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糖尿病口服藥物新思維  內分泌新陳代謝科    林文玉醫師
視網膜病變的流行率: NHANES III                                        A1C    2hPG   FPG          18          16          14       R...
血糖是主角嗎?     Diabetes Care 32: 2007-2032, 2009
Association of A1c and Fasting PlasmaGlucose levels With Diabetes Retinopathy                       Diabetes Care 32: 2007...
Glycemic Thresholds for Diabetes- Specific              Retinopathy                          Diabetes Care 34:145–150, 2011
從大型臨床研究學到什麼?•   DCCT and EDIC•   UKPDS and extended study•   ACCORD•   ADVANCE•   VADT
Complications (DCCT)                15                13                                                                  ...
DCCT: intensive control reduces                     complications in type 1 diabetes                    Conventional versu...
DCCT/EDIC: long-term follow-up and                                     legacy effect                                9     ...
UKPDS    Glucose Control Study SummaryThe intensive glucose control policy maintained a lower HbA1c bymean 0.9 % over a me...
UKPDS: intensive control reduces                           complications in type 2 diabetes                   9           ...
UKPDS: long-term follow-up and legacy effect                                                      Intervention            ...
Legacy EffectDifferences in glycosylated hemoglobin (HbA1c) levelsbetween intensively and conventionally treated patientsd...
The Action to Control Cardiovascular riskin Diabetes study group ( ACCOD trial )
ACCORD Results
Outcomes: Summary of ACCORD, ADVANCE and                          VADT*ACCORD (Action to Control Cardiovascular Risk in Di...
Adverse Outcomes:                           ACCORD, ADVANCE and VADTACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE C...
Intervention Works...but at a                                                 Price: DCCT and UKPDS                       ...
Asymptomatic Episodes of       Hypoglycemia May Go Unreported                       100                       75          ...
Why was mortality increased in         intensive treatment group in ACCORD?           •   Not certain           •   Speed ...
Increased Mortality, Myocardial Infarction, and           Hypoglycemia With Intensive Therapy:                         ACC...
Gl
Type 2 Diabetes Prevention• Finnish Diabetes Prevention Study (DPS): randomized 522 overweight    (average BMI 31 kg/m2) m...
Whether lower HbA1c relates to lowermortality rate in cases of IGT, or HBA1C lessthan 6.5%, by lifestyle modification or n...
Summary• DM development is preventable via life style modification or  anti-diabetic agents such as Metformin, TZD and Aca...
Weight gainDM in itself:1. Physical inactivity2. Hyperinsulinemia3. Delay satiety and easily hungry ( polyphagia )Hypoglyc...
UKPDS 33: intensive therapy was associated                      with weight gain                                      10.0...
RESULTS— Individuals trying to lose weight had a 23% lower mortality rate (hazard rateratio [HRR] 0.77, 95% CI 0.61– 0.99)...
Satiety• Decline of beta-cell function: impaired secretion of insulin and  hIAPP ( Amylin).• Impaired secretion of CCK-8• ...
Does ghrelin explain accelerated gastricemptying in the early stages of type 2 DM?        Am J Physiol Regul Integr Comp P...
Regulation of gastric emptying          DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008
Melanocortin System and Regulation of Appetite              And Body Weight                                           NTS ...
Central Melanocortin System and                     AgRP/NPY•   This system is involved in body weight regulation through ...
Ominous OctetBeta cell, fat, muscle, liver, gut, alfa cell, kidney, brain                     Ralph A. DeFronzo Diabetes, ...
Increased renal glucose reabsorption In animal models of both type 1 and type 2 diabetes, the maximal renal  tubular reab...
Cerebral insulin resistanceAfter glucose ingestion, two hypothalamic areas with consistentinhibition were noted: the lower...
Pathogenesis of type 2 DM:           Implication for Therapy Effective treatment of type 2 diabetes requires multiple  dr...
In Clinical Aspects                  “Ideal oral drug”• Targeting underlying pathogenesis, including lowering insulin  res...
Incretin-based therapy是不是糖尿病用藥的”藍海” ?
