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- 4. • Almost everyone has heard the saying, “If you want to keep a friend, never talk about religion or politics.” In regard to the specific management of type 2 diabetes, we can alter this phrase somewhat and suggest, “If you want to keep a colleague, never talk about diabetes guidelines!” 06:02:07 DIABETES CARE, VOLUME 35, JUNE 2012 1201 為了保有同事情誼 不要討論糖尿病治療指引
- 5. IGT/IFG Diagnosed Type 2 Diabetes Diabetes Complications (CVD,ESRD) The progression of diabetes… 第 2 型糖尿病的不歸 路 ( 病人說：好像宣判死 刑 )
- 8. •糖尿病的藥物治療策略 1.依據證據醫學 ( 降血糖效果： A1C) 來選藥 2.依據病理生理學來矯正 3.Patient-Centered ADA-EASD Position Statement Management of Hyperglycemia in T2DM: A Patient-Centered Approach Diabetes Care April 2012
- 9. ADA consensus statement DCCT and UKPDS ： a strong correlation between mean A1C levels over time and the development and progression of retinopathy and nephropathy => it is reasonable to judge and compare blood glucose–lowering medications, as well as combinations of such agents, primarily on the basis of their capacity to decrease and maintain A1C levels and according to their safety, specific side effects, tolerability, ease of use, and expense. Diabetes Care 32:193–203, 2009 小血管病變的證據醫學：向 A1C 看齊
- 10. 快速有效
- 11. 薑是老的辣 • 2008 年第 68 屆美國 糖尿病學會 (ADA) 年會 最高科學獎 Banting 獎 ：美國德克薩斯大學 Ralph DeFronzo 教授 • American Diabetes Association's Most Prestigious Science Award
- 12. TZD, metfmormin Su, TZD, GLP-1, DPP-4 inhibitor TZD, metmormin TZD GLP-1, DPP-4 inhibitor GLP-1, DPP-4 inhibitor GLP-1, DPP- 4? Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
- 13. Lifestyle + Triple combination: TZD + Metformin + Exenatide A1C<6%A1C<6% Metformin ： insulin sensitivity 、 antiatherogenic effects ( 飯前 ) TZD ： insulin sensitivity 、 b-cell function 、 antiatherogenic effects ( 飯前 ) Exenatide ： b-cell function 、 weight loss ( 飯前、 後 ) 憑我數十年的功力 ，第 2 型糖尿病 這樣治療準沒錯 ~~
- 14. Lifestyle + Triple combination: TZD + Metformin + Exenatide A1C<6%A1C<6% Metformin ： insulin sensitivity 、 antiatherogenic effects ( 飯前 ) TZD ： insulin sensitivity 、 b-cell function 、 antiatherogenic effects ( 飯前 ) Exenatide ： b-cell function 、 weight loss ( 飯前、 後 )
- 16. 為何要 Patient-Centered Approach? • 致病機轉多重 ( 糖尿病是一群導致血糖上升的代 謝問題 ) • 病人狀況、病人意願差異大 –Age –Weight –Sex/racial/ethnic/genetic differences –Comorbidities •Coronary artery disease •Heart Failure •Chronic kidney disease •Liver dysfunction •Hypoglycemia
- 17. 糖尿病照護個人化 • 治療目標： Patient-Centered • 治療方式： Patient-Centered
- 18. 治療目標： Patient-Centered • Glycemic targets – HbA1c < 7.0% (mean PG ∼150-160 mg/dl [8.3- 8.9 mmol/l]) – Pre-prandial PG <130 mg/dl (7.2 mmol/l) – Post-prandial PG <180 mg/dl (10.0 mmol/l) – Individualization is key: • Tighter targets (6.0 - 6.5%) - younger, healthier • Looser targets (7.5 - 8.0%+) - older, co-morbidities, hypoglycemia prone, etc. – Avoidance of hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 PG = plasma glucose
- 19. Figure 1 Diabetes Care, Diabetologia. 19 April 2012 (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554) A1C 6-6.5% A1C 7.5-8%
- 21. 06:02:07
- 22. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle 個人化 (personalization) -Weight optimization -Healthy diet -Increased activity level Diabetes Care, Diabetologia. 19 April 2012 治療方式： Patient-Centered
- 23. 我們手上的武器 ANTI-HYPERGLYCEMIC THERAPY • Therapeutic options: Oral agents & non-insulin injectables - Metformin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibitors - GLP-1 receptor agonists - Meglitinides - α-glucosidase inhibitors - Bile acid sequestrants - Dopamine-2 agonists - Amylin mimetics Diabetes Care, Diabetologia. 19 April 2012
- 24. Pharmacology and Therapeutics 124 (2009) 113-138 明日之星 ? 明日之星 ? GLP-1 mimetics DPP-4 inhibitor
