1、老年糖尿病患者的治疗策略,李诗洋,糖尿病患病人数 (20-79岁) 排名前10位的国家/地区 单位:百万,最新IDF流行病学数据显示： 20102030年糖尿病在全球迅速流行,中国糖尿病患病人数已居世界第一,Diabetes Atlas, 5th edition, IDF, 2011.,China in 2010,11.6% prevalence of diabetes in adults in China in 2010 based on cross-sectional study of 98,658 adults in China in 2010 estimated prevalence
2、any diabetes in 11.6% (12.1% in men and 11% in women) prediabetes in 50.1% Reference - JAMA 2013 Sep 4;310(9):948, editorial can be found in JAMA 2013 Sep 4;310(9):916,我国老年人群糖尿病患病率显著增加,我国老年人的标准大于等于60岁,中华内科杂志. 2014;53(3):243-251,Background,Diabetes mellitus type 2 is a common endocrine disorder chara
3、cterized by variable degrees of insulin resistance and deficiency, resulting in hyperglycemia.It is often identified through routine screening beginning in middle age, or through targeted screening of adults with risk factors such as obesity, metabolic syndrome, polycystic ovary syndrome, a history
4、of gestational （妊娠期的）diabetes, or other concerning familial, clinical, or demographic characteristics.,Also called,diabetes mellitus type II type 2 diabetes type II diabetes non-insulin-dependent diabetes mellitus (NIDDM) adult-onset diabetes（成人型） insulin-resistant diabetes,Who is most affected,pers
5、ons with obesity(2) mean age at diagnosis of type 2 diabetes in United Stated decreased from 52 years in 1988-1994 to 46 years in 1999-2000 (Ann Fam Med 2005 Jan-Feb;3(1):60 full-text) diabetes prevalence similar in men and women globally, but slightly higher in men 60 years old and in women at olde
6、r ages (Diabetes Care 2004 May;27(5):1047 full-text) American Indians/Alaska Natives (AI/ANs) have higher prevalence of diabetes from 1994 to 2002, age-adjusted prevalence of diabetes among United States adults increased from 4.8% to 7.3%, but among AI/AN adults, from 11.5% to 15.3% (MMWR Morb Morta
7、l Wkly Rep 2003 Aug 1;52(30):702 full-text) from 1994 to 2004, age-adjusted prevalence of diagnosed diabetes in AI/ANs 35 years old increased from 0.85% to 1.71%; prevalence in 2004 increased with age from 0.22% at age 15 years to 4.68% at ages 25-34 years (MMWR Morb Mortal Wkly Rep 2006 Nov 10;55(4
8、4):1201 full-text),Likely risk factors,Prediabetesimpaired fasting glucose（空腹血糖受损） - plasma glucose 110-125 mg/dL (6.1-6.9 mmol/L) using WHO criteria, or 100-125 mg/dL (5.6-6.9 mmol/L) using ADA criteriaimpaired glucose tolerance （糖耐量减低）- 2-hour plasma glucose 140-199 mg/dL (7.8-11 mmol/L) during 75
9、 g oral glucose tolerance test (WHO and ADA criteria) HbA1c 5.7%-6.4% (ADA criteria),Likely risk factors,obesity metabolic syndrome polycystic ovary syndrome（多囊卵巢综合征） gestational diabetes mellitus (GDM)（妊娠期糖尿病）,Diagnostic criteria,fasting plasma glucose 126 mg/dL (7 mmol/L) (after no caloric intake
10、for 8 hours) symptoms of hyperglycemia（高血糖） with random plasma glucose 200 mg/dL (11.1 mmol/L) 2-hour plasma glucose 200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test HbA1c 6.5% (HbA1c may not be accurate for diagnosis if there is pregnancy, hemoglobinopathy(血红色异常), certain anemias（贫