IN-CRET-IN           INtestine seCRETion INsulin Definition: gut derived factors that increase glucose stimulated insulin ...
Incretin effect on insulin secretion                 80       Control subjects (n=8)                            80       P...
What is GLP-1?                        Increased insulin response                                            Key observatio...
Effects of GLP-1 on Insulin and GlucagonShown to Be Glucose Dependent in Type 2 Diabetes                       15.0       ...
Why not GIP ?
Because of its short half-life, native GLP-1 has               limited clinical value             DPP-IV                  ...
GLP-1 enhancement                   GLP-1 secretion is impaired in Type 2                                 diabetes        ...
DPP-4 Inhibitor – mechanism of action                                                              Glucose-dependent      ...
Sitagliptin Consistently and Significantly Lowers A1C With                         Once-Daily Dosing in Monotherapy       ...
Sitagliptin Lowers Post-meal Glucose                                            Excursion and Enhances Insulin Secretion  ...
Sitagliptin Improved Markers of Beta-Cell               Function: 24-Week Monotherapy Study                    Proinsulin/...
GLP-1R expression in mouse           cardiac and vascular tissue          Polycloal Anti-GLP-1R Ab   Pre-absorption       ...
Extracellular signal-regulated kinasesEndocrine Review, April 2012, 33(2): 187-215
Linagliptin significantly lowers albuminuria vs.               placebo in pooled phase III study dataAlbuminuria:         ...
DDP-4 inhibitors               Control                                                      Risk Ratio (95% CI),          ...
Adverse events in patients with type 2 diabetes treatedwith DDP-4 inhibitors (Sitagliptin and Viltagliptin)*              ...
Adverse events in patients with type 2 diabetes  treated with DDP-4 inhibitors (Sitagliptin and Viltagliptin)*            ...
Sitagliptin or sitagliptin/metformin          (marketed as Januvia and Janumet)                 Acute pancreatitis warning...
Summary about DPP 4i Smart way of insulin secretion with minimal risk of    hypoglycemia   No need of preventive intake ...
糖尿病口服藥物新思維
糖尿病口服藥物新思維
糖尿病口服藥物新思維
糖尿病口服藥物新思維
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糖尿病口服藥物新思維

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糖尿病口服藥物新思維

  1. 1. 糖尿病口服藥物新思維 內分泌新陳代謝科 林文玉醫師
  2. 2. 視網膜病變的流行率: NHANES III A1C 2hPG FPG 18 16 14 Retinopathy (%) 12 10 8 6 4 2 0FPG (mg/dl) 42 87 90 93 96 98 101 104 109 1202hPG (mg/dl) 34 75 86 94 102 112 120 133 154 195A1C (%) 3.3 4.9 5.1 5.2 5.4 5.5 5.6 5.7 5.9 6.2 Diabetes Care, 20(7):1183-1997.
  3. 3. 血糖是主角嗎? Diabetes Care 32: 2007-2032, 2009
  4. 4. Association of A1c and Fasting PlasmaGlucose levels With Diabetes Retinopathy Diabetes Care 32: 2007-2032, 2009
  5. 5. Glycemic Thresholds for Diabetes- Specific Retinopathy Diabetes Care 34:145–150, 2011
  6. 6. 從大型臨床研究學到什麼?• DCCT and EDIC• UKPDS and extended study• ACCORD• ADVANCE• VADT
  7. 7. Complications (DCCT) 15 13 Retinop 11 9RELATIVE RISK Neph 7 5 Neurop 3 1 6 7 8 9 10 11 12 Mean A1C DCCT Research Group, N Engl J Med 1993, 329:977- 986.
  8. 8. DCCT: intensive control reduces complications in type 1 diabetes Conventional versus intensive insulin therapy (n = 1,441) 11 0 10 Conventional treatment (n = 730) 9 20 Reduction (%) HbA1c (%) 8 P < 0.001 39% 7 40 54% 54% 6 Intensive treatment 60% 60 0 (n = 711) 76% 0 1 2 3 4 5 6 7 8 9 10 80 Year of study*Subdivided to primary and secondary prevention of retinopathy. Age 27 years, HbA1c 8.8%.Insulin dose (U/kg/d) 0.62 (primary), 0.71 (secondary). DCCT Research Group. N Engl J Med 1993; 329:977–986.
