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gliptin talk
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gliptin talk
gliptin talk
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gliptin talk
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gliptin talk

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  • 1. Chris Sainsbury Clinical Lecturer, BHF Glasgow Cardiovascular Research Centre Hon Consultant Physician (Diabetes / Endocrinology), Western Infirmary
  • 2. New options for Type 2 Diabetes - Incretin hormones
  • 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. 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. 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. 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. $ 2004 5% total NHS spend 2004 £ 111 / second 2011 10% total NHS spend
  • 8. aims of diabetes treatment CV risk factors / mortality morbidity cost
  • 9. limited options SU metformin
  • 10. evolution of therapy pathophysiogical knowledge time targeted therapies
  • 11. pathophysiological targeting treatment of T2DM
  • 12. Type 2 Diabetes - 2 major pathophysiological defects islet (beta cell) dysfunction peripheral insulin resistance glitazones
  • 13. insulin glucose
  • 14. islet cell function glucose glucagon insulin
  • 15. islet cell dysfunction glucose glucagon insulin
  • 16. incretins
  • 17. GLP - 1 glucagon like peptide - 1 GIP gastric inhibitory polypeptide
  • 18. gut secreted (in response to food intake) multiple actions only work when [glucose] above basal levels
  • 19. food ingestion GLP-1 / GIP increase insulin secretion suppress glucagon secretion
  • 20. the incretin effect
  • 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. 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. food ingestion GLP-1 / GIP increase insulin secretion suppress glucagon secretion slow gastric enptying promote satiety
  • 24. food ingestion GLP-1 / GIP increase insulin secretion suppress glucagon secretion very short half - life slow gastric enptying promote satiety
  • 25. incretins and T2DM reduced GLP-1 level
  • 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. Incretin therapy 2 approaches incretin analogue - exenatide, liraglutide, exenatide LAR DPP-4 antagonists - sitagliptin, vildagliptin, saxagliptin
  • 28. Incretin therapy 2 approaches incretin analogue - exenatide, liraglutide, exenatide LAR DPP-4 antagonists - sitagliptin, vildagliptin, saxagliptin
  • 29. Exenatide
  • 30. Exenatide 50% similarity to human GLP-1 longer half life licensed in USA 2005 parenteral administration only
  • 31. Exenatide - actions insulin secretion glucagon secretion delays gastric emptying weight
  • 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. Exenatide - clinical use likely to be insulin replacement, using 10ug BD dose additional benefit over insulin - weight loss
  • 34. Exenatide - clinical use likely to be insulin replacement, using 10ug BD dose additional benefit over insulin - weight loss ...but BD injection
  • 35. DPP-4 antagonists - sitagliptin (vildagliptin, saxagliptin) DPP-4 - ubiquitous serine protease
  • 36. food ingestion breakdown DPP-4 GLP-1 / GIP increase insulin secretion suppress glucagon secretion slow gastric enptying promote satiety
  • 37. food ingestion gliptins DPP-4 GLP-1 / GIP increase insulin secretion suppress glucagon secretion slow gastric enptying promote satiety
  • 38. long acting OD dosing
  • 39. DPP-4 antagonists - efficacy HbA1c reductions as monotherapy additional benefits in combination weight neutral well tolerated no additional risk of hypoglycaemia
  • 40. vildagliptin monotherapy rosiglitazone
  • 41. sitagliptin studies [sitagliptin + metformin] vs metformin [sitagliptin + pioglitazone] vs pioglitazone [sitagliptin + metformin] vs [glipizide + metformin]
  • 42. [sitagliptin + metformin] vs metformin
  • 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. 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. 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. [sitagliptin + pioglitazone] vs pioglitazone
  • 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. 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. [sitagliptin + metformin] vs [glipizide + metformin]
  • 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. 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-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. 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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