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Incretin Therapy


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  • The incretin hormones play a crucial role in a healthy insulin responseThe effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before they received an oral glucose load of 50 g/400 ml or an isoglycaemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venous plasma glucose concentration was similar with both glucose interventions. However, insulin concentration was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion. ReferenceNaucket al. Diabetologia1986;29:46–52
  • Rasmussen HB, Branner S, Wiberg FC, et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol. 2003;10(1):19-25
  • The half-life of GLP-1 is very short, 1 to 2 minutes, but can be prolonged markedly with a DPP-4 inhibitor. Adapted from Rothenberg P, Kalbag J, Smith M, et al. Treatment with a DPP-IV inhibitor, NVP-DPP728, increases prandial intact GLP-1 levels and reduces glucose exposure in humans. Diabetes. 2000;49(suppl 1):A39.
  • DPP-4 inhibition with sitagliptin, 25 mg, causes a near maximal increase in active GLP-1 (9-36) amide in patients with T2DM. However, these levels are significantly less than those observed with subcutaneous injection of GLP-1 or exenatide (see slide 15).  Adapted from Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619.
  • Sitagliptin has an excellent safety profile and is associated with significantly fewer drug-related adverse events than glipizide. Stein P. Presented at: ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.
  • Compared to placebo, sitagliptin therapy for 24 weeks reduced the proinsulin/insulin ratio and increased HOMA-beta, suggesting a beneficial effect on beta-cell function. Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;2(12):2632-2637.
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    • 1. Role of Incretin in the management of diabetes
    • 2. Outline       Core defect in Type 2 DM What is Incretin? Evidences Safety DPP4 Inhibitor GLP 1
    • 3. Defect in Type 2 DM One Hormone Theory Insulin Deficiency Two Hormone Theory Insulin Deficiency Glucagon Excess Three Hormone Theory Insulin Deficiency,Glucagon Excess Decreased Incretin effect
    • 4. Multiple Defects Underlie the Pathophysiology of Type 2 Diabetes Impaired Incretin Effect Insulin Resistance Relative Insulin Deficiency Prediabetes and Type 2 Diabetes Kendall DM, Cuddihy, RM, Bergenstal RM. Provided by David M. Kendall. MD.
    • 5. Pathophysiology of Type 2 Diabetes The Glucagon Factor • In response to a carbohydrate-containing meal, individuals without diabetes not only increase insulin secretion but also simultaneously decrease pancreatic alpha-cell glucagon secretion. • The decrease in glucagon is associated with a decrease in hepatic glucose production, and along with the insulin response, results in a very modest increase in postprandial glucose. N Engl J Med. 1971;285:443-449.
    • 6. Pathophysiology of Type 2 Diabetes The Glucagon Factor • In contrast, the glucagon secretion in type 2 diabetics is not decreased, and may even be paradoxically increased. • These insulin and glucagon abnormalities produce an excessive postprandial glucose excursion. • More than 35 years ago, Roger Unger presciently stated, "One wonders if the development of a pharmacologic means of suppressing glucagon to appropriate levels would increase the effectiveness of available treatments for diabetes”. N Engl J Med. 1971;285:443-449.
    • 7. Major Pathophysiologic Defects in Type 2 Diabetes1,2 Islet-cell dysfunction Glucagon (alpha cell) Pancreas Hepatic glucose output Insulin (beta cell) Insulin resistance Glucose uptake Hyperglycemia Liver Muscle Adipose tissue Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. 1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
    • 8. Pathophysiology of Type 2 Diabetes The Gastric Emptying Factor • Many factors can affect the rate of gastric emptying. • Studies suggest that all other factors being equal, most people with type 1 and type 2 diabetes have accelerated gastric emptying compared to those without diabetes. Gastroenterology. 1990;98:A378.
    • 9. Pathophysiology of Type 2 Diabetes Another observation • In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion. • In 1986 Nauck demonstrated that a glucose infusion graded to achieve plasma glucose levels identical of those achieved with oral glucose led to a insulin response that was only one quarter as great. J Clin Endocrinol Metab. 1986;63:492-498. • Incretin hormones were discovered during researchers trials to find out interpretation to this phenomenon which has been called the incretin effect.
