慢性照護模式 THE CHRONIC CARE MODEL 104年12月18日鄭泰春主任.

慢性照護模式 THE CHRONIC CARE MODEL 104年12月18日鄭泰春主任

第一章改善提升照護的策略建議以病患為中心的溝通模式考慮病患的喜好評估識字及算數能力重視文化差異造成照護的障礙治療的決策應及時
第一章改善提升照護的策略建議以病患為中心的溝通模式考慮病患的喜好評估識字及算數能力重視文化差異造成照護的障礙治療的決策應及時以實證醫學為基準依個案之意願預後及共病症予以客製化個別化的修定醫療決策照護應依循慢性照護模式 (CCM)之要件以確保已被充分告知主動活耀之病患與已做好充分準備積極前瞻的執業團隊之間建設性的互動如果可以照護體系應支持團隊照護、結合社區、註冊及提供病患決策所需工具

目前慢性疾病照護的缺失不足 Those deficiencies in current management of diseases include
醫療執業人員草率的未依已建立之準則 Rushed practitioners not following established practice guidelines 照護缺乏協調整合 Lack of care coordination 未主動追蹤以確保達成最佳成效 Lack of active follow-up to ensure the best outcomes 病患未被妥切教育訓練以管理其疾病 Patients inadequately trained to manage their illnesses

模式之六大基礎項目 Model Elements
The Chronic Care Model (CCM) identifies the essential elements of a health care system that encourage high-quality chronic disease care. These elements are 健康照護體系 the health system 照護輸送設計 delivery system design 決策之支持 decision support 臨床資訊系統 clinical information systems. 自我管理之支持 self-management support 社區 the community Evidence-based change concepts under each element, in combination, foster productive interactions between informed patients who take an active part in their care and providers with resources and expertise.

慢性照護模式由來與發展 Development of the Chronic Care Model
1990 1997 1998 2003 five additional themes were incorporated into the CCM 後續增加之議題: 病患安全 Patient Safety (in Health System); 文化智能Cultural competency (in Delivery System Design); 照護整合 Care coordination (in Health System and Clinical Information Systems) 社區政策Community policies (in Community Resources and Policies); 個案管理 Case management (in Delivery System Design).

健康體系 Health System 明顯可見地在組織各層面支持改革提升,並由資深領導人開始重視推動有效的改善策略聚焦在全面的體系的改變
在健康體系內建構一種文化組織架構與機轉以提升安全與高品質的照護明顯可見地在組織各層面支持改革提升,並由資深領導人開始重視推動有效的改善策略聚焦在全面的體系的改變鼓勵開放的、系統性的處理錯誤及品質問題以改善照護成效在照護品質的提升上予以激勵誘導發展促進組織內部及組織間照護整合之共識健康體系 Health System

輸送系統設計 Delivery System Design
確保有效果且有效率之臨床照護及提供自我管理之支持明定組織成員之角色責任並分配工作任務運用有計畫的內部互動機制以支持以實證醫學為基礎之照護對複雜度高之病患提供臨床個案照護管理服務確認照護團隊有定期追蹤管理提供病患能理解並符合並其文化背景之照護服務

決策支援 Decision Support 依據實證醫學並以病患為優先之照護以提升臨床診療成效實證醫學準則融入日常臨床診療
依據實證醫學並以病患為優先之照護以提升臨床診療成效實證醫學準則融入日常臨床診療與病患分享實證醫學之準則與資訊以鼓勵病患參與運用證明有效的教育方法給照護提供者整合專科之專業與基層醫療

臨床資訊系統 Clinical Information Systems
整理分析病患個人及族群資料加速有效率有成效之照護提供及時警示提醒予照護者及病患發現高危險群予主動提前照護推動個別化之照護計畫分享資訊予病患及照護者以協調調整照護方式監控執行團隊及整體照護系統之表現

自我健康管理支持 Self-Management Support
賦能並為病患做好自我健康管理及健康照護之準備強調病患在健康照護管理上之中心角色運用有效之自我照護支持策略包括評估、目標設定、行動計畫、問題解決與後續追蹤組織內部及社區資源以提供支持病患之自我照護

社區 The Community 鼓勵病患參與社區有效益之活動與社區組織成為夥伴關係以支持發展出病患所需之服務缺口
啟動社區資源以補強病患所需鼓勵病患參與社區有效益之活動與社區組織成為夥伴關係以支持發展出病患所需之服務缺口提倡支持提升改善病患照護之政策(2003 update)

103年十大死因

Diabetes Mellitus in the US: Health Impact of the Disease 糖尿病對健康的衝擊
6th leading cause of death 死亡 (第5位) Renal failure* 腎衰竭(第1位) Life expectancy to 10 yr 壽命 Blindness*眼盲(第1位) Diabetes Cardiovascular disease 2X to 4X 心血管疾病 Nerve damage in 60% to 70% of patients 神經損害 Amputation*截肢(第1位) *Diabetes is the no. 1 cause of renal failure, new cases of blindness, and nontraumatic amputations Diabetes Statistics. October 1995 (updated 1997). NIDDK publication NIH Harris MI. In: Diabetes in America. 2nd ed. 1995:1-13. 18

Causes of Death Among People With Diabetes 糖尿病患死因
% of Deaths Ischemic heart disease 缺血性心臟病 Other heart disease 其他心臟病 Diabetes (acute complications) 糖尿病 Cancer 癌症 Cerebrovascular disease 腦中風 Pneumonia/influenza 肺炎 All other causes 其他 40 15 13 10 4 5 Geiss LS et al. In: Diabetes in America. 2nd ed. 1995: 19

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY降血糖治療 Glycemic targets 血糖控制目標糖化血色素HbA1c < 7.0% (mean PG  mg/dl [ mmol/l]) 飯前Pre-prandial PG <130 mg/dl (7.2 mmol/l) 飯後Post-prandial PG <180 mg/dl (10.0 mmol/l) 個別化Individualization is key: 嚴格Tighter targets ( %) - younger, healthier 寬鬆Looser targets ( %+) - older, comorbidities, hypoglycemia prone, etc. 避免低血糖Avoidance of hypoglycemia PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Figure 1 病患態度期望低血糖其他不良反應罹病時間預期剩餘壽命重大合併症已產生血管病併發症資源支持系統
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] 重大合併症已產生血管病併發症資源支持系統 Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554) 21 21

3. ANTI-HYPERGLYCEMIC THERAPY降血糖治療 Therapeutic options: Lifestyle 生活型態 Weight optimization 體重 Healthy diet 飲食 Increased activity level活動量 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options 藥物選擇: Oral agents & non-insulin injectables 口服及非胰島素注射劑 Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Bile acid sequestrants Dopamine-2 agonists Amylin mimetics Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Relative Risk for Type 2 Diabetes in US Men by Family History
51,529 male health professionals. 家族史 Yes No Relative Risk for Type 2 Diabetes in US Men by Family History These data are from The Health Professionals Follow-up Study of 51,529 male health professionals. To assess dietary patterns, a 131-item food-frequency questionnaire was administered in 1986, 1990, and Using factor analysis based on data from these questionnaires, two major dietary patterns, “prudent” and “western”, were validated. A prudent diet was characterized by the consumption of more vegetables, fruit, fish, poultry, and whole grains. A western diet was characterized by a higher consumption of red meat, processed meat, french fries, high-fat dairy, refined grains, and sweets and desserts. The relative risk of type 2 diabetes in the cohort based on quintile of the western dietary pattern score was then determined. The relative risk for type 2 diabetes was lowest in the quintile with the lowest western dietary pattern score and highest in quintile 5 with the highest western dietary pattern score. Across all quintiles the relative risk of type 2 diabetes was significantly greater if there was a family history of diabetes than if there was not. Reference: van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136(3): Family History Quintile 1 Quintile 2-4 Quintile 5 Quintile of Western Dietary Pattern Score西化飲食量表 van Dam RM, et al. Ann Intern Med. 2002;136: ©2002 ACP-ASIM. Reprinted with permission. 24

