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1 糖尿病與心血管疾病雲林基督教醫院心臟內科陳雅珮

3 危險性糖尿病 = 冠心病冠心病是糖尿病人最常見的合併症及死亡原因

4 糖尿病的慢性併發症死亡率上升!!!

5 22-year mortality rates in people with and without diabetes in the baseline NHANES I study First National Health and Nutrition Examination Survey (NHANES1) Diabetes Care 1998;21(7):

6 The most common cause of death among patients with diabetes is cardiovascular disease ~70% Diabetes Care 1998;21(7):

7 Hazard ratio (1.4, 95% CI ) for death from CHD for groups 1 & 4 were similar suggesting similar risks of infarction in the two groups. * p < 0.001

8 A 7-year risk of myocardial infarction in middle-aged patients with diabetes was 20%, similar to that of patients with a previous myocardial infarction.

9 國人 DM 的大血管併發症盛行率 : 30% - 週邊血管疾病盛行率 : 10-15% - 中風盛行率 : 7.5% Type 1 DM 及 type 2 DM 的死亡主因 : 冠狀動脈疾病 - DM 死於冠狀動脈疾病 : 2-3X - DM 死於冠狀動脈疾病 : 3-5X 糖尿病應視為心血管疾病的高危險族群或已有心血管疾病

10 血管硬化致病機轉

12 Treatment Life modification Sugar control BP control Lipid control Aspirin

13 Sugar control

14 血糖控制好, 併發症減少 1% reduction in HbA 1c ( 糖化血色素每下降 1%) Risk reduction* Deaths from diabetes ( 糖尿病死亡率 -21%) 1% Myocardial Infarction ( 心肌梗塞 -14%) Microvascular complications ( 微小血管併發症 -37%) UKPDS 35. BMJ 2000;321: Peripheral vascular disorders ( 週邊血管疾病 -43%) *p< N = 3,642

心肌梗塞 -14%) Microvascular complications ( 微小血管併發症 -37%) UKPDS 35.

15 1% increase in HbA1c ( 糖化血色素每增加 1%) Risk increase* CHD Stroke 13-28% PAD Ann Intern Med. 2004;141(6):

16 ACCORD Trial

18 primary outcome was the first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes

21 ADVANCE Trial 積極控制血糖減少小血管併發症

22 HR: 0.9( ) HR: 0.94( ) HR: 0.86( ) HR: 0.93( )

23 VADT Trial

25 Achieved HbA1C level in intensive treatment group ACCORD. NEJM 2008;358: ADVANCE. NEJM 2008;358: AVDT. NEJM 2009;360:

26 Diabetologia, 2009 Nov; 52(11):

27 Diabetologia, 2009 Nov; 52(11):

28 Effects on severe hypoglycaemia Overall, there were 1,443 events (1,071 in the more-intensive group, 372 in the less-intensive group). Allocation to more-intensive glycaemic control was associated with a more than doubling in the risk of severe hypoglycaemia (HR 2.48, 95% CI ) and there was significant heterogeneity among the trials (Q = 10.74, p = 0.01, I 2 = 72.1%)

29 Diabetologia, 2009 Nov; 52(11):

30 Ominous Octet of T2DM β-cells decline increased blood level of free-fatty acid (GLP-1, GIP etc ) increased activity of α-cells Kidney gluconeogenesis Insulin resistance in muscle Insulin resistance in liver Insulin resistance in brain DeFronzo RA. Diabetes. 2009;58:

31 Number of classes of antihyperglycaemic agents 100-year history of antihyperglycemic therapeutics Bile acid sequestrant DPP-4 inhibitor Amylinomi metic SGLT-2 inhibitor Bromocriptin e-qr GLP-1 receptor agonist Glini Basal insulin de 6 Thiazolidinedio analogue Alpha-glucosidase ne inhibitor Phenform Human 4 Sulphonyl in insulin Rapid-acting insulin Metformi Intermediate-acting urea analogue n 2 insulin Phenformin withdrawn Soluble 0 insulin UGDP, DCCT and UKPDS studies. Year

