gliptin talk

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gliptin talk

  1. 1. Chris Sainsbury Clinical Lecturer, BHF Glasgow Cardiovascular Research Centre Hon Consultant Physician (Diabetes / Endocrinology), Western Infirmary
  2. 2. New options for Type 2 Diabetes - Incretin hormones
  3. 3. obesity trends - men 5050 45 4040 35 % population 3030 25 2020 15 1010 5 0 1975 1980 1985 1990 1995 2000 2005 2010 2015 1975 1985 1995 2005 2015 Adapted from The Information Centre. Statistics on Obesity, Physical Activity and Diet: England, 2006. London: TIC, 2006.
  4. 4. obesity trends - women 5060 50 40 40 % population 30 30 20 20 10 10 0 1975 1980 1985 1990 1995 2000 2005 2010 2015 1975 1985 1995 2005 2015 Adapted from The Information Centre. Statistics on Obesity, Physical Activity and Diet: England, 2006. London: TIC, 2006.
  5. 5. prevalence of diabetes increases with BMI 14 12 10 prevalence 8 Male Female 6 4 2 0 18.5 or under 18.5 to 25 25 to 30 30 to 40 Over 40 BMI Adapted from Department of Health. Health Survey for England 2003. London: The Department of Health.
  6. 6. diabetes prevalence is increasing in the UK 3.5 3.0 2.5 % population 2.0 1.5 1.0 0.5 0 1940 1960 1980 1996 2004 2005 2010 Adapted from: 1. Diabetes UK. Diabetes in the UK 2004. Diabetes UK, London, 2004. 2. Diabetes UK. State of the Nation 2005. Diabetes UK, London, 2005.
  7. 7. $ 2004 5% total NHS spend 2004 £ 111 / second 2011 10% total NHS spend
  8. 8. aims of diabetes treatment CV risk factors / mortality morbidity cost
  9. 9. limited options SU metformin
  10. 10. evolution of therapy pathophysiogical knowledge time targeted therapies
  11. 11. pathophysiological targeting treatment of T2DM
  12. 12. Type 2 Diabetes - 2 major pathophysiological defects islet (beta cell) dysfunction peripheral insulin resistance glitazones
  13. 13. insulin glucose
  14. 14. islet cell function glucose glucagon insulin
  15. 15. islet cell dysfunction glucose glucagon insulin
  16. 16. incretins
  17. 17. GLP - 1 glucagon like peptide - 1 GIP gastric inhibitory polypeptide
  18. 18. gut secreted (in response to food intake) multiple actions only work when [glucose] above basal levels
  19. 19. food ingestion GLP-1 / GIP increase insulin secretion suppress glucagon secretion
  20. 20. the incretin effect
  21. 21. healthy subjects (n=8) Oral glucose (50 g/400 ml) Isoglycaemic intravenous glucose venous plasma glucose mmol/l 80 20 60 insulin (mU/l) 15 40 10 * * * 20 * * 5 * * 0 0 –10 –5 60 120 180 –10 –5 60 120 180 Time (minutes) 6. Adapted from Nauck M et al Diabetologia 1986;29:46–52.
  22. 22. Type 2 Diabetes (n=14) Oral glucose (50 g/400 ml) Isoglycaemic intravenous glucose 20 80 venous plasma glucose mmol/l 15 60 insulin (mU/l) 10 40 * * * 5 20 0 0 –10 –5 60 120 180 –10 –5 60 120 180 Time (minutes) 6. Adapted from Nauck M et al Diabetologia 1986;29:46–52.