Relative Risk for Type 2 Diabetes in US Men by BMI
51,529 male health professionals. 身體質量指數 Relative Risk for Type 2 Diabetes in US Men by BMI These data are from The Health Professionals Follow-up Study of 51,529 male health professionals. To assess dietary patterns, a 131-item food-frequency questionnaire was administered in 1986, 1990, and Using factor analysis based on data from these questionnaires, two major dietary patterns, “prudent” and “western”, were validated. A prudent diet was characterized by the consumption of more vegetables, fruit, fish, poultry, and whole grains. A western diet was characterized by a higher consumption of red meat, processed meat, french fries, high-fat dairy, refined grains, and sweets and desserts. The relative risk of type 2 diabetes in the cohort based on quintile of the western dietary pattern score was then determined. The relative risk for type 2 diabetes was lowest in the quintile with the lowest western dietary pattern score and highest in quintile 5, with the highest western dietary pattern score. Across all quintiles of western but not prudent dietary pattern score, the relative risk of type 2 diabetes in these US male health professionals increased as the body mass index increased. Reference: van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med Feb 5;136(3): >30 25-29 <25 BMI, kg/m2 Quintile 1 Quintile 2-4 Quintile 5 Quintile of Western Dietary Pattern Score 西化飲食量表 van Dam RM, et al. Ann Intern Med. 2002;136: ©2002 ACP-ASIM. Reprinted with permission. 25

Relative Risk for Type 2 Diabetes in US Men by Age
51,529 male health professionals. 年齡 Relative Risk for Type 2 Diabetes in US Men by Age These data are from The Health Professionals Follow-up Study of 51,529 male health professionals. To assess dietary patterns, a 131-item food-frequency questionnaire was administered in 1986, 1990, and Using factor analysis based on data from these questionnaires, two major dietary patterns, “prudent” and “western”, were validated. A prudent diet was characterized by the consumption of more vegetables, fruit, fish, poultry, and whole grains. A western diet was characterized by a higher consumption of red meat, processed meat, french fries, high-fat dairy products, refined grains, and sweets and desserts. The relative risk of type 2 diabetes in the cohort based on quintile of the western dietary pattern and the prudent dietary pattern scores was then determined. The relative risk for type 2 diabetes increased from the lowest to the highest quintile of western dietary pattern score but was not significantly different across the quintiles of prudent dietary pattern score. Across all quintiles of western dietary pattern score participants 65 years old were at increased risk of type 2 diabetes compared to those 65 years old. Reference: van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136(3): >65 <65 Age Quintile 1 Quintile 2-4 Quintile 5 Quintile of Western Dietary Pattern Score 西化飲食量表 van Dam RM, et al. Ann Intern Med. 2002;136: ©2002 ACP-ASIM. Reprinted with permission. 26

英國前膽性糖尿病研究證實 (UKPDS*) HbA1C 每降低 1 % 便能明顯減少慢併症之發生
小血管病變糖尿病因死亡心肌梗塞所有病因死亡 *UKPDS: the United Kingdom prospective diabetes study Adapted from the UKPDS results are from an epidaemiological analysis 27 27

Relative Risk for Type 2 Diabetes in US Men by Physical Activity Level
51,529 male health professionals. 活動量 Relative Risk for Type 2 Diabetes in US Men by Physical Activity Level These data are from The Health Professionals Follow-up Study of 51,529 male health professionals. To assess dietary patterns, a 131-item food-frequency questionnaire was administered in 1986, 1990, and Using factor analysis based on data from these questionnaires, two major dietary patterns, “prudent” and “western”, were validated. A prudent diet was characterized by the consumption of more vegetables, fruit, fish, poultry, and whole grains. A western diet was characterized by a higher consumption of red meat, processed meat, french fries, high-fat dairy products, refined grains, and sweets and desserts. The relative risk of type 2 diabetes in the cohort based on quintile of the western dietary pattern score was then determined. The relative risk for type 2 diabetes was lowest in the quintile with the lowest western dietary pattern score and highest in quintile 5 with the highest western dietary pattern score. When segregated by quintile of self-reported physical activity (lowest physical activity is quintile 1), the relative risk of diabetes based on the western dietary pattern score was increased further in those who participated in little or no physical activity. It is also apparent from these data that physical activity alone does not completely offset the increased relative risk of type 2 diabetes associated with eating foods that are high in saturated fats and refined sugars. Reference: van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136(3): Quintile 1 Quintile 2-4 Quintile 5 Physical Activity Quintile 1 Quintile 2-4 Quintile 5 Quintile of Western Dietary Pattern Score 西化飲食量表 van Dam RM, et al. Ann Intern Med. 2002;136: ©2002 ACP-ASIM. Reprinted with permission. 28

Clinical Impact of Diabetes Mellitus 糖尿病的衝擊
二-四倍第一名第一名第一名 A 2- to 4- fold increase in cardiovascular mortality 心血管疾病 Clinical Impact of Diabetes Mellitus The leading cause of new cases of end stage renal disease 腎衰竭 The leading cause of new cases of blindness in working- aged adults 視力喪失 The leading cause of nontraumati c lower extremity amputations 截肢 29

Causes of Death in People With Diabetes糖尿病患死因
Percent of deaths 缺血性心臟病其他心藏病糖尿病惡性腫瘤腦中風所有其他肺炎 Causes of Death in People With Diabetes Based on data collected from 4 cohort studies in the US conducted between 1965 and 1988, it was determined that the leading causes of death listed on the death certificates of persons with diabetes were diseases of the heart (55%), diabetes (13%), malignant neoplasms (13%), and cerebrovascular disease (10%). Despite variation in the way underlying cause of death was classified, the proportion of persons dying from these causes was similar across the 4 studies. Geiss et al also found that the risk of heart disease mortality and ischemic heart disease mortality was 2 to 4 times higher in persons with diabetes than in persons without diabetes. For persons with diabetes, the excess risk of dying from heart disease and ischemic heart disease was higher than the excess risk of mortality for all other causes combined. While the studies may not have distinguished between insulin-dependent diabetes and non-insulin-dependent diabetes (NIDDM), it was assumed that the diabetes deaths were NIDDM deaths because of the older age of the populations and the increased prevalence of NIDDM in older age groups. Reference: Geiss LS, Herman WH, Smith PJ. Mortality in Non-Insulin-Dependent Diabetes. In: National Diabetes Data Group, eds. Diabetes in America. 2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995. Diabetes All other Other heart disease Malignant neoplasms Pneumonia/ influenza Cerebrovascular disease Ischemic heart disease 4 cohort stuy US Geiss LS, et al. In: Diabetes in America. National Institutes of Health;1995. 30