FORXIGA inhibits SGLT2 by an insulin-independent mechanism to remove excess glucose in the urine 1 Reduced glucose reabsorption FORXIG A SGLT2 Proximal tubule SGLT2 Glucose FORXIGA Glucose filtration

33 FORXIGA inhibits SGLT2 by an insulin-independent mechanism to remove excess glucose in the urine 1 Reduced glucose reabsorption FORXIG A SGLT2 Proximal tubule SGLT2 Glucose FORXIGA Glucose filtration Remaining glucose is reabsorbed by SGLT1 (10%) By inhibiting SGLT2, FORXIGA removes excess glucose in the urine and lowers HbA 1 1c FORXIGA is >1400-times more selective for SGLT2 versus SGLT1 1 Increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*) FORXIGA may be used without dosing reduction in patients with mild renal impairment, but is not recommended for use in patients with moderate-to-severe renal impairment (egfr <60 ml/min/1.73 m 2 or CrCl <60 ml/min). 1 Increases urinary volume by only ~1 additional void/day (~375 ml/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes. 1 CrCl, creatinine clearance; egfr, estimated glomerular filtration rate; SGLT, sodium-glucose co-transporter. 1. FORXIGA. Summary of product characteristics, 2014.

34 NEJM 2015;373:

35 NEJM 2015;373:

36 This article was published on June 13, 2016, at NEJM.org.

37 This article was published on June 13, 2016, at NEJM.org.

38 This article was published on June 13, 2016, at NEJM.org.

39 This article was published on June 13, 2016, at NEJM.org.

40 在醫界中, 死亡被視為所有疾病的預後中最糟糕的預後, 能夠改善死亡率這件事, 會大幅影響到藥物的選擇上糖尿病的治療, 當醣化血色素控制到一個程度後, 心血管死亡率和大血管病變的風險就沒辦法再下降, 等於就是已經到治療的極限更積極的血糖控制, 僅僅能預防小血管病變, 無法改變因心血管死亡的嚴重預後而 EMPA-REG 和 LEADER 實驗, 改善這些高危險群的死亡風險 22~38% 可以說 Empagliflozin 和 Liraglutide 可以明顯改變這群高危險群的糖尿病患者的死亡風險可以想見的,EMPA-REG 和 LEADER 實驗的結果, 將會大幅改變糖尿病患者的用藥針對有高度心血管風險的糖尿病患者, 將不會是各種藥物皆可做為二線用藥使用, 而是必須優先思考使用 Empagliflozin 或是 Liraglutide 這些會明顯減少患者死亡的藥物糖尿病的治療, 將因此帶到一個新的世代 : 我們不只透過藥物治療去改變患者的小血管病變預後, 更要透過藥物治療去預防患者的死亡

41 41 圖片出處 peaks.wordpress.com/

42 血脂治療

43 高血脂與動脈硬化動脈硬化病灶好發生於全身血管, 最常發生的部位為冠狀動脈頸動脈及腸骨動脈 1. 腦部腦梗塞腦出血 ( 俗稱腦中風 ) 2. 腎臟血管腎性高血壓腎衰竭 3. 下肢動脈間歇性跛行 ( 走一段路腿疼, 休息一下又好了 ) 4. 冠狀動脈血管壁因阻塞而血流減少心肌缺氧心絞痛 ( 胸口有壓迫感胸痛等症狀 ) 血管壁阻塞變大或硬化斑塊破裂 > 心肌梗塞一般言之, 血液中總膽固醇濃度每下降 10%, 冠狀動脈心臟病的得病風險可減少 20-30% 冠心病的病人接受 statin 藥物治療時, 總膽固醇濃度每下降 10%, 死亡風險可減少 15%

44 NCEP 的專家會議依據研究而認為, 降低 1% 的 LDL-C 可以使心血管疾病的風險降低 1%, 而提昇 1% 的 HDL-C 則可以使心血管疾病的風險降低 3% 之多, 血脂的控制與整個心血管疾病的風險有很大的關聯

45 壞膽固醇 LDL 降越低, 心血管疾病的發生率越低 LDL (md/dl)