    • 10. The incretin hormones play a crucial role in a healthy insulin response Insulin response 15 180 5 90 60 120 Time (min) 180 0 Oral glucose load (50 g) Insulin (mU/L) 10 0 –10 –5 80 270 Plasma glucose (mg/dL) Plasma glucose (mmol/L) Plasma glucose 60 40 Incretin effect 20 0 –10 –5 60 120 Time (min) 180 IV glucose infusion • Insulin response is greater following oral glucose than IV glucose, despite similar plasma glucose concentration Nauck et al. Diabetologia 1986;29:46–52, healthy volunteers (n=8)
    • 11. History of Incretins • Concept proposed in 1906 by Moore; secretin proposed as gut hormone that enhanced postprandial insulin release • Term incretin introduced 1932 by LaBerre • Berson and Yalow developed RIA for insulin in 1960s, after which several groups found plasma insulin levels were higher after PO than IV glucose when BG was the same • Term entero-insular axis coined by Unger (1969) • GIP isolated by Brown in 1969 (Gastric Inhibitory Peptide) • GLP-1 (7-36) discovered in 1988 (Göke) • Term incretins (glucoincretins, insulinotrophic hormones) today refer to hormones/peptides that reduce glucose excursions into blood after a meal via various mechanisms
    • 12. What are incretins? • Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis. • Two hormones:  Gastric inhibitory polypeptide (GIP)  Glucagon-like peptide-1 (GLP-1). INCRETIN= INtestinal+seCRETion of INsulin
    • 13. GLP-1 and GIP Are Incretin Hormones GLP-1 GIP  Is released from L cells in ileum and colon1,2  Is released from K cells in duodenum1,2  Stimulates insulin response from beta cells in a glucose-dependent manner1  Stimulates insulin response from beta cells in a glucose-dependent manner1  Inhibits gastric emptying1,2  Has minimal effects on gastric emptying2  Reduces food intake and body weight2  Has no significant effects on satiety or body weight2  Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1  Does not appear to inhibit glucagon secretion from alpha cells1,2 1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. 2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
    • 14. The two primary incretin hormones are Glucagon-like Polypeptide -1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP) GLP-1 GIP 30 amino acid peptide1 42 amino acid peptide2 Synthesised and released by L cells of ileum and colon2 Synthesised and released from K cells of jejunum and duodenum2 Sites of action1: Pancreatic β-cells and α-cells GI tract CNS Lungs Heart Sites of action2: Pancreatic β-cells Adipocytes • Circulating GIP and GLP-1 levels are regulated by multiple factors2 – Low in the basal fasting state; they rise rapidly following a meal from neuronal, neuroendocrine, and direct nutrient stimulation of intestinal cells 1Wei Y, et al. FEBS Lett 1995;358:219–224; 2Drucker DJ. Diabetes Care 2003;26:2929–2940.
    • 15. Incretin Physiology in Type 2 Diabetes Mellitus GLP-1 & GIP Secretion in Type 2 Diabetes Mellitus
    • 16. Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes * * * * * * * (10-15) Meal Meal Started Finished *P<0.05, Type 2 diabetes vs NGT. Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab. 2001;86:3717–3723. Copyright © 2001, The Endocrine Society.
    • 17. Glucose-Dependent Insulinotropic Polypeptide (GIP) Response During OGTT
    • 18. Gastric Inhibitory Polypeptide (GIP) Insulinotrophic polypeptide • Type 2 diabetes patients are resistant to its action (high blood level), making it a less attractive therapeutic target. • In contrast to GLP-1 levels, plasma GIP is increased in patients with T2DM during an OGTT, while the plasma insulin response is diminished. This suggests resistance to the stimulator effect of GIP on insulin secretion and, in fact, this has been demon-strated by Holst et al. • Jones IR, Owens DR, Luzio S, et al. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32(9):668-677. • Holst JJ, et al. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287: 199-206.
