20130418 糖尿病治療策略


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  • 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).
  • 20130418 糖尿病治療策略

    1. 1. 糖尿病治療策略羅東博愛醫院 新陳代謝科陳煥文 醫師102.04.1806:02:06
    2. 2. 吃飯皇帝大、請細嚼慢嚥有餘力再請抬頭看幾張投影片
    3. 3. 為了保有同事情誼大家還是專心吃飯好了
    4. 4. • Almost everyone has heard the saying, “Ifyou want to keep a friend, never talk aboutreligion or politics.” In regard to thespecific management of type 2 diabetes,we can alter this phrase somewhat andsuggest, “If you want to keep a colleague,never talk about diabetes guidelines!”06:02:07DIABETES 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. 5. IGT/IFGDiagnosedType 2 DiabetesDiabetesComplications(CVD,ESRD)Theprogressionof diabetes…第 2 型糖尿病的不歸路( 病人說:好像宣判死刑 )
    6. 6. 控制血糖沒路用?我害了病人了嗎?
    7. 7. •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-CenteredADA-EASD Position StatementManagement of Hyperglycemia in T2DM: APatient-Centered ApproachDiabetes Care April 2012
    8. 8. ADA consensus statementDCCT and UKPDS : a strong correlationbetween mean A1C levels over time and thedevelopment and progression of retinopathy andnephropathy=> it is reasonable to judge and compare bloodglucose–lowering medications, as well ascombinations of such agents, primarily on thebasis of their capacity to decrease and maintainA1C levels and according to their safety, specificside effects, tolerability, ease of use, andexpense.Diabetes Care 32:193–203, 2009小血管病變的證據醫學:向 A1C 看齊
    9. 9. 快速有效
    10. 10. 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 DiabetesAssociations MostPrestigious Science Award
    11. 11. TZD,metfmorminSu, TZD, GLP-1,DPP-4 inhibitorTZD,metmorminTZDGLP-1, DPP-4inhibitorGLP-1, DPP-4inhibitorGLP-1, DPP-4?Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
    12. 12. Lifestyle + Triple combination:TZD + Metformin + ExenatideA1C<6%A1C<6%Metformin : insulin sensitivity 、 antiatherogeniceffects ( 飯前 )TZD : insulin sensitivity 、 b-cellfunction 、 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~~
    13. 13. Lifestyle + Triple combination:TZD + Metformin + ExenatideA1C<6%A1C<6%Metformin : insulin sensitivity 、 antiatherogeniceffects ( 飯前 )TZD : insulin sensitivity 、 b-cellfunction 、 antiatherogenic effects ( 飯前 )Exenatide : b-cell function 、 weight loss ( 飯前、後 )
    14. 14. 一次要吃那麼多藥是不是表示我的糖尿病很嚴重?
    15. 15. 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
    16. 16. 糖尿病照護個人化• 治療目標: Patient-Centered• 治療方式: Patient-Centered
    17. 17. 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 hypoglycemiaDiabetes Care, Diabetologia. 19 April 2012PG = plasma glucose
    18. 18. Figure 1Diabetes 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%
    19. 19. 06:02:07台灣糖尿病學會增加的項目
    20. 20. 06:02:07
    21. 21. ANTI-HYPERGLYCEMIC THERAPYTherapeutic options: Lifestyle 個人化 (personalization)-Weight optimization-Healthy diet-Increased activity levelDiabetes Care, Diabetologia. 19 April 2012治療方式: Patient-Centered
    22. 22. 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 mimeticsDiabetes Care, Diabetologia. 19 April 2012
    23. 23. Pharmacology and Therapeutics 124 (2009) 113-138明日之星?明日之星?GLP-1 mimeticsDPP-4 inhibitor
    24. 24. KEY POINTS• Glycemic targets & BG-lowering therapies must beindividualized.• Diet, exercise, & education: foundation of any T2DMtherapy program• Unless contraindicated, metformin = optimal 1st-linedrug.• After metformin, data are limited.with 1-2 other oral / injectable agents is reasonable;minimize side effects.• Ultimately, many patients will require insulin therapyalone / in combination with other agents to maintain BGcontrol.• All treatment decisions should be made in conjunctionwith the patient (focus on preferences, needs & values.)• Comprehensive CV risk reduction - a major focus oftherapy.Diabetes Care, Diabetologia. 19 April 2012Combination therapy
    25. 25. A1C 6.5 – 7.5%**MonotherapyMET +GLP-1 or DPP41TZD 2Glinide or SU 5TZD + GLP-1 or DPP4 1MET +ColesevelamAGI32 - 3 Mos.***2 - 3 Mos.***2 - 3 Mos.***Dual TherapyMET +GLP-1 orDPP4 1+TZD 2Glinide or SU 4,7A1C > 9.0%No SymptomsDrug Naive Under TreatmentINSULIN± OtherAgent(s) 6SymptomsINSULIN± OtherAgent(s) 6INSULIN± OtherAgent(s) 6Triple TherapyAACE/ACE Algorithm for GlycemicControl CommitteeCochairpersons:Helena W. Rodbard, MD, FACP, MACEPaul S. Jellinger, MD, MACEZachary T. Bloomgarden, MD, FACEJaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACEJames R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACEEdward S. Horton, MD, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACEStanley 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 agent1 DPP4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑ PPG2 TZD if metabolic syndrome and/ornonalcoholic fatty liver disease (NAFLD)3 AGI if ↑ PPG4 Glinide if ↑ PPG or SU if ↑ FPG5 Low-dose secretagogue recommended6 a) Discontinue insulin secretagoguewith multidose insulinb) Can use pramlintide with prandial insulin7 Decrease secretagogue by 50% when addedto GLP-1 or DPP-48 If A1C < 8.5%, combination Rx with agentsthat cause hypoglycemia should be used withcaution9 If A1C > 8.5%, in patients on Dual Therapy,insulin should be consideredMET +GLP-1or DPP4 1± SU 7TZD 2GLP-1or DPP4 1 ± TZD 2A1C 7.6 – 9.0%Dual Therapy 82 - 3 Mos.***2 - 3 Mos.***Triple Therapy 9INSULIN± OtherAgent(s) 6MET +GLP-1 or DPP41or TZD 2SU or Glinide 4,5MET +GLP-1or DPP4 1 + TZD 2GLP-1or DPP4 1+ SU 7TZD 2MET †DPP4 1 GLP-1 TZD 2AGI 3Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
    26. 26. ADA-EASD Position StatementManagement of Hyperglycemia in T2DM:A Patient-Centered ApproachDiabetes Care April 201206:02:09 AM 27
    27. 27. • 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
    28. 28. 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 ?
