Add-on to DPP-4i GLP-1RA ± Mono- to to to other to ±other ±other Monotherapy to MET to SU to PIO to MET + SU AHAs Sita Met therapy MET MET/SU MET/Pio AHAs SU AHAs AHAs N = 558 N = 546 N = 596 N = 420 N = 216 N = 807 N = 447 0.4 BL (%) 7.92 8.06 8.11 8.38 8.16 8.53 7.9 0.17 Placebo 0.2 0.14 0.1 0.04 0 0.01 0.0 0 -0.2 CANA 100 mg -0.13 -0.17 -0.4 -0.30 -0.13 -0.23 -0.30 -0.2 -0.17 -0.6 -0.42 -0.26 CANA 300 mg -0.50* -0.4 -0.8 P <0.05 vs -1.0 -0.82* -0.46 -0.84* -0.86* -0.90* placebo for CI 95% with (%) A1C -0.89* ∆ -0.97* A1c (%) -1.2 -0.6 both CANA -0.63 -0.64 doses in all -0.72 -0.7 studies 10 mg Placebo -0.8 -0.77 -0.79 -0.79 *Statistically significant vs. placebo using Dunnett’s correction -0.85 -0.83 -0.89 -0.89 Adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF) -1 -0.95 -1.03 -1.03 1. Ferrannini E, et al. Diabetes Care 2010; doi:10.2337/dc10-0612. 5. Matthaei S, et al. EASD Annual Meeting 2013. Abstract 937. -1.06 2. Bailey CJ, et al. Lancet 2010; 375:2223-33. 6. Wilding J, et al. Diabetes 2010; 59 (suppl 1):A21-A22. Abstract 0078-OR. -1.2 3. Nauck M, et al. Diabetologia 2010; 53 (suppl 1):S107. Abstract 241. 7. www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/ 4. Stroiek K. Diabetologia 2010; 53 (suppl 1):S347. Abstract 870. Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs 8. Jabbour S et al. Diabetes Care 2013. Published online Oct. 21, 2013. /EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013; Wysham C et al. ADA 2013; Abstract 1080‐P. 3 9/22/2015 SGLT2 Inhibitors and Body Weight: Empagliflozin: Mean Placebo-Subtracted Change from Baseline in A1C Change from Baseline in Placebo-Controlled Trials Pooled Placebo-Controlled Trials Monotherapy Add-on to Add-on to Add-on to Add-on to Met Met + SU Pio ± Met Basal Insulin (24 wks) (24 wks) (24 wks) ± Met and/or SU (24 wks) Canagliflozin Weight BL ~ 7.9% BL ~7.9% BL~8.1% BL~8.1% (78 wks) BL~8.3% Treatment Group (%) 0.2 0.08 CANA 100 mg -2.4 0.0 CANA 300 mg -3.0 -0.02 -0.2 -0.11 -0.13 -0.17 -0.4 Dapagliflozin Weight -0.6 -0.48* Treatment Group (kg) -0.66* -0.59* -0.64* -0.8 -0.70* -0.72* DAPA 10 mg -1.8 -0.77* -0.77* -0.78* -0.82* Change in A1C (%) A1C Change in -1.0 -1.2 Empagliflozin Weight -1.4 Empagliflozin 10 mg Empagliflozin 25 mg Placebo Treatment Group (kg) -1.6 EMPA 10 mg -1.8 *Significant vs placebo EMPA 25 mg -2.0 2/3 of the weight loss is fat mass Roden M et al. ADA Annual Meeting 2013. Abstract 1085-P. Haring H et al. ADA Annual Meeting 2013. Abstract 1092-P. Blonde L et al. ADA Annual Meeting 2013. Abstract 1110‐P. Musso G et al. Annals of Medicine 2012;44:375‐393. Hach T et al. ADA Annual Meeting 2013. Abstract 69‐LB. Haring H et al. ADA Annual Meeting 2013. Abstract 1082-P. Kovacs C et al. ADA Annual Meeting 2013. Abstract 1120-P. Cefalu W et al. Lancet 2013;382:941-950. Bolinder J et al. J Clin Endocrinol Metab. 97; 2012. Rosenstock J et al. ADA Annual Meeting 2013. Abstract 1102-P. SGLT2 Inhibitors and SBP: Mean Placebo-Subtracted Change from Baseline in UTIs and GTIs with SGLT2 Pooled Placebo-Controlled Trials Inhibitors Canagliflozin SBP Treatment Group (mmHg) • Mild to moderate in intensity CANA 100 mg -3.5 CANA 300 mg -4.6 • Most respond to initial course of standard therapy Dapagliflozin SBP • More common in women than men Treatment Group (mmHg) DAPA 10 mg -4.4 • Rarely lead to treatment discontinuation (0.1 to 0.9%) Empagliflozin SBP Treatment Group (mmHg) • Most have only one event in 24 to 102 wk EMPA 10 mg -3.4 trials EMPA 25 mg -3.8 • Upper UTIs rare Blonde L et al.
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  • Comparison of Tofogliflozin 20 Mg and Ipragliflozin 50 Mg Used Together