11、血）, or abnormal erythrocyte（红细胞） loss or replacement) Repeat testing for confirmation in the absence of unequivocal （明确的）hyperglycemia. (WHO/IDF 2006 PDF) WHO Consultation Report 2011 PDF,Additional testing and evaluation,a fasting lipid profile liver transaminases serum creatinine, estimated glomer
12、ular filtration rate, spot urine microalbumin（微量蛋白） to creatinine ratio a dilated eye exam to detect retinopathy（视网膜）a Semmes-Weinstein monofilament （震动阈值）exam to detect peripheral neuropathy （周围神经病变）,Individualize glycemic goals,Strong recommendation targets in adults with type 2 diabetes are HbA1c
13、 7% in most nonpregnant adults and 6% in pregnant women with preexisting（既往） diabetes,Consider individualized lipid goals and blood pressure goals; generally recommended targets in adults with type 2 diabetes are low-density lipoprotein (LDL) cholesterol 100 mg/dL (2.6 mmol/L) and blood pressure 130
14、/80 mm Hg or 140/90 mm Hg (Weak recommendation).,Provide support for dietary management, maintaining physical activity, and diabetes self-management education and support (Strong recommendation),Prescribe glucose-lowering medications,Prescribe glucose-lowering medications if there is inadequately im
15、proved hyperglycemia with lifestyle modifications (Strong recommendation),Metformin（二甲双胍） is the first-line drug of choice for type 2 diabetes (Strong recommendation). The initial dosing is 500 mg twice daily or 850 mg once daily. Increase dose by 500 mg/day weekly or 850 mg/day every other week. Th
16、e maximum dose is 1 g twice daily or 850 mg 3 times daily.,Add a second drug if glycemic goals are not met on the maximal tolerated dose of metformin monotherapy (Strong recommendation) and a third drug if glycemic goals are not met on a 2-drug combination;,In hospitalized patients: Avoid the sole u
17、se of sliding scale insulin in the hospitalized patients (Strong recommendation). For noncritically ill patients, subcutaneous （皮下）insulin suggested in patients with persistent hyperglycemia 180 mg/dL (10 mmol/L) (Weak recommendation). Use basal（基础） plus+ correction insulin for those who are taking
18、nothing by mouth or have limited oral intake and use basal, nutritional, plus correction insulin for those with good nutritional intake. (Strong recommendation). A target glucose of 140-180 mg/dL is appropriate for most patients (Weak recommendation).,For critically ill patients, use IV（静脉） insulin
19、infusion and consider using a protocol that allows for an adjustment of the rate of infusion based on glycemic fluctuations (Weak recommendation). A target glucose of 140-180 mg/dL (7.8-10 mmol/L) is appropriate for most patients (Strong recommendation). A more stringent target, such as 110-140 mg/d
20、L (6.1-7.8 mmol/L), may be appropriate for selected patients (Weak recommendation).,follow-up monitoring,Provide follow-up monitoring including (Strong recommendation) HbA1c at least 2 times/year at least annually: fasting lipid panel (consider every 2 years if lipid levels are low risk) serum creat