  23. 23. food ingestion GLP-1 / GIP increase insulin secretion suppress glucagon secretion slow gastric enptying promote satiety
  24. 24. food ingestion GLP-1 / GIP increase insulin secretion suppress glucagon secretion very short half - life slow gastric enptying promote satiety
  25. 25. incretins and T2DM reduced GLP-1 level
  26. 26. incretins and T2DM effects of 6 week infusion of GLP-1 in T2DM - 1 reduced fasting glucose 2 reduced post-prandial glucose excursions 3 reduced glucagon levels / secretion 4 increased beta cell response 5 reduced food intake
  27. 27. Incretin therapy 2 approaches incretin analogue - exenatide, liraglutide, exenatide LAR DPP-4 antagonists - sitagliptin, vildagliptin, saxagliptin
  28. 28. Incretin therapy 2 approaches incretin analogue - exenatide, liraglutide, exenatide LAR DPP-4 antagonists - sitagliptin, vildagliptin, saxagliptin
  29. 29. Exenatide
  30. 30. Exenatide 50% similarity to human GLP-1 longer half life licensed in USA 2005 parenteral administration only
  31. 31. Exenatide - actions insulin secretion glucagon secretion delays gastric emptying weight
  32. 32. Exenatide - efficacy improves glycaemic control in combination with SU or metformin weight decreases on treatment (up to 3kg) increased risk of hypoglycaemia in comb with SU nausea rate ~30%
  33. 33. Exenatide - clinical use likely to be insulin replacement, using 10ug BD dose additional benefit over insulin - weight loss
  34. 34. Exenatide - clinical use likely to be insulin replacement, using 10ug BD dose additional benefit over insulin - weight loss ...but BD injection
  35. 35. DPP-4 antagonists - sitagliptin (vildagliptin, saxagliptin) DPP-4 - ubiquitous serine protease
  36. 36. food ingestion breakdown DPP-4 GLP-1 / GIP increase insulin secretion suppress glucagon secretion slow gastric enptying promote satiety
  37. 37. food ingestion gliptins DPP-4 GLP-1 / GIP increase insulin secretion suppress glucagon secretion slow gastric enptying promote satiety
  38. 38. long acting OD dosing
  39. 39. DPP-4 antagonists - efficacy HbA1c reductions as monotherapy additional benefits in combination weight neutral well tolerated no additional risk of hypoglycaemia
  40. 40. vildagliptin monotherapy rosiglitazone
  41. 41. sitagliptin studies [sitagliptin + metformin] vs metformin [sitagliptin + pioglitazone] vs pioglitazone [sitagliptin + metformin] vs [glipizide + metformin]
  42. 42. [sitagliptin + metformin] vs metformin
  43. 43. 24-week Add-on Therapy to Metformin Study Mean change in HbA1c over time9 Placebo + metformin* Sitagliptin 100 mg o.d. + metformin* 8.2 8.0 n=224 7.8 Reduction in HbA1c % HbA1c of 0.65% 7.6 p< 0.001 versus placebo 7.4 n=453 7.2 7.0 0 0 6 12 18 24 Weeks *Dose of metformin was ≥1,500 mg/day in both arms. 53 All-patients-as-treated population LSM between-group dierences at week 24 (95% CI): Δ in HbA1C vs placebo = –0.65% [–0.77, –0.53] (P0.001); Copyright © 2006 American Diabetes Association. From 9. Diabetes Care, Vol. 29,2006; 2638–2643 Reprinted with permission from the American Diabetes Association.
  44. 44. 24-week Add-on Therapy to Metformin Study Proportion of patients achieving HbA1c 7.0% at week 249 60 P0.001 50 (% to goal) 40 Patients 30 20 10 n=4 n=21 0 1 3 Placebo + metformin* Sitagliptin 100 mg o.d. + metformin* (n=224) (n=453) *Dose of metformin was ≥1,500 mg/day in both arms. 54 Mean baseline values: sitagliptin, 7.96 ± 0.81%; placebo,8.03 ± 0.82% All-patients-as-treated population Adapted from 9. Charbonnel et al. Diabetes Care. 2006;29:2638–2643.
  45. 45. 24-week Add-on Therapy to Metformin Study Incidence of hypoglycaemia9 5.0 Placebo + metformin* (n=237) Sitagliptin 100 mg o.d. + metformin* (n=464) 4.0 Patients (%) 3.0 2.1% 2.0 1.3% 1.0 0.0 Patients with at least 1 episode of hypoglycaemia over 24 weeks 55 *Dose of metformin was ≥1,500 mg/day in both arms. All-patients-as-treated population Adapted from 9. Charbonnel et al. Diabetes Care. 2006;29:2638–2643.
