常用降糖药物对心血管系统的影响 及 心血管系统药物对糖脂代谢的影响

Presentation on theme: "常用降糖药物对心血管系统的影响 及 心血管系统药物对糖脂代谢的影响"— Presentation transcript:

1 常用降糖药物对心血管系统的影响 及 心血管系统药物对糖脂代谢的影响
常用降糖药物对心血管系统的影响 及 心血管系统药物对糖脂代谢的影响 卫生部北京医院 郭立新

2 提 纲 糖尿病的危害 糖尿病对心血管系统的影响 常用及新型降糖药物对心血管系统的影响 常用心血管药物对糖脂代谢的影响

3 中国糖尿病患病率明显升高 调研涵盖省份 中华医学会糖尿病分会 2007.6-2008.5 11.71 11.25 13.34 12.83
10.65 10.29 2 4 6 8 10 12 14 16 原始 标化 患病率(%) 全体 n=44732 男性 n=17607 女性 n=27125 海南 黑龙江 吉林 辽宁 河北 山东 福建 江西 安徽 湖北 湖南 广东 广西 上海 河南 山西 内蒙古 陕西 宁夏 甘肃 青海 四川 贵州 云南 西藏 新疆 江苏 浙江 北京 台湾 中华医学会糖尿病分会 调研涵盖省份

4 2型糖尿病慢性并发症 卒中 糖尿病 视网膜病变 心血管死亡率和卒中率增加2－4倍5 成人失明的首要原因1,2 心血管疾病 80%的糖尿病患者死于心血管事件6 糖尿病肾病 糖尿病神经病变 终末期肾病的首要原因3,4 Serious microvascular and macrovascular complications of type 2 diabetes have a devastating effect on quality of life and impose a heavy burden on healthcare systems. Diabetic retinopathy: present in 21% of people at the time type 2 diabetes is diagnosed,1 diabetic retinopathy is the leading cause of new blindness among adults aged 20–74 years.2 Diabetic nephropathy: present in 18% of people diagnosed with diabetes;3 diabetes is a leading cause of end-stage renal disease.4 Stroke: diabetes is associated with a 2- to 4-fold increase in cardiovascular mortality and stroke.5 Cardiovascular disease: 75% of individuals with type 2 diabetes die from cardiovascular causes.6 Diabetic neuropathy: present in 12% of people at diagnosis,1 diabetic neuropathy affects approximately 70% of people with diabetes7 and is a leading cause of non-traumatic lower extremity amputations.8 In the UKPDS, 50% of individuals with diabetes already had complications at diagnosis.9 Early detection and treatment of diabetes is essential in order to reduce the impact of its serious complications. 1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S The Hypertension in Diabetes Study Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672– Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, Blackwell Sciences. 7King’s Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79. 9UKPDS Group. Diabetologia 1991; 34:877–890. 非外伤性远端截肢的首要原因7,8 1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes Study Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676. 6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, Blackwell Sciences. 7King’s Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

5 糖尿病与心血管疾病： 沉重的经济负担 10 8 6 4 2 1999年开支(x1,000 US$) 无CVD, 无糖尿病 无CVD, 糖尿病
1999年开支(x1,000 US$) 无CVD, 无糖尿病 n=13,286 无CVD, 糖尿病 n=11,130 CVD, 无糖尿病 n=2,894 CVD 合并糖尿病 n=5,050 $2,562 $4,402 $6,396 $10,172 31.9% 48.1% 20.0% 28.6% 40.3% 31.2% 17.2% 31.8% 51.0% 21.1% 28.0% 50.9% 药房配药 门诊患者 住院患者 Slide 4: CVD drives the economic burden of type 2 diabetes Cardiovascular disease (CVD) is the most important cause of morbidity and premature mortality in type 2 diabetes patients. A study by Nichols and Brown showed that CVD is nearly 75% more prevalent in patients with diabetes compared with age- and sex-matched individuals without diabetes.1 The prevalence of acute myocardial infarction and congestive heart failure was particularly high in people with diabetes. Furthermore, patients with diabetes were more than twice as likely to have multiple CVD diagnoses than diabetes-free individuals. In addition to the heavy burden of morbidity and mortality, CVD has a major impact on diabetes-related healthcare costs. Based on 1999 prices, the average annual medical care cost for a diabetes patient with CVD was more than $10,000. This figure is almost four times that for a patient with no CVD or diabetes, and more than double that for patients with diabetes but no CVD. These data highlight the significant financial burden of diabetes and the associated cardiovascular complications. Prevention of CVD in diabetes patients and/or prevention of type 2 diabetes would therefore have a large impact on the overall costs associated with these conditions. 1. Nichols GA, Brown JB. The impact of cardiovascular disease on medical care costs in subjects with and without type 2 diabetes. Diabetes Care 2002;25:482–6. CVD: cardiovascular disease Nichols GA, Brown JB. Diabetes Care 2002;25:482–6. Copyright ©2002 American Diabetes Association; reprinted with permission from The American Diabetes Association.