21、inine, urine albumin excretion comprehensive foot exam specialist retinal（视网膜） exam (consider every 2 years if the exam is normal) Neuro（神经） exam (vibration（震动） threshold, pinprick, light touch, ankle reflexes) to screen for distal （末梢）symmetric polyneuropathy consider cardiovascular reflex testing
22、to detect asymptomatic cardiovascular autonomic dysfunction,老年糖尿病特点,患病率高，知晓率低、诊断率、治疗率待提高老年前患糖尿病和老年后新发症状隐匿多器官功能减退异质性大,老年糖尿病的特点,患病率高，以2型糖尿病为主：2010年中国流行病学调查研究显示，我国60岁以上人群糖尿病患病率 约20.4%，70岁以上人群糖尿病患病率约22.0%以餐后血糖升高多见新诊断老年DM患者单纯餐后血糖升高者占50%以上合并症多，用药复杂老年糖尿病患者常合并多种代谢紊乱，如血脂紊乱、高尿酸血症、高凝状态等，加之并存的各系统的疾病，导致用药品种和数量繁多
23、，极易出现药物之间的相互作用,老年糖尿病的特点,老年糖尿病患者多伴有各重要脏器功能减退对许多药物的代谢、效应和毒副作用与其他年龄段患者有着明显的不同。尤其是随着年龄的增长肾功能的减退可能导致降糖药物的缓慢蓄积，使得低血糖的发生率高达35.5%。肝功能的潜在减退导致各种药物之间相互作用，不仅影响治疗疗效，更为重要的是可能增加毒副作用。部分患者治疗依从性差老年DM患者还可能出现一些特殊的表现如DM性肌病、精神心理改变等,？,老年糖尿病究竟与其他年龄段的糖尿病管理有何不同,临床问题,谁是老年糖尿病的管理对象 如何进行功能评估和危险分层 建立个体化控制目标的依据 如何确定治疗方案,确定管理对象,什么是
24、老年 什么是老年糖尿病特殊性在哪里,65岁以上 70岁以上认知障碍 生活功能障碍或丧失 情绪障碍社区 养老院 住院患者,临床问题,谁是老年糖尿病的管理对象 如何进行功能评估和危险分层 建立个体化控制目标的依据 如何确定治疗方案,评估,确定评估内容 建立评估方法 解读评估结果,2012 ADA建议评估内容,What issues need to be considered in individualizing treatment recommendations for older adults?Comorbidities and Geriatric Syndromes Cognitive Dys
25、function Functional Impairment Falls and Fractures DepressVision and Hearing Impairmention Depression Other Commonly Occurring Medical Conditions Unique Nutrition Issues Unique Needs in Diabetes Self-Management Education/ Training and Support Physical Activity and Fitness Age-Specific Aspects of Pha
26、rmacotherapy（药物治疗） Antihyperglycemic Medication Use in Older Adults Vulnerability to Hypoglycemia（低血糖） Risks of Undertreatment of Hyperglycemia Life Expectancy Shared Decision-Making Racial and Ethnic Disparities Settings Outside the Home Hospitals,2013 中国老年糖尿病专家共识,2013 IDF建议的评估工具,IDF assessment too
27、ls,评估结果,类别 1: 功能完全独立 类别 2: 功能依赖 类别 3: 生命末期照顾,亚类 A: 衰弱 亚类 B: 痴呆,指患严重疾病或恶性肿瘤，预期寿命小于1年,包括生活功能独立；没有主要的日常生活能力受损；不需要或仅需要极少生活照料,日常生活能力ADL： 穿衣 吃饭 梳洗 上厕所 控制大小便 移动 工具性日常生活活动能力 IADL： 打电话 使用交通工具 购物、备餐、家务、洗衣、服药、理财,评估工具之衰弱及解读,FRAIL评分： 3-5=衰弱 1-2 衰弱前状态Fatigue: 您感觉疲倦吗？ Resistance: 您不能爬一段楼梯吗？ Aerobic: 您不能步行一个街区吗？ Il
28、lnesses: 您是否患有5种以上疾病？ Loss of weight: 您的体重在过去6月中你是否减轻超过5%？,Fried 等基于美国心血管健康研究的数据，提出了衰弱的可操作性定义，即衰弱综合征（衰弱表型或心血管研究中的衰弱定义法），满足以下5 条标准的3 条或以上为衰弱： 1、不明原因的体重下降（1 年内体重下降超过4.5kg 或体重的5%）； 2、步行速度减慢（4.5 米的步行时间延长）3、握力下降； 4、体力活动下降； 5、疲劳。 满足其中1 种或2 条的老年人为衰弱前期。,评估工具之痴呆量表及解读,common comorbidities,very common co morbi
29、dities associated with type 2 diabetes include obesity hypertension dyslipidemia other common diabetes-associated conditions include depression obstructive sleep apnea fatty liver disease cancer of liver, pancreas, endometrium, colon/rectum, breast, or bladder fractures cognitive impairment low test
30、osterone in men periodontal disease hearing impairment heart failure anxiety arthritis,Associated cardiovascular conditions, 50% of adults with coronary artery disease may have diabetes or impaired glucose metabolism 32% of patients scheduled for coronary angiography may have diabetes, almost half o
