Glp 1 edffect of cardiovascular system


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Glp 1 edffect of cardiovascular system

  1. 1. GLP-1 Beyond blood sugar lowering effectThe effect of cardiovascular system 大里仁愛醫院新陳代謝科 林文玉醫師 月眉福容 June 30, 2012
  2. 2. Introduction
  3. 3. IN-CRET-IN INtestine seCRETion INsulinDefinition: gut derived factors that increase glucose stimulated insulin secretionTwo hormones: (1) glucagon-like peptide-1 (GLP-1) (2) glucose-dependent insulinotropic polypeptide (GIP) Source :Creutzfeldt Diabetologia 28: 5645 1985
  4. 4. Discovery and identification of regulatory peptides in gastrointestional tract. Peptides may actas hormones, neurotransmitters, and growth factors. Sometimes 1 peptide acts in 2 or all ofthe 3 roles. Physiological Reviews vol. 78, No 4, October 1998
  5. 5. Gut HormonesGut hormones signals the brain (hypothalamus) toachieve efficient nutrient digestion and absorption: gut-brain interaction ( your brain in your gut )
  6. 6. Melanocortin System and Regulation of Body WeightAnd Energy Expenditure NTS
  7. 7. Central Melanocortin System and AgRP/NPY• This system is involved in body weight regulation through its role in appetite and energy expenditure via leptin, grhelin and Agouti related protein. It receives inputs from hormone, nutrients and afferent neural inputs, and is unique in its composition of fibers which express both agonists and antagonists of melanocortin receptors.• The melanocortin receptors, MC3-R and MC4-R, are directly positive linked to metabolism and negative to body weight control. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone) and antagonized by the agouti-related protein.• Agouti-related protein also called Agouti-related peptide (AgRP) is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is only synthesised in NPY containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with Neuropeptide Y and works by increasing appetite and decreasing metabolism and energy expenditure ( increased weight ). It is one of the most potent and long-lasting of appetite stimulators
  8. 8. Regulation of gastric emptying DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008
  9. 9. Regulation of Gastric Emptying• Normally, the rate of gastric emptying is tightly regulated as a result of neural and hormonal feedback triggered by the interaction of nutrients within the small intestine known as the ileal break mechanism or “extrinsic pathway” of control. This feedback is caloric load dependent, relates to the length of small intestine exposed to nutrient, and regulates the overall rate of emptying to about 2–3 kcal/min.• The intrinsic pathway is dependent upon the action of hyper- or hypoglycemia on gastric emptying. The increase in hIAPP and decrease in ghrelin both slow the gastric emptying rate by producing a parasympathetic signal. Ghrelin secretion enhances antropyloric coordination, a signal transmitted via the vagus nerve, which accelerates gastric emptying.
  10. 10. Rates of Remission of Diabetes Adjustable Roux-en-Y BiliopancreaticGastric Banding Gastric Bypass Diversion 48% (Slow) 84% (Immediate) >95% (Immediate)
  11. 11. Foregut or Hindgut ?• The “foregut hypothesis” raised by Rubino et al suggests that nutrient interactions in the duodenum are diabetogenic and, hence, bypassing the duodenum would reverse this defect. Their conclusions come from experiments in rodents that underwent jejunoileal bypass and subsequent refeeding through the bypassed intestine.• The “hindgut hypothesis” raised by Cummings et al suggests that accelerated transit of concentrated nutrients (particularly glucose) to the distal intestine results in increased production of insulinotropic and appetite-controlling substances, which account for the reversal of hyperglycemia and obesity.
  12. 12. Improvement of Glycemia after MetabolicSurgery is Independent of Body Weight Loss
  13. 13. In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion.In 1932, the name incretin was coined.
  14. 14. In 1986 Nauck demonstrated that a glucose infusion graded toachieve plasma glucose levels identical to those with oral load led to a insulin response that was only one quarter as great. J Clin Endocrinol Metab. 1986;63:492-498.