  9. 9. DCCT/EDIC: long-term follow-up and legacy effect 9 Glucose Conventional treatment similar BUT CV events 8 still higher HbA1C (%) Intensive treatment 7 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years DCCT (intervention period) EDIC (observational follow-up) 0.06Cumulative incidence ofnon-fatal MI, stroke or 57% risk reduction in non-fatal MI, stroke or CVD death* Conventional 0.04 treatmentdeath from CVD 0.02 Intensive treatment 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years DCCT (intervention period) EDIC (observational follow-up) *Intensive vs conventional treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986. Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.
  10. 10. UKPDS Glucose Control Study SummaryThe intensive glucose control policy maintained a lower HbA1c bymean 0.9 % over a median follow up of 10 years from diagnosis oftype 2 diabetes with reduction in risk of: 12% for any diabetes related endpoint p=0.029 25% for microvascular endpoints p=0.0099 16% for myocardial infarction p=0.052 24% for cataract extraction p=0.046 21% for retinopathy at twelve years p=0.015 33% for albuminuria at twelve years p=0.000054
  11. 11. UKPDS: intensive control reduces complications in type 2 diabetes 9 0 Conventional Relative risk reduction (%) 6% –5Median HbA1C (%) P = 0.44 8 –10 12% –15 P = 0.029 16% Intensive –20 P = 0.052 7 25% –25 6.2% = upper limit of normal range P = 0.0099 –30 6 0 0 5 10 15 UKPDS randomized years Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853.
  12. 12. UKPDS: long-term follow-up and legacy effect Intervention ends UKPDS UKPDS Active Follow-up 0 10 9 –5 Conventional 9%Median HbA1c (%) –10 P = 0.040 Relative risk reduction (%) 13% 8 Biochemical 15% data no longer P = 0.007 collected –15 P = 0.014 7 Intensive –20 24% 6 –25 P = 0.001 0 5 10 15 5 10 –30 1977 1997 2007 Years from randomization Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247. Holman RR, et al. N Engl J Med 2008; 359:1577–1589.
  13. 13. Legacy EffectDifferences in glycosylated hemoglobin (HbA1c) levelsbetween intensively and conventionally treated patientsdisappeared within 1 year of the trial’s end.Nevertheless, outcomes continued to favor the intensivelytreated group: During post-trial follow-up, the significantrelative reduction in microvascular disease persisted, andsignificant reductions in myocardial infarction and all-causemortality emerged in the intensive-control group.
  14. 14. The Action to Control Cardiovascular riskin Diabetes study group ( ACCOD trial )
  15. 15. ACCORD Results
  16. 16. Outcomes: Summary of ACCORD, ADVANCE and VADT*ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial halted intensive glucose group (2/6/08)† significant difference between intensive and standard groupACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008
  17. 17. Adverse Outcomes: ACCORD, ADVANCE and VADTACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008
  18. 18. Intervention Works...but at a Price: DCCT and UKPDS Severe Hypoglycemia 100 DCCT (Type 1) UKPDS (Type 2) Major Episodes 5 80 Major Episodes Incidence (%) Rate/100 Patient Years 4 60 Intensive 3 Intensive 40 2 20 1 Conventional Conventional 0 0 5 6 7 8 9 10 11 12 13 14 0 3 6 9 12 15 HbA1c (%) During Study Years from RandomizationDCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998
  19. 19. Asymptomatic Episodes of Hypoglycemia May Go Unreported 100 75 • In a cohort of patients with 62.5 55.7 diabetes, more than 50% had Patients, % 46.6 asymptomatic (unrecognized) 50 hypoglycemia, as identified by continuous glucose monitoring. 25 • Other researchers have n=70 n=40 n=30 0 reported similar findings All patients Type 1 Type 2 with diabetes diabetes diabetes Patients With ≥1 Unrecognized Hypoglycemic Event, %1. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Permission pending.2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.