OASIS Study Mortality by Diabetes and CVD Status 依糖尿病及心臟病有無之死亡率
Diabetes/CVD (n=1,148) RR=2.88 ( ) RR=1.99 ( ) No Diabetes/CVD (n=3,503) Diabetes/No CVD (n=569) RR=1.71 ( ) No Diabetes/No CVD (n=2,796) RR=1.00 糖尿病沒心血管病糖尿病+心血管病 Event rate 心血管病沒糖尿病沒糖尿病沒心血管病 OASIS Study Mortality by Diabetes and CVD Status Data from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry were analyzed to determine the 2-year prognosis of diabetic and nondiabetic patients who were hospitalized with unstable angina or non–Q-wave myocardial infarction. Outcomes that were studied included total mortality, cardiovascular death, new myocardial infarction, stroke, and new congestive heart failure. A total of 1,718 of the 8,013 registry patients had diabetes (21%). Because patients with diabetes were more likely to have established cardiovascular disease (CVD) at baseline, stratified analyses were performed according to prior CVD and diabetes status. The 2-year mortality rate for diabetic patients was 20.3% for those with prior CVD compared to 13.0% for those without prior CVD. For patients without diabetes, the rate was 12.9% for those with prior CVD compared to 6.9% for those without prior CVD. The P value was <0.001 for a comparison of patients with and without diabetes within the 2 CVD strata. Diabetic patients without prior CVD had the same event rates for total mortality, and all other outcomes, as nondiabetic patients with previous CVD. The CV death rate for diabetic patients with prior CVD was 16.6% compared to 9.3% for those without prior CVD. For patients without diabetes, the rate was 10.5% for those with prior CVD compared to 5.1% for those without prior CVD. The P value was also <0.001 for a comparison of patients with and without diabetes within the 2 CVD strata. Reference: Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation. 2000;102(9): 1718/8013 3 6 9 12 15 18 21 24 Months OASIS=Organization to Assess Strategies for Ischemic Syndromes CVD=cardiovascular disease RR=relative risk (95% confidence intervals) Malmberg K, et al. Circulation. 2000;102: 31

Relative Risk for Type 2 Diabetes in US Men by Age
51,529 male health professionals. 年齡 Relative Risk for Type 2 Diabetes in US Men by Age These data are from The Health Professionals Follow-up Study of 51,529 male health professionals. To assess dietary patterns, a 131-item food-frequency questionnaire was administered in 1986, 1990, and Using factor analysis based on data from these questionnaires, two major dietary patterns, “prudent” and “western”, were validated. A prudent diet was characterized by the consumption of more vegetables, fruit, fish, poultry, and whole grains. A western diet was characterized by a higher consumption of red meat, processed meat, french fries, high-fat dairy products, refined grains, and sweets and desserts. The relative risk of type 2 diabetes in the cohort based on quintile of the western dietary pattern and the prudent dietary pattern scores was then determined. The relative risk for type 2 diabetes increased from the lowest to the highest quintile of western dietary pattern score but was not significantly different across the quintiles of prudent dietary pattern score. Across all quintiles of western dietary pattern score participants 65 years old were at increased risk of type 2 diabetes compared to those 65 years old. Reference: van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136(3): >65 <65 Age Quintile 1 Quintile 2-4 Quintile 5 Quintile of Western Dietary Pattern Score 西化飲食量表 van Dam RM, et al. Ann Intern Med. 2002;136: ©2002 ACP-ASIM. Reprinted with permission. 39

7-Year Incidence of Fatal and Nonfatal MI 致命及非致命性心肌梗塞發生率
Incidence rate (%) 45 % 20 % 19 % 4% 7-Year Incidence of Fatal and Nonfatal MI In this study of 1,373 nondiabetic and 1,059 diabetic subjects, the 7-year incidence of fatal and nonfatal myocardial infarction (MI) was examined to determine whether patients with diabetes who have not had MI should be treated as aggressively for cardiovascular (CV) risk factors as patients who have had MIs. In both diabetic and non-diabetic subjects, a history of MI at baseline was significantly associated with an increased incidence of MI during 7 years of follow-up. These data suggest that diabetic patients without previous MI have the same risk of MI as non-diabetic patients with previous MI. Reference: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4): No Prior MI* No Prior MI* Prior MI Prior MI Nondiabetic Diabetic 1,373 nondiabetic (n=1,373) (n=1,059) 1,059 diabetic *At baseline MI=myocardial infarction P<0.001 for prior MI vs. no prior MI and for diabetes vs. no diabetes Haffner SM, et al. N Eng J Med. 1998;339: 45

Increased Risk of CV Events Over 7 years in Type 2 Diabetics 心血管事件發生率
Myocardial Infarction Stroke CV Death 腦中風無糖尿病 & 無心肌梗塞 (n=1,304) 心血管病因死亡 Incidence rate (%) 心肌梗塞糖尿病 & 無心肌梗(n=890) 無糖尿病 & 心肌梗塞 (n=69) P<0.001* 糖尿病 & 心肌梗塞 (169) P<0.001* P<0.001* Increased Risk of CV Events Over 7 Years in Type 2 Diabetics In this study of 1,373 nondiabetic and 1,059 diabetic subjects, the 7-year incidence of fatal and nonfatal myocardial infarction (MI) was examined to determine whether patients with diabetes who have not had MIs should be treated as aggressively for cardiovascular (CV) risk factors as patients who have had MIs. In both diabetic and non-diabetic subjects, a history of MI at baseline was significantly associated with an increased incidence of MI during 7 years of follow-up. Further, a history of MI at baseline was also associated with an increased incidence of stroke and death from CV causes. Reference: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4): -MI=no prior myocardial infarction/+MI=prior myocardial infarction CV=cardiovascular *For diabetes vs. no diabetes and prior MI vs. no prior MI 1,373 nondiabetic 1,059 diabetic Haffner SM, et al. N Engl J Med. 1998;339: 46

Presence of CVD and Increased Mortality心血管疾病之有無與死亡率
1,000-person years Death rate per 68.7 Normal 正常 IGT 葡萄糖耐受不良 Diabetic 糖尿病 53.7 40 41.3 30.7 24.4 17.8 Diabetes (n=1,343), IGT (n=1,433), normal (n=2,421) 12.8 Presence of CVD and Increased Mortality The purpose of this study was to evaluate the relation of patients with subclinical cardiovascular disease (CVD), diabetes, and impaired glucose tolerance, and normal subjects and the risk of clinical CVD. Diabetes (n=1,343), impaired glucose tolerance (n=1,433), and normal (n=2,421) were defined by World Health Organization criteria. Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. All-cause mortality was strongly associated with diabetes (P=0.001). The relative risk of death associated with the presence of diabetes and clinical disease was 5.3 (95% CI 3.9 to 7.2) and was 2.3 (95% CI 1.7 to 3.2) for diabetes and subclinical disease compared to death not associated with diabetes or subclinical disease. Reference: Kuller LH, Velentgas P, Barzilay J, Beauchamp NJ, O'Leary DH, Savage PJ. Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Arterioscler Thromb Vasc Biol. 2000;20(3): 9.8 No Subclinical CVD Subclinical CVD Clinical CVD CVD=cardiovascular disease IGT=Impaired glucose tolerance Kuller LH, et al. Arterioscler Thromb Vasc Biol. 2000;20: With permission from Lippincott Williams & Wilkins. 47

7-Year Incidence of Fatal and Nonfatal MI 致命及非致命性心肌梗塞發生率
Incidence rate (%) 45 % 20 % 19 % 4% 7-Year Incidence of Fatal and Nonfatal MI In this study of 1,373 nondiabetic and 1,059 diabetic subjects, the 7-year incidence of fatal and nonfatal myocardial infarction (MI) was examined to determine whether patients with diabetes who have not had MI should be treated as aggressively for cardiovascular (CV) risk factors as patients who have had MIs. In both diabetic and non-diabetic subjects, a history of MI at baseline was significantly associated with an increased incidence of MI during 7 years of follow-up. These data suggest that diabetic patients without previous MI have the same risk of MI as non-diabetic patients with previous MI. Reference: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4): No Prior MI* No Prior MI* Prior MI Prior MI Nondiabetic Diabetic 1,373 nondiabetic (n=1,373) (n=1,059) 1,059 diabetic *At baseline MI=myocardial infarction P<0.001 for prior MI vs. no prior MI and for diabetes vs. no diabetes Haffner SM, et al. N Eng J Med. 1998;339: 49