    Comparison of Tofogliflozin 20 Mg and Ipragliflozin 50 Mg Used Together

    2017, 64 (10), 995-1005 Original Comparison of tofogliflozin 20 mg and ipragliflozin 50 mg used together with insulin glargine 300 U/mL using continuous glucose monitoring (CGM): A randomized crossover study Soichi Takeishi, Hiroki Tsuboi and Shodo Takekoshi Department of Diabetes, General Inuyama Chuo Hospital, Inuyama 484-8511, Japan Abstract. To investigate whether sodium glucose co-transporter 2 inhibitors (SGLT2i), tofogliflozin or ipragliflozin, achieve optimal glycemic variability, when used together with insulin glargine 300 U/mL (Glargine 300). Thirty patients with type 2 diabetes were randomly allocated to 2 groups. For the first group: After admission, tofogliflozin 20 mg was administered; Fasting plasma glucose (FPG) levels were titrated using an algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using continuous glucose monitoring (CGM); Tofogliflozin was then washed out over 5 days; Subsequently, ipragliflozin 50 mg was administered; FPG levels were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using CGM. For the second group, ipragliflozin was administered prior to tofogliflozin, and the same regimen was maintained. Glargine 300 and SGLT2i were administered at 8:00 AM. Data collected on the second day of measurement (mean amplitude of glycemic excursion [MAGE], average daily risk range [ADRR]; on all days of measurement) were analyzed. Area over the glucose curve (<70 mg/dL; 0:00 to 6:00, 24-h), M value, standard deviation, MAGE, ADRR, and mean glucose levels (24-h, 8:00 to 24:00) were significantly lower in patients on tofogliflozin than in those on ipragliflozin.
  • 202293Orig1s000

    202293Orig1s000

    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202293Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Final Risk Evaluation and Mitigation Strategy (REMS) Review Date: December 20, 2013 Reviewer(s): Amarilys Vega, M.D., M.P.H, Medical Officer Division of Risk Management (DRISK) Team Leader: Cynthia LaCivita, Pharm.D., Team Leader DRISK Drug Name(s): Dapagliflozin Therapeutic Class: Antihyperglycemic, SGLT2 Inhibitor Dosage and Route: 5 mg or 10 mg, oral tablet Application Type/Number: NDA 202293 Submission Number: Original, July 11, 2013; Sequence Number 0095 Applicant/sponsor: Bristol-Myers Squibb and AstraZeneca OSE RCM #: 2013-1639 and 2013-1637 *** This document contains proprietary and confidential information that should not be released to the public. *** Reference ID: 3426343 1 INTRODUCTION This review documents DRISK’s evaluation of the need for a risk evaluation and mitigation strategy (REMS) for dapagliflozin (NDA 202293). The proposed proprietary name is Forxiga. Bristol-Myers Squibb and AstraZeneca (BMS/AZ) are seeking approval for dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Bristol-Myers Squibb and AstraZeneca did not submit a REMS or risk management plan (RMP) with this application. At the time this review was completed, FDA’s review of this application was still ongoing. 1.1 BACKGROUND Dapagliflozin. Dapagliflozin is a potent, selective, and reversible inhibitor of the human renal sodium glucose cotransporter 2 (SGLT2), the major transporter responsible for renal glucose reabsorption.
  • Open-Label Study to Assess the Efficacy of Ipragliflozin for Reducing

    Open-Label Study to Assess the Efficacy of Ipragliflozin for Reducing

    Clinical Drug Investigation (2019) 39:1213–1221 https://doi.org/10.1007/s40261-019-00851-z ORIGINAL RESEARCH ARTICLE Open‑Label Study to Assess the Efcacy of Ipraglifozin for Reducing Insulin Dose in Patients with Type 2 Diabetes Mellitus Receiving Insulin Therapy Hisamitsu Ishihara1 · Susumu Yamaguchi2 · Toshifumi Sugitani2 · Yoshinori Kosakai2 Published online: 24 September 2019 © The Author(s) 2019 Abstract Background and Objective To avoid insulin-induced hypoglycemia and weight gain, the minimum dose of insulin should be used. In this study, therefore, we examined insulin dose reduction by ipraglifozin add-on therapy in Japanese patients with type 2 diabetes mellitus treated with long-acting basal insulin. Methods In this multicenter, open-label study, patients received one ipraglifozin 50-mg tablet once daily in combination with basal insulin for 24 weeks. The primary efcacy endpoint was the change and percent change in insulin dose from base- line to Week 24. Secondary efcacy endpoints included changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), glycoalbumin, cholesterol, leptin, adiponectin, C-peptide, glucagon, body weight, and blood pressure, and number of patients achieving withdrawal of insulin at the end of treatment (EOT). Treatment-emergent adverse events (TEAEs) were evaluated for safety. Results In total, 114 patients were screened, 103 were registered, and 97 completed the study. The mean age was 59 years and 72.8% of patients were male. The mean change in insulin dose from baseline at Week 24 was − 6.6 ± 4.4 units/day (p < 0.001); the mean percent change was − 29.87%. HbA1c, FPG, glycoalbumin, glucagon levels, body weight, and blood pressure signifcantly decreased from baseline to EOT (p < 0.05).