Vildagliptin in the management of Type 2 Diabetes mellitus

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Presented by Dr. A B M Kamrul Hasan in CME of Endocrinology Department, BSMMU on 30th October, 2013

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  • ANIMATED SLIDE
  • * P = 0.0013¥ p= 0.4289
  • Vildagliptin in the management of Type 2 Diabetes mellitus

    1. 1. WELCOME to CME PROGRAM
    2. 2. VILDAGLIPTIN IN THE MANAGEMENT OF TYPE 2 DM Presenter: DR. A.B.M. KAMRUL HASAN MD Final Part (E&M) Department of Endocrinology BSMMU
    3. 3. DM: GLOBAL BURDEN • One of the greatest challenges faced by the modern world is diabetes mellitus and its consequences • Once considered a disease of the West, diabetes is now a global health problem • The prevalence of diabetes is rapidly rising all over the globe at an alarming rate
    4. 4. DM: GLOBAL BURDEN Prevalence (%) DM and IGT: World Prevalence and projection 2010 and 2030 9 8 7 6 5 4 3 2 1 0 8.4 7.9 7.8 6.6 2010 2030 DM IGT DM and IGT International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009. Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.
    5. 5. DM: GLOBAL BURDEN DM and IGT: World prevalence and projection- 2010 and 2030 Number of people (millions) 500 472 439 400 300 344 285 2010 200 2030 100 0 DM IGT DM and IGT International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009. Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.
    6. 6. Top 10 countries for numbers of diabetes in 2010 and 2030 (population aged 20-79 years) 2010 Country 2030 No. of DM (millions) No. of DM (millions) Country 1 India 50.8 87.0 India 1 2 China 43.2 62.6 China 2 3 USA 26.8 36.0 USA 3 4 Russian Federation 9.6 13.8 Pakistan 4 5 Brazil 7.6 12.7 Brazil 5 6 Germany 7.5 12.0 Indonesia 6 7 Pakistan 7.1 11.9 Mexico 7 8 Japan 7.1 10.4 Bangladesh 8 9 Indonesia 7.0 10.3 Russian Federation 9 10 Mexico 6.8 8.6 Egypt 10 International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009. Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.
    7. 7. Major Metabolic Defects in Type 2 Diabetes Decreased pancreatic insulin secretion Peripheral insulin resistance in muscle and fat tissue Deficient incretin hormones response Increased hepatic glucose output
    8. 8. Recent research has implicated at least 5 other pathophysiological defects intimately involved in the development of T2DM • Decreased incretin effects from GIT • Dysregulated pancreatic α-cell activity • Lipotoxicity • Maldaptive kidney responses • Central neurotransmitter dysfunction
    9. 9. Pathophysiology of T2DM Insulin secretion Incretin effect glucagon secretion Hyperglycemia Hepatic glucose production Neurotransmitter dusfunction DeFronzo R. Diabetes 2009;58:773-95. Lipolysis glucose reabsorption Glucose uptake
    10. 10. Traditional current oral therapies do not address all islet cell dysfunction Pancreatic Islet Dysfunction Insulin Resistance (Impaired insulin action) Inadequate glucagon suppression ( -cell dysfunction) Metformin TZDs Insufficient Insulin secretion (β-cell dysfunction) Sulfonylureas Glinides TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40. Progressive decline of β-cell function
    11. 11. Traditional current oral therapies do not address all islet cell dysfunction Pancreatic Islet Dysfunction Insulin Resistance (Impaired insulin action) Inadequate glucagon suppression ( -cell dysfunction) Metformin TZDs Insufficient Insulin secretion (β-cell dysfunction) Progressive decline of β-cell function GLP-1 DPP-4 inhibitors Sulfonylureas GLP-1 DPP-4 inhibitors Glinides GLP-1 DPP-4 inhibitors TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.