    29. 29. 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(?)
    30. 30. Hazard Ratio(HR lowerCL,HR upper CL)Hypoglycaemia – a major predictor ofcardiovascular death in the VADT studyPrior eventHbA1cHDLAge3.116 (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 10P ValueHypoglycaemia 4.042 (1.449,11.276)Duckworth W.(VADT): results. 2008. Available fromhttp://webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?type=0&lid=3853, Accessed: 20 Oct 2009.<<0.010.01
    31. 31. 低血糖有多害 ?Desouza CV, et al. Diabetes Care. 2010; 33:1389–394
    32. 32. 低血糖後易再低血糖AntecedenthypoglycemiaReduced sympathoadrenalresponses to hypoglycemiaReducedsympatheticneural responsesHypoglycemiaunawarenessDefective glucosecounter regulationReduced epinephrineresponsesAntecedentexerciseSleepRecurrenthypoglucemiaCryer PE. J Clin Invest. 2006;116:1470–1473hypoglycemia-associated autonomic failure (HAAF)
    33. 33. 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
    34. 34. AACE 2010Goals as priorities in the selection of medications• Inclusion of major classes of FDA-approved glycemicmedication, including incretin-based therapies• Minimizing risk and severity of hypoglycemia• Minimizing risk and magnitude of weight gain• Consideration of both fasting and postprandialglucose levels as end points• In many cases, delaying pharmacotherapy to allow for lifestylemodifications is inappropriate because these interventions are usually notadequate• Consideration of total cost of therapy to the individual andsociety at large, including costs related to medications, glucose monitoringrequirements, hypoglycemic events, drug-related adverse events, andtreatment of diabetes-associated complications• The major cost is related to the treatment of the complications of diabetes. Webelieve that identification of the safest and most efficacious agents is essential.
    35. 35. 腸泌素治療藥物
    36. 36. 06:02:07
    37. 37. Incretin therapy 比較06:02:07
    38. 38. Incretin 效果meta-analysis
    39. 39. Incretin 效果 ~ 降 A1c
    40. 40. Incretin 效果 ~ 降空腹血糖
    41. 41. Incretin 效果 ~ 降體重
    42. 42. DPP-4i 和其他抗糖尿病藥對體重影響輸贏贏
    43. 43. DPP-4i 間的差異Clin Pharmacokinet 2012; 51 (8): 501-514
    44. 44. DPP-4 i 的安全性Edema in meta-analysesVascular Health and Risk Management 2011:7 49–57
    45. 45. DPP-4i + ACEI 要小心angioedema06:02:06
    46. 46. Angioedema 的原因 ?06:02:06
    47. 47. • Age: Older adults– Reduced life expectancy– Higher CVD burden– Reduced GFR– At risk for adverse events from polypharmacy– More likely to be compromised fromhypoglycemia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
    48. 48. 老人有沒有效?a pooled analysis of five monotherapy trials comparing the effects of 24 weeksof vildagliptin treatment in younger (<65 years, n = 1231) and older (>65 years, n= 238) patientsDiabetes Obes Metab. 2011;13:55–64.
    49. 49. 老人安不安全?SYE-adj, subject year exposure-adjustedHosp Pract (Minneap). 2011 Feb;39(1):7-21.
    50. 50. DPP 4i 與糖尿病有關的議題06:02:07
    51. 51. DPP-4i 增加 b-cell in rats06:02:07
    52. 52. DPP-4i 改善 DM footExp Diabetes Res. 2012:892706. doi: 10.1155/2012/892706. Epub 2012 Nov 1.vascular endothelial growth factor
    53. 53. ischemia-induced neovascularizationin normal and high glucoseGiacco F , Brownlee M Circulation Research 2010;107:1058-1070
    54. 54. DPP-4 inhibitor 對心血管的保護作用06:02:08
    55. 55. DPP-4i 治療在 type 1 DM 可能的角色06:02:08
    56. 56. 再好的演講也不該耽誤午睡時間歡 迎 指 教