  20. 20. Why was mortality increased in intensive treatment group in ACCORD? • Not certain • Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months) • Drug combinations • Unidentified hypoglycemia • Weight gain • Hypoglycemia unawareness (associated cardiac autonomic neuropathy) Analysis proves that the increased mortality rates are not related to 1. Specific OAD ( Rosiiglitazone, SU , Insulin etc) 2. Changes in other medications( Statins, Aspirin etc)Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192
  21. 21. Increased Mortality, Myocardial Infarction, and Hypoglycemia With Intensive Therapy: ACCORD Trial Mortality (% per year) ≥1 severe hypoglycemia (n = 705) 3.1 No hypoglycemia 1.2 (n = 9,546) a Defined by requirement for medical or paramedical intervention, with documented glucose <50 mg/dL and relief by parenteral or oral glucose or by glucagon.1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.
  22. 22. Gl
  23. 23. Type 2 Diabetes Prevention• Finnish Diabetes Prevention Study (DPS): randomized 522 overweight (average BMI 31 kg/m2) middle-aged individuals, weight loss 5% and exercise with at least 30 minutes per day of combined aerobic activity and resistance training; At the 3-year follow-up, the group reduced their cumulative risk by 58% compared to the control subjects.• Diabetes Prevention Program (DPP): randomized 3,234 overweight participants with IGT and elevated fasting glucose from 22 sites in the USA to one of three interventions: intensive lifestyle intervention (ILS), metformin, or placebo. 58% ( ILS ), 31% ( Metformin )• Study to Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM) : 25% reduction in incidence• Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial: 62% reduction• China Da Qing Diabetes Prevention Study: 43.8% in the diet group, 41.1% in the exercise group, and 46% in the diet-plus-exercise group .
  24. 24. Whether lower HbA1c relates to lowermortality rate in cases of IGT, or HBA1C lessthan 6.5%, by lifestyle modification or non- insulin secretagogue anti-diabetic agents? Unknown
  25. 25. Summary• DM development is preventable via life style modification or anti-diabetic agents such as Metformin, TZD and Acarbose.• Intensive glycemic control slows down progress of diabetic complications, microvascular and probably macrovascular.• Intensive glycemic control has patient risk hypoglycemia, and risk higher CV mortality.• Severe hypoglycemia increased CV mortality 3.1X than otherwise.• Insulin sensitizer, acarbose, or DDP-IV inhibitor causing rare hypoglycemia, benefit patient with early DM, even HbA1c < 6.5% ?• Safety is a dominant issue in the following era.
  26. 26. Weight gainDM in itself:1. Physical inactivity2. Hyperinsulinemia3. Delay satiety and easily hungry ( polyphagia )Hypoglycemic agents related:1. Hyperinsulinemia ( SU, glitinide, insulin )2. Hypoglycemia with preventive intake ( insulin, SU, glinide )3. Fluid water retention ( TZD, distal convoluted tubule, ENAC; insulin )4. Adipogenesis, and transdifferentiation from myocyte ( TZD ). PNAS Vol. 92, pp. 9856-9860, October 1995 Cell Biology
  27. 27. UKPDS 33: intensive therapy was associated with weight gain 10.0 Insulin Chlorpropamide Glibenclamide Mean change in weight (kg) 7.5 Conventional 5.0 2.5 0 0 3 6 9 12 15 Years from randomisation Dashed lines indicate patients followed for 10 years Solid lines indicate all patients assigned to regimenAdapted from: Lancet 1998;352:837–53
  28. 28. RESULTS— Individuals trying to lose weight had a 23% lower mortality rate (hazard rateratio [HRR] 0.77, 95% CI 0.61– 0.99) than those who reported not trying to lose weight. Thisassociation was as strong for those who failed to lose weight (0.72, 0.55– 0.96) as for thosewho succeeded in losing weight (0.83, 0.63–1.08). Trying to lose weight was beneficial foroverweight (BMI 25–30 kg/m2) individuals (0.62, 0.46–0.83) but not for obese (BMI 30)individuals (1.17, 0.72–1.92). Overall weight loss, without regard to intent, was associatedwith an increase of 22% (1.22, 0.99 –1.50) in the mortality rate. This increase was largelyexplained by unintentional weight loss, which was associated with a 58% (1.58, 1.08 –2.31)higher mortality rate. Diabetes care 27:657-662, 2004
  29. 29. Satiety• Decline of beta-cell function: impaired secretion of insulin and hIAPP ( Amylin).• Impaired secretion of CCK-8• Impaired GLP-1 secretion• Lower level of PYY• Rapid gastric emptying in spite of solid and liquid meals, in early type II diabetic patients.• Non-suppressible ghrelin level after feeding
  30. 30. Does ghrelin explain accelerated gastricemptying in the early stages of type 2 DM? Am J Physiol Regul Integr Comp Physiol 294: R1807–R1812, 2008.