31、f which may be undiagnosed 17% of adults may have had silent myocardial infarction by time of diagnosis with type 2 diabetes postural hypotension and postural dizziness may be associated with diabetes mellitus type 2 insulin use may be associated with higher risk of hypertension in adults with type
32、2 diabetes 10%-48% adults with type 2 diabetes may have obstructive sleep apnea (OSA) type 2 diabetes may be associated with vitamin D deficiency,临床问题,谁是老年糖尿病的理想管理对象？ 如何进行功能评估和危险分层： 建立个体化控制目标的依据 如何确定治疗方案,2012 ADA老年糖尿病人群分类, 健康，几乎没有并发的慢性疾病，认知功 能和功能状态完好； 病情复杂/ 中等健康，存在多种慢性合并疾病，或 2 项日常活动受限，或轻- 中度认知功能受损；
33、非常复杂/ 健康较差，需长期护理，或伴有终末期慢性疾病，或中- 重度认知功能受损，或 2项日常活动无法自理。,2013IDF 老年DM人群功能分类,CATEGORY 1:FUNCTIONALLY INDEPENDENT CATEGORY 2:FUNCTIONALLY DEPENDENTSubcategory A: FrailSubcategory B: Dementia CATEGORY 3:END OF LIFE CARE,2012 ADA以HbA1c为参考的策略,HbA1c 与死亡率呈 U 型曲线 HbA1c 在 7.5% 死亡风险比率最 低（IQR 7.5% 7.6%） HbA1c6.0
34、% 或 11.0% 死亡风险均增加。 (2012ADA),2013ACCE,The A1c target must be individualized, based on numerous factors, such as age, co-morbid conditions, duration of diabetes, risk of hypo-glycemia, patient motivation, adherence, life expectancy, etc. An A1c of 6.5% or less is still considered optimal if it can be
35、 achieved in a safe and affordable manner, but higher tar-gets may be appropriate and may change in a given individual over time.,根据功能状况，老年2型糖尿病患者的常规血糖目标,INTERNATIONAL DIABETES FEDERATION MANAGING OLDER PEOPLE WITH TYPE 2 DIABETES GLOBAL GUIDELINE（2013年）,老年2型糖尿病患者的HbA1c目标值,2016 ADA,老年糖尿病治疗策略的优化新观点：
36、美国糖尿病协会(ADA)和美国老年病学会(AGS)发表的共识,个性化控制目标的制定 健康，极少伴随其他慢性疾病，无认知障碍，功能状态无受损。糖化血红蛋白控制目标可定为75病情复杂，伴多种慢性疾病，或日常活动能力有2项或更多项受损，或轻中度认知障碍。目标可能需要放宽到8以降低低血糖和跌倒风险病情非常复杂健康状况很差，或伴终末期慢性疾病，或中重度认知障碍，或2项或更多项日常生活不能自理。目标定为85,Diabetes in Older Adults: A Consensus Report Journal of the American Geriatrics Society; v:60 i:12 p
37、:2342-2356; 12/2012,老年糖尿病治疗策略的优化,（三）个性化控制目标的制定老年糖尿病诊疗措施专家共识（年版） 中国老年学学会老年医学会老年内分泌代谢专业委员会（） HbAlc7.5%：相应FPG7.5mmol/L和2hPG10.Ommol/L。适用于预期生存期10年、较轻并发症及伴发疾病，有一定低血糖风险，应用胰岛素 促泌剂类降糖药物或以胰岛素治疗为主的2型和1型糖尿病患者。（2）HbAlc8.O%：对应的FPG8.Ommol/L和2hPG11.Immol/L。适用于预期生存期5年、中等程度并发症及伴发疾病，有低血糖风险，应用胰岛素促泌剂类降糖药物或以多次胰岛素注射治疗为主的
38、老年糖尿病患者。（3）HbAlc8.5%：如有预期寿命5年、完全丧失自我管理能力等情况,中华内科杂志. 2014;53(3):243-251,临床问题,谁是老年糖尿病的理想管理对象？ 如何进行功能评估和危险分层： 建立个体化控制目标的依据 如何确定治疗方案,治疗理念：重视基础治疗,（一）重视基础治疗 1 糖尿病教育 2 饮食 3 运动其中，糖尿病教育是公认的提高糖尿病治疗水平的重要措施。而饮食和运动治疗则应贯穿于糖尿病治疗的始终,中华内科杂志. 2014;53(3):243-251,2013 IDF老年2型糖尿病药物治疗路径,生活方式干预,此后，在每一步骤，如果未达到个体化的HbA1c 目标,
39、考虑一线治疗,考虑二线治疗：在一线药物基础上增加为两药治疗,考虑三线治疗：三种口服药物治疗、胰岛素或GLP-1RA,后续治疗选择,二甲双胍,磺脲或 DPP-4抑制剂,二甲双胍 （若未作为一线用药）,磺脲 或 DPP-4抑制剂,DPP-4抑制剂 或磺脲,基础胰岛素 或预混胰岛素,或,GLP-1RA,GLP-1RA,基础+餐时 胰岛素,替换口服药物或 基础胰岛素或 预混胰岛素,常规治疗路径,备选治疗路径,其它治疗选择 （按字母排序）,阿卡波糖或 格列奈类或 胰岛素或 SGLT2抑制剂或 噻唑烷二酮,阿卡波糖或 格列奈类或 GLP-1RA或 胰岛素或 SGLT2抑制剂或 噻唑烷二酮,阿卡波糖或 格列
40、奈类或 SGLT2抑制剂或 噻唑烷二酮,需考虑的患者因素： 身体功能 虚弱 痴呆 疾病终末期,药物选择考虑因素： 肾功能 磺脲的低血糖风险 药物副作用 药物所致体重降低的潜在危害 费用 可获得性 当地处方法规 停用无效药物,2013 IDF Global Guideline for Managing Older People with Type 2 Diabetes. http:/www.idf.org/guidelines/managing-older-people-type-2-diabetes,中国老年医学会老年糖尿病诊疗措施 专家共识（2013年版）降糖治疗路径,中华内科杂志. 201
