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insulin Metformin Intermediate-acting insulin Phenformin Describe the potential uses of these therapies in the 2 withdrawn Soluble insulin treatment of type 2 diabetes 0 1920 1940 1960 1980 2000 2020 Year UGDP, DCCT and UKPDS studies.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.