  46. 46. [sitagliptin + pioglitazone] vs pioglitazone
  47. 47. 24-week Add-on Therapy to Pioglitazone Study Mean values in HbA1c over time10 Placebo + pioglitazone* 8.2 Sitagliptin 100 mg o.d. + pioglitazone* 8.0 n=174 7.8 % HbA1c Reduction in HbA1c 7.6 of 0.7% p 0.001 versus 7.4 placebo n=163 7.2 7.0 0 0 6 24 18 12 24 6 0 1 18 Weeks 2 *Dose of pioglitazone was 30-45 mg/day in both arms. 57 All-patients-as-treated population LSM between-group dierence at week 24: Δ in HbA1C vs placebo = –0.70% (95% CI, –0.85, –0.54; P0.001) Adapted from 10. Rosenstock et al. Clin Ther. 2006;28:1556–1568.
  48. 48. 24-week Add-on Therapy to Pioglitazone Study Proportion of patients achieving HbA1c 7.0% at week 2410 60 P0.001 50 (% to goal) 40 Patients 30 20 10 0 Placebo + pioglitazone* Sitagliptin 100 mg o.d. + pioglitazone* *Dose of pioglitazone was 30-45 mg/day in both arms. Mean baseline values: sitagliptin, 8.05%; placebo, 8.00% All-patients-as-treated population 58 Adapted from 10. Rosenstock et al. Clin Ther. 2006;28:1556–1568.
  49. 49. [sitagliptin + metformin] vs [glipizide + metformin]
  50. 50. 52-week Sitagliptin vs Sulphonylureaa Add-on Therapy to Metformin Study Sitagliptin once daily showed comparable glycaemic eficacy to sulphonylurea when added to metformin (52 8.4 Glipizide 5-20 mg/day + metformin* 8.2 (n=411) Sitagliptin 100 mg o.d + metformin* 8.0 (n=382) Mean change from baseline (for both groups): - 7.8 Mean change in HbA1c 0.67% 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 0 12 24 38 52 Time (weeks) *Dose of metformin was ≥1,500 mg/day in both arms. 60 aSpecifically glipizide; Per-protocol population; LS = least squares Adapted from 11. Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
  51. 51. 52-week Sitagliptin vs Sulphonylureaa Add-on Therapy to Metformin Study Greater reductions in HbA1c are associated with higher baseline HbA1c11 Baseline HbA1C category 7% ≥7 to 8% ≥8 to 9% ≥9% n=117 112 179 167 82 82 33 21 0.0 n=117 -0.2 -0.14 Change from baseline in -0.4 -0.26 -0.6 -0.53 -0.59 HbA1c (%) -0.8 -1.0 -1.2 -1.11 -1.13 -1.4 -1.6 Sitagliptin 100 mg o.d + metformin* (n=382) -1.68 -1.8 Glipizide 5-20 mg/day + metformin* (n=411) -1.76 -2.0 *Dose of metformin was ≥1,500 mg/day in both arms. Per-protocol population; a Specifically glipizide; 61 Adapted from 11. Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
  52. 52. 52-week Sitagliptin vs Sulphonylureaa Add-on Therapy to Metformin Sitagliptin provided weight reduction (vs weight Study gain) and a much lower incidence of hypoglycaemia11 LS mean change in body weight over timeb Hypoglycaemiab 50 Sitagliptinb 100 mg o.d + metformin* (n=389) 3 Glipizide 5-20 mg/day + metformin* (n=416) 40 2 32% Incidence (%) Body weight (kg ± SE) 1 P0.00 30 1 0 20 -1 10 5% -2 0 -3 0 12 24 38 52 Week 52 Weeks Sitagliptinb 100 mg o.d + metformin* (n=584) Glipizide 5-20 mg/day + metformin* (n=588) a Specifically glipizide; bAll-patients-as-treated population. *Dose of metformin was ≥1,500 mg/day in both arms. LS = least squares; LSM between-group dierence at week 52 (95% CI): Δ in body weight = –2.5 kg [–3.1, –2.0] (P0.001); 62 LSM change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P0.001) Adapted from 11. Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
  53. 53. License restrictions not licensed as monotherapy Exenatide - only as additional to MF / SU when treatment failed (glitazones not mentioned) Sitagliptin - 2nd line in combination with MF or glitazone triple therapy not licensed but a logical combination.

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