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Developments in the Treatment of T2DM

Developments in the Treatment of T2DM. Dr John Clark. 3 million. 2 million. Type 1. Type 2. 1 million. 0. 2013. 2000. 1995. Diabetes Prevalence. Audit of West Suffolk Hospital In-Patients. One day (23/9/12) 440 in-patients, in total, in WSH that day 75 known to have Diabetes

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Developments in the Treatment of T2DM

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  1. Developments in the Treatment of T2DM Dr John Clark

  2. 3 million 2 million Type 1 Type 2 1 million 0 2013 2000 1995 Diabetes Prevalence

  3. Audit of West Suffolk Hospital In-Patients • One day (23/9/12) • 440 in-patients, in total, in WSH that day • 75 known to have Diabetes • 17% of in-patients are Diabetic (1 in 6)

  4. Glycaemic Control Drugs to use (prior to 2010) • Drug of choiceMetformin • Next StageMetformin + Sulphonylurea or Metformin + Pioglitazone • Next Stage Metformin + Pioglitazone + SU • Final StageMetformin + basal insulin

  5. New Developments • The incretin effect and GLP-1 • Treatments A) DPP-4 Inhibitors • Treatments B) GLP-1 Agonists

  6. The Incretin Effect UK/LR/0809/0384 Date of preparation: August 2009 Insulin response 80 60 Incretineffect Insulin (mU/L) 40 20 0 –10 –5 60 120 180 Time (min) Plasma glucose 15 10 Plasma glucose (mmol/L) 5 0 –10 –5 60 120 180 Time (min) Oral glucose load (50 g) iv. glucose infusion • Insulin response is greater following oral glucose than i.v. glucose, despite similar plasma glucose concentration Healthy volunteers (n=8); i.v.: intravenousNauck et al. Diabetologia 1986;29:46–52

  7. The Incretin Effect is Reduced in Subjects with Type 2 Diabetes Oral Glucose Intravenous Glucose Control subjects Subjects with type 2 diabetes 80 80 60 60 Insulin (mU/L) Insulin (mU/L) 40 40 * 20 20 * * * * * * * * * 0 0 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Time (min) The Incretin Effect accounts for ~ 60% of total Insulin release following a meal Time (min) Nauck MA, et al. Diabetologia 1986;29:46–52. *P ≤.05 compared with respective value after oral load.

  8. Studies of the entero-insular axis following pancreas transplantation in man: neural or hormonal control?Clark JDA, Wheatley T, Brons IG, Bloom SR, Calne RY.Department of Medicine and Surgery, Addenbrooke's Hospital, Cambridge, UK. Diabetic Medicine. 1989 Dec,6, 813-7. • To study the role of hormonal and neural factors in the control of the entero-insular axis, the responses to oral and intravenous glucose were investigated in 5 patients who had received a combined kidney and paratopic pancreas transplant • As the incretin effect was preserved, despite a denervated pancreas, hormonal rather than neural factors may be more important in mediating increased insulin secretion after oral carbohydrate. The normal GIP response is compatible with its proposed role as an insulinotropic hormone.

  9. Incretin Effect • Larger insulin response to oral rather than IV glucose. Why? • Oral glucose stimulates release of GLP-1 from small intestine • GLP-1 augments insulin release from B cells of pancreas

  10. What is glucagon-like peptide-1 (GLP-1)? UK/LR/0809/0384 Date of preparation: August 2009 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Lys Ala Ala Gln Gly Glu Leu Tyr Glu Phe Lys Ile Ala Trp Val Gly Arg Leu Gly • A 31 amino acid peptide • Cleaved from proglucagon in L-cells in the GI tract • Secreted in response to meal ingestion GI: gastrointestinalDrucker & Nauck. Lancet 2006;368:1696–705

  11. GLP-1: Effects in Humans GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite b-cells:Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying GLP-1: Glucagon-like peptide 1 Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Adapted from Drucker DJ. Diabetes.1998;47:159-169.

  12. Native GLP-1 is rapidly degraded by DPP-4 (Di-Peptidyl Peptidase-4) UK/LR/0809/0384 Date of preparation: August 2009 Human ileum, GLP-1-producing L-cells Capillaries, DPP-4 Double immunohistochemical staining for DPP-4 (red) and GLP-1 (green) in the human ileum Hansen et al. Endocrinology 1999;140:5356–63

  13. The family of incretin-based therapies UK/LR/0809/0384 Date of preparation: August 2009 Incretin-based therapies DPP-4 inhibitors, sitagliptin vildagliptin saxagliptin linagliptin GLP-1 receptor agonists Exendin-based therapies, exenatide + lixisenatide Human GLP-1 analogues, liraglutide

  14. DPP-4 Inhibitors (Gliptins) • Oral • Weight neutral • Minimal hypoglycaemia • NICE – must lower HbA1c by 0.5% within 6/12

  15. Mr K S age 65 • Type 2 Diabetes for 10 years • Gradual increase in OHA dosage • June 2010 HbA1c 7.8% • Metformin 500mg bd + glipizide 10mg bd

  16. Mr K S • June 2010 - Add in Sitagliptin 100 mg od • October 2010 - HbA1c 7.4% • Glipizide reduced to 2.5 mg am, 5 mg pm.