Increased Risk of CV Events Over 7 years in Type 2 Diabetics 心血管事件發生率
Myocardial Infarction Stroke CV Death 腦中風無糖尿病 & 無心肌梗塞 (n=1,304) 心血管病因死亡 Incidence rate (%) 心肌梗塞糖尿病 & 無心肌梗(n=890) 無糖尿病 & 心肌梗塞 (n=69) P<0.001* 糖尿病 & 心肌梗塞 (169) P<0.001* P<0.001* Increased Risk of CV Events Over 7 Years in Type 2 Diabetics In this study of 1,373 nondiabetic and 1,059 diabetic subjects, the 7-year incidence of fatal and nonfatal myocardial infarction (MI) was examined to determine whether patients with diabetes who have not had MIs should be treated as aggressively for cardiovascular (CV) risk factors as patients who have had MIs. In both diabetic and non-diabetic subjects, a history of MI at baseline was significantly associated with an increased incidence of MI during 7 years of follow-up. Further, a history of MI at baseline was also associated with an increased incidence of stroke and death from CV causes. Reference: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4): -MI=no prior myocardial infarction/+MI=prior myocardial infarction CV=cardiovascular *For diabetes vs. no diabetes and prior MI vs. no prior MI 1,373 nondiabetic 1,059 diabetic Haffner SM, et al. N Engl J Med. 1998;339: 50

Presence of CVD and Increased Mortality心血管疾病之有無與死亡率
1,000-person years Death rate per 68.7 Normal 正常 IGT 葡萄糖耐受不良 Diabetic 糖尿病 53.7 40 41.3 30.7 24.4 17.8 Diabetes (n=1,343), IGT (n=1,433), normal (n=2,421) 12.8 Presence of CVD and Increased Mortality The purpose of this study was to evaluate the relation of patients with subclinical cardiovascular disease (CVD), diabetes, and impaired glucose tolerance, and normal subjects and the risk of clinical CVD. Diabetes (n=1,343), impaired glucose tolerance (n=1,433), and normal (n=2,421) were defined by World Health Organization criteria. Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. All-cause mortality was strongly associated with diabetes (P=0.001). The relative risk of death associated with the presence of diabetes and clinical disease was 5.3 (95% CI 3.9 to 7.2) and was 2.3 (95% CI 1.7 to 3.2) for diabetes and subclinical disease compared to death not associated with diabetes or subclinical disease. Reference: Kuller LH, Velentgas P, Barzilay J, Beauchamp NJ, O'Leary DH, Savage PJ. Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Arterioscler Thromb Vasc Biol. 2000;20(3): 9.8 No Subclinical CVD Subclinical CVD Clinical CVD CVD=cardiovascular disease IGT=Impaired glucose tolerance Kuller LH, et al. Arterioscler Thromb Vasc Biol. 2000;20: With permission from Lippincott Williams & Wilkins. 51

Multivariate Relative Risk of Fatal CHD in Women* 女性致命性心血管疾病之危險因子
Nurses’ Health Study 121,046 women aged 30 to 55 11.9 Multivariate Relative Risk of Fatal CHD in Women This study involved a prospective analysis of the impact of type 2 diabetes and history of prior CHD on mortality in 121,046 women aged 30 to 55 with type 2 diabetes in the Nurses’ Health Study. Among this cohort, the risk of CHD mortality increased monotonically with increased duration of diabetes.The age-adjusted relative risks of fatal CHD increased from 2.75 to 11.9 in women with diabetes for 5 or fewer years compared to those with diabetes for more than 25 years, respectively (P<0.001 for trend). The relative risk of fatal CHD for those with prior CHD compared to those without prior CHD was 5.29. Reference: Hu FB, Stampfer MJ, Solomon CG, Liu S, Willett WC, Speizer FE, Nathan DM, Manson JE. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med. 2001;161(14): 5.49 6.38 5.51 3.63 2.75 1 1 No DM 5 6-10 11-15 16-25 >25 No prior CHD Prior CHD Duration of diabetes, y 罹患糖尿病的時間 CHD=coronary heart disease DM=diabetes mellitus *P<0.001 for trend across categories of duration Hu FB, et al. Arch Intern Med. 2001;161: Copyright ©2001, American Medical Association. 52

Multivariate Relative Risk
Multivariate Relative Risk* of Fatal CHD in Women With and Without History of CHD 女性致死性心血管疾病之危險性 30.0 Women without history of CHD無心血管病史 Relative risk Women with history of CHD 心血管病史 Nurses’ Health Study 121,046 women aged 30 to 55 15.4 13.1 11.0 8.61 8.66 Multivariate Relative Risk of Fatal CHD in Women With and Without History of CHD This study involved a prospective analysis of the impact of type 2 diabetes and history of prior CHD on mortality in 121,046 women aged 30 to 55 with type 2 diabetes in the Nurses’ Health Study. Among this cohort, the risk of CHD mortality increased monotonically with increased duration of diabetes.The age-adjusted relative risks of fatal CHD increased from 2.75 to 11.9 in women with diabetes for 5 or fewer years compared to those with diabetes for more than 25 years, respectively (P<0.001 for trend). The relative risk of fatal CHD for those with prior CHD compared to those without prior CHD was 5.29. The increased risk of fatal CHD with increased duration of diabetes was apparent in women with and without diabetes. For women without a history of CHD, the presence of diabetes for 15 or more years was associated with a similar risk of fatal CHD. Women with diabetes for 15 or more years had a relative risk of 30 for fatal CHD. Reference: Hu FB, Stampfer MJ, Solomon CG, Liu S, Willett WC, Speizer FE, Nathan DM, Manson JE. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med. 2001;161(14): 7.59 4.24 1 3.07 No diabetes 5 6-10 11-15 >15 Duration of diabetes, y CHD=coronary heart disease *P<0.001 for trend across categories of duration Hu FB, et al. Arch Intern Med. 2001;161: Copyright ©2001, American Medical Association. 53

CVD mortality/ 1,000 person years
Age-Adjusted CVD Mortality by Quintile* of Fasting Serum Triglyceride (mmol/l) 三酸甘油脂與心血管因死亡率 Men Women * * CVD mortality/ 1,000 person years Age-Adjusted CVD Mortality by Quintile of Fasting Serum Triglyceride In this study of 4,743 participants in the World Health Organization Multi-National Study of Vascular Disease in Diabetes (WHO MSVDD), the association between classic cardiovascular risk factors and diabetes-specific risk factors and the incidence of fatal and non-fatal cardiovascular disease outcomes was determined. The relation between CVD mortality and quintiles of fasting serum triglyceride was positive for both type 2 diabetic men (P=0.001 for trend) and women (P= for trend). Reference: Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: the WHO Mutinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44[Suppl 2]:S54-64. Q1 Q2 Q3 Q4 Q5 Q1 Q2 Q3 Q4 Q5 CVD=cardiovascular disease *P<0.01 compared to Q1 Q1<1.10; Q2= ; Q3= ; Q4= ; Q5>2.94. 4,743 DM Fuller JH, et al. Diabetologia. 2001;44[suppl2]:S54-S64. Copyright ©2001, Springer-Verlag. Reprinted with permission. 54

