醫(yī)學(xué)專題潘長玉2型糖尿病血糖控制的意義及實踐

1、2型糖尿病血糖控制的意義及實踐解放軍總醫(yī)院 潘長玉2003年03月15日2021/7/19 星期一1糖尿病治療學(xué)上的重大問題血糖控制與并發(fā)癥上世紀20年代初胰島素問世，歡呼糖尿病治療已徹底解決4050年代經(jīng)胰島素治療的患者2030年后出現(xiàn)多種糖尿病并發(fā)癥心血管、腎臟、神經(jīng)、視網(wǎng)膜并發(fā)癥的防治提上議事日程加強血糖控制能否降低并發(fā)癥發(fā)生率意見矛盾哈佛學(xué)派(含Joslin Clinic)支持嚴格控制血糖預(yù)防并發(fā)癥，耶魯學(xué)派認為血糖控制與并發(fā)癥無關(guān)，雙方皆同意需作前瞻性研究澄清這一問題2021/7/19 星期一2美國大學(xué)組糖尿病計劃(UGDP)目的：澄清“嚴格”控制或“較松”控制血糖對糖尿病并發(fā)癥的影

2、響多中心、12所大學(xué)、長程、前瞻性、隨機、雙盲、安慰劑對照試驗1958年開始，歷時14年1027例NIDDM隨機分為5組，每組約200例 甲苯磺丁脲1.5克/天 苯乙雙胍100 mg/天 固定劑量胰島素(按體表面積) 調(diào)節(jié)胰島素劑量控制血糖接近正常安慰劑患者皆接受飲食控制2021/7/19 星期一3UGDP主要結(jié)果甲苯磺丁脲組因猝死率較高，估計為心血管原因，提前停止苯乙雙胍組晚18個月開始，亦因不良反應(yīng)較安慰劑組高而提前中止安慰劑、固定胰島素、按需胰島素3組相比UGDP未能證實較好的血糖控制可預(yù)防或延緩并發(fā)癥的發(fā)生2021/7/19 星期一4UGDP 607例患者不按隨機分組而按血糖控制程度分

3、析，所顯示的致命及非致命事件發(fā)生率 血糖控制 好(183例) 尚可(239例) 差(185例)視網(wǎng)膜病變(滲出)38.548.257.3血清肌酐1.5 mg/dl11.614.014.4高血壓(WHO)標準52.371.375.4心血管死亡 占死亡數(shù)%27.432.140.5 占總數(shù)%12.611.318.3結(jié)論：血糖控制差者并發(fā)癥及心血管死亡率皆較高2021/7/19 星期一5高血糖毒性作用仍要受到重視糖尿病干預(yù)治療及并發(fā)癥的流行病學(xué)研究（EDIC 19942006)受試者 DCCT兩組情況（6年）2000年 原常規(guī)組 原強化組HbA1c 8.1% 8.2%IMT 10% 7.6%2021/

4、7/19 星期一6UKPDS血糖試驗主要RCT結(jié)果終點(事件數(shù)) RR下降 p 值任何糖尿病相關(guān)終點(1401) 12 % 0.029微血管病變(346) 25 % 0.0099糖尿病相關(guān)死亡(414) 10 % 0.34所有原因死亡(702) 6 % 0.44心肌梗死(573) 16 % 0.052卒中 (203) +11 % 0.52周圍血管病變 (47) 35 % 0.15(下肢截肢或致命性病變)心衰 (116) 9 % 0.632021/7/19 星期一7UKPDS血糖與并發(fā)癥觀察性研究目的：不同層次血糖控制與并發(fā)癥的關(guān)系了解微血管病變及心血管病變出現(xiàn)是否有閾值納入3642例患者作事件

5、相對危險性研究由每例患者年HbA1c測定均值算出逐年HbA1c總平均值每例按HbA1c總平均值進行分層，各層中位數(shù)如下(%): 5.6， 6.5， 7.5， 8.4， 9.4此研究中含6 %空腹血糖(調(diào)節(jié))減退者(血糖110125 mg/dl)事件發(fā)生率計算法：發(fā)生某一并發(fā)癥例數(shù)除以隨訪的人年數(shù)，以事件數(shù)/1000人年計算上述計算事件發(fā)生率按性別、種族、糖尿病診斷時年齡、糖尿病病程加以校正按基線血壓、血脂、吸煙等因子校正后，仍然有效2021/7/19 星期一82021/7/19 星期一9UKPDS血糖與并發(fā)癥觀察性研究結(jié)論2型糖尿病患者，糖尿病并發(fā)癥的危險與患者的高血糖明顯相關(guān)與HbA1c正常