6 如果糖尿病没有血管并发症， 糖尿病将不再是一个重大的公共 健康难题 ——第64届ADA大会Banting奖得主Brownlee博士

7 提 纲 糖尿病的危害 糖尿病对心血管系统的影响 常用及新型降糖药物对心血管系统的影响 常用心血管药物对糖脂代谢的影响

8 关联：心内科-心血管与内分泌科 糖尿病已经成为全球性的公共健康问题 血糖控制是减少并发症的主要措施之一
糖尿病血管病变高发，糖尿病与心内科联系密切，早期全面控制糖尿病的代谢异常可以减少心血管事件的发生；出现心血管事件后代谢紊乱的控制直接影响患者预后 降糖药物的安全性、有效性以及常用心血管药物对糖脂代谢的影响是我们需要关注的问题

9 糖尿病与心力衰竭 新诊断DM的心血管病发病率达25％或以上 糖尿病人群的心血管病发病率高达50％，因心血管病死亡者65％左右
在心衰患者中，糖调节受损发生率达43％ ＨbA1c每升高1％，心衰发生的危险可增加8％～15％ 心衰患者的糖尿病发病率达20％，糖尿病合并心衰的发生率明显高于非糖尿病合并心衰者

10 2型糖尿病的自然病程与血管病变的发生 年龄 0-15+ 15-40+ 15-60+ 25-70+ 致残 死亡 致残 遗传背景 比如:
遗传背景 比如: 胰岛素敏感性 胰岛素分泌 并发症 微血管并发症 : 环境因素 营养 肥胖 体力活动过少 致残 糖耐量受损 餐后高血糖 空腹血糖升高 死亡 胰岛素抵抗 高胰岛素血症 ↓ 高密度脂蛋白胆固醇 ↑ 甘油三酯 高血压 动脉粥样硬化加速 假性正常胰岛素 视网膜病变 肾病 神经病变 低胰岛素血症 失明 肾衰 截肢 缺血性心脏病 中风 Key Points In type 2 diabetes we see varying degrees of glucose intolerance; some people have no symptoms while others have severe symptoms. A patient’s genetic susceptibility to type 2 diabetes is a factor, and one that is not usually responsive to interventions. Other factors considered important in the progression of type 2 diabetes are pancreatic beta-cell dysfunction and insulin resistance, but insulin resistance may be modifiable. The progression to type 2 diabetes, therefore, is characterized by development of insulin resistance, followed by impaired glucose tolerance, and insulin secretory failure. As the progression occurs, individuals are at higher risk for the development of the microvascular and macrovascular complications we see outlined here. 致残 大血管病变 10

11 糖尿病血管疾病的定义/临床后果 与糖尿病相关的特异性的心血管系统异常 微血管病变 自主神经病变 大血管病变与其他血管损伤 界定 临床后果
小血管和毛细血管循环损伤 内脏神经受损 大中血管的动脉粥样硬化性改变 血管内膜/内膜下受损 动脉壁病变 临床后果 视网膜病变 肾病 神经病变 糖尿病足 脉搏异常 体位性体血压 足溃疡 阳痿 胃肠道功能紊乱 血流紊乱异常 血管壁薄弱 加重微血管病变 动脉粥样硬化/ 大血管病变