CHD Incidence by HbA1c Levels in Elderly Type 2 Diabetics 老年糖尿病患者 A1C 與心血管疾病發生率
CHD death CHD death and nonfatal MI † * Incidence (%) CHD Incidence by HbA1c Levels in Elderly Type 2 Diabetics This study of 1,069 nondiabetic and 229 type 2 diabetic subjects sought to evaluate whether non-insulin-dependent diabetes (NIDDM) and its metabolic control and duration predict coronary heart disease (CHD) events during a 3.5 year follow-up in a population of 65 to 74 year-olds. During follow-up. 3.4% of nondiabetic and 14.8% of diabetic subjects died from CHD or had a non-fatal myocardial infarction. The risk of CHD death and all CHD events was considerably higher in type 2 diabetic subjects with HbA1c 7.0% compared with those with HbA1c <7.0%. For subjects with HbA1c 7.0%, compared with those with HbA1c <7.0%, the odds ratios for CHD death and all CHD events were 4.3 [95% CI, ] and 2.2 [95% CI, ], respectively. Reference: Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes. 1994;43(8): Low <6% Middle 6%-7.9% High >7.9% Low <6% Middle 6%-7.9% High >7.9% HbA1c tertile HbA1c tertile CHD=coronary heart disease MI=myocardial infarction *P<0.01 compared with lowest tertile; †P<0.05 compared with lowest tertile 1,069 nondiabetic 229 type 2 diabetic 65 to 74 year-olds Kuusisto J, et al. Diabetes. 1994;43:960–967. Copyright ©1994, American Diabetes Association. Reprinted with permission. 55

Impact of Diabetes on Cardiovascular Mortality in MRFIT 糖尿病與心血管疾病死亡率
Mortality per 10,000 person years Nondiabetic (n=342,815) Diabetic (n=5,163) 347,978 men Impact of Diabetes on Cardiovascular Mortality in MRFIT A total of 347,978 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were studied to assess predictors of cardiovascular disease (CVD) mortality among men with and without diabetes, and to assess the effect of diabetes on CVD death. Participants were 35 to 57 years old. The outcome measure was CVD mortality. To evaluate the effects of 3 CV risk factors, serum cholesterol, systolic blood pressure, and reported number of cigarettes smoked per day, participants were grouped into 8 strata for comparison: level of serum cholesterol <200 or 200 mg/dL; SBP <120 or 120 mmHg, and also <140 and 140 mmHg; and cigarette use or no cigarette use. CVD death rates for those with and without diabetes were compared according to the presence of 1, 2, or 3 of these risk factors. The relative risk for CVD death in participants with none of the risk factors was 5.10 for diabetics compared to nondiabetics. With all 3 risk factors, the relative risk for CVD death was 2.64 for diabetics compared to nondiabetics. Reference: Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16(2): Number of risk factors* 危險因子數目 Copyright ©1993 American Diabetes Association from Diabetes Care, Vol. 16, 1993; Reprinted with permission from The American Diabetes Association. MRFIT=Multiple Risk Factor Intervention Trial *Risk factors analyzed: smoking抽菸, hypercholesterolemia高膽固醇, and hypertension高血壓. 56

Systolic BP and CV Death in MRFIT 血壓與心血管死亡率
Nondiabetic (n=342,815) CV mortality rate per 10,000 person-years Diabetic (n=5,163) 347,978 men Systolic BP and CV Death in MRFIT A total of 347,978 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were studied to assess predictors of cardiovascular disease (CVD) mortality among men with and without diabetes and to assess the effect of diabetes on CVD death. Participants were 35 to 57 years old. The outcome measure was CVD mortality. To evaluate the effects of 3 CV risk factors, serum cholesterol, systolic blood pressure, and reported number of cigarettes smoked per day, participants were grouped into 8 strata for comparison: level of serum cholesterol <200 or 200 mg/dL; SBP <120 or 120 mmHg, and also <140 and 140 mmHg; and cigarette use or no cigarette use. CVD death rates for those with and without diabetes were compared according to the presence of 1, 2, or 3 of these risk factors. The relative risk for CVD death in participants with none of the risk factors was 5.10 for diabetics compared to nondiabetics. With all 3 risk factors, the relative risk for CVD death was 2.64 for diabetics compared to nondiabetics. Systolic blood pressure was positively related to CVD death risk with a significant trend in both diabetics and nondiabetics (P<0.001). For men with diabetes, CVD death rates increased from 53.6 to deaths per 10,000 person years, and from 12.2 to in those without diabetes. As with serum cholesterol and cigarette smoking, at every level of SBP the CVD death rate was greater for diabetic compared to nondiabetic men. Reference: Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16(2): <120 200 Systolic BP (mmHg) BP= blood pressure CV=cardiovascular MRFIT=Multiple Risk Factor Intervention Trial Stamler J, et al. Diabetes Care. 1993;16: 57

Incidence of MI and Microvascular Endpoints by Mean SBP and HbA1c in UKPDS
Myocardial infarction Myocardial infarction Adjusted incidence per 1000 person-years (%) Adjusted incidence per 1000 person-years (%) Incidence of MI and Microvascular Endpoints by Mean SBP and HbA1c in UKPDS In the UK Prospective Diabetes Study (UKPDS) reported by Adler et al, the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes was considered. Rates for both myocardial infarction and microvascular endpoints were strongly associated, to a similar degree, with increasing systolic blood pressure. Each 10 mmHg decrease in updated mean systolic blood pressure was associated with reductions of risk of 11% for myocardial infarction (14% to 7%, P<0.0001), and 13% for microvascular complications (16% to 10%, P<0.0001). In the UKPDS study reported by Stratton et al, the relation between exposure to glycemia over time and the risk of microvascular or macrovascular complications in patients with type 2 diabetes was considered. The incidence of clinical complications was associated significantly with glycemia. Each 1% reduction in updated mean HbA1c was associated with reductions in risk of 14% for myocardial infarction (21% to 8%, P<0.0001), and 37% for microvascular complications (41% to 33%, P<0.0001). References: Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321(7258): Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258): Microvascular endpoints Microvascular endpoints 110 120 130 140 150 160 170 5 6 7 8 9 10 11 Mean SBP (mmHg) Updated mean HbA1c concentration (%) MI=myocardial infarction SBP=systolic blood pressure Adler AI, et al. BMJ. 2000;321: Stratton IM, et al. BMJ. 2000;321: Reprinted with permission from the BMJ Publishing Group. 35 , 36 58

Diabetes Increases Hypertension-Related Cardiovascular Risk: MRFIT 血壓提高心血管疾病之危險性
Nondiabetic Men (n = 342,815) Diabetic Men (n = 5,163) Cardiovascular Mortality Rate per 10,000 Person-Years Diabetes Increases Hypertension-Related Cardiovascular Risk: MRFIT Among a total of 347,978 men screened for the Multiple Risk Factor Intervention Trial (MRFIT), those participants who were between the ages of 35 to 57 years at the initial screening were studied to assess predictors of cardiovascular disease (CVD)-related mortality and to assess the effect of diabetes on CVD-related death. The CVD-related death rates for diabetic and nondiabetic men were compared according to the presence of the following risk factors: serum cholesterol level ≥200 mg/dL, systolic blood pressure ≥140 mm Hg, and cigarette use. The relative risk for CVD death among participants who did not have the risk factors was 5.10 for those who were diabetic when compared to those who were not diabetic. When all 3 risk factors were present, the relative risk for CVD death was 2.64 for participants who were diabetic when compared to those who were not. Systolic blood pressure was positively related to CVD death risk, with a significant trend observable in both diabetic and nondiabetic participants (P < 0.001). The CVD death rates increased from 53.6 to deaths per 10,000 person-years in men who were diabetic and from 12.2 to in those who were not. As with serum cholesterol and cigarette smoking, the CVD death rate was greater at every level of systolic blood pressure for men who were diabetic when compared to those who were not. Reference: Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16: <120 120139 140159 160179 180199 ≤200 Systolic Blood Pressure (mm Hg) MRFIT = Multiple Risk Factor Intervention Trial 347,978 men Stamler J, et al. Diabetes Care. 1993;16: 59 59