  31. 31. Regulation of gastric emptying DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008
  32. 32. Melanocortin System and Regulation of Appetite And Body Weight NTS (-)
  33. 33. 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 to lowering body weight. 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
  34. 34. Ominous OctetBeta cell, fat, muscle, liver, gut, alfa cell, kidney, brain Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
  35. 35. Increased renal glucose reabsorption In animal models of both type 1 and type 2 diabetes, the maximal renal tubular reabsorptive capacity, or Tm, for glucose is increased. In humans with type 1 diabetes, Mogensen et al. have shown that the Tm for glucose is increased. Cultured human proximal renal tubular cells from type 2 diabetic patients demonstrate markedly increased levels of SGLT2 mRNA and protein and a fourfold increase in the uptake of -methyl-D- glucopyranoside (AMG), a nonmetabolizeable glucose analog Thus, an adaptive response by the kidney to conserve glucose, which is essential to meet the energy demands of the body, especially the brain and other neural tissues, which have an obligate need for glucose, becomes maladaptive in the diabetic patient Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
  36. 36. Cerebral insulin resistanceAfter glucose ingestion, two hypothalamic areas with consistentinhibition were noted: the lower posterior hypothalamus, whichcontains the ventromedial nuclei, and the upper posteriorhypothalamus, which contains the paraventricular nuclei. In bothof these hypothalamic areas, which are key centers for appetiteregulation, the magnitude of the inhibitory response followingglucose ingestion was reduced in obese, insulin-resistant, normalglucose tolerant subjects, and there was a delay in the time takento reach the maximum inhibitory response, even though theplasma insulin response was markedly increased in the obesegroup. Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
  37. 37. Pathogenesis of type 2 DM: Implication for Therapy Effective treatment of type 2 diabetes requires multiple drugs used in combination to correct multiple pathophysiological defects. Treatment should be based on known pathogenic abnormalities and not simply on reduction of A1C. Therapy must be started early in the natural history of type 2 diabetes to prevent progressive beta-cell failure.
  38. 38. In Clinical Aspects “Ideal oral drug”• Targeting underlying pathogenesis, including lowering insulin resistance ( Metfromin, TZD ), recovering beta-cell function ( SU, glinide, DPP-4i ) and reducing hepatic glucose production ( Metformin ).• Safe, minimal hypoglycemia ( Metformin, TZD, AGI, DPP- 4i,, SGLT-2i )• No weight gain ( Metfromin, AGI, DPP-4i, SGLT-2i)• Satiety promotion ( ? AGI, DPP-4i,Metformin )• Weight losing ( MC4R agonist ? Metformin, DPP 4i, AGI, SGLT- 2i )• Beta-cell neogenesis ( ? TZD, DPP 4i )• Reduced CV risk ( Metformin, AGI, DPP 4i )
  39. 39. Incretin-based therapy是不是糖尿病用藥的”藍海” ?
  40. 40. IN-CRET-IN INtestine seCRETion INsulin Definition: 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
  41. 41. 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
  42. 42. 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 Time (min) secretion and decreases glucagon secretion 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.