- 25. KEY POINTS • Glycemic targets & BG-lowering therapies must be individualized. • Diet, exercise, & education: foundation of any T2DM therapy program • Unless contraindicated, metformin = optimal 1st-line drug. • After metformin, data are limited. with 1-2 other oral / injectable agents is reasonable; minimize side effects. • Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control. • All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values.) • Comprehensive CV risk reduction - a major focus of therapy. Diabetes Care, Diabetologia. 19 April 2012 Combination therapy
- 26. A1C 6.5 – 7.5%** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI 3 2 - 3 Mos.*** 2 - 3 Mos.*** 2 - 3 Mos.*** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) 6 Symptoms INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely † Preferred initial agent 1 DPP4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑ PPG 2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3 AGI if ↑ PPG 4 Glinide if ↑ PPG or SU if ↑ FPG 5 Low-dose secretagogue recommended 6 a) Discontinue insulin secretagogue with multidose insulin b) Can use pramlintide with prandial insulin 7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 A1C 7.6 – 9.0% Dual Therapy 8 2 - 3 Mos.*** 2 - 3 Mos.*** Triple Therapy 9 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET † DPP4 1 GLP-1 TZD 2 AGI 3 Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
- 27. ADA-EASD Position Statement Management of Hyperglycemia in T2DM: A Patient-Centered Approach Diabetes Care April 2012 06:02:09 AM 27
- 28. • 血糖可以降最多 • 藥錢可以省最大 • 但是得承受 • 低血糖 • 體重增加 • 注射不便 省小錢、 花大錢 ? 健保沒錢 時
- 29. Adapted Recommendations: When Goal is to Avoid Weight Gain • 血糖還是可以降不少 • 藥錢會花很大 • 但是賺到 • 不會低血糖 • 不會體重增加 • 保護 島細胞胰 不想變胖胖 錢花的 不值 得值 ?
- 30. Adapted Recommendations: When Goal is to Avoid Hypoglycemia 不要低血 糖 •血糖還是可以降不少 •藥錢會花很大 •但是賺到 •不會低血糖 •保護 島細胞胰 錢花得值 不 得值 ? •TZD 增加體重、膀胱癌 (?)
- 31. Hazard Ratio (HR lower CL, HR upper CL) Hypoglycaemia – a major predictor of cardiovascular death in the VADT study Prior event HbA1c HDL Age 3.116 (1.744, 5567) 1.213 (1.038,1.417) 0.699 (0.536, 0.910) 2.090 (1.518, 2877) 120 2 4 6 8 10 P Value Hypoglycaemia 4.042 (1.449,11.276) Duckworth W.(VADT): results. 2008. Available from http://webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx? type=0&lid=3853, Accessed: 20 Oct 2009. <0.01 0.02 0.01 <0.01 0.01
- 32. 低血糖有多害 ? Desouza CV, et al. Diabetes Care. 2010; 33:1389–394
- 33. 低血糖後易再低血糖 Antecedent hypoglycemia Reduced sympathoadrenal responses to hypoglycemia Reduced sympathetic neural responses Hypoglycemia unawareness Defective glucose counter regulation Reduced epinephrine responses Antecedent exercise Sleep Recurrent hypoglucemia Cryer PE. J Clin Invest. 2006;116:1470–1473 hypoglycemia-associated autonomic failure (HAAF)
- 34. Metformin + other OADs 的降血糖效果 和低血糖風險 Adapted from: Phung, et al. JAMA. 2010;303(14):1410–1418
- 35. AACE 2010 Goals as priorities in the selection of medications • Inclusion of major classes of FDA-approved glycemic medication, including incretin-based therapies • Minimizing risk and severity of hypoglycemia • Minimizing risk and magnitude of weight gain • Consideration of both fasting and postprandial glucose levels as end points • In many cases, delaying pharmacotherapy to allow for lifestyle modifications is inappropriate because these interventions are usually not adequate • Consideration of total cost of therapy to the individual and society at large, including costs related to medications, glucose monitoring requirements, hypoglycemic events, drug-related adverse events, and treatment of diabetes-associated complications • The major cost is related to the treatment of the complications of diabetes. We believe that identification of the safest and most efficacious agents is essential.
- 36. 腸泌素治療藥物
- 37. 06:02:07
- 40. Incretin 效果 ~ 降 A1c
- 41. Incretin 效果 ~ 降空腹血糖
- 42. Incretin 效果 ~ 降體重
- 44. DPP-4i 間的差異 Clin Pharmacokinet 2012; 51 (8): 501-514
- 45. DPP-4 i 的安全性 Edema in meta-analyses Vascular Health and Risk Management 2011:7 49–57
- 46. DPP-4i + ACEI 要小心 angioedema 06:02:06
- 48. • Age: Older adults – Reduced life expectancy – Higher CVD burden – Reduced GFR – At risk for adverse events from polypharmacy – More likely to be compromised from hypoglycemia Less ambitious target HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety Less ambitious target HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety
- 49. 老人有沒有效？ a pooled analysis of five monotherapy trials comparing the effects of 24 weeks of vildagliptin treatment in younger (<65 years, n = 1231) and older (>65 years, n = 238) patients Diabetes Obes Metab. 2011;13:55–64.
- 50. 老人安不安全？ SYE-adj, subject year exposure-adjusted Hosp Pract (Minneap). 2011 Feb;39(1):7-21.
- 52. DPP-4i 增加 b-cell in rats 06:02:07
- 53. DPP-4i 改善 DM foot Exp Diabetes Res. 2012:892706. doi: 10.1155/2012/892706. Epub 2012 Nov 1. vascular endothelial growth factor
- 54. ischemia-induced neovascularization in normal and high glucose Giacco F , Brownlee M Circulation Research 2010;107:1058-1070
- 57. DPP-4i 治療在 type 1 DM 可能的角色 06:02:08
- 58. 再好的演講 也不該耽誤午睡時間 歡 迎 指 教
Notas del editor
- Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [ref 20]
- Fig. 2C should be considered when the goal is to minimize costs. This reflects prevailing costs in the North America and Europe in early 2012; costs of certain drugs may vary considerably from country to country and as generic formulations become available.
- Fig. 2A should be considered when the goal is to avoid hypoglycemia. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the risk of hypoglycemia when using the hidden agents will be, in part, dependent on the baseline degree of hyperglycemia, the treatment target, and the adequacy of patient education.
- Fig. 2B should be considered when the goal is to avoid weight gain. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the chances of weight gain when using the hidden agents will be mitigated by more rigorous adherence to dietary recommendations and optimal dosing.
- In the VADT study, hypoglycaemia, together with HbA 1c levels, HDL levels, age and a history of prior events, was a major predictor of cardiovascular mortality Reference: Duckworth W ( VADT): results. 2008. Available from http:// webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?type=0&lid=3853, Accessed: 20 Oct 2009.
- Hypoglycemic events may trigger inflammation by inducing the release of C-reactive protein (CRP), IL-6, and vascular endothelial growth factor (VEGF). Hypoglycemia also induces increased platelet and neutrophil activation. The sympathoadrenal response during hypoglycemia increases adrenaline secretion and may induce arrhythmias and increase cardiac workload. Underlying endothelial dysfunction leading to decreased vasodilation may also contribute to cardiovascular risk. Desouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care. 2010; 33: 1389-1394.
- Episodes of hypoglycemia, even asymptomatic episodes, impair defenses against subsequent hypoglycemia by causing hypoglycemia-associated autonomic failure (HAAF), the clinical syndromes of defective glucose counterregulation and hypoglycemia unawareness, and therefore a vicious cycle of recurrent hypoglycemia. The shift of the glycemic thresholds for sympathoadrenal responses to lower plasma glucose concentrations caused by recent antecedent hypoglycemia (or by sleep or prior exercise) could be the result of alterations in the peripheral afferent or efferent components of the autonomic nervous system or within the CNS. Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J. Clin. Invest. 2006;116:1470–1473
- Model of ischemia-induced neovascularization in normal and high glucose. A, In the presence of normal glucose concentration, ischemia-stabilized HIF-1α forms heterodimers with ARNT which bind the coactivator p300. This complex binds to the hypoxia response element (HRE) and activates expression of genes required for neovascularization. B, High glucose–induced methylglyoxal (MG) modifies HIF-1α and p300, inhibiting complex binding to the HREs of genes required for neovascularization. Data are from Thangarajah et al34 and Ceradini et al.35 (Illustration Credit: Ben Smith/Cosmocyte).