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insulin Metformin Intermediate-acting insulin Phenformin Describe the potential uses of these therapies in the 2 withdrawn Soluble insulin treatment of type 2 diabetes 0 1920 1940 1960 1980 2000 2020 Year UGDP, DCCT and UKPDS studies.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

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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.

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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.

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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. ADA Annual Meeting 2013. Abstract 1110‐P. Musso G et al. Annals of Medicine 2012;44:375‐393. Nicolle L et al. ADA Annual Meeting 2013. Abstract 1139-P. Kim G et al. ADA Annual Meeting 2013. Abstract 74-LB Hach T et al. ADA Annual Meeting 2013. Abstract 69‐LB. Nyirjesky P et al. ADA Annual Meeting 2013. Abstract 1069‐P.

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Ongoing Cardiovascular Outcome Trials: SGLT2 Inhibitors Therapies # Population Endpoints Results

CANVAS Canagliflozin/ 4,363 CVD or CV death, June 2018 Placebo high-risk for NF MI or NF CVD stroke DECLARE Dapagliflozin/ 17,150 CVD or CV death, April 2019 Placebo high-risk for NF MI or NF Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D.,David CVD stroke Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D.,Michaela Mattheus, EMPA-REG Empagliflozin/ 7,000 CVD CV death, Data Dipl. Biomath., Theresa Devins, Dr.P.H.,Odd Erik Johansen, M.D., Ph.D., Hans Placebo NF MI or NF presented J. Woerle, M.D., Uli C. Broedl, M.D.,and Silvio E. Inzucchi, M.D., for the EMPA- stroke at EASD sept 17 REG OUTCOME Investigators 2015 CVD protection. Downloaded from nejm.org on September 17, 2015. Copyright © 2015 Massachusetts Superiority achieved. Medical Society. All rights reserved.

Adapted from: www.Clinicaltrials.gov 18

Trial design Pre-specified primary outcome Placebo (n=2333)

Randomised Screening Empagliflozin 10 mg and treated (n=11531) (n=2345) (n=7020) • Primary outcome – 3-point MACE: Time to first occurrence of CV death, non-fatal Empagliflozin 25 mg MI or non-fatal stroke (n=2342)

• Study medication was given in addition to standard of care – Glucose-lowering therapy was to remain unchanged for first 12 weeks • Treatment assignment double masked • The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event 19 20

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Primary outcome: 3-point MACE CV death

HR 0.86 HR 0.62 (95.02% CI 0.74, 0.99) (95% CI 0.49, 0.77) p=0.0382* p<0.0001

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498) Cumulative incidence function. HR, hazard ratio 21 22

Hospitalisation for heart failure All-cause mortality

HR 0.65 HR 0.68 (95% CI 0.50, 0.85) (95% CI 0.57, 0.82) p=0.0017 p<0.0001

Cumulative incidence function. HR, hazard ratio Kaplan-Meier estimate. HR, hazard ratio 23 24

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FDA Drug Safety Communication: FDA Warns that SGLT2 Summary of Observed Efficacy Inhibitors for Diabetes May Result in a Serious Condition of of SGLT2 Inhibitors Ketoacidosis May 15 2015  Similar to other oral anti-hyperglycemic agents • The U.S. Food and Drug Administration (FDA) is warning that SGLT2 inhibitors may in A1C reduction lead to ketoacidosis, a serious condition where the body produces high levels of blood – Reduces both FPG and PPG acids called ketones that may require hospitalization.  Modest weight loss • The AE Reporting System identified 20 post-marketing cases of diabetic ketoacidosis in patients treated with a SGLT2 inhibitor between March, 2013 and June, 2014 – ~3 kg at 26 weeks vs placebo • FDA will continue to investigate this safety issue and will determine whether changes – Slightly greater weight loss at 52 weeks are needed in the prescribing information for this class of drugs. Weight loss vs placebo sustained at 102 weeks – • Patients should pay close attention for any signs of ketoacidosis and seek medical  Modest blood pressure reduction attention immediately if they experience symptoms such as: • difficulty breathing, nausea, vomiting, abdominal pain, – 2-7 mm Hg vs placebo confusion, and unusual fatigue or sleepiness.  Minimal improvements in TG and HDL • Do not stop or change your diabetes medicines without first talking to your prescriber. • Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms; discontinue SGLT2 *Abnormally frequent urination inhibitors if acidosis is confirmed; and take appropriate measures to correct the Hasan et al. Diabetes Res Clin Pract. 2014;104:297‐322. acidosis and monitor sugar levels. Tahrani et al. Lancet Diabetes Endocrinol. 2013;1:140‐51. 26 25 http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm accessed May 15 2015

Health Canada: Information Update: FDA Drug Safety Communication Forxiga, Invokana: Health Canada begins safety Data summary review of diabetes drugs known as SGLT2 inhibitors and risk of ketoacidosis