Parving HH et al. Am J Kidney Dis 1993; 22: 188-95
糖尿病腎病變與高血壓：即使未使用ACEI/ARB，降低血壓就能減緩腎功能的惡化及降低蛋白尿。 Parving HH et al. Am J Kidney Dis 1993; 22: 60 60

嚴密的血壓控制比血糖控制更重要 (UKPDS)
Stroke Any Diabetic Endpoint DM Deaths Microvascular Complications 5% 10% 12% -10 -20 24% % Reduction In Relative Risk * 32% 32% -30 * 37% *P <0.05 compared to tight glucose control * -40 44% Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL) Tight BP Control (Average 144/82 mmHg) * -50 Bakris GL, et al. Am J Kidney Dis. 2000;36(3): 61 61

Survival (all-cause mortality)
Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes 蛋白尿為糖尿病死亡之危險因子 1.0 Normoalbuminuria (n=191) 0.9 Microalbuminuria (n=86) 0.8 Survival (all-cause mortality) 存活率 0.7 Macroalbuminuria (n=51) 0.6 Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes In this study, the impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 non-insulin-dependent diabetic patients followed for 5 years. During follow-up, 51 patients died (16%). A total of 18 out of 51 patients with macroalbuminuria died (35%) compared to 17 out of 86 with microalbuminuria (20%), and 16 out of 191 with normoalbuminuria (8%). Reference: Gall MA, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving HH. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;44(11): 0.5 1 2 3 4 5 6 P< normoalbuminuria vs microalbuminuria P<0.001 normoalbuminuria vs macroalbuminuria P< microalbuminuria vs macroalbuminuria Years 328 type 2 diabetic For 5 years. Gall MA, et al. Diabetes. 1995;44: Copyright ©1995, American Diabetes Association. Reprinted with permission. 62

Proteinuria and Hypertension in Type 2 Diabetes 蛋白尿高血壓與糖尿病死亡率之關係
Standardized mortality ratio Status of Proteinuria (P) and Hypertension (H) in Type 2 Diabetics Proteinuria and Hypertension in Type 2 Diabetes In this stratified random sample of 4,714 diabetic patients in the World Health Organization Multinational Study of Vascular Disease in Diabetes (WHO MSVDD), the relationship between excess mortality and proteinuria/hypertension was examined. Standardized mortality ratios (SMRs) for type 2 diabetic patients (n=3,448) were similar for men and women. Compared with the background population, type 2 diabetic patients with both hypertension and proteinuria experienced high excess mortality: 5-fold for men and 8-fold for women. Patients with only proteinuria tended to have higher SMRs than those with only hypertension. SMRs were in general higher for patients with type 1 diabetes. Reference: Wang SL, Head J, Stevens L, Fuller JH. Excess mortality and its relation to hypertension and proteinuria in diabetic patients. The world health organization multinational study of vascular disease in diabetes. Diabetes Care Apr;19(4): -P-H +P-H -P-H +P-H -P+H +P+H -P+H +P+H Men Women 4,714 diabetic Wang SL, et al. Diabetes Care. 1996;19: Copyright ©1996, American Diabetes Association. Reprinted with permission. 63

降血糖A1C的益處腦中風心肌梗塞心衰竭白內障摘除小血管病變心血管併發症截肢及致命性末稍血管疾病

同時合併糖尿病與慢性腎臟病急性心肌梗塞腦中風末梢血管病變死亡

嚴格控制血壓可減緩腎功能惡化蛋白尿惡化 Cr 上昇兩倍 BUN上昇兩倍

嚴密控制血壓所產生的明顯效益與糖尿病相關的死亡全部的死亡腦中風心肌梗塞微蛋白尿

口服降血糖藥與腎功能惡化

3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options 治療的選擇: Oral agents & non-insulin injectables 口服藥及非胰島素針劑 Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Bile acid sequestrants Dopamine-2 agonists Amylin mimetics Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages Cost
Biguanides Activates AMP-kinase  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low SUs / Meglitinides Closes KATP channels  Insulin secretion  Microvasc. risk Hypoglycemia Weight gain Low durability ? Ischemic preconditioning TZDs PPAR-g activator  insulin sensitivity Durability  TGs,  HDL-C ?  CVD (pio) Edema / heart failure Bone fractures ?  MI (rosi) ? Bladder ca (pio) High a-GIs Inhibits a-glucosidase Slows carbohydrate absorption Nonsystemic  Post-prandial glucose ?  CVD events Dosing frequency Modest  A1c Mod. Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

DPP-4 inhibitors Inhibits DPP-4 Increases GLP-1, GIP No hypoglycemia Well tolerated Modest  A1c ? Pancreatitis Urticaria High GLP-1 receptor agonists Activates GLP-1 R  Insulin,  glucagon  gastric emptying  satiety Weight loss ? Beta cell mass ? CV protection GI Medullary ca Injectable Amylin mimetics Activates amylin receptor  glucagon  PPG Hypo w/ insulin Dosing frequency Bile acid sequestrants Bind bile acids  Hepatic glucose production Nonsystemic  Post-prandial glucose  CVD events Dopamine-2 agonists Activates DA receptor Modulates hypothalamic control of metabolism  insulin sensitivity No hypoglyemia ?  CVD events Dizziness/syncope Nausea Fatigue Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

嚴密控制血壓所產生的明顯效益與糖尿病相關的死亡全部的死亡腦中風心肌梗塞微蛋白尿

口服降血糖藥與腎功能惡化

3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options 治療的選擇: Oral agents & non-insulin injectables 口服藥及非胰島素針劑 Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Bile acid sequestrants Dopamine-2 agonists Amylin mimetics Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Biguanides Activates AMP-kinase  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low SUs / Meglitinides Closes KATP channels  Insulin secretion  Microvasc. risk Hypoglycemia Weight gain Low durability ? Ischemic preconditioning TZDs PPAR-g activator  insulin sensitivity Durability  TGs,  HDL-C ?  CVD (pio) Edema / heart failure Bone fractures ?  MI (rosi) ? Bladder ca (pio) High a-GIs Inhibits a-glucosidase Slows carbohydrate absorption Nonsystemic  Post-prandial glucose ?  CVD events Dosing frequency Modest  A1c Mod. Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

DPP-4 inhibitors Inhibits DPP-4 Increases GLP-1, GIP No hypoglycemia Well tolerated Modest  A1c ? Pancreatitis Urticaria High GLP-1 receptor agonists Activates GLP-1 R  Insulin,  glucagon  gastric emptying  satiety Weight loss ? Beta cell mass ? CV protection GI Medullary ca Injectable Amylin mimetics Activates amylin receptor  glucagon  PPG Hypo w/ insulin Dosing frequency Bile acid sequestrants Bind bile acids  Hepatic glucose production Nonsystemic  Post-prandial glucose  CVD events Dopamine-2 agonists Activates DA receptor Modulates hypothalamic control of metabolism  insulin sensitivity No hypoglyemia ?  CVD events Dizziness/syncope Nausea Fatigue Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Insulin Activates insulin receptor  peripheral glucose uptake Universally effective Unlimited efficacy  Microvascular risk Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements “Stigma” Variable Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

