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How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
How to link glucose control to cv outcomes
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How to link glucose control to cv outcomes

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Outline …

Outline
1.CV risk of DM patient
2.Glucose to CV outcome - Intensive control vs Conventional control
3.Hypoglycemia
4.Different drugs, different outcomes
5.Expect to Future

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  • 1. 藥師:陳翊齊 報告日期:103. 04. 18
  • 2. Why this Topic ?? 糖尿病共照網納入藥師 小弟熟悉的領域 流行病學 藥物流行病學
  • 3. 聲明 本人無與任何廠商有關係 本人無領任何廠商的演講費 本人無購買任何廠商的股票 MOS早餐是由本人自掏腰包購買 逐片吐司審查,絕無下毒,安心食用 藥師 陳翊齊
  • 4. Outline  CV risk of DM patient  Glucose - Intensive control vs Conventional control  Hypoglycemia  Different drugs, different outcomes  Expect to Future
  • 5. 糖尿病藥物發展  1980 年代以前  SulfonylUrea  Insulin (NPH & RI)  1990 年代  Metformin  α-glucosidase inhibitor  Meglitinide  2000 年代至今  PPAR-γ agonist  新型胰島素  DPP-4 inhibitor  GLP-1 agonist  SGLT-2 antagonist Exubera® Afrezza® Bydureon® Tanzeum® Canagliflozin Dapagliflozin
  • 6. Mortality and Causes of Death in a National Sample of Diabetic Patients in Taiwan Diabetes Care 27:1605–1609, 2004 28.8% + 9.0% + 10.5% +0.3% = 48.6%
  • 7. Diabetes Care 23:1103–1107, 2000 49.4% Cardiovasucular death 49.1% Cardiovasucular death Diabetes Care July 1998 vol. 21 no. 7 1138-1145
  • 8. 7-year incidence rates of MI (fatal and nonfatal) 0 5 10 15 20 25 30 35 40 45 50 no DM, no prior MI no DM, prior MI DM, no prior MI DM, prior MI N Engl J Med 1998;339:229-34.) 3.5% 18.8% 20.2% 45% P<0.001 P<0.001
  • 9. UK Prospective Diabetes Study  Multicenter RCT  1977 to 1997  5,102 patients with newly-diagnosed type 2 diabetes recruited between 1977 and 1991
  • 10. UKPDS Study design Intensive Conventional Intensive 2,729 Intensive with sulfonylurea(glibenclamide or chlorpropramide)/insulin 1,138 (411 overweight) Conventional with diet 342 (all overweight) Intensive with metformin UKPDS 33 Trial end 1997 P 5,102 Newly-diagnosed type 2 diabetes 744 Diet failure FPG >15 mmol/l 149 Diet satisfactory FPG <6 mmol/l Dietary Run-in 4209 Randomisation 1977-1991 UKPDS 34 N Eng J Med 2008; 359
  • 11. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35)  Prospective observational study  3642 patients BMJ 2000;321:405–12
  • 12. UKPDS 33  Multicenter RCT  3867 newly diagnosed type 2 DM  Intensive (SU/insulin) vs conventional  Follow 10 years  HbA1c 7.0% vs 7.9% 0 0.2 0.4 0.6 0.8 1 1.2 DM related endpoint Any DM related death All cause mortality End point RR=0.88(0.79-0.99) P=0.029 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Myocardial infraction Stroke Amputation or death from PVD Microvascular endpoint End point RR=0.84(0.71-1.00) P=0.052 RR=0.75(0.60-0.93) P=0.0099 Lancet 1998; 352: 837–53
  • 13. UKPDS 80  10-year Post-Trial Monitoring from 1997 to 2007  Annual follow-up of the survivor cohort  Clinic-based for first five years  Questionnaire-based for last five years  Median overall follow-up 17 (16 to 30) years Intensive (SU/Ins) vs. Conventional glucose control N Engl J Med 2008;359:1577-89.
  • 14. ACCORD study  Action to Control CardiOvascular Risk in Diabetes study  10,251 type 2 DM patients (Mean history 10 years)  Primary outcome:CVD event  Baseline HbA1c 8.3% (Mean)  End of the trial HbA1c:6.4% vs 7.5% N Engl J Med 2008;358:2545-59.
  • 15. ACCORD study N Engl J Med 2008;358:2545-59.
  • 16. ADVANCE study  Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation  11,140 type 2 DM patients (Mean history 8 years)  5 years of follow-up  Primary outcome:Macro and Microvascular event  Baseline HbA1c:7.5%  End point HbA1c:6.5% vs 7.3% N Engl J Med 2008;358:2560-72.
  • 17. ADVANCE study N Engl J Med 2008;358:2560-72.