12 提 纲 糖尿病的危害 糖尿病对心血管系统的影响 常用及新型降糖药物对心血管系统的影响 常用心血管药物对糖脂代谢的影响

13 各种降糖药的主要作用位点 葡萄糖 脂肪组织 肠道 肝脏 磺脲类和格列奈类1 二甲双胍1 肌肉 胰腺 胰岛素 a-糖苷酶抑制剂1
13 各种降糖药的主要作用位点 葡萄糖 脂肪组织 肠道 肝脏 磺脲类和格列奈类1 二甲双胍1 肌肉 胰腺 胰岛素 a-糖苷酶抑制剂1 噻唑烷二酮类4 DPP-4 一抑制剂2 DPP-4 GLP-1 GLP 类似物3 SGLT2抑制剂5 肾 Sulphonylureas (e.g. glyburide, glipizide, chlorpropamide) lower fasting blood glucose concentrations primarily by stimulating insulin secretion through interaction with potassium-sensitive ATP channels in the pancreatic β-cell membrane, resulting in calcium uptake and insulin release.1 Meglitinides (e.g. repaglinide) bind to ATP-sensitive potassium channels on pancreatic β-cells, increase insulin secretion, and reduce blood glucose.1 Metformin lowers blood glucose by inhibiting hepatic glucose production and enhancing insulin-stimulated glucose transport in skeletal muscle.1 -glucosidase inhibitors (e.g. acarbose) slow the rate of carbohydrate digestion, thereby providing an alternative means to reduce postprandial hyperglycaemia.1 DPP-4 inhibitors (e.g. sitagliptin, vildagliptin) prevent the inactivation of glucagon-like peptide-1 (GLP‑1). This increases circulating levels of active GLP-1, stimulates insulin secretion and inhibits glucagon secretion, resulting in lowering of glucose levels.2 GLP-1 agonists (e.g. exenatide, liraglutide) mimic the action of GLP-1, a gut hormone released post-prandially, which stimulates insulin secretion and insulin gene expression as well as pancreatic β-cell growth.3 Thiazolidinediones (e.g. rosiglitazone, pioglitazone) decrease insulin resistance in fat, muscle and liver. In addition, they improve estimates of -cell function.4 Sodium glucose transporter-2 inhibitors (currently in clinical development, e.g. dapagliflozin, sergliflozin) suppress renal glucose reabsorption and increase urinary glucose excretion.5 Kobayashi M. Diabetes Obes Metab 1999;1(Suppl. 1):S32–S40. Ahren B. Expert Opin Emerg Drugs 2008;3:593–607. Todd JF, et al. Diabet Med 2007;24:223–232. Nattrass M, et al. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13:309–329. Jabbour S and Goldstein B. Int J Clin Pract 2008;62:1279–1284. 1Adapted from Krentz A and Bailey C. Drugs 2005;65:358–411. 2Ahren B. Expert Opin Emerg Drugs 2008;3:593– Todd JF, et al. Diabet Med 2007;24:223–232. 4Nattrass M, et al. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13: 309–329. 5Jabbour S and Goldstein B. Int J Clin Pract 2008;62:1279–1284. 13 13

14 常用及新型降糖药物的获益与风险 药物 优点 缺点 二甲双胍1 不影响体重 可能改善血脂谱 胃肠道副反应 乳酸酸中毒（罕见） 磺脲类1
14 常用及新型降糖药物的获益与风险 药物 优点 缺点 二甲双胍1 不影响体重 可能改善血脂谱 胃肠道副反应 乳酸酸中毒（罕见） 磺脲类1 疗效确切 体重增加 低血糖 噻唑烷二酮类1 持久控制血糖 体液潴留，充血性心力衰竭 体重增加，骨折 格列奈类1 起效快，作用时间短 频繁给药 胰岛素2 无剂量限制 改善血脂谱 注射 -糖苷酶抑制剂1 不会引起低血糖 胃肠道副反应常见 每天3次给药 Amylin类似物3 体重减轻 注射,胃肠道副反应常见 临床经验有限 DPP-4抑制剂4 GLP-1类似物4 Biguanide (metformin) has additional clinical benefits such as weight stabilisation/reduction, reduction in hypertriglyceridaemia, lowering plasma fatty acids and HDL cholesterol. Common adverse events include abdominal discomfort and other gastrointestinal adverse effects. The most serious adverse event associated with metformin is lactic acidosis; although rare, the mortality rate is high.1 Sulphonylureas (e.g. glimepiride, glipizide) have been extensively used for the treatment of type 2 diabetes for nearly 50 years. Hypoglycaemia is the most common adverse effect of sulphonylurea therapy. Weight gain is regarded as a class effect of sulphonylurea therapy, typically amounting to 1–4kg and stabilising after approximately 6 months. Thiazolidinediones (e.g. pioglitazone, rosiglitazone) improve whole-body insulin sensitivity via multiple actions on gene regulation. Thiazolidinediones are associated with fluid retention with increased plasma volume, a reduced haematocrit and a decrease in haemoglobin concentration.1 Meglitinides (e.g. nateglinide, repaglinide) have a rapid onset of action and a short duration of hypoglycaemic effect which make them suitable for pre-prandial administration. A small increase in bodyweight can be expected in patients. Among insulin therapies (e.g. insulin aspart, insulin glulisine), options include rapid-acting, intermediate-acting, and long-acting human insulin preparations. Weight gain and hypoglycaemia are associated with insulin therapy.2 -glucosidase inhibitors (e.g. acarbose, miglitol) do not cause weight gain, can reduce post-prandial hyperinsulinaemia and have lowered plasma triglyceride concentrations in some studies. Their use has been limited by adverse gastrointestinal effects.1 Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. Nausea is the most common side effect.3 DPP-4 inhibitors (e.g. sitagliptin, vildagliptin) are generally well tolerated and weight neutral. Long-term data on cardiovascular outcomes and safety are needed.4 GLP-1 agonists (e.g. exenatide, liraglutide) have shown a favourable effect on weight, are not associated with hypoglycaemia, but common side effects include gastrointestinal disturbances.4 Krentz A and Bailey C. Drugs 2005;65:385–411. Carver C. Diabetes Educ 2006;32:910–917. Krentz A, et al. Drugs 2008;68:2131–2162. Bosi E, et al. Diabetes Res Clin Pract 2008;82:S102–S107. 1Krentz A and Bailey C. Drugs 2005;65:385–411. 2Carver C. Diabetes Educ 2006;32:910 3Krentz A, et al. Drugs 2008;68:2131– Bosi E, et al. Diabetes Res Clin Pract 2008;82:S102 14 14