  43. 43. Effects of GLP-1 on Insulin and GlucagonShown to Be Glucose Dependent in Type 2 Diabetes 15.0 Placebo (mmol/L) GLP-1 infusion 12.5 Glucose 10.0 * 7.5 * * * * 5.0 * * Infusion With hyperglycemia GLP-1 stimulated insulin 250 (pmol/L) and suppressed glucagon. Insulin 200 150 100 * * * 50 * * * * When glucose levels * approached normal, insulin levels declined Glucagon (pmol/L) 20 15 and glucagon was no 10 * * * * longer suppressed. 5 0 60 120 180 240 Time (minutes)N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drugschedule was allowed for one day between the experiments with GLP-1 and placebo.*p<0.05 GLP-1 vs. placeboAdapted from Nauck MA et al Diabetologia 1993;36:741–744. 11
  44. 44. Why not GIP ?
  45. 45. 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.
  46. 46. 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 • exenatide degrades GLP-1: • liraglutide • Sitagliptin • Vildagliptin • Linagliptin Injectables Oral agentsDrucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
  47. 47. DPP-4 Inhibitor – mechanism of action Glucose-dependent insulin secretion ß-cellsFood intake Increases glucose utilisation by muscle and adipose tissue Pancreas α-cells Glucose-dependent Decreases hepatic glucose release glucagon suppression improving overall glucose control Inactive Active DPP2-4 GLP1-1 (9-36) Intestine GLP1-1 (7-36) amide 2 amino acids DPP-4 cleaved from inhibitor amino terminusSource: Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87–100; Ahrén B. Curr Diab Rep.2003;3:365–372 51
  48. 48. Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy 18-Week study 24-Week study Japanese study Change vs -0.6% -0.79% -1.05% placebo* (P<.001) (P<.001) 8.4 (P<.001) 8.4 8.4 8.0 8.0 8.0A1C (%) A1C (%) A1C (%) 7.6 7.6 7.6 7.2 Placebo (n=74) Placebo (n=244) Placebo (n=75) 7.2 Sitagliptin 100 mg (n=168) 7.2 6.8 Sitagliptin 100 mg (n=229) Sitagliptin 100 mg (n=75) 0 6 12 18 0 5 10 15 20 25 0 4 8 12 Time (wk) Time (wk) Time (wk) *Between group difference in LS means. Nonaka K et al; A201. Abstracts presented at: 66th Scientific Sessions of ADA; June 9-13, 2006; Washington, DC. 52
  49. 49. Sitagliptin Lowers Post-meal Glucose Excursion and Enhances Insulin Secretion P<0.05 for between group difference Japanese Monotherapy Study 70 Placebo Sitagliptin 100 mg qd 60 Baseline Baseline Plasma Insulin (µU/mL) Week 12 Week 12 50 40 320Plasma Glucose (mg/dL) 30 11.7 mg/dL 20 280 10 -69.2 240 mg/dL 0 0 0.5 1.0 2.0 0 0.5 1.0 2.0 0.5 Insulinogenic Index (µU/mg) Placebo Time (hr) 200 0.4 Sitagliptin 100 mg qd 0.3 160 Placebo Sitagliptin 100 mg qd 0.2 120 0.1 0 0.5 1. 2.0 0 0. 1. 2.0 0 5 0 0 Time (hr) P<0.001 for difference in change from baseilne in 2-hr PPG Week 0 Week 12 Between group difference (P<0.001) Insulinogenic index = ∆ I30 / ∆ G30 Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. 53
  50. 50. Sitagliptin Improved Markers of Beta-Cell Function: 24-Week Monotherapy Study Proinsulin/insulin ratio HOMA-β 0.48 75 p< 0.001* p< 0.001* 0.46 70 0.44 65 0.42 60 0.4 55 0.38 50 0.36 45 0.34 40 0.32 35 0.3 30 Placebo Sitagliptin Placebo Sitagliptin Red = baseline ∆ from baseline vs = 13.2 +/- 3.3 ∆ from baseline vs pbo = 0.078 Yellow = Week 24 (95% CI -0.114, -0.023) pbo (95% CI 3.9, 21.9)* P value for change from baseline compared to placeboAschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. 54
  51. 51. 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
  52. 52. Extracellular signal-regulated kinasesEndocrine Review, April 2012, 33(2): 187-215
  53. 53. Linagliptin significantly lowers albuminuria vs. placebo in pooled phase III study dataAlbuminuria: 24 weeks treatment Effect of linagliptin on albuminuria in humans• Early marker for renal damage Adjusted mean change in albuminuria (24 weeks)• Marker for endothelial Placebo Lina dysfunction• Cardiovascular risk factor -4%• Lowering of albuminuria might be associated with -29% kidney & CV protection p < 0.05 -33% n 59 168 -29% in albuminuria vs. placebo after 24wks treatment** This was achieved on the background of ACE/ARB, n=2472 Poster: 953-P, American Diabetes Association 72nd Scientific Sessions, June 8–12, 2012, Philadelphia, USA.