41、4;53(3):243-251,2016 ADA,2016 ADA,所有的治疗均需建立在以下项目基础上,综合评估和危险分层 functional status 功能状态 Hypoglycaemia 低血糖 Hyperglycaemia and their consequences 高血糖及结果 Falls 跌倒pain 疼痛 medicine related adverse events 药物相关不良反应 Cost consideration and cost benefit analysis (if available) 经济 Level of comorbid illness and/or
42、 frailty 共病/衰弱 Life expectancy including when to implement palliative care 预期寿命/姑息,IDF 2型糖尿病老年患者管理指南,一线治疗推荐： 二甲双胍（没有肾功能减退和其他禁忌时） 低血糖发生风险低的磺脲类（避免使用格列本脲）,International Diabetes Federation. Global Guideline for Managing Older People with Type 2 Diabetes (2013). Available at www.idf.org,老年糖尿病患者低血糖发生风险高,
43、一项在德国进行的研究，对2009年6月至2010年3月间口服降糖药物治疗的3810名糖尿病患者低血糖事件进行回顾性分析，老年糖尿病患者低血糖发生率高,Bramlage et al. Cardiovascular Diabetology 2012, 11:122,老年患者更易发生严重低血糖,动脉血糖（mmol/L）,年轻患者,感知低血糖阈值,发生严重低血糖阈值,老年人不仅对低血糖感知阈值下降 而且严重低血糖的阈值高于年轻人,Diabetes Care. 1997 Feb;20（2）:135-41.,老年患者,0.80.1,ACCORD： 低血糖可能抵消2型糖尿病患者控制血糖获得的受益,研究第1年
44、，强化治疗组和标准治疗组糖化血红蛋白稳定的中位水平分别为6.4%和7.5%。但是发现强化治疗组的死亡率更高，导致平均随访3.5年后中止强化治疗（强化治疗组和标准治疗组的死亡率分别为5.0%和4.0%，P=0.04）。,ACCORD：治疗对血糖控制的影响,ACCORD：治疗对全因死亡率的影响,HbA1c(%),时间(年),时间(年),强化治疗,强化治疗,标准治疗,标准治疗,发生事件的患者(%),Accord Study Group NEJM 2008 358 24 2545,DPP-4抑制剂治疗的特点,通过延长体内自身GLP-1的作用改善糖代谢 主要降低餐后血糖 对于老年患者有较多获益（A*）
45、低血糖风险很小 耐受性和安全性比较好 不增加体重,中国老年学学会老年医学会老年内分泌代谢专业委员会,老年糖尿病诊疗措施专家共识编写组.中华内科杂志 2014,53(3):243-251.,*A级 多个随机对照试验的Meta分析或系统评价；多个随机对照试验或1个样本量足够的高质量随机对照研究,2012 ADA/EASD 立场声明 DPP-4抑制剂作用机制与特点,2012 ADA/EASD共识指出，DPP-4抑制剂机制与特点如下1： 口服DPP-4抑制剂增加活性GLP-1及GIP水平1,2 DPP-4抑制剂主要作用为胰岛素与胰高糖素双调节 DPP-4抑制剂不增加体重 肠促胰素类药物自身不会引起低血
46、糖,Inzucchi SE, et al. Diabetes Care. 2012 Jun;35(6):1364-79. Deacon CF, Diabetes Obes Metab 2011;13:718.,合并多种代谢异常的治疗,1.控制高血压目标值：140/80mmHg.药物选择：ACEI/ARB CCB -B 2.控制血脂大血管危险因素 LDL-C 2.6mmol/L心脑血管危险 LDL-C 1.8mmol/L 3.缺血性脑梗死,Recommendations for Statin and Combination Treatment in Persons With Diabetes,C
47、ardiovascular risk management,Blood pressureBP 140/90 mmHg for people with diabetes （JNC8）Initial treatment （ACEI ARB CCB diuretic ）all people with chronic kidney disease (CKD) should receive an ACE inhibitor or an angiotensin-II receptor antagonist as part of their antihypertensive regimen Beta-blo
48、ckers are not contraindicated in people with diabetes,Lipidsthe patient is over age 75 years or is not a candidate for high-dose statins. moderate-intensity statins are recommended.,Smoking cessation Patients who smoke should be provided with smoking cessation resources, and be provided with smoking
49、 cessation assistance The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.,Antiplatelet therapyThe ADA recommends that aspirin therapy be considered for primary prevention in adults with type 2 diabetes with a 10-year cardiovascular risk 10% men and women over 50 years of age who have at least one additional major risk factor (family history of cardiovascular disease; hypertension; smoking; dyslipidaemia; or albuminuria).,