    12. 12. Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM Sulfonylureas Increase insulin secretion from pancreatic -cells Glinides Increase insulin secretion from pancreatic -cells Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14. Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver -glucosidase inhibitors Delay intestinal carbohydrate absorption
    13. 13. Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM GLP-1 analogues Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake Sulfonylureas Increase insulin secretion from pancreatic -cells Glinides Increase insulin secretion from pancreatic -cells DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14. Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver -glucosidase inhibitors Delay intestinal carbohydrate absorption
    14. 14. What is Incretin? • Incretins are gut hormones that enhance glucose stimulated insulin secretion • Incretin effect designates amplification of insulin secretion following oral glucose load
    15. 15. NATURAL INCRETINS Two types: 1. Glucose dependent insulinotropic polypeptide (GIP) 2. Glucagon like peptides (GLPs) -GLP-1 These two hormones are rapidly degraded by an enzyme DPP-4
    16. 16. GLP-1 and GIP are the 2 major incretins in human • Both are peptide hormones (30 and 42 amino acids) • Secreted from endocrine cells in the small intestinal mucosa • GLP-1: distal, L-cells (mainly ileum, colon) • GIP: proximal, K-cells (mainly duodenum) • Released in response to meal ingestion GLP-1 positive endocrine Lcells in human small intestine
    17. 17. WHAT IS DPP-4? • Dipeptidyl Peptidase-4 (DPP-4) is an enzyme found free in the circulation and tethered to endothelium and epithelial cells in most tissues, especially in the intestinal mucosa • It clears and inactivates GLP-1 and GIP with in few minutes • It cleaves the N-terminal dipeptide from peptides.
    18. 18. GLP-1: an incretin hormone with multiple direct effects on human physiology α β Pancreas Brain Satiety Intestine β Glucose-dependent insulin secretion β Insulin synthesis α Glucose-dependent glucagon secretion GLP-1 Stomach Gastric emptying Heart Cardioprotection Liver Glucose production Cardiac function L-cells secrete GLP-1 degraded by DPP-4 Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57
    19. 19. EFFECTS OF GLP-1 & GIP
    20. 20. THE PROBLEM  Because of very short half life (1-2 min) therapeutic efficacy is challenged  This led to idea of producing drugs that act as analogue or receptor agonist but longer half life  Another idea was to develops drugs that inhibit DPP-4 enzyme responsible for breakdown of GLP-1 or GIP  Thus one group of drugs is called incretin mimetics and the other group is known as incretin enhancers
    21. 21. NEW THERAPIES: INCRETIN SYSTEM Ingestion of food GI tract Release of active incretins GLP-1 and GIP X Exenatide Gliptin Inactive GLP-1 Pancreas DPP-4 enzyme Inactive GIP Beta cells Glucose depende  Insulin nt (GLP-1and GIP)  Glucose uptake by peripheral tissue  Blood glucose in fasting and postprandial states Alpha cells Glucosedependent  Glucagon (GLP-1)  Hepatic glucose production GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
    22. 22. SITES OF ACTION OF GLIPTINS
    23. 23. INCRETIN MIMETICS AND DPP-4 INHIBITORS: MAJOR DIFFERENCES Properties/effect Incretin mimetics DPP-4 inhibitors Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect Yes Unknown Restitution of insulin secretion (2 phases) Yes (exenatide) Yes Hypoglycaemia No No Inhibition of gastric emptying Yes Marginal Effect on body weight Weight loss Weight neutral Side effects Nausea None observed Administration Subcutaneous Oral Gallwitz. Eur Endocr Dis. 2006