  54. 54. DDP-4 inhibitors Control Risk Ratio (95% CI), Adverse events Incretin Mean % (95% CI) Mean % (95% CI) Achieving Control Achieving Control vs. ControlHypoglycemiaAll DDP4 inhibitors vs comparator 0.97(0.50-1.86) 1.6 (0.7-3.2) 1.4 (0.6-3.4)Sitagliptin vs comparator 0.92 (0.30-2.87) 1.8 (0.9-3.3) 1.5 (0.2-8.5)Vildagliptin vs comparator 0.84 (0.50-1.19) 1.4 (0.4-4.8 1.2 (0.3-5.7)NauseaAll DDP4 inhibitors vs comparator 0.89 (0.58-1.36) 2.7 (2.1-3.4) 3.1 (2.0-4.7)Sitagliptin vs comparator 1.46 (0.88-2.43) 2.1 (1.4-3.0) 1.4 (0.7-2.4)Vildagliptin vs comparator 0.57 (0.37-0.88) 3.4 (2.6-4.6) 5.2 (3.6-7.4)VomitingAll DDP4 inhibitors vs comparator 0.69 (0.42-1.15) 1.3 (0.8-2.2) 1.5 (0.9-2.6)Sitagliptin vs comparator 0.86 (0.45-1.65) 1.1 (0.6-2.0) 1.2 (0.8-1.9)Vildagliptin vs comparator 0.49 (0.21-1.1.11) NR NRDiarrheaAll DDP4 inhibitors vs comparator 0.80 (0.42-1.54) 3.8 (2.8-5.1) 4.0 (1.8-4.6)Sitagliptin vs comparator 1.21 (0.81-1.80) 3.6 (2.5-5.1) 2.8 (1.8-4.6)Vildagliptin vs comparator 0.34 (0.14-0.80) 4.0 (2.0-8.0) 9.9 (2.7-30.7) DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence intervalAmori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis.JAMA. 2007;298:194-206.
  55. 55. Adverse events in patients with type 2 diabetes treatedwith DDP-4 inhibitors (Sitagliptin and Viltagliptin)* DDP-4 inhibitors Control Adverse events Risk Ratio (95% CI), Mean % (95% CI) Mean % (95% CI) Incretin Achieving Control Achieving Control vs. ControlAbdominal painAll DDP4 inhibitors vs comparator 0.73 (0.36-1.45) 2.4 (1.8-3.2) 3.2 (1.7-5.7)Sitagliptin vs comparator 0.92 (0.47-1.80) 2.5 (1.8-3.3) 2.6 (1.7-3.9)Vildagliptin vs comparator 0.32 (0.16-0.66) NR NRCouphAll DDP4 inhibitors vs comparator 1.07 (0.65-1.78) 2.9 (2.1-4.0) 2.4 (1.7-3.5)Sitagliptin vs comparator 0.95 (0.54-1.78) 2.5 (1.7-3.5) 2.6 (1.8-3.9)Vildagliptin vs comparator 1.86 (0.57-6.11) 4.8 (2.6-8.6) 1.7 (0.7-4.1)InfluenzaAll DDP4 inhibitors vs comparator 0.87 (0.64-1.19) 4.1 (3.3-5.1) 4.4 (3.4-5.8)Sitagliptin vs comparator 0.95 (0.65-1.39) 4.0 (3.1-5.1) 5.3 (3.7-7.4)Vildagliptin vs comparator 0.73 (0.42-1.27) 4.2 (2.5-7.1) 6.1 (5.0-7.4)NasopharyngitisAll DDP4 inhibitors vs comparator 1.17 (0.98-1.40) 6.4 (5.1-7.8) 4.5 (3.0-6.7)Sitagliptin vs comparator 1.38 (1.06-1.81) 5.3 (3.5-7.9) 7.3 (6.0-8.9)Vildagliptin vs comparator 1.02 (0.80-1.29) 7.3 (5.8-9.3) 6.4 (4.9-8.4)DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.