• T2DM was noted as indication in most cases; T1DM noted June 22, 2015, OTTAWA: Health Canada initiated a safety review for dapagliflozin and in a few cases canagliflozin and the risk of ketoacidosis, a serious condition that leads to high levels of blood acids called ketones. • Potential DKA-triggering factors that were identified in some • Ketoacidosis predominantly develops in people with type 1 diabetes when insulin levels cases included: are too low, and is associated with high blood sugar levels. There have been international reports of ketoacidosis with the use of SGLT2 inhibitors in patients with T2DM who had • Acute illness only slightly increased blood sugar levels. • Because ketoacidosis is unexpected and can appear with only slightly increased blood • Recent significant changes such as infection, urosepsis, trauma sugar levels in people with T2DM, it is possible it may not be quickly identified or treated. • Reduced caloric or fluid intake For HCPs: • Evaluate patients with type 2 diabetes taking an SGLT2 inhibitor who show signs of • Reduced insulin dose diabetic ketoacidosis, regardless of blood sugar levels. • Treatment with an SGLT2 inhibitor should be discontinued if acidosis is confirmed, and • Potential factors, other than hypoinsulinemia, contributing to the appropriate measures should be taken to treat the acidosis and monitor sugar levels. development of a high anion gap metabolic acidosis identified in For Patients: the cases included hypovolemia, acute renal impairment, • Symptoms of ketoacidosis include difficulty breathing, feeling very thirsty, vomiting, abdominal pain, nausea, loss of appetite, confusion, and unusual tiredness. Seek urgent hypoxemia, reduced oral intake, and a history of alcohol use medical attention if you think you have these symptoms. • You should not stop treatment with Dapa or Cana without first consulting an HCP • Talk to your doctor or pharmacist if you have any concerns about your diabetic treatment.

http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm accessed May 15 2015 http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/forxiga-invokana-eng.php (accessed on June 22, 2015)

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SGLT-2 Inhibitors and DKA*: CAUTION!!!!

 Accumulating cases of DKA in the setting of type 1 ( and Type 2 ) diabetes treated with SGLT-2 inhibitor.  Unusual feature: minimally hyperglycemic DKA  Current recommendation: REPURPOSED DRUGS – If feeling unwell, check urine or finger-stick ketones (Abbott Precision Xtra or Nova Biomedical Statstrip) even if glucose is normal – If feeling unwell, do not take SGLT-2 inhibitor, continue insulin and consume carbohydrates to allow at least full dose insulin therapy – If feeling unwell make sure to drink extra liquids

*Off-label use. SGLT-2 inhibitors are NOT approved for use in type 1 diabetes Peters et al. Diabetes Care 2015:1-7 (e-pub online ahead of print)

Bromocriptine-QR (Cycloset)

Insulin resistant Insulin sensitive Glucose intolerant Glucose tolerant Lipolytic activity Lipolytic activity  Hepatic GNG  Hepatic GNG

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Insulin resistant Insulin sensitive Glucose intolerant Glucose tolerant • No increase of hypoglycemia Lipolytic activity Lipolytic activity • No weight effects  Hepatic GNG  Hepatic GNG • Reduced triglycerides and postprandial FFA Serotonin, NA Serotonin, NA  Dopamine  Dopamine Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010 DeFronzo RA. Diabetes Care 2011;34:789-794.

NNT = 79 Gazaino JM. Diabetes Care 2010;33:1503-1508.

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Summary

• Novel formulation of bromocriptine • Increases dopamine levels in early AM Bile Acid Sequestrant: and promotes insulin sensitivity, reduces Colesevelam A1C, reduces postprandial FFA and triglycerides • Nausea is primary deterrent • Possible CV benefit – mechanism is unclear

Colesevelam Placebo-subtracted A1C reduction in Colesevelam Add-On Therapy Trials

Metformin Sulfonylurea Insulin • Indicated for glucose lowering in adults GLOWS Week 26 Week 26 Week 16 Week 12 N=300 N=436 N=280 with type 2 diabetes (USA) -0.10

• Indicated for lipid lowering -0.20 • Not for Type 1 diabetes or DKA *P≤0.007 -0.30 n=>1,000

-0.40

• Bile acid sequestrant in A1C (%)

Mean Change Mean Change -0.50 -0.50* -0.50* -0.60 -0.54* -0.54*

Zieve FJ et al. Clin Ther. 2007;29:74. Bays H et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April 2007. Abstract 204. Fonseca VA et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April 2007. Abstract 409. Goldberg RB, Truitt K. Presented at: AHA Scientific Sessions; November 2006; Chicago, IL. Poster 1581.

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What Do Providers and Patients Want from an Antihyperglycemic Medication?

#1—Efficacy • New drugs should have excellent efficacy in the setting of their optimal intended use, in combination with metformin ( +/‐ other agents) early in the disease course. #2—Tolerability • antihyperglycemic medications must be well tolerated Safety above all Especially CV safety.FDA requirement for all new anti diabetic medications

Kahn SE and Buse JB. Diabetologia, in press.

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