    24. 24. DIPEPTIDYL PEPTIDASE - 4 INHIBITORS Drugs belonging to this class: • Sitagliptin (FDA approved 2006) • Vildagliptin (EU approved 2008) • Saxagliptin (FDA approved 2009) • Linagliptin (FDA approved 2011)
    25. 25. 25
    26. 26. VILDAGLIPTIN: PHARMACOKINETICS • Rapidly absorbed (tmax <2 hours) & highly bioavailable (85%) after oral administration • Low plasma protein binding (9%) • Plasma half life 1.5 - 4.5 hours • Majority (approx. 69%) undergo renal metabolism to inactive metabolites
    27. 27. VILDAGLIPTIN: PHARMACOKINETICS • Negligible involvement metabolism of CYP450 isoforms in • Most (85%) is eliminated via urine • A dose of 50-100mg of vildagliptin provides: o Almost complete inhibition of DDP-4 approximately 12 hours o About 40% inhibition by 24 hours for
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    29. 29. Secretion of incretins decreased in IGT and T2DM T2DM patients vs healthy individuals – following meal 20 GLP-1 2.5 2.0 P <0.001 1.5 1.0 0.5 0.0 Normal GT Impaired GT T2DM GIP AUC (nmol/L*240 min) GLP-1 AUC (nmol/L*240 min) 3.0 GIP P=0.095 15 10 5 0 Normal GT Impaired GT GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; GT=glucose tolerance; T2DM=type 2 diabetes mellitus Toft-Nielsen, et al. J Clin Endocrinol Metab 2001: 3717-3723. T2DM
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    32. 32. Β-CELL FUNCTION CONTINUES TO DECLINE REGARDLESS OF INTERVENTION IN T2DM Sulfonylurea (n=511) Progressive Loss of β-cell Function Occurs prior to Diagnosis 100 Diet (n=110) Metformin (n=159) β-cell Function (%)* 80 60 40 20 0 –5 –4 –3 –2 –1 0 1 Years since Diagnosis T2DM=type 2 diabetes mellitus *β-cell function measured by homeostasis model assessment (HOMA) Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258. 2 3 4 5 6
    33. 33. EFFECT OF VILDAGLIPTIN ON -CELL PRESERVATION AND -CELL REGENERATION Insulin Vehicle Vildagliptin P <0.001 100 75 50 25 0 Vehicle Vildagliptin 60 mg/kg/d Apoptosis 2.5 2.0 1.5 P <0.05 1.0 0.5 0.0 Vehicle Week 1 Vildagliptin decreased islet apoptosis and increased -cell replication Adapted from Duttaroy A, et al. Diabetes. 54 (suppl 1): A141.Abstract 572-P. Vildagliptin 60 mg/kg/d Total islet mass % islet area x pancreatic weight (mg) Replication Apoptotic cells / islet area ( 105) BrdU-positive cells / islet area ( 105) Neonatal rat model of pancreatic islet growth 0.14 P <0.05 0.12 0.10 0.08 0.06 0.04 Vehicle Vildagliptin 60 mg/kg/d Week 3 Resulted in increased insulin-positive islet mass
    34. 34. VILDAGLIPTIN ENHANCES ISLET CELL FUNCTION BY INCREASING INSULIN AND DECREASING GLUCAGON SECRETION OGTT 30 min after single oral dose of vildagliptin (100 mg) 75 g glucose Insulin (pmol/L) 120 Placebo (n=16) Vildagliptin 100 mg (n=15) 100 Dose 80 60 40 20 0 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 Glucose (mmol/L) 22.5 17.5 12.5 7.5 Glucagon (ng/L) 140 120 100 80 60 OGTT=oral glucose tolerance test *P <0.01. He YL, et al. J Clin Pharmacol 2007; 47: 633-641. Time
    35. 35. VILDAGLIPTIN ENHANCES Β-CELL SENSITIVITY TO GLUCOSE Glucose sensitivity Basal secretory tone 260 Secretion at 7 mM glucose (pmol/min/m2) Glucose sensitivity (pmol/min/m2/mM) 75 70 65 60 55 50 240 220 200 180 45 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) Vildagliptin 50 mg once daily Placebo Mari A, et al. J Clin Endocrinol Metab 2008; 93: 103-109.