  • 18. VADT study  investigators in the Veterans Affairs Diabetes Trial  1791 military veterans (type 2 DM history:11.5 years)  5.6 years follow-up  Primary outcome:CVD event  Baseline HbA1c:9.4%  End point HbA1c:6.9% vs 8.4%
  • 19. META-ANALYSIS  UKPDS  ACCORD  ADVANCE  VADT Diabetologia (2009) 52:2288–2298
  • 20. Intensive Glucose Control  Lowering Macrovascular outcomes  Longer follow up  Early intervention (Legacy effect)  Meta - Analysis  Lowering Microvascular outcomes  QOL improve  Early intervention
  • 21. Revisiting the links between glycaemia, diabetes and cardiovascular disease Diabetologia (2013) 56:686–695
  • 22. Emergency Hospitalization for Adverse Drug Events in Older Americans N Engl J Med 2011;365:2002-12.
  • 23. Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes Diabetes Care 36:894–900, 2013  Taiwan Data base (10 years)  PAI-FENG HSU MD
  • 24. Hypoglycemia  ADVANCE group  Severe Hypoglycemia and Risks of Vascular Events and Death N Engl J Med 2010;363:1410-8. BMJ 2010;340:b4909
  • 25. Hypoglycemia – a major predictor of cardiovascular death in VADT http://spo.escardio.org/eslides/view.aspx?ee vtid=48&fp=3914
  • 26. Hypoglycemia & Arrhythmia Diabetes Care Volume 37, January 2014
  • 27. Hypoglycemia  ORIGIN study  12537 IFG, IGT, Type 2 DM patients  Insulin Glargine vs. Standard care  Follow 6.2 years  End point HbA1c:6.3% vs 6.5% N Engl J Med 2012;367:319-28. European Heart Journal doi:10.1093/eurheartj/eht332
  • 28. Total mortality in ACCORD Diabetes Care 33:983–990, 2010
  • 29. UKPDS 34 (Metformin)  Multicenter RCT  753 Overweight type 2 DM patients (New diagnosed )  Intensive (Metformin) vs. Conventional  Follow 10 years  End point HbA1c: 7.4% vs 8.0% 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Any DM related End point DM related death All-cause mortality Myocardial Infraction End point (Metformin) HR = 0.68 (0.53-0.87) HR = 0.58 (0.37-0.91) HR = 0.64 (0.45-0.91) HR = 0.61 (0.41-0.89) HR = 0.58 (0.37-0.91) HR = 0.64 (0.45-0.91) HR = 0.61 (0.41-0.89) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Any DM related End point DM related death All-cause mortality Myocardial Infraction End point (SU/Insulin) 0 0.5 1 1.5 2 2.5 Stroke Peripheral vascular disease Microvascular disease End point (Metformin) Lancet 1998; 352: 854–65
  • 30. Metformin 使用限制  GI upset (20-30%)  Chronic Heart Failure  Creatinine > 1.5 mg/dL in males & >1.4mg/dL in females  Radiologic Contrast study for 48 hr after
  • 31. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study  10,920 hospitalised for first time HF with DM  Observational time:2.5 years Diabetologia (2010) 53:2546–2553
  • 32. Creatinine ??  Metformin Maxium dose:3000 mg  eGFR > 30 mL/min per 1.73 m2  Metformin  eGFR > 60:Safe  eGFR 60-45:Increase Creatinine monitor frequence  eGFR 45-30:Half dose initially  eGFR < 30:Stop Metformin Diabetes Care 2011; 34: 1431-7. • ADA • EASD • NICE • Diabetes Australia • CDA • JDS • NKF KDOQI
  • 33. Sulfonylurea  Association of sulfonylurea treatment with all-cause and cardiovascular mortality:A systematic review and meta-analysis of observational studies  20 studies (n = 551,912 patients)  SU vs non-SU Sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1479164112465442
  • 34. Sulfonylurea  Retrospective nationwide cohort study  Danmark  1997-2006  9876 users of GLDs admitted with MI Cardiovascular Diabetology 2010, 9:54
  • 35. European Heart Journal (2011) 32, 1900–1908
  • 36. Data From the CPRD  New analysis reported at the EASD meeting,  UK Clinical Practice Research Datalink (CPRD)  More than 10 million patients  SU vs Metformin (Monotherapy) European Association for the Study of Diabetes. Abstracts 200 and 201, presented Thursday, September 26, 2013. All-cause mortality 1000 person-years Metformin 13.6 death Sulfonylurea 44.6 death
  • 37. Sulfonylurea receptor  Sulfonylurea Receptor-1  Sulfonylurea Receptor-2A J Am Coll Cardiol. 1998;31(5)950-956
  • 38. Acarbose  STOP-NIDDM  Acarbose vs. Placebo  IGT patient HR = 0.51(0.28-0.95) p=0.03 JAMA 2003; 290:486-494
  • 39. Alpha-glucosidase inhibitors for type 2 diabetes mellitus  It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes.  Conversely, they have a significant effect on glycemic control and insulin levels. DOI: 10.1002/14651858.CD003639.pub2
  • 40. Ace study  Multicentre, RCT  China & Hong Kong  7500 patients with CVD or IGT  Hu Dayi (Cardiology)  Pan Changyu (Endocrine)
  • 41. Thiazolidinedione  IGT Prevent to T2DM  Mono-therapy failure in T2DM  Pioglitazone  Rosiglitazone:DREAM, ADOPT, RECORD  Pioglitazone:PROACTIVE
  • 42. Rosiglitazone (DREAM)  The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial  Prevent IGT progress to Type 2 DM  5269 IFT or IGT patient HR = 0.40 (0.35-0.46) Increase BW = +2.2 kg (p<0.0001) The Lancet 2006 DOI:10.1016/S0140-6736(06)69420-8
  • 43. Rosiglitazone (ADOPT)  4360 patients Newly type 2 DM  Rosiglitazone, Metformin, Glyburide Edema:14.1% vs 7.2% vs 8.5% N Engl J Med 2006;355:2427-43.
  • 44. Dr. Steven Nissen
  • 45. Meta-Analysis of Rosiglitazone N Engl J Med 2007;356:2457-71.
  • 46. JAMA. 2007;298(10):1189-1195 Meta-Analysis of Rosiglitazone
  • 47. RECORD study N Engl J Med 2007;357:28-38.
  • 48. Pioglitazone (PROACTIVE)  PROspective pioglitAzone Clinical Trial In macroVascular Events  5238 patients with type 2 diabetes  primary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Lancet 2005; 366: 1279–89
  • 49. Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus A Meta-analysis of Randomized Trials JAMA. 2007;298(10):1180-1188
  • 50. Bladder Cancer of Pioglitazone News of 103.04.08
  • 51. Bladder Cancer of Pioglitazone Diabetes Care 34:916–922, 2011
  • 52. Bladder Cancer of Pioglitazone  Retrospective cohort study (Case-control analysis)  115,727 new users of oral hypoglycaemic agents BMJ 2012;344:e3645
  • 53. Bladder Cancer of Pioglitazone Study of Taiwanese  2006 - 2009  1,000,000 individuals were randomly sampled from the National Health Insurance database Diabetes Care 35:278–280, 2012
  • 54. Aleglitazar (PPAR α/γ Agonist) Late Breaking Clinical Trials – ACC 2014 Unpublished DATA
  • 55. SAVOR TIMI-53 N Engl J Med 2013;369:1317-26.
  • 56. EXAMINE N Engl J Med 2013;369:1327-35. Sattar N, Results from SAVOR and EXAMINE. DPP-4 inhibitors and CVD, EASD 2013 Sep 26
  • 57. Why we failure in DPP-4 inhibitor?? N Engl J Med 2013;369:1317-26. N Engl J Med 2013;369:1327-35.
  • 58. CV outcome trials of DPP-4 inhibitor & GLP-1 agonist Trial Name Drug Number of patients Publish date SAVOR Saxagliptin 16500 Online 2013/09 EXAMINE Alogliptin 5400 Online 2013/09 TECOS Sitagliptin 14500 2014 CAROLINA Linagliptin (vs SU) 6000 2018 EXSCEL Exenatide QW 9500 2018 LEADER Liraglutide 8754 2017
  • 59. CV outcome trials of SGLT-2 inhibitor Trial Name Drug Number of patients Publish date CANVAS Canagliflozin Ongoing DECLARE TIMI 58 Dapagliflozin Ongoing
  • 60. Summary  Half of T2DM patient died from Cardiovascular Events  DM patient’s MI risk was equal to post-MI patient  UKPDS 35 shows that HbA1c was a risk marker in T2DM  Intensive glucose control  Lowering Macrovascular outcomes  Longer follow up & Meta – Analysis  Lowering Microvascular outcomes  Early intervention  Risk maker relationship:BP > LDL > HbA1c
  • 61. Summary  Hypoglycemia was main reason of emergency Hospitalizated Adverse Drug event  Hypoglycemia link to poor CV outcomes in cohort studies, arrhythmia may be a main concern  Metformin is still First line choice of T2DM  eGFR may be better to limit Metformin use  Sulfonylurea increased risk of CV mortality & All-cause mortality (not included Gliclazide )  Acarbose remains unclear in T2DM, but could reduce CV risk in IGT or IFG patients
  • 62. Summary  TZD may prevented that IGT or IFG progress to T2DM, but increased HF risk  Rosiglitazone increased MI risk in Meta-analysis, but Pioglitazone didn’t  Bladder cancer may be a concern of Pioglitazone, but didn’t show in TW data  DPP-4 inhibitor was safe in CV outcomes, but not in HF hospitalization  Expect GLP-1 Agnoist & SGLT-2 Inhibitor

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