  15. 15. Incretin effect on insulin secretion 80 Control subjects (n=8) 80 People with Type 2 diabetes (n=14) 60 60 Insulin (mU/l)Insulin (mU/l) 40 Incretin 40 effect 20 20 0 0 0 60 120 180 0 60 120 180 Time (min) Time (min) Oral glucose load Intravenous glucose infusion Nauck et al. Diabetologia. 1986
  16. 16. Gastrointestinally mediated glucose disposal ( GIGD ): 20-80%, normal > 70%If 25g iv glucose is required to copy a 75g oral glucose load ( glucose excursion ), TheGIGD amounts to 100x (75-25)/75 = 66% Diabetes care, Volume 34, Supplement 2, May 2011
  17. 17. What is GLP-1? Increased insulin response Key observations 80 • A 31 amino acid peptide • Cleaved from proglucagon in 60 L-cells in the GI-tract (and neurons inIR-insulin (mU/l) hindbrain/hypothalamus) Incretin effect • Secreted in response to meal ingestion 40 (direct luminal and indirect neuronal stimulation) * * 20 * * * • Member of incretin family (GIP, GLP-1 and * * others) 0 • GLP-1 has following effects: –10 –5 60 120 180 • Glucose-dependently stimulates insulin secretion and decreases glucagon secretion Time (min) Insulin response to oral glucose load (50 g/400 • Delays gastric emptying ml, ●) and during isoglycaemic i.v. glucose infusion • Decreases food intake and induces satiety (●) • Stimulates -cell function and preserves or increases -cell mass in animal models Nauck et al. Diabetologia 1986;29: 46–52, *p ≤ 0.05.
  18. 18. Glucose-lowering effect of GLP-1 Endocrine Review, April 2012, 33(2):187-215
  19. 19. Why not GIP ?
  20. 20. Because of its short half-life, native GLP-1 has limited clinical value DPP-IV i.v. bolus GLP-1 (15 nmol/l) His Ala Glu Gly Thr Phe Thr Ser Asp 1000 Healthy individuals Intact GLP-1 (pmol/l) Val Type 2 diabetes 7 9 Ser 500 Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe 37 0 Ile Ala Trp Leu Val Lys Gly Arg Gly –5 5 15 25 35 45 Time (min) Enzymatic cleavage t½ = 1.5–2.1 minutes High clearance (i.v. bolus 2.5–25.0 nmol/l) (4–9 l/min)Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.
  21. 21. GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues Block DPP-4, the with longer half-life: enzyme that degrades • exenatide GLP-1: • liraglutide • Sitagliptin • Vildagliptin • Linagliptin Injectables Oral agentsDrucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
  22. 22. Pharmacokinetic Properties of DPP-4 Inhibitors Sitagliptin Vildagliptin Saxagliptin Alogliptin Linagliptin (Merck)1 (Novartis)2 (BMS/AZ)3 (Takeda)5 (BI)6–9Absorption tmax 2 h (4 h for active 1–4 h 1.7 h 1–2 h 1.34–1.53 h(median) metabolite)Bioavailability ~87% 85% >75 %4 N/A 29.5%Half-life (t1/2) at 2.5 h (parent) 12.4–21.4 h 113–131 hclinically relevant 12.4 h ~2–3 h 3.1 h (metabolite) (25–800 mg) (1–10 mg)dose Prominent concentration- dependent proteinDistribution 38% protein bound 9.3% protein bound Low protein binding N/A binding: <1 nM: ~99% >100 nM: 70%–80% 69% metabolized HepaticMetabolism ~16% metabolized mainly renal (active metabolite) <8% metabolized ~10% metabolized (inactive metabolite) CYP3A4/5 Feces 81.5% Renal 75% Renal (74.1% unchanged); Renal 87% Renal 85%Elimination (24% as parent; 36% as (60%–71% (79% unchanged) (23% unchanged) Renal 5.4% active metabolite) unchanged) (3.9% unchanged)DPP-4=dipeptidyl peptidase-4.1. EU-SPC for JANUVIA, 2010. 2. EU-SPC for Galvus, 2010. 3. EU-SPC for Onglyza, 2010. 4. EPAR for Onglyza. Accessed May 4, 2011. 5. Christopher R 22et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840. 8. Fuchs H et al. JPharm Pharmacol. 2009;61:55–62. 9. Blech S et al. Drug Metab Dispos.2010;38:667–678.
  23. 23. The majority of Linagliptin is excreted unchanged via bile and gut Absorption Metabolism Tablet intake: 5mg QD, independent of food Absolute bioavailability: ~30%, with or without food ~90% ~10% transferred (inactive) unchanged ~95% bound to plasma proteins metabolite (in essence DPP-4) Excretion1: ~ 95% of orally administered ~ 5% of orally administered linagliptin is excreted via the linagliptin is excreted via the bile and gut kidneys1 At steady stateSource: US prescribing information
  24. 24. Linagliptin is the first only DPP-4 inhibitor that does not require dose adjustment Linagliptin Sitagliptin Vildagliptin Saxagliptin (Trajenta®) (Januvia®) (Galvus®) (Onglyza®) No renal 100 mg issues 50 mg BID 5 mg At risk 5 mg of renal impairment Mild renal impairment 50 mg 25 mg 2.5 mg Moderate 50 mg QD renal impairment Severe renal impairment
  25. 25. Influence of hepatic impairment on pharmacokinetics & exposure of LinagliptinPatients with mild moderate and severe hepatic impairment(according to the Child-Pugh classification A-C) Child-Pugh Grade Points A Well-compensated disease 5-6 1.5 Fold Increase in exposurerelative to B Significant functional compromise 7-9 Fold increase in exposure relative C Decompensated disease 10-15 normal hepatic function to normal hepaticfunction 1 0.5 0 Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C) Hepatic impairment (Child-Pugh classification) n=8 n=7 n=9 n=8 No dosage adjustment for linagliptin is necessary for patients with mild, moderate or severe hepatic impairmentSource: Data on file
  26. 26. Effect on Cardiovascular System
  27. 27. GLP-1R expression in mouse cardiac and vascular tissue Polycloal Anti-GLP-1R Ab Pre-absorption Mesenteric arerty Anti-SM (red ) Anti-GLP-1 (green ) Nuclear stain ( blue ) In media SMEndocardium Circulation. 2008;117:2340-2350
  28. 28. Effects of GLP-1 in p’ts with AMI and LV dysfunction after successful reperfusion• Glucose-insulin-potassium (GIK) infusions benefit patient with AMI, with enhancement of myocardial glucose uptake and oxidation and the efficacy of generating ATP.• Dutch investigators reported beneficial effects of GIK therapy in patients with AMI s/p PCI, the benefits were limited to those in Killip class I. Patients with CHF (Killip class III–IV) exhibited an adverse trend with GIK therapy.• Glucagon-like peptide-1 (GLP-1 [7–36] amide, with insulinotrophic and insulinmimetic effect, minimizing risks of hypoglycemia and the need for glucose infusion.• If a continuous 72 hr infusion of GLP-1( post PCI ) improves global and regional ventricular function? Lazaros A. Nikolaidis, Circulation 2004 109:962-965
  29. 29. Effects of GLP-1 in patients with AMI and LV dysfunction after successful reperfusion Circulation 2004 109:962-965
  30. 30. The benefits of GLP-1 were independent of AMI location or history of Diabetes Circulation 2004 109:962-965
  31. 31. GLP-1R Agonist liraglutide: cardioprotective pathways, treated before ischemic episode • Whether liraglutide exerts cardioprotective actions in a preclinical murine model of experimental ischemia after coronary artery occlusion. • If treatment with liraglutide before induction of ischemia leads to activation of prosurvival kinases and cytoprotective genes in the heart and limits infarct size, expansion, and cardiac rupture in the normal and diabetic heart? • Moreover, liraglutide increases cAMP and reduces apoptosis in a GLP-1R– dependent manner in murine cardiomyocytes cultured in vitro.Mohammad Hossein Noyan-Ashraf, Diabetes 58: 975-983, 2009
  32. 32. GLP-1R Agonist Improves Outcomes After Experimental Myocardial Infarction in Mice ( n=20 )Non-diabetic ) ( n=35 ) ( n=60) ( n=60) ( Lir75 + WL, n= 25 ) Diabetic blood sugar lowering Mohammad Hossein Noyan-Ashraf, Diabetes 58: 975-983, 2009
  33. 33. Cardiac Rupture Post-MI Mohammad Hossein Noyan-Ashraf, Diabetes 58: 975-983, 2009
  34. 34. After weight correction, No percent difference between.Diabetes vol. 58, April 2009
  35. 35. Liraglutide increases cAMP and reduces apoptosis in a GLP-1R–dependent mannerIn murine cardiomyocytes in vitro.Forskolin is commonly used to raise levels of cAMP in the study andresearch of Cell physiology. Indian Coleus: Forskoin ( adenylate cyclase activator ) Diabetes vol. 58, April 2009
  36. 36. Lira 200 for 7 d, Killed before MI ( wild type ) 4 days after MI Diabetes vol. 58, April 2009
  37. 37. • Liraglutide administration induces changes in the expression of cardioprotective proteins in normal non-AS murine heart, by phosphorylation of Akt and GSK3β and increased expression of Nrf2, PPAR- β/ δ and HO-1.• Reduced levels of MMP-9 and cleaved caspase 3 in the infarct region at day 4 post-MI.
  38. 38. Extracellular signal-regulated kinasesEndocrine Review, April 2012, 33(2): 187-215
  39. 39. Direct Effects of GLP-1 on Myocardial Contractivity and Glucose Uptake in Normal and Postischemic Rat Heart• GLP-1 increased heart rate and blood pressure in intact rodents through sympathostimulatory effect ( Barragan 1994, 1996; Yamamoto, 2002 ).• But depressed myocardial contractivity in isolated rat ventricular myocytes ( Vila petroff, 2001 ).• GLP-1 enhanced recovery of LV function after transient coronary occlusion. Whether it is from GLP-1 direct effects and/or from increased myocardial glucose uptake ( like insulin effect ). Tingcun Zhao, JPET 317:1106-1113, 2006
  40. 40. GLP-1 or insulin on LV dev. P, LV dP/dt, heart rateand coronary flow ( normal heart rat ) JPET 317:1106-1113, 2006
  41. 41. The effect of GLP-1 or insulin on myocardial glucose uptake and myocardial lactate production (normal heart rat ) JPET 317:1106-1113, 2006
  42. 42. GLP-1 increased myocardial glucose uptakethrough a non-Akt-1-dependent mechanism, distinct from insulin JPET 317:1106-1113, 2006
  43. 43. The effect of GLP-1 or insulin on coronary flow, LV dev. P, LV dP/dt and LVEDP during 30 min of low flow ischemia ( 5% baseline ) and 30 min of reperfusion JPET 317:1106-1113, 2006
  44. 44. After 30 min of low flow ischemia,the change of myocardial glucose uptake and lactate production JPET 317:1106-1113, 2006
  45. 45. Myocardial signal transduction withincreased myocardial glucose uptake in postischemic myocardium JPET 317:1106-1113, 2006
  46. 46. • GLP-1 and insulin has comparable effects on myocardial glucose uptake, but via different cellular mechanism. Insulin-mediated glucose uptake was associated with Akt-1 phosphorylation and GLUT-4 translocation. In contrast, GLP-1 did not increased Akt-1 and GLUT-4, but did result in increased GLUT-1 expression in sacrolemma.• The benefits of GLP-1 and insulin to improve postischemic contractile dysfunction are related simply to enhanced glucose uptake.
  47. 47. Extracellular signal-regulated kinasesEndocrine Review, April 2012, 33(2): 187-215
  48. 48. GLP-1R expression in mouse cardiac and vascular tissue Pre-absorption Anti-SM (red ) Polycloal Anti-GLP-1R Ab Anti-GLP-1 (green ) Nuclear stain ( blue ) In media SMEndocardium Loading control: GADPH, beta-actin
  49. 49. Cardioprotective and Vasodilatory Actions of GLP-1 Receptor Are Mediated Through Both GLP-1 Receptor-Dependent and –Independent Pathways Circulation. 2008;117:2340-2350
  50. 50. Functional recovery after I/R injury in WT and Glp 1r-/- hearts with GLP-1 (9-36). Circulation. 2008;117:2340-2350
  51. 51. GLP-1 ( 9-36 ) Vasodilatory effect might be through NO release Only GLP-1 (7-36) Rae GLP-9-26 Circulation. 2008;117:2340-2350
  52. 52. 1. Both GLP-1 and GLP-1(9-36) produced increased coronary flow in constant-pressure perfused isolated hearts and vasodilatation of resistance-level mesenteric arteries from WT and Glp1r -/- mice. Furthermore, this vasodilatory effect correlated with presumably NO-dependent cGMP release. But exendin-4 did not in that exendin-4 cannot bind to novel receptor of GLP-1 (9-36 )--- GLP-1 independent pathway.
  53. 53. What about endothelium?
  54. 54. GLP-1 Prevents Reactive Oxygen species-Induced Endothelial Cell Senescence Arteriolscle Thromb Vasc Biology 2010; 30: 1407-1414
  55. 55. The PI3K/Akt Survival pathway Is Not required for the GLP-1Protective Effect in HCAEC Arteriolscle Thromb Vasc Biology 2010; 30: 1407-1414
  56. 56. GLP-1 Protective effect Is cAMP/PKA DependentH89: inhibitor of Forkolin Arteriolscle Thromb Vasc Biology 2010; 30: 1407-1414
  57. 57. Liraglutide attenuates induction of PAI-1 and vascular adhesion molecules Journal of endocrinology ( 2009 ) 201, 59-66
  58. 58. Liraglutide attenuates induction of PAI-1 and vascular adhesion molecules Journal of endocrinology ( 2009 ) 201, 59-66
  59. 59. Real-time Q-PCR of the effects of Liraglutide treatment on Nur77 mRNA expression Journal of endocrinology ( 2009 ) 201, 59-66
  60. 60. • GLP-1 administration attenuates endothelial cell dysfunction in diabetic patients and inhibits TNF α -mediated PAI-1 induction in human vascular endothelial cells.
  61. 61. Endocrine Review, April 2012, 33(2): 187-215
  62. 62. Conclusion
  63. 63. Ongoing Trials
  64. 64. CAROLINA will evaluate CV safety of Linagliptin in patients with T2DM at high CV risk Inclusion if at least one of the following is fulfilled 1. Previous vascular complications 2. Evidence of end organ damage such as e.g. albuminuria 3. Age > 70 years 4. Two or more specified traditional CV risk factors With or without metformin background therapy (including patients with contraindication to Metformin use in renal impairment) Linagliptin 5mg vs. Glimepiride 1-4mg1 n= 6,000; approx. 6-7 year follow up Primary endpoint: Time to the first occurrence of the primary composite endpoint: 1. CV death (including fatal stroke and fatal MI) 3. Non-fatal stroke 2. Non-fatal MI 4. Hospitalization for unstable angina pectoris1 16 weeks titration phase of glimepiride up to 4mg/dayRosenstock J., et al. ADA 2011 Poster NCT01243424
  65. 65. Thanks for your attention!!