  17. Do Exenatide/Liraglutide/Lixisenatide Work?

  18. Exenatide vs. Insulin Glargine Reductions in HbA1c 0.0 60 48% 50 46% -0.5 40 32% % Change in HbA1c % Patients Achieving HbA1c targets 30 25% -1.0 20 -1.1% 10 -1.1% -1.5 0 HbA1c <7% HbA1c <6.5% Exenatide (n=275) Insulin glargine (n=260) ITT population; Mean ± SE shown. Heine RJ et al. Ann Intern Med. 2005;143:559-569.

  19. Exenatide vs. Insulin GlargineChange in Body Weight Exenatide (n = 275) Insulin glargine (n = 260) 2 +1.8 kg 1 4.1 kg 0 Change inbody weight (kg) * -1 * * -2 * -2.3 kg * * -3 0 2 4 8 12 18 26 Time (weeks)

  20. HbA1c and weight loss:from LEAD trials 1–6 Weight gain HbA1c increase HbA1c decrease % patients Weight loss

  21. HbA1c and weight change: sulphonylurea LEAD-2. ITT, LOCF. n=232 Glimepiride 4 mg Weight gain 51% 12% HbA1c increase HbA1c decrease Weight loss 32% 5% Data on file Composite Endpoint, Novo Nordisk

  22. HbA1c and weight change: thiazolidinedione LEAD-1. ITT, LOCF. n=224 Pioglitazone Weight gain 15% 10% HbA1c increase HbA1c decrease Weight loss 49% 26% ITT, intention-to-treat; LOCF, last observation carried forward Data on file, Composite Endpoint, Novo Nordisk

  23. HbA1c and weight change: glargine LEAD-5. ITT, LOCF. n=224 Glargine 24 IU Weight gain 63% 10% HbA1c increase HbA1c decrease Weight loss 25% 2% Data on file Composite Endpoint, Novo Nordisk

  24. HbA1c and weight change: exenatide LEAD-6. ITT, LOCF. n=196 Exenatide 10 μg BD Weight gain 14% 5% HbA1c increase HbA1c decrease Weight loss 72% 9% Data on file Composite Endpoint, Novo Nordisk

  25. HbA1c and weight change: liraglutide 1.2 mg LEAD-2. ITT, LOCF. n=231 Liraglutide 1.2 mg Weight gain 10% 4% HbA1c increase HbA1c decrease Weight loss 72% 13% Data on file Composite Endpoint, Novo Nordisk

  26. Comparison : shifting the paradigm Weight gain HbA1cdecrease HbA1c increase Pioglitazone 15% Weight loss 25% Glargine 24 IU 32% Glimepiride 4 mg 72% 72% Exenatide 10 μg BID Liraglutide 1.2 mg 72% Lixisenatide 20ug od Data on file Composite Endpoint, Novo Nordisk

  27. Diabetes Clinic (1/9/10) Weight HbA1c Exenatide • NJ 120 – 92kg 8.5 – 6.1 1year • JH 117 – 96kg 7.8 – 6.0 6 months • NT 123 – 112kg 9.2 – 7.3 6 months

  28. NICE Guidance 2010(must satisfy all criteria) • HbA1c > 7.5% • Already on OHAs • Weight related health problems • BMI > 35 • By 6 months must achieve both targets • weight loss of 3% • drop in HbA1c of 1%

  29. WSH Audit 2011 312 patients initiated on Exenatide since May 2008 207 patients completed 6 months treatment by December 2010

  30. WSH Data: Exenatide success @ 6/12Insulin v Non-Insulin Group

  31. New Drug - Dapagliflozin • Blocks reabsorption of glucose in kidneys • Increased urinary glucose loss • Oral medication 5-10mg once daily

  32. DapagliflozinBenefits • HbA1c drops by 0.5-1.0% • Weight loss of 2-3 kg over 6 months • Low risk of hypos (not reliant on insulin) • Additive effect when combined with other diabetic treatments, including insulin.

  33. DapagliflozinSide-effects • Urinary tract infection • Polyuria • Genital fungal infection

  34. Bariatric Surgery • 30 Kg weight loss • 50% achieve HbA1c < 6.5% • High rate of remission of diabetes • But no long term studies

  35. Summary of Targets • HbA1c < 7.5 % (Metformin) • BP 140 / 80 or less (ACE-I or ARB) • Cholesterol < 4.0 (Statin)

  36. Glycaemic Control Drugs to use Drug of choice Metformin Next Stage Metformin with Sulphonylurea or Pioglitazone or Sita/Vilda/Saxa/Lina

  37. Glycaemic Control Drugs to use • Next Stage Metformin with GLP-1 injection • Final Stage Metformin with basal Insulin • Consider Dapagliflozin • Last resort Bariatric surgery

  38. Glycaemic Control Drugs to use • Drug of choice Metformin • Next Stage Metformin with Sulphonylurea or Pioglitazone or Sita/Vilda/Saxa/Linagliptin • Next Stage Metformin with Exenatide/Liraglutide/Lixisenatide • Final Stage Metformin with basal Insulin • Consider Dapagliflozin • Last resort Bariatric surgery

  39. WSH COST DATAExenatide Success @ 6/12Insulin v Non-Insulin Group

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