DPP-4 代謝途徑

降血糖製劑降血糖以外之效用 Endocrinology Update

3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin 胰島素 - Neutral protamine Hagedorn (NPH) - Regular - Basal analogues (glargine, detemir) - Rapid analogues (lispro, aspart, glulisine) - Pre-mixed varieties Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin 胰島素 Rapid (Lispro, Aspart, Glulisine) Short (Regular) Insulin level Intermediate (NPH) Diagrammatic representation of the approximate pharmacokinetic properties of various insulin formulations. Long (Detemir) Long (Glargine) lantus Hours Hours after injection 105 105

3. ANTI-HYPERGLYCEMIC THERAPY Implementation strategies執行之策略: Initial therapy 初期 Advancing to dual combination therapy兩種合併 Advancing to triple combination therapy三種合併 Transitions to & titrations of insulin 轉換為胰島素 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Guidelines for Glycemic, BP, & Lipid Control ABC準則
American Diabetes Assoc. Goals HbA1C糖化血色素 < 7.0% (individualization個別化) Preprandial glucose飯前血糖 mg/dL Postprandial glucose飯後血糖 < 180 mg/dL Blood pressure血壓 < 130/80 mmHg Lipids血脂肪 LDL低密度膽固醇: < 100 mg/dL < 70 mg/dL (with overt CVD) HDL高密度膽固醇: > 40 mg/dL > 50 mg/dL TG三酸甘油脂: < 150 mg/dL Avoiding ‘glucocentricity’ is key in the comprehensive management of the patient with T2DM. Cardiovascular risk factor reduction must incorporate blood pressure and lipid control, in addition to, where indicated, anti-platelet therapy. HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides. ADA. Diabetes Care. 2012;35:S11-63 143

Metabolic Staging of Type 2 Diabetes
Peripheral insulin resistance Hyperinsulinemia Impaired glucose tolerance Defective glucorecognition Early diabetes b-cell failure Late diabetes Saltiel AR, Olefsky JM. Diabetes. 1996;45: 3 144 3

Pathophysiology of Type 2 Diabetes 二型糖尿病致病機轉
Peripheral Tissues (Muscle) Receptor + postreceptor defects 接受體障礙 Insulin Resistance 胰島素阻抗 Glucose Liver Increased glucose production 葡萄糖糖製造增加 Pancreas Impaired insulin secretion 胰島素分泌功能不良 Saltiel AR, Olefsky JM. Diabetes. 1996;45: 1 145 1

Main Pathophysiological Defects in T2DM
? gut carbohydrate delivery & absorption incretin effect pancreatic insulin secretion + - pancreatic glucagon secretion HYPERGLYCEMIA peripheral glucose uptake hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 146

Insulin Resistance Type 2 diabetes糖尿病 Other associated conditions 其他狀況
Aging老化 Genetics 基因胰島素阻抗 Other conditions其他: acromegaly Cushing’s disease lipodystrophy anti-insulin receptors Obesity肥胖/ sedentary lifestyle 活動缺乏 Olefsky JM. In: Endocrinology. 2nd ed. 1989: Reaven GM. Clinical Diabetes. 1994;12: Seely BL, Olefsky JM. In: Insulin Resistance. 1993: 2 147 2

Insulin Resistance: Definition 胰島素阻抗定義
Condition in which greater than normal amounts of insulin are required to produce a normal biological response 胰島素量需增加以達正常生理反應之狀態 Olefsky JM. In: Ellenberg and Rifkin’s Diabetes Mellitus. 5th ed. 1997: 148

DCCT: Risk of Sustained Retinopathy Progression by HbA1c Level and Years of Follow-up眼底病變
24 Mean HbA1c = 11% 10% 9% 20 16 Rate Per 100 Person-Years 12 8% 8 7% 4 1 2 3 4 5 6 7 8 9 Time During Study (yr) DCCT Research Group. Diabetes. 1995;44: 4 149 4

達成治療目標的比例 Patients (%) Intensive† therapy Conventional‡ therapy 80
10 20 30 40 50 60 70 80 Intensive† therapy Conventional‡ therapy Patients (%) HbA1c TC TG SBP DBP <6.5% <175 mg/dL <150 mg/dL <130 mm Hg <80 mm Hg P=0.06 P<0.001 P=0.19 P=0.21 P=0.001 150 150

Steno-2:發生心血管病變之案件數 130 DM + Microalbuminuria
85 CVD events in 35 ’conventional’ patients 33 CVD events in 19 ’intensive’ patients Number of events Myocardial infarction PCI or CABG Vascular surgery CVD death Stroke Amputation 經皮冠狀動脈擴張術繞道術 Intensive Conventional

Multifactorial Intervention and CV Events in Type 2 Diabetes: Steno-2
7.8年發生所有心血管事件之比較傳統治療 Multifactorial Intervention and CV Events in Type 2 Diabetes: Steno-2 In the Steno-2 Study, intensive, target-driven therapy aimed at multiple risk factors reduced the risk of cardiovascular events by about 50% in patients with type 2 diabetes and microalbuminuria. This slide shows Kaplan-Meier estimates of the composite study endpoint, which consisted of nonfatal myocardial infarction, death from cardiovascular causes, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, and surgery for peripheral atherosclerotic artery disease. The divergence of the curves suggests that continued intensive therapy may have resulted in an even better prognosis. A course of conventional therapy was completed by 63 patients while 67 patients completed intensive therapy, which consisted of stepped administration of behavior modification (diet, exercise) and pharmacologic therapy that targeted hyperglycemia (oral hypoglycemic agents, insulin), hypertension (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II-receptor blockers, diuretics, calcium-channel blockers, b-blockers), dyslipidemia (statins, fibrates), microalbuminuria, and cardiovascular risk (aspirin). Mean age of all patients in the study was 55 years and mean follow-up was 7.8 years. There were 118 cardiovascular events during follow-up; 85 events in 35 conventionally treated patients and 33 events in 19 intensively treated patients. Nephropathy developed in 31 conventionally treated patients and in 16 intensively treated patients, retinopathy in 51 conventionally treated patients and in 38 intensively treated patients, and neuropathy in 43 conventionally treated patients and in 24 intensively treated patients. Compared with the conventionally treated group, the risk ratios for the intensive-therapy group were 0.47 for cardiovascular disease, 0.39 for nephropathy, 0.42 for retinopathy, and 0.37 for neuropathy. Gaede P et al. N Engl J Med. 2003;348: 積極治療 152

認真治療7.8年後續觀察5.5年的結果

Steno-2: Percentage of Patients at Treatment Goals at End of Study
研究結束時達成治療目標的比例 Steno-2: Percentage of Patients at Treatment Goals at End of Study 130 DM + Microalbuminuria Steno-2: Percentage of Patients at Treatment Goals at End of Study Intensified multifactorial intervention, which consists of tight glucose regulation and the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents, has been demonstrated to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes and microalbuminuria. Gaede et al evaluated whether intensified multifactorial intervention influences the rates of death from any cause and from cardiovascular causes. As part of the Steno-2 study, 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80). The mean treatment period was 7.8 years. A total of 130 patients (67 with intensive therapy; 63 with conventional therapy) completed the treatment period. Subsequently, patients were observed for a mean of 5.5 years. A total of 93 patients (55 with intensive treatment; 38 with conventional therapy) reached the end of the observational follow-up period. At 13.3 years of follow-up, the primary endpoint was the time to death from any cause. This figure shows the percentage of patients in each group who reached the treatment goals for the intensive-therapy group at the end of the study. Overall, risk factors for the two groups tended to converge during the follow-up period and were similar after 13.3 years. There were no significant differences between the percentage of patients in each group who achieved specific treatment goals regarding A1C, cholesterol, and systolic and diastolic blood pressure. However, a significantly greater percentage of patients in the intensive-therapy group compared with the conventional-therapy group reached the triglyceride goal (P=0.005). In this study, intensive intervention with multiple drug combinations and behavior modification provided sustained benefits with regard to rates of death from any cause as well as rates of death from cardiovascular causes. Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, intensive therapy, treatment goals, A1C 154