46 Lancet Aug 21-27;364(9435):

57 FIBRATE FIELD study fibrates were compared with placebo, there was no decrease in events, likely because of high statin use in the placebo arm, but men with low HDL and triglycerides higher than 200 mg/dl benefited from a reduction in cardiovascular events. Cardiovasc Drugs Ther 2009;23(5):403 8

58 5518 patients, type 2 DM, open-label simvastatin + fenofibrate or placebo combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as com-pared with simvastatin alone N Engl J Med 2010;362(17):

59 Fish oil an effective treatment for hypertriglyceridemia Earlier studies in the cardiovascular literature suggested a possible mortality decrease in patients with heart disease. N Engl J Med 2012;367(4):

60 with early diabetes and high cardiovascular risk, using 1 g of fish oil per day, did not reduce their risk of cardiovascular events or mortality. N Engl J Med 2012;367(4):

61 血壓治療

62 高血壓的定義 ~~ 根據診間血壓 140/ 90

63 高血壓的定義 ~~ 根據家中血壓 135/ 85

64 控制血壓的好處每降低 2mm 收縮壓, 可以降低 7% 心血管疾病死亡率降低 10% 中風死亡率

65 血壓的目標值

67 UKPDS 36 prospective observation study 4,801 patients, F/U for 10 years Each 10 mm Hg decrease in mean SBP was associated with 12% reductions in the risk of any complication related to diabetes (P < ) 15% reduction in deaths related to diabetes (P < ) 11% reduction in myocardial infarction (P < ) 13% reduction in micro-vascular complications (P < ) No threshold of risk was observed for any end point. The risk of all diabetes-related macro- and microvascular endpoints were lowest in those patients with a SBP less than 120 mm Hg, without any J-curve phenomenon. BMJ 2000;321:412-9.

68 SANDS trial In the SANDS trial - aggressive SBP lowering strategy (<115 mmhg) - standard strategy (<130 mmhg), final values of SBP: 117 vs 129 mmhg There was a significant regression of carotid intimal medial thickness and greater decrease in left ventricular mass in the aggressive treatment group. However,clinical events did not differ significantly between groups. JAMA 2008;299:

69 UKPDS 38 trial In the UKPDS 38 trial: - tight control strategy: BP of <150/85 mm Hg - less tight control strategy BP of <180/105 mm Hg 1148 hypertensive patients with type 2 diabetes (mean age 56, mean BP at entry 160/94 mm Hg). median follow-up of 8.4 years, mean BP: - tight BP control group: 144/82 mmhg - less tight control group:154/87 mm Hg (P < ) There was significant reduction in almost all of the macro- and microvascular events: - 24% in diabetes-related end points (P=0.0046) - 32% in deaths related to diabetes (P =0.019) - 44% in strokes (P =0.013) - 37% in microvascular end points (P =0.0092) Therewas also a non-significant reduction in all-cause mortality BMJ 1998;317:

70 ACCORD trial In the ACCORD trial: patients with type 2 diabetes - intensive therapy, targeting a SBP <120 mmhg - standard therapy, targeting a SBP<140 mmhg At 1 year: - mean SBP: mmhg in the intensive-therapy group - mean SBP: mmhg in the standard-therapy group After a mean follow-up of 4.7 years: the annual rate of the primary outcome % in the intensive-therapy group % in the standard-therapy group (hazard ratio, 0.88; P =0.20) Non-fatal myocardial infarction was decreased by 13% in the intensivetherapy group (P =0.25) Though there was no significant difference in total mortality, the annual rate of stroke, a pre-specified secondary outcome, was decreased by41% (P =0.01). The serious adverse events was more common in the intensive-therapy group (3.3% vs 1.3%, P < 0.001). N Engl J Med 2010;362:

71 ACCORD trial It should be known that the ACCORD trial was comparing BP targets of <120 mmhg vs <140 mmhg, not <130 mmhg vs 140 mmhg. While a SBP target <120 mmhg was not supported by the ACCORD trial, one cannot deny the intensive BP target of <120 mmhg was beneficial in reducing stroke risk, which is the most important cardiovascular event in East Asia. It should also be noted that there was no increase in the risk of myocardial infarction. In fact, non-fatal myocardial infarction was decreased by 13%, though not statistically significant. N Engl J Med 2010;362:

72 HOT trial The HOT trial is the most important RCT to test optimal DBP in hypertensive patients. A total of 18,790 hypertensive patients from 26 countries, with a DBP between 100 mm Hg and 115 mm Hg (mean 105 mm Hg), were randomly assigned to 3 target DBP groups: <90, <85, and <80 mmhg. The lowest incidence of major cardiovascular events occurred at a mean achieved DBP of 82.6 mmhg. Further reduction below this level was safe. In a subgroup analysis of patients with diabetes, there was a 51% reduction in major cardiovascular events, including myocardial infarction, stroke, and CV deaths, in target group <80 mm Hg compared with the group <90 mmhg (P =0.005). The percentages of previous cardiovascular diseases and risk factor were well balanced between the 3 groups. There was also a trend favoring a target of <80 mmhg in reducing total mortality (relative risk =1.77 for a target of <90 mmhg, P =0.068). Lancet 1998;351:

73 BP control in DM The BP target for diabetes is probably the most controversial issue in the management of hypertension. The 2013 ESH/ESC hypertension guidelines, the 2014 JNC report, and the hypertension guidelines of the American Society of Hypertension/ International Society of Hypertension all suggested a loosening of the target BP to <140/90 mmhg for diabetes. Standards of Medical Care in Diabetes-2014, proposed by the American Diabetes Association, suggested SBP targets of <140/80 mmhg, but a SBP target <130 mmhg may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. Based on meta-analyses and the status of diabetes control in Taiwan, we set BP targets of <130/80 mmhg in this guideline, similar to recent hypertension guidelines from the Japanese Society of Hypertension, the Global Guideline for Type 2 Diabetes from International Diabetes Federation Guideline Development Group, and the 2014 Canadian Hypertension Guidelines. Journal of the Chinese Medical Association xx (2014) 1e47

74 Development of Antihypertensive Therapies Effectiveness Tolerability 1940s s 1970s 1980s 1990s 2007 Peripheral sympatholytics Ganglion blockers Veratrum alkaloids Direct vasodilators Thiazide diuretics Central alpha 2 agonists Non-DHP CCBs Beta blockers Alpha blockers ACE inhibitors DHP CCBs ARBs Renin ihhibitor Vaccine? DHP, dihydropyridine; CCB, calcium channel blocker; ARB, angiotensin II receptor blocker.

76 ACEI or ARB??? Calcium channel Blocker 這個藥? 還是那個藥? Beta-Blocker Diuretics

78 Taiwan Hypertension Guidelines

80 First-line therapy

81 Aspirin

82 ASPIRIN The role of aspirin in the treatment of cardiovascular disease is well established. use of aspirin for primary prevention?

83 In type 2 diabetes, low-dose aspirin as primary prevention did not reduce the risk of cardiovascular events. JAMA 2008;300(18):

84 for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events no benefit when each of the events (strokes, myocardial infarctions, mortality) was evaluated separately MACE: non-fatal myocardial infarction, nonfatal stroke, and cardiovascular death) Cardiovasc Diabetol 2011;10:25

85 Decreased mortality with low-dose aspirin has been found in a study of patients with an average age of 60 years, with the most significant benefit in older and male participants. Diabetes Care 2010;33(2):317 21

86 Consider aspirin therapy ( mg/ day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%). This includes most men aged >50 years or women aged >60 years who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). Diabetes Care, Supplement 1, 2014

87 American Heart Association advocates starting therapy for patients older than 40 with risk factors.81 Aspirin therapy (75 to 162 mg/d) should be recommended as a primary prevention strategy in those with DM at increased cardiovascular risk, including those who are 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). Circulation 2007;115(1):114 26

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