    • 19. Summary of Pharmacologic Incretin Actions on Different Target Tissues Heart Brain Neuroprotection Appetite Stomach Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver GI Tract Insulin Secretion β-Cell Neogenesis + Glucose Production Drucker DJ. Cell Metab. 2006;3:153-165. Muscle β-Cell Apoptosis Glucose Uptake Glucagon Secretion
    • 20. EVIDENCE? GLP-1 modes of action in humans Upon ingestion of food… • Stimulates glucose-dependent insulin secretion • Suppresses glucagon secretion • Slows gastric emptying GLP-1 is secreted from the L-cells in the intestine • Reduces food intake • Improves insulin sensitivity Long term effects demonstrated in animals… This in turn… Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171 • Increases beta-cell mass and maintains beta-cell efficiency
    • 21. GLP-1 effects are glucose-dependent in type 2 diabetes Placebo (PBO) GLP-1 * 10 5 0 -30 0 * * * 300 * * * Insulin (pmol/L) Glucose (mmol/L) 15 PBO GLP-1 PBO GLP-1 200 100 60 120 180 240 Time (min) Mean (SE); N = 10; *P < 0.05. Nauck MA, et al. Diabetologia 1993;36:741–744. * * 0 -30 0 * * * * * * 60 120 180 240 Time (min) Glucagon (pmol/L) PBO GLP-1 20 10 0 -30 0 * * * * 60 120 180 240 Time (min)
    • 22. Effect of GLP-1 (7-36)amide SC on Gastric Emptying Subcutaneous injection of GLP-1 reduces the postmeal plasma glucose concentration, stimulates insulin secretion, and delays gastric emptying of a liquid meal.
    • 23. Exenatide Increases Gastric Half-Emptying Time (T50) for Solid Meal (Tc-Labeled Eggs) Exenatide causes a doseresponse inhibition of gastric emptying of a solid meal.
    • 24. GLP-1 Regulates Central Feeding Behavior Intracerebrov entricular injection of GLP-1 causes a doseresponse decrease in food intake in rats. As shown in the insert in the upper right, GLP-1 receptors are abundant in the paraventricu ar nucleus of the hypothalamu s and the central nucleus of the amygdala.
    • 25. Change in Body Weight Over 24 Weeks: Sitagliptin Monotherapy Studies In a 24-week study, sitagliptin was shown to have no effect on body weight in patients with T2DM.
    • 26. Sitagliptin + Pioglitazone Are Weight Neutral Compared to Pioglitazone Alone in T2DM
    • 27. Actions of GLP-1 The Problem • Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion).
    • 28. The solution Two options: • Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists. • Dipeptidyl peptidase-IV (DPP-IV) antagonists inhibit the breakdown of GLP-1.
    • 29. What Is DPP-4? • A serine protease widely distributed throughout the body • Cleaves N-terminal amino acids of a number of biologically active peptides, including the incretins GLP-1 and gastric inhibitory peptide (GIP), resulting in inactivation • Its effects on GLP-1 and GIP have been shown to affect incretin activity • Inactivates GLP-1 >50% in ~1 to 2 minutes Ahrën B. Curr Enzyme Inhib. 2005;1:65-73.
    • 30. DPP-4
    • 31. Inhibition of DPP-4 Increases Active GLP-1
    • 32. GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Meal Intestinal GIP and GLP-1 release GIP-(1–42) GLP-1(7–36) Intact DPP-4 Enzyme Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes GIP and GLP-1 Actions Deacon CF et al. Diabetes. 1995;44:1126–1131. *Meier JJ et al. Diabetes. 2004;53:654–662. GIP-(3–42) GLP-1(9–36) Metabolites
    • 33. Native GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) Human ileum, GLP-1 producing L-cells Capillaries, DPP-4 (Di-Peptidyl Peptidase-4) Double immunohistochemical staining for DPP-4 (red) and GLP-1 (green) in the human ileum Adapted from: Hansen et al. Endocrinology 1999;140:5356–63
    • 34. DPP-4 Inhibitors Enhance Incretin and Insulin Secretion Food intake DPP-4 inhibitor DPP-4 Beta-cells Increases and prolongs GLP-1 and GIP effects on beta-cells: Insulin release Stomach Net effect: Pancreas GI tract Incretins Blood glucose Increases and prolongs GLP-1 effect on alpha-cells: Glucagon secretion Alpha-cells Intestine Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70 Drucker DJ, Nauck MA. Nature 2006;368:1696-705 Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65
    • 35. Dipeptidyl Peptidase-IV Antagonists Sitagliptin and Vildagliptin • Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval. • Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients. ADA meeting, Chicago, June 2007. • They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin. • They look to be at least weight neutral.
    • 36. Plasma Levels of Bioactive Intact GLP-1 (9-36)amide After Sitagliptin Administration in T2DM
    • 37. Sitagliptin Reduces Glucose AUC After a Glucose Load
    • 38. Sitagliptin Once Daily Improves Both Fasting and Postmeal Glucose Concentration Part 3 Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632-2637. Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group
    • 39. Sitagliptin Monotherapy and Coadministration With Metformin Sitagliptin monotherapy and metformin monotherapy produce similar reductions in A1C in patients with T2DM and, when given in combination, provide an additive effect to reduce A1C.
    • 40. Sitagliptin: Proportion of Patients Achieving A1C Goals Sitagliptin monotherapy and metformin monotherapy allow a similar percentage of participants with T2DM to achieve an A1C <7.0% and have an additive effect to reduce A1C to <7.0%.
    • 41. Sitagliptin: Active-Comparator (Glipizide) Add-on to Metformin The addition of sitagliptin to metformin produces a similar decrease in A1C as the addition of glipizide to metformin over a 1-year period.
    • 42. Sitagliptin: Effect on Baseline A1C The addition of sitagliptin to metformin produces a similar decrease in A1C, irrespective of the starting baseline A1C, as does the addition of glipizide to metformin over a 1-year period.
    • 43. Clinical Adverse Events in ActiveComparator Add-on to Metformin Study Sitagliptin has an excellent safety profile and is associated with significantly fewer drug-related adverse events than glipizide. Patients With Adverse Events, n (%) Sitagliptin 100 mg (n=588) Glipizide (n=584) One or more AEs 419 (71.3) 444 (76.0) Drug-related AEs 85 (14.5) 177 (30.3) Serious AEs (SAEs) 43 ( 7.3) 44 ( 7.5) Serious drug-related AEs 0 ( 0.0) 2 ( 0.3) Died 1 ( 0.2) 2 ( 0.3) 16 ( 2.7) 21 ( 3.6) Discontinued due to drug-related AEs 8 ( 1.4) 8 ( 1.4) Discontinued due to SAEs 6 ( 1.0) 7 ( 1.2) Discontinued due to serious drug-related AEs 0 ( 0.0) 0 ( 0.0) Discontinued due to AEs Stein P. ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.
    • 44. Sitagliptin and Measures of -Cell Function Compared to placebo, sitagliptin therapy for 24 weeks reduced the proinsulin/insulin ratio and increased HOMA-beta, suggesting a beneficial effect on beta-cell function
    • 45. Sitagliptin: B-Cell Response to Glucose During the frequently sampled meal tolerance test (MTT) performed before and after 18 weeks, sitagliptin significantly augmented insulin secretion compared to the placebotreated group.
    • 46. Sitagliptin Studies: Summary1 As monotherapy, sitagliptin was as effective in reducing A1C as metformin and pioglitazone and was completely additive in decreasing A1C when given to metformintreated patients with T2DM.
    • 47. Incretin mimetics Exenatide • The first incretin-related therapy available for patients with type 2 diabetes. • Naturally occurring peptide from the saliva of the Gila Monster. • Has an approximate 50% amino acid homology with GLP-1. • Binds to GLP-1 receptors and behaves as GLP-1.
    • 48. Incretin mimetics Exenatide • Resistant to DPP-IV inactivation. Following injection, it is measurably present in plasma for up to 10 hours. Suitable for twice a day administration by subcutaneous injection. Regul Pept. 2004;117:77-88. Am J Health Syst Pharm. 2005;62:173-181.
    • 49. Conclusion As there is no proven link between use of incretin therapies and pancreatic cancer Diabetes UK does not advocate any change in its management. In particular, patients should NOT stop their medication unless advised to by their doctor. At the same time vigilance is required of patients on such therapies for any side effects suggestive of pancreatic disease. It also reminds clinicians and people with diabetes to be aware that incretin therapies are contraindicated in people with previous pancreatitis.
    • 50. At this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.
    • 51. The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1–based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.
    • 52. Considerations for Healthcare Professionals: •Be aware of the possibility for and monitor for the emergence of the signs and symptoms of pancreatitis such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back. •Discontinue sitagliptin or sitagliptin/metformin if pancreatitis is suspected. •Understand that if pancreatitis is suspected in a patient, supportive medical care should be instituted. The patient should be monitored closely with appropriate laboratory studies such as serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, and lipase. •Inform patients of the signs and symptoms of acute pancreatitis so they are aware of and able to notify their healthcare professional if they experience any unusual Advice: Health care person should honestly discuss with patient about risk of acute pancreatitis
    • 53. The three organizations firmly believe that people taking these medications, or those who may consider taking them, should be informed of all that is currently known about their potential risks and advantages in order to make the best possible decisions about their treatment and care, in consultation with their health care providers. At this time, there is insufficient information to modify current treatment recommendations.
    • 54. Old Antidiabetes drugs Incretin
    • 55. Thank you 