    36. 36. VILDAGLIPTIN ENHANCES Α-CELL SENSITIVITY TO GLUCOSE Vildagliptin 24 Placebo 24 Vilda wk 0 (50 mg twice daily, n=14) Vilda wk 12 (50 mg twice daily, n=14) 22 Glucagon (pmol/L) 22 Glucagon (pmol/L) Placebo wk 0 (n=14) Placebo wk 12 (n=14) 20 18 16 * 14 * 8.0 12.0 16.0 18 16 14 * 12 4.0 20 * 20.0 24.0 Glucose (mmol/L) wk=week; vilda=vildagliptin *P <0.05 vs wk 0. Data on file, Novartis Pharmaceuticals, LAF237A2344. 12 28.0 4.0 8.0 12.0 16.0 20.0 Glucose (mmol/L) 24.0 28.0
    37. 37. VILDAGLIPTIN ENHANCES INSULIN SENSITIVITY Duration: 6 weeks Vildagliptin vs placebo Hyperinsulinemic euglycaemic clamp 7.0 * Glucose Rd (mg/kg•min) 6.5 6.1 Mean Rd difference=0.7 mg/kg•min 6.0 5.5 Insulin infusion 80 mU/m2•min 5.4 Vildagliptin 50 mg twice daily (n=16) Placebo (n=16) 5.0 4.5 4.0 Rd=rate of disappearance *P <0.05. Azuma K, et al. J Clin Endocrinol Metab 2007; [Epub].
    38. 38. Vildagliptin improves postprandial lipid and lipoprotein metabolism Plasma TG Chylomicron TG 0.8 4.0 Before vilda, week 0 (n=13) 0.6 3.0 mmol/L mmol/L 3.5 2.5 2.0 0.4 0.2 1.5 1.0 −1 0 1 2 3 4 5 6 7 8 0.0 −1 0 1 2 3 4 5 6 7 8 Chylomicron apo B-48 Chylomicron cholesterol 0.08 0.50 0.06 0.20 0.10 0.00 −1 0 1 2 3 4 5 6 7 8 Time (h) TG=triglycerides; vilda=vildagliptin Matikainen N, et al. Diabetologia 2006; 49: 2049-2057. mmol/L mg/L 0.40 0.30 Vilda 50 mg twice daily, week 4 (n=15) 0.04 0.02 0.00 −1 0 1 2 3 4 5 6 7 8 Time (h)
    39. 39. VILDAGLIPTIN ENHANCES Β-CELL FUNCTION AND INSULIN SENSITIVITY OVER 52 WEEKS Patients on stable metformin therapy 300 0.050 0.045 Adaptation index * * * 0.040 0.035 0.030 0.025 275 * * 250 225 200 0 12 24 52 Time (week) 0 12 24 52 Time (week) nmolC-peptide · mmolglucose-1 · mL-1 · m-2 Insulin sensitivity mL · min-1 · m -2 pmol/L 30 min/(mmol/L) Insulin secretion 14 12 * * 10 8 6 0 12 24 Time (week) Vildagliptin 50 mg daily / metformin Placebo / metformin *P <0.05 vs placebo; †P <0.01 vs placebo. Adapted from Ahrén B, et al. Diabetes Care 2005; 28: 1936–1940. † 52
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    52. 52. COMPARISON OF OADs
    53. 53. VECTOR: Results 1 • Hypoglycaemic events (HE) • No patients treated with Vildagliptin experienced hypos including no severe events, compared with 34 hypos in 15 patients, including one severe event with SU – 53 Mean between-group difference in patients who experienced at least one HE was –41·7% (p = 0·0002) 1. VECTOR. doi:10.1185/03007995.2011.579951
    54. 54. VECTOR: Results1 • HbA1c • 1. Vildagliptin significantly lowered HbA1c (7·7% to 7·2%) versus SU (7·2% to 7·3%) postRamadan. The between group difference being −0·5% (p = 0·0262) VECTOR. doi:10.1185/03007995.2011.579951
    55. 55. VECTOR: Results1 • Adherence • The mean number of missed doses was markedly lower with Vildagliptin than with SU (0·2 vs 7·6; between-group difference −7·4 doses; p = 0·0204). That is, on average, patients had 7 fold more missed doses with SUs than Vildagliptin  Only 1 patient in the Vildagliptin group missed at least one dose, compared with 10 patients in the SU group 1. VECTOR. doi:10.1185/03007995.2011.579951
    56. 56. Vildagliptin Vs Other DPP-4i
    57. 57. Vildagliptine Vs. Sitagliptine & Sexagliptine: Powerful 1.1% reduction in HbA1c Superior HbA1c reduction data from 2 separate studies with different baseline HbA1c values2
    58. 58. Vildagliptine Vs. Sitagliptine: Longer duration of DPP-4 binding & increased Active GLP 1 than sitagliptin Tight substrate-like binding of galvus leads to potent DPP-4 inhibition Greater increases in active GLP-1 levels with GALVUS compared with sitagliptin is likely due to tighter and longer-lasting binding