15 治疗糖尿病药物与低血糖 抗高血糖药： 降血糖药： 双胍类：二甲双胍 噻唑烷二酮：罗格列酮、吡格列酮 -糖苷酶抑制剂：阿卡波糖 伏格列波糖
（单独应用不引起低血糖） 噻唑烷二酮：罗格列酮、吡格列酮 -糖苷酶抑制剂：阿卡波糖 伏格列波糖 降血糖药： 磺脲类 （可能引起低血糖） 苯甲酸衍生物：瑞格列奈 D-苯丙氨酸衍生物：那格列奈 胰岛素及胰岛素类似物 GLP-4类似物及DPP-4抑制剂及其他新药

16 急性低血糖时的生理反应 增加拮抗激素的分泌，以拮抗胰岛素的作用，升高血糖 使心血管系统发生相应变化，以利于葡萄糖在体内各种组织间的转运
产生一系列预警症状，如饥饿，以迅速纠正低血糖

17 低血糖患者心脏缺血事件明显增加 美国19例72小时血糖检测研究 * * 发生事件数 低血糖 无快速波动 的正常血糖 高血糖 全部事件
这是一项对19例患者进行72小时血糖检测的研究。 记录心肌缺血（胸痛）症状和低血糖症状。结果记录到54次低血糖发作，59次高血糖. 54次低血糖发作中，10次与胸痛症状相关，其中4例心电图异常。而只有1例胸痛发生在59次高血糖期间。血糖正常时无胸痛和心电图异常发生.。提示低血糖患者心脏缺血事件明显增加。 * N/A 全部事件 胸痛/心梗 心电图异常 *P<0.01 与高血糖和血糖正常期间事件数相比 Desouza C, et al. Diabetes Care 26:1485–1489, 2003.

18 Pan C, et al. Curr Med Res Opin. 2009 Jan;25(1):39-45
联合用药增加不良反应的发生 糖尿病患多需要联合用药 39.3% 联合用药患者比例达到60％ Pan C, et al. Curr Med Res Opin Jan;25(1):39-45

19 Which ones to Prescribe?
Safe Tolerable Effective Price Simple STEPS Bottom line on prescribing new drugs Go slowly: See what six to 12 months of post-marketing experience reveals in terms of both efficacy and side effects. Weigh carefully the risks associated with a new drug against the value for a specific patient. When discussing new drugs with pharmaceutical reps, ask for head-to-head studies with older, standard drugs in comparable doses, and ask for the absolute risk reduction (not relative risk reduction), the number needed to treat and the size of clinical trials. (If you aren't familiar with these terms, see "Understanding the Risks of Medical Interventions," FPM, May 2000.) Use unbiased resources for your decision making. The Prescriber's Letter, The Medical Letter, Epocrates, knowledgeable colleagues and your local pharmacists and pharmacologists are excellent resources. Scrutinize new drugs that end with XL, CR, ER, SR or XR. Does the drug offer clinically relevant new efficacy, safety or adherence benefits, or is it simply a "me too" product? Finally, get smart about the costs of the prescriptions you write every day. Engage your patients to find out if they are able to buy the drugs you prescribe. I use the line, "Lots of my patients are having a hard time paying for their prescriptions. Will this $20 drug be a problem for you?" While many new drugs do represent advances in patient care, many others are not far superior to their older, cheaper counterparts. It is our job as physicians to sort out these issues and prescribe drugs that are truly in our patients' best interests.