  56. 56. Adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors (Sitagliptin and Viltagliptin)* DDP-4 inhibitors Control Adverse events Risk Ratio (95% CI), Mean % (95% CI) Mean % (95% CI) Incretin Achieving Control Achieving Control vs. ControlUpper respiratory tract infectionAll DDP4 inhibitors vs comparator 0.99 (0.81-1.21) 6.3 (5.1-7.7) 6.4 (4.9-8.4)Sitagliptin vs comparator 1.09 (0.84-1.43) 5.7 (4.0-8.0) 4.7 (2.8-8.0)Vildagliptin vs comparator 0.88 (0.65-1.18) 6.8 (5.3-8.6) 8.0 (6.5-9.8)SinusitisAll DDP4 inhibitors vs comparator 0.61 (0.34-1.12) 2.0 (1.3-3.1) 3.4 (2.4-4.8)Sitagliptin vs comparator 0.81 (0.41-1.58) 2.2 (1.4-3.4) 2.5 (1.6-3.9)Vildagliptin vs comparator 0.20 (0.05-0.78) 1.2 (0.3-4.1) 5.4 (3.1-9.2)Urinary tract infectionAll DDP4 inhibitors vs comparator 1.52 (1.04-2.21) 3.2 (2.3-4.5) 2.4 (1.8-3.2)Sitagliptin vs comparator 1.42 (0.95-2.11) 3.1 (2.1-4.6) 2.6 (1.9-3.5)Vildagliptin vs comparator 2.72 (0.85-8.68) 3.6 (1.5-8.3) 1.3 (0.5-3.3)HeadacheAll DDP4 inhibitors vs comparator 1.38 (1.10-1.72) 5.1 (4.1-6.4) 3.9 (3.1-4.8)Sitagliptin vs comparator 1.24 (0.82-1.87) 3.6 (2.9-4.5) 3.1 (1.9-4.9)Vildagliptin vs comparator 1.47 (1.12-1.94) 6.3 (5.0-8.0) 4.4 (3.4-5.6)DPP4: dipeptidyl peptidase 4 ; Comparator :placebo ororal hypoglycemic agent or insulin; CI :confidence interval* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.
  57. 57. Sitagliptin or sitagliptin/metformin (marketed as Januvia and Janumet) Acute pancreatitis warning In 2009, FDA has completed a review of 88 cases of acute pancreatitis in patients using sitagliptin or sitagliptin/metformin. The cases were reported to FDA’s Adverse Event Reporting System (AERS) between October 2006 and February 2009. Hospitalization: 66% of the patients, 4 to the intensive care unit. Two cases of hemorrhagic or necrotizing pancreatitis. 21% of pancreatitis cases occurred within 30 days of starting sitagliptin, sitagliptin/metformin. The most common adverse events were abdominal pain, nausea and vomiting. FDA , U.S. Food and Drug Adminstration
  58. 58. Summary about DPP 4i Smart way of insulin secretion with minimal risk of hypoglycemia No need of preventive intake for hypoglycemia, so as to prevent from weight gain. Inducing satiety and reduced intake Delay gastric emptying, minimizing hungry sensation Acceptable side effect profile No human evidence of cancer risk now Preliminary data of CV and renal benefits available

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