    59. 59. Vildagliptine Vs. Sitagliptine: Vildagliptin Sitagliptin •Efficacy in add on to metformin: 1.1% HbA1C reduction vs •Efficacy in add on to metformin: 0.7% HbA1C reduction •Skin reaction not observed •Hypersensitivity reaction observed in post marketing •Durability over 02 years •Durability 01 year Recent Advancement of Vildagliptin Labeling: •No more Caution in CHF •Recommended in moderate to severe renal impairment also
    60. 60. VILDAGLIPTIN APPROVED IN EU FOR T2DM PATIENTS WITH MODERATE OR SEVERE RENAL IMPAIRMENT
    61. 61. VILDAGLIPTIN APPROVED IN EU FOR T2DM PATIENTS WITH MODERATE OR SEVERE RENAL IMPAIRMENT • Renal impairment affects approximately 25 percent of patients with T2DM • Majority of currently available medications are not recommended, contraindicated or have to be taken with caution in this population
    62. 62. VILDAGLIPTIN APPROVED IN EU FOR T2DM PATIENTS WITH MODERATE OR SEVERE RENAL IMPAIRMENT • 24-week, multi-center, randomized, double-blind, parallelgroup, placebo-controlled study (n=515) assessed the safety and tolerability of vildagliptin (50 mg qd) in patients with type 2 diabetes and moderate or severe renal impairment • The trial showed that vildagliptin had a similar safety profile to placebo in these patients6 and resulted in significant improvements in glycemic control when added to existing anti-diabetic therapy
    63. 63. TIME COURSE OF HBA1C DURING RESCUE-FREE TREATMENT IN PATIENTS WITH MODERATE RI
    64. 64. TIME COURSE OF HBA1C DURING RESCUE-FREE TREATMENT IN PATIENTS WITH MODERATE RI
    65. 65. Overall summery of AEs by Rx & severity of RI
    66. 66. Summery of common AEs by Rx & severity of RI
    67. 67. VILDAGLIPTIN IN HEPATIC IMPAIRMENT • The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function. • The exposure to vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to vildagliptin for subjects with severe impairment was increased by 22%.
    68. 68. VILDAGLIPTIN IN HEPATIC IMPAIRMENT • The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is not considered to be clinically relevant • There was no correlation between the severity of hepatic function impairment and changes in exposure to vildagliptin
    69. 69. VILDAGLIPTIN IN HEPATIC IMPAIRMENT • The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST > 2.5x the upper limit of normal
    70. 70. VILDAGLIPTIN IN HEPATIC IMPAIRMENT • Liver function should be monitored quarterly in the first year and periodically thereafter • Vildagliptin should be stopped if ALT rises 3 times upper normal limit
    71. 71. TAKE HOME MESSAGE • Incretins are gut hormones that enhance glucose stimulated insulin secretion • Amplification of insulin secretion following oral glucose load- “incretin effect” • This effect is severely reduced or lost in type 2 DM
    72. 72. TAKE HOME MESSAGE • Biologic incretins are ineffective in clinical use because of short half-life • Therapeutic benefit is obtained by DPP-4 resistant GLP-1 analogue and DPP-4 enzyme inhibitors • Incretin based therapy has shown a new pathway of treatment of T2DM, with a promise for weight loss and β cell generation
    73. 73. TAKE HOME MESSAGE • Gliptins are weight neutral and does not cause hypoglycaemia • Gliptins may increase beta cell mass in human • Vildagliptin is safe and effective in type 2 diabetic patients with moderate to severe renal impairment
    74. 74. Acknowledgement • Prof. Md. Fariduddin Chairman & Course Co-ordinator, Department of Endocrinology, BSMMU • Dr. M.A. Hasanat Associate Prof, Department of Endocrinology, BSMMU • Novartis Pharma, Bangladesh
    75. 75. Thank You All 76

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