Steno-2: Effect of Multifactorial Intervention on Various CV Events in Type 2 Diabetes
研究13.3 年發生心血管疾病的案件數 130 DM + Microalbuminuria Steno-2: Effect of Multifactorial Intervention on Various CV Events in Type 2 Diabetes In the Steno-2 study, 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80). Intensive therapy consisted of multiple drug combinations and behavior modification. Patients were observed for a total mean period of 13.3 years (mean treatment period, 7.8 years; mean observational follow-up period, 5.5 years). This figure shows the number of events for each component of the composite endpoint. During the 13.3-year study period, there were 51 events among 25 patients in the intensive-therapy group and 158 events among 48 patients in the conventional-therapy group. The mean number of major cardiovascular events was 0.6 with intensive therapy and 2.0 with conventional therapy. The number of events in each category was greater for conventional therapy than for intensive therapy. Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, cardiovascular events, intensive therapy, treatment, stroke, MI 155

積極介入對死亡率之影響 130 DM + Microalbuminuria

Key words: Steno-2, mortality, intensive therapy, treatment
Steno-2: Effect of Multifactorial Intervention on Mortality in Type 2 Diabetes 積極介入對死亡率之影響 130 DM + Microalbuminuria 年 Steno-2: Effect of Multifactorial Intervention on Mortality in Type 2 Diabetes A total of 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80) in the Steno-2 study. The mean treatment period was 7.8 years, and patients were subsequently observed for a mean of 5.5 years. The primary endpoint at 13.3 years of follow-up was the time to death from any cause. As depicted in this Kaplan-Meier curve, there were significantly fewer deaths in the intensive-therapy group than in the conventional-therapy group (24 [30%] vs 40 [50%] deaths; hazard ratio, 0.54; 95% confidence interval, 0.32 to 0.89; P=0.02) by the end of the 13.3-year follow-up period. There was an absolute risk reduction for death from any cause of 20% among patients who received intensive therapy versus those who received conventional therapy. In at-risk patients with type 2 diabetes, earlier intensive intervention with multiple drug combinations and behavior modification provided sustained carryover benefits with regard to rates of death from any cause. Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, mortality, intensive therapy, treatment 157

Steno-2: Effect of Multifactorial Intervention on Diabetic Neuropathies
自主神經病變之惡化神經病變之惡化 Steno-2: Effect of Multifactorial Intervention on Diabetic Neuropathies In the Steno-2 study, 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80). Intensive therapy consisted of multiple drug combinations and behavior modification. Patients were observed for a total mean period of 13.3 years (mean treatment period, 7.8 years; mean observational follow-up period, 5.5 years). During the entire observation period, autonomic neuropathy progressed in a significantly lower number of patients in the intensive-therapy group than in the conventional-therapy group (39 vs 52 patients, respectively; relative risk [RR], 0.53; 95% confidence interval [CI], 0.34–0.81; P=0.004). Peripheral neuropathy progressed in a similar number of patients in the intensive-therapy and conventional-therapy groups (44 vs 46 patients, respectively; RR, 0.97; 95% CI, 0.62–1.51; P=0.89). Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, intensive therapy, treatment, neuropathy 158

Steno-2: Effect of Multifactorial Intervention on Diabetic Complications
神經病變之發生眼底病變 Steno-2: Effect of Multifactorial Intervention on Diabetic Complications In the Steno-2 study, 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80). Intensive therapy consisted of multiple drug combinations and behavior modification. Patients were observed for a total mean period of 13.3 years (mean treatment period, 7.8 years; mean observational follow-up period, 5.5 years). During the entire observation period, diabetic nephropathy developed in a significantly lower number of patients in the intensive therapy group than in the conventional-therapy group (20 vs 37 patients, respectively; relative risk [RR], 0.44; 95% confidence interval [CI], 0.25–0.77; P=0.004). Progression of diabetic retinopathy occurred in a significantly lower number of patients in the intensive-therapy group than in the conventional-therapy group (41 vs 54 patients, respectively; RR, 0.57; 95% CI, 0.37–0.88; P=0.01). Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, intensive therapy, treatment, neuropathy, retinopathy 159

Steno-2: Effect of Multifactorial Intervention on CV Events in Type 2 Diabetes
發生任一心血管事件之危險比差距 29% Steno-2: Effect of Multifactorial Intervention on CV Events in Type 2 Diabetes A total of 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80) in the Steno-2 study. The mean treatment period was 7.8 years, and patients were subsequently observed for a mean of 5.5 years. This Kaplan-Meier curve shows the cumulative incidence of a secondary composite endpoint of cardiovascular (CV) events, including death from CV causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention, revascularization for peripheral atherosclerotic artery disease, and amputation. After a total mean follow-up period of 13.3 years, intensive therapy was associated with a significant 29% absolute risk reduction for CV events (hazard ratio, 0.41; 95% confidence interval, 0.25 to 0.67; P<0.001). There was no indication that the hazard ratio changed after the formal treatment period (P=0.20). Therefore, earlier intensive intervention with multiple drug combinations and behavior modification provided sustained carryover benefits with respect to CV complications in at-risk patients with type 2 diabetes. Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, cardiovascular events, intensive therapy, treatment, CV complications 160

Steno-2: Effect of Multifactorial Intervention on CV Events in Type 2 Diabetes
發生任一心血管事件之危險比差距 29% Steno-2: Effect of Multifactorial Intervention on CV Events in Type 2 Diabetes A total of 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80) in the Steno-2 study. The mean treatment period was 7.8 years, and patients were subsequently observed for a mean of 5.5 years. This Kaplan-Meier curve shows the cumulative incidence of a secondary composite endpoint of cardiovascular (CV) events, including death from CV causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention, revascularization for peripheral atherosclerotic artery disease, and amputation. After a total mean follow-up period of 13.3 years, intensive therapy was associated with a significant 29% absolute risk reduction for CV events (hazard ratio, 0.41; 95% confidence interval, 0.25 to 0.67; P<0.001). There was no indication that the hazard ratio changed after the formal treatment period (P=0.20). Therefore, earlier intensive intervention with multiple drug combinations and behavior modification provided sustained carryover benefits with respect to CV complications in at-risk patients with type 2 diabetes. Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Key words: Steno-2, cardiovascular events, intensive therapy, treatment, CV complications 182

所有死亡率心血管事件視網膜增生腎臟病

急性心肌梗塞腦中風末稍血管病變死亡

重要的腰圍

Atherosclerosis

Anatomic Changes Microanerysms
Damage to endothelial cells leads to dilated capillaries and venules These altered vessels allow serum and blood to leak into the retina

慢性照護模式 THE CHRONIC CARE MODEL 104年12月18日鄭泰春主任.

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慢性照護模式 THE CHRONIC CARE MODEL 104年12月18日鄭泰春主任.

Presentation on theme: "慢性照護模式 THE CHRONIC CARE MODEL 104年12月18日鄭泰春主任."— Presentation transcript: