DR. SUBHASH K. WANGNOO

Transcription

1 Photograph DR. SUBHASH K. WANGNOO M.D, D.M, FRCP (London) Senior Consultant, Endocrinologist & Diabetologist Apollo Centre for Obesity, Diabetes and Endocrinology Indraprastha Apollo Hospital, Sarita Vihar, Delhi Established and currently heading the Apollo Centre for Obesity, Diabetes and Endocrinology (ACODE) Has numerous publications in International and National journals of repute, is on various Advisory boards and Guideline forming bodies Actively involved in teaching and training of DNB Endocrinology students for last 8 years, the only amongst the Apollo group of hospitals having DNB Endocrinology program

2 Incretin Based TherapyNow and Down the Road Subhash Kumar Wangnoo MD, DM, FRCP (London) Apollo Centre for Obesity, Diabetes and Endocrinology (ACODE) Indraprastha Apollo Hospital New Delhi

3 Incretin Based Therapy Current Understanding

4 Medical Clinics 2015;99:

5 What is known about GLP-1 receptor agonists and DPP-4 inhibitors Year 2015 DPP-4 inhibitors GLP-1 in physiological range Limited by endogenous secretion Moderate efficacy GLP-1 receptor agonists Pharmacological levels of GLP-1 Not limited by endogenous secretion Greater efficacy HbA1c reduction (0.5 1 %) Weight neutral Virtually no hypoglycemia Well tolerated Oral HbA1c reduction ( %) Weight loss (3-5 kg) Virtually no hypoglycemia GI side effects Injection Complimentary to other OADs and insulins As of yet no specific cardiovascular, pancreatic or malignancy signals GLP-1 analogs. Cochrane Database 2013 DPP-IV inhibitors. Cochrane Database 2013

6 Incretin Based Therapies Teneligliptin approval (DCGI) Linagliptin approval Vildagliptin (+metformin) approval* 2005 Alogliptin approval (Japan) Saxagliptin approval* Sitagliptin approval Lixisenatide approval* Exenatide approval Liraglutide approval Exenatide (Extended Release) approval Dulaglutide approval Albiglutide approval *EMA

7 Incretin Based Therapies Approved In India GLP-1 receptor agonists DPP IV inhibitors Exenatide Liraglutide Sitagliptin Vildagliptin Saxagliptin Linagliptin Teneligliptin GLP-1 receptor agonists increase GLP-1 concentrations 8-10 fold DPP IV inhibitors increase GLP-1 concentrations 2-3 fold

8 GLP-1 Receptor Agonists And DPP-4 Inhibitors: Worldwide GLP-1 receptor agonists DPP-4 inhibitors Exenatide BID Sitagliptin Liraglutide Vildagliptin Exenatide OW Saxagliptin Lixisenatide Linagliptin Albiglutide Alogliptin (Japan) Dulaglutide Teneligliptin (Japan & India) Gemigliptin (Korea)

9 Are GLP-1 Analogues different? Structurally YES Functionally Not So!

10 All are suffering from Me-too syndrome

11 What about DPP IV inhibitors? The answer is still the same! Structurally YES Functionally Not So!

12 We need to live by the fact that comparative data will be limited to begin with when a new drug hits the market!! Head-to Head data are often too limited to allow a firm conclusion about comparative effectiveness

13 Safety Issues C- cell No evidence to support the concern that GLP-1 agonists increase the risk of C-cell cancer development in humans Contraindicated in patients with personal or family history of medullary carcinoma and multiple endocrine neoplasia type 2 Pancreatitis Several large claims database studies have found no association between pancreatitis and exenatide and sitagliptin use in >1,000,000 patients Immunogenicity No bearing on clinical response or outcomes Renal Parameters Appropriate dose adjustments depending upon the class used CVD Available data encouraging CAROLINA (phase 3), EXAMINE, SAVOR-TIMI, TECOS data re-assuring Ongoing trials EXCEL, LEADER, CAROLINA, AWARD, HARMONY will give us the rosy picture (hopefully?) by 2018 FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain (September 2015) Garg et al. Diabetes Care 2010 Wenten et al. Diabetes 2010 Bjerre K et al. Endocrinology 2010 NEJM 2013 Pendergrass et al. Diabetes 2010 Dore et al. Diabetes Obes Metab 2011 Buse et al JCEM 2011 NEJM 2015 Dore et al. Curr Med Res Opin 2009 Romley et al. Diab Techn Ther 2012 Nauck: Diabetes Care 2013

14 CV Trials GLP-1 RA DPP 4 Inhibitors Completed

15 Incretin Based Therapies: Position in Diabetes Management Algorithms

16 Type 2 Diabetes Management Algorithm: An Update to ADA/ EASD Position Statement Diabetes Care 2015;38:

17 AACE Diabetes Management Algorithm

18 Incretin Based TherapyDown the Road

19 Need of the Hour Cost Issues Once weekly therapy Alternative routes of administration eg. Oral Fixed dose combinations with basal insulin Better tolerability

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21 Lixisenatide (once daily) September 2015: Accepted for review by FDA FIX-FLEX DEVICE FOR JOINT ADMINISTRATION OF LIXISENATIDE+ LANTUS Phase 3 trials completed recently

22 Albiglutide t1/2: 6 8 days Once a week GLP-1 analog FDA approved April 2014

23 Dulaglutide t1/2 ~4 days Once a week FDA Approved September 2014 EASD 2013

24 Semaglutide T ½: 160 hrs Once a week GLP-1 analog Phase 3 trials

25 Langlenatide (HM11260C) t1/2 150h Once a week EASD 2013

26 GLP-1 Agonist/Basal Insulin Fixed-dose Combinations CURRENT STATUS: 1. Liraglutide + Degludec Approved in Europe 2014 FDA approval pending 2. Lixisenatide + Glargine Submitted for FDA approval

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28 In pipeline: Oral Exenatide TGR5 agonist Oral GLP-1 GPCR119 Oral GLP-1

29 In pipeline: Oral Semaglutide Oral Semaglutide Once daily Doses of 3 mg, 7 mg and 14 mg Phase 3 trials (PIONEER) to begin in 2016

30 Addressing Unmet Needs via GLP-1 Based Multifunctional Peptides

31 Other Novel approaches VRS-859 (Peptides coupled to biological polymers Xtenylation ) Xten is genetically fused to exenatide GLP-1/glucagon co-agonists GLP-1/GIP coagonists GLP-1/PYY Combination ZP2929 Mar701 Phase 1 trial TT401 MAR709 t1/2 150h t1/2? Once a month Once a month Phase 1 Phase 1 trials Habegger et al. Diabetes 2013, 62, NCT NLM Identifier: NCT Hamilton, B.; Herring, C.; Paulik, M. WO 2011/039096, 2011.

32 Newer Gliptins on the Horizon Trelagliptin Once weekly oral DPP 4 inhibitor Approved in Japan, March 2015 Omarigliptin Once weekly oral DPP 4 inhibitor Approved in Japan, September 2015 Dutogliptin Phase 3 studies done

33 That`s all Folks till we discover something new!