20 药物的安全性是依从性的关键 药物耐受性良好 费用 其它 有效药物 依从性 ⇓ 治疗达标 ⇓ 彰显临床效果

21 糖尿病合并心血管病的特点 高龄患者多 糖尿病病程长 冠脉病变多复杂 心功能差 多种伴发疾病 同时合并多种代谢异常 肥胖 胰岛素抵抗 高血压
脂代谢异常

22 合并心血管疾病的糖尿病用药原则 平稳降糖，安全达标，关注降糖效能 心血管安全性 减少低血糖事件发生 与其他药物的相互作用
并发症或伴发病的情况

23 磺酰脲类药物的心血管不良作用 严重低血糖 影响心肌缺血预适应（部分药物） 体重增加

24 一些磺脲类不为心脏或胰腺 KATP 通道选择
Kir6.2 SFU SUR2A 一些磺脲类不为心脏或胰腺 KATP 通道选择 68% 同源性 Kir6.2 磺脲类对KATP 通道的影响 一些磺脲类比其它磺脲类对胰腺KATp 通道有更高的选择性。 KATP 通道, 是磺脲类受体(SUR2A and SUR1) 和钾通道(Kir6.2)的复合体，在葡萄糖介导的胰腺细胞分泌胰岛素中起到关键的作用。格列美脲没有阻断心脏组织线粒体KATP 通道的开放，格列本脲没有如此选择性，会阻断心脏组织KATP 通道的反应。这一发现对于2型糖尿病、有心肌梗塞危险的患者的治疗有一定意义。 Pancreas SFU SUR1 KATP 通道, 磺脲类受体(SUR2A, SUR1) 和钾通道(Kir6.2)的组合， 是葡萄糖介导的胰腺细胞分泌胰岛素的关键

25 磺脲类药物的其他不良反应 消化系统不良作用 血液学反应 皮肤损害表现 过敏反应

26 CDS: chronic disease score
二甲双胍对心血管事件的影响 CDS: chronic disease score

27 双胍类药物的其他不良反应 心衰患者禁用 AMI、ACS等急性应激状态禁用 重度OSAHS禁用 进行造影检查时停用
乳酸酸中毒：死亡率大于50% 消化道副反应：最常见，约见于20%病人 皮疹/贫血

28 罗格列酮的心血管安全性- RECORD研究
研究流程 1971例完成研究或死亡 189例未完成计划的最终访视，但获悉在研究结束时仍存活 60例失访 2220例罗格列酮 例联合应用二甲双胍 1103例联合应用磺脲类 随机4458例 2228例既往服用二甲双胍 2230例既往服用磺脲类 11例未服用研究药物 2227例阳性对照组 2227例二甲双胍 + 磺脲类 67例失访 1955例完成研究或死亡 205例未完成计划的最终访视，但获悉在研究结束时仍存活

29 RECORD:心血管住院或心血管死亡 罗格列酮 321个事件 二甲双胍/SU 323个事件
事件累积 发生率 (%, SE) 18 罗格列酮 321个事件 二甲双胍/SU 323个事件 16 HR 0.99 (0.85,1.16) p=0.93 14 12 10 8 6 4 2 事件率 2.8%每年 从事件累积发生率曲线看，2组曲线在研究过程中基本重合。主要终点的结果显示，平均治疗5.5年后，两组的心血管住院或心血管死亡（包括心脏病发作、充血性心力衰竭和脑卒中）没有统计学差异（达到了排除风险升高20%的非劣效性界值）。具体来说，接受文迪雅治疗的患者发生了321次事件（14.5%），接受对照药物治疗的患者发生了323次事件（也是14.5%）（风险比=0.99，95%可信区间=0.85－1.16）。 1 2 3 4 5 6 时间(年) 存在风险的患者 罗格列酮 2220 2086 1981 1883 1795 1720 918 二甲双胍/SU 2227 2101 1995 1895 1798 1697 908

30 RECORD:次要终点 罗格列酮 对照组 HR (95% CI) p-值 (n=2220) (n=2227) 死亡
全因 (0.68–1.08) 心血管 (0.59–1.18) 心肌梗死* (0.80–1.63) 脑卒中* (0.49–1.06) 心血管死亡, 心梗或卒中 (0.74–1.15) 心力衰竭* (1.35–3.27) 在次要终点方面，罗格列酮组的全因死亡、心血管死亡、主要心血管不良事件（MACE）的复合终点事件数都少于对照组，但无统计学差异。尤其在脑卒中这一中国人群高发疾病的次要终点上，罗格列酮组更是比对照组少17例。在CHF方面，RECORD看到的数据与既往的研究以及TZD的说明书一致，即罗格列酮组发生CHF的事件数高于对照组，有统计学差异。在心肌梗死事件方面，罗格列酮组较对照组多8例，HR1.14, 但无统计学差异。 * 致死性和非致死性

31 RECORD:罗格列酮心血管安全 关于缺血性心脏病史的亚组分析
有IHD病史 无IHD病史 发生事件的人数(n) 罗格列酮 (n=383) 对照组 (n=389) 罗格列酮 (n=1837) 对照组 (n=1838) 心血管死亡/住院 105 88 216 235 全因死亡 34 45 93 112 心血管死亡 23 24 37 47 心肌梗死 20 19 44 37 脑卒中 对有无IHD病史的亚组单独分析看到，罗格列酮组与对照组相比，有IHD病史的患者在死亡、心梗、卒中事件数上与对照组基本一致，较对照组多的终点事件主要是心衰和不稳定心绞痛，而心衰无论既往有无缺血性心脏病史罗格列酮组都相对较高，这可能还是与TZD类药物已知的体液潴留的效应有关。因此，有IHD病史的患者并不是不能使用罗格列酮，而应衡量药物的效益风险综合考虑，若决定使用罗格列酮应注意监测心衰和心绞痛相关的症状和实验室指标，采取合适的干预措施已降低可能风险，在安全的基础上保证罗格列酮的疗效最大化。 10 9 36 54 心力衰竭 17 8 44 21 不稳定型心绞痛 15 10 9 14

32 TZD引起的心血管风险 水钠潴留、体重增加,加重心衰风险
机制不明 血管扩张 水钠潴留 可能原因1 直接血管活性效应 毛细血管内皮细胞通透性 水肿患者慎用 心衰NYHA分级Ⅰ和Ⅱ级密切监测 有心衰危险的患者密切监测 心功能NYHAⅢ、Ⅳ级心衰禁用2 心衰及其他心血管疾病慎用3 水肿和体重增加 加重心衰风险 TZD的一个显著不良反应是液体潴留。机制并不清楚，但研究表明可能是由于TZD导致血管扩张，毛细血管内皮细胞通透性增加和直接的血管活性效应。液体潴留导致水肿和体重增加，并能加重心衰风险。因此ADA和ESC/EASD指南明确指出心功能NYHAⅢ、Ⅳ级心衰禁用，心衰及其他心血管疾病慎用。药品说明书指出，水肿患者慎用，心衰NYHAⅠ和Ⅱ级和有心衰危险的患者需要密切监测。 美国纽约心脏病学会（NYHA）1928年提出的心功能分级方案： Ⅰ级：患者患有心脏病，但活动量不受限制，平时一般活动不引起疲乏、心悸、呼吸困难或心绞痛。 Ⅱ级：心脏病患者的体力活动受到轻度的限制，休息时无自觉症状，但平时一般活动下可出现疲乏、心悸、呼吸困难或心绞痛。 Ⅲ级：心脏病患者的体力活动明显受限，小于平时一般活动即引起上述的症状。 Ⅳ级：心脏病患者不能从事任何体力活动，休息状态下也出现心衰的症状，体力活动后加重。 The combination of blood pressure reduction, fluid retention, and edema formation is compatible with changes in the peripheral circulation resulting in capillary leakage. This may be induced by certain actions of TZDs, such as improved insulin-mediated vasodilatation, direct vasoactive effects (8), or increased endothelial permeability (9). Interestingly, the incidence of edema increases substantially when rosiglitazone (10) or pioglitazone (11) is used in combination with insulin. 1.Diabetes Care 2006; 29:581–587. 2. Eur Heart J 2007;28: 3. Diabetes Care Jan;30 Suppl 1:S4-S41. 32 32

33 格列奈类 格列奈类心血管益处可能原因 格列奈类的心血管安全性 --降低氧化应激； --降低餐后血糖漂移； --继发改善脂代谢；
--低血糖，联合用药时严重低血糖； --体重增加； --钾通道的影响？

34 胰岛素及胰岛素类似物的 心血管风险 严重低血糖，诱发心血管事件，尤其与促泌剂联合应用时 体重增加，与促泌剂和TZD联合时尤甚
心衰风险增加，尤其与噻唑烷二酮类联合应用时

35 使用胰岛素的患者体重增加与心血管风险增加有关
–10 –8 –6 –4 –2 2 4 6 8 收缩压 总胆固醇 舒张压 LDL HDL 距基线变化的百分比 * # 第一个四分之一体重增加 第四个四分之一体重增加 使用胰岛素的患者体重增加与心血管风险增加有关 Here, data from DCCT are presented for changes in CV risk markers, stratified by the lowest and highest quartiles of weight gain. While the first quartile showed improvements in parameters of cardiovascular risk, the fourth quartile showed universally negative and significant changes to these parameters. Thus, improved glycaemic control did not result in secondary improvements in the CV risk profile for these weight gainers. While the association of weight gain/obesity and increased CV risk profile is well known, it should be noted that a causal relationship cannot be demonstrated. (data from DCCT) *p<0.01 与基线相比 胰岛素强化治疗患者– 随访时 距基线的变化(平均 6.1年) #p<0.01 与第一个四分之一 随访结果相比 Purnell et al. JAMA 1998;280:140–6 35

36 TZD与胰岛素联合可增加 水钠潴留、心衰的风险
格列酮类与胰岛素联合对β细胞具有积极作用 可有效改善血脂 但可提高水潴留的风险 不是指南，是一份综述 Diabetes Care 31 (Suppl. 2):S131–S135, 2008 36

37 AHA和ADA联合声明： TZD联合胰岛素治疗是 发生心衰的危险因素
DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004：256

38 胰岛素的心血管系统作用 胰岛素在联系代谢过程和心血管稳态方面具有重要作用
在血管内皮细胞，胰岛素介导N O依赖性的血管舒张和E T-1依赖性的血管收缩之间的平衡 改善血管内皮细胞功能和胰岛素抵抗，有利于恢复胰岛素介导的血管舒张和收缩作用之间的平衡关系，改进血流动力学和代谢的稳态环境

39 胰岛素治疗的心血管风险 低血糖 体重增加 水钠潴留，充血性心力衰竭 尤其是与磺脲类、非磺脲类促泌剂、格列酮类合用时

40 Role of Incretins in Glucose Homeostasis
Ingestion of food Glucose-dependent  Insulin from beta cells (GLP-1 and GIP) Glucose uptake by muscles2,4 Release of gut hormones — Incretins1,2 Pancreas2,3 GI tract Blood glucose Beta cells Alpha cells Active GLP-1 & GIP Glucose production by liver Role of Incretins in Glucose Homeostasis Speaker notes After food is ingested, GIP is released from K cells in the proximal gut (duodenum), and GLP-1 is released from L cells in the distal gut (ileum and colon).1–3 Under normal circumstances, DPP-4 (dipeptidyl-peptidase 4) rapidly degrades these incretins to their inactive forms after their release into the circulation.1,2 Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated.2,3 The subsequent increase in glucose uptake in muscles3,4 and reduced glucose output from the liver2 help maintain glucose homeostasis. Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner.2,3 GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.2,5 Glucose dependent  Glucagon from alpha cells (GLP-1) DPP-4 enzyme Purpose: To demonstrate how the incretin pathway is part of the normal physiology of glucose homeostasis. Takeaway: After food ingestion, incretins stimulate insulin release from beta cells and suppress glucagon release from alpha cells in a glucose-dependent manner, resulting in downstream effects that regulate glucose homeostasis. Inactive GLP-1 Inactive GIP DPP-4 = dipeptidyl-peptidase 4 1.Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2.Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. References 1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441. 5. Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744. 40

41 GLP-1注射改善慢性心力衰竭病人的左室射血分数和心功能
NYHA分级III或IV级的心衰病人，5周，12例注射GLP-1（2.5pmol/kg/min）加常规治疗，9例单纯常规治疗。GLP-1明显改善了超声心动图、VO2max、6分钟步行实验、明尼苏达心衰生存质量评分（MNQOL）等指标。在糖尿病和非糖尿病病人都观察到GLP-1的益处。

42 GLP-1 在严重充血性心力衰竭病人中的心脏效应
对照 GLP-1 左室射血分数的平均变化(%) 6分钟步行距离的变化 5 10 15 20 25 30 基线 第五周 p<.001 p<.001 300 DISCUSSION Insulin resistance is present in the setting of congestive heart failure. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties. In patients with severe heart failure, chronic infusion of GLP-1 significantly improved left ventricular function, functional status, and quality of life as measured by improvement in short term exercise capacity BACKGROUND This was a single centre, open-label, nonrandomised pilot study, designed to evaluate the safety and efficacy of a 5 week infusion study of GLP-1 at a dose of 2.5 pmol/kg/min. GLP-1 therapy was added to the standard therapy in 12 patients with New York Heart Association class III/IV heart failure and compared the results with those of 9 patients with heart failure on standard therapy alone. Study groups included a similar proportion of patients with and without diabetes. Benefits of GLP-1 therapy were seen in both diabetic and nondiabetic heart failure patients. GLP-1 was well tolerated with minimal episodes of hypoglycaemia and gastrointestinal side effects. There were no significant changes in any of the parameters in the control patient group on standard therapy. Left ventricular ejection fraction (LVEF) improved from 21 + 3% to % (p<.001) in the GLP-1 treated patients, but was unchanged in the control group (21 + 4% to %). GLP-1 improves LVEF and functional status in patients with systolic heart failure. Quality of life was measured by the 6-minute walk test which improved significantly from m to m (p<.001) in the GLP-1 treated patients, but not in the control group ( m to m) Sokos GG, et al. J Card Fail. 2006;12(9): 250 200 Meters LVEF (%) 150 100 50 基线 第五周 Mean ± SEM. Patients had New York Heart Association class III or IV congestive heart failure. Control Group, N=9 (5 patients with diabetes); GLP-1 Group, N=12 (8 patients with diabetes). LVEF = Left ventricular ejection function. Sokos GG, et al. J Card Fail. 2006;12:

43 钠葡萄糖转运子2抑制剂 SGLT-2介导了90%以上滤过葡萄糖的重吸收；
临床Ⅰ、Ⅱ期研究显示可降低HbA1c水平和体重（4.51 kg及4.30 kg）。研究显示尚有降低血压作用。 该药总体不良事件发生率与安慰剂相似，低血糖反应少见，可有头痛、多尿、泌尿系感染。 新药，心血管及其它方面安全性有待观察

44 当前联合用药 是否存在一定的风险？ 低血糖的风险增加 体重增加 磺脲 双胍 格列奈 胰岛素 α-糖苷酶抑制剂
均增加体液潴留，从而增加心脏负荷 TZDs 那联合用药不当会对患者造成怎样的危害呢？图中分析了当前联合用药中存在的风险： 首先，双胍类和磺脲类药物联用是目前临床上常见的用药组合，但一个是胰岛素增敏剂，一个是胰岛素促泌剂是否会增加风险呢？2008年在Diabetes Care上发表了一篇研究，明确指出联合使用胰岛素促泌剂和双胍类药物值增加合并缺血性心脏病的2型糖尿病患者的死亡率。 其次，磺脲类或格列奈类药物和胰岛素联用，都会增加低血糖和体重增加的风险。 再者，噻唑烷二酮类药物和胰岛素联用，二者均会增加体液潴留，从而增加心脏负荷。 44 44

45 提 纲 糖尿病的危害 糖尿病对心血管系统的影响 常用及新型降糖药物对心血管系统的影响 常用心血管药物对糖脂代谢的影响

46 钙拮抗剂 曾有研究显示，硝苯地平可改善伴糖耐量减低的EH患者的糖耐量及IS抵抗,增强其IS敏感性。
在糖尿病人群作的短期实验（顿服或短于2W）显示，CCB在一定程度上干扰糖代谢和胰岛素分泌，长期（6m）实验无影响 多数学者认为，CCB对糖脂代谢无影响

47 利尿剂 长期用噻嗪类可引起血糖、HbA1c升高、胰岛素敏感性降低，大剂量利尿剂或与 受体阻断剂合用可促进血糖升高，短期用药或袢利尿剂很少引起糖代谢障碍 可能与利尿剂所致低血钾有关，低钾可抑制胰岛素释放和外周组织对葡萄糖的利用 利尿剂刺激肾素-血管紧张素-醛固酮系统，有可能加速糖原分解，有可能加速DN进展 利尿剂可使TG升高，TG与葡萄糖竞争进入细胞内，干扰胰岛素与受体结合，加重IR

48 肾上腺素受体阻滞剂 低血糖期间儿茶酚胺可刺激胰升糖素通路的b-2受体，这些受体被抑制使糖原分解和糖原异生障碍，并可延迟低血糖的恢复。
低血糖的特异症状易被掩盖，可延误对低血糖的诊断 部分非选择性b-受体阻滞剂有可能使TG、LDL-C增加，HDL-C降低 心脏选择性b-1受体阻滞剂对糖代谢影响较小 a-受体阻滞剂对糖代谢影响较小

49 ACEI ACEI对糖脂代谢无不良影响 有研究显示，其可使Lp(a)、TC、vLDL、LDL-c下降 ACEI可使糖尿病患者的IS增加

50 ARB类 降压效果与ACEI类似 目前多数研究显示其有良好的肾脏保护作用， 可改善IS，对血脂无不良影响
其机制之一可能是促进骨骼肌细胞膜葡萄糖载体蛋白-4的表达，使葡萄糖摄取增加 其机制之一可能是阻断肾素-血管紧张素系统，降低交感神经兴奋性，扩张外周血管，增加骨骼肌血流有关

51 调脂药对糖脂代谢的影响 一般认为血脂异常（TG）与IR有一定联系 研究发现降低周围组织 中FFA可使周围组织中胰岛素介导的葡萄糖摄取增加
多数研究显示贝特类有次类作用 烟酸类一般不宜用于糖尿病(使Ins需量增大)、高尿酸患者（约20%的用药者UA升高） 阿西莫司（acipimox,氧甲吡嗪）？

52 强心甙与抗心律失常药 一般认为强心甙对血糖、胰岛素无明显影响 一般认为抗心律失常药对血糖、胰岛素无明显影响

53 抗凝、抗聚药 阿司匹林：水杨酸抑制血浆皮质激素水平，使胰岛素水平升高，有助于DM的血糖控制
阿司匹林能明显地降低链脲佐菌素糖尿病大鼠的血糖水平,改善胰岛的分泌功能,并能使动物体重的增加明显加快 其它抗凝、抗聚药对血糖、胰岛素影响较小

54 谢谢！