6、者(6%)相比，血糖愈高并發(fā)癥發(fā)生率愈高不存在明顯的發(fā)生并發(fā)癥的血糖閾值提示降低血糖可降低并發(fā)癥發(fā)生率微血管病變與血糖升高的關(guān)系更為密切大血管病變與血糖升高也有關(guān)，但還有其他致病因素，血糖亦起重要作用卒中及心衰發(fā)生率與高血糖有關(guān)，但與高血壓關(guān)系更密切2021/7/19 星期一10 2型糖尿病的藥物冶療增加胰島素的可用牲Sulfonylurease.g. Glipizide /Glipizide XL, Glyburide, GlimepirideMeglitinides (very short acting)Repaglinide, NateglinideInsulin增加葡萄糖的吸收-glu

7、cosidase inhibitorsAcarboseMiglitol 減少肝糖輸出 Metformin胰島素增敏劑ThiazolidinedionesPioglitazoneRosiglitazone減肥藥Reduce Fat AbsorptionOrlistatReduce AppetiteSibutraminePhentermine2021/7/19 星期一11磺脲類藥物特征long-acting insulin secretagoguesrapid benefitsome potential differences among agents指征monotherapycomb with

8、TZD or metformincomb with insulin優(yōu)點50 years of experiencegood efficacyvery effective in combination therapyproven microvascular outcomes inexpensive不足cause hypoglycemiamodest weight gaincardiovascular benefits to be proven 2021/7/19 星期一12短效促胰島素分泌劑特征long Nateglinide is a D-phenylalanine deriv.Repagli

9、nide is a meglitinide Rapid onset/short dur.Pimarily affect ppg指征monotherapycomb. with metforminPotential優(yōu)點possibly less hypoglycemia and less weight gain than SUs e.g missed meals; nightOK in renal failuretargets postprandial不足expensiverequire more dosesNateglinide is less effective than SU or repa

10、glinide2021/7/19 星期一13Metformin特征longPrimary mechanism is reduction of hepatic glucose productionImproved insulin sensitivity in livermoderately rapid affect指征monotherapycomb with TZD or secretagogue comb with insulin優(yōu)點long experiencegood efficacyweight benefitsproven microvascular & macrovascular o

11、utcomes moderate cost不足GI side effectsmany contraindicationslactic acidosis2021/7/19 星期一14噻唑烷二酮類特征longtrue skeletal muscle sensitizersreduce FFAeffective once dailyrelatively slow onset 指征monotherapycomb with SU or Metcomb with insulin*優(yōu)點very effective in highly insulin resistant pts.OK in renal dis

12、easepossible cv benefit (?)-cell protective (?)不足expensiveweight gainedemacan induce CHF* rosiglitazone not approved for this use2021/7/19 星期一15 2型糖尿病的聯(lián)合用藥There exist four classes of pharmacologic agents Combining agents from different classes provides at least additive benefits without additive tox

13、icityPotential Indications:improve glucose control when maximally effective dose of a single agent has failed to keep the HbA1C 7.0%avoid adverse effects that occur with high doses of single agentlimit insulin dose in highly resistant patients (e.g. 1u/kg/d)Long-term and comparative benefits of vari

14、ous combinations have not been studied2021/7/19 星期一16口服藥治療失效加用睡前胰島素Continue the two oral agents may reduce SU to 1/2 max doseAdd Glargine or NPH at bedtime or 70/30 or Humalog Mix 75/25 before dinnerbegin with 0.15 u/kg; dose by 4-6 u q 3-5 days until fasting BG is 120; then more slowly to 100 mg/dl

15、If evening insulin s FBS to 100 but acD is go to multiple daily injections or premixedIf FBS and acD are ok but HS is high 70/30 acD or give short-acting at dinnerReduce one of the two oral agents if BGs 7.0 非空腹： 4.48.0 10.0 10.0 7.5 130/80 140/90 140/90男性： 25 27 27女性： 24 26 26 1.1 1.10.9 0.9 1.5 2.

16、2 2.2 4.0理想 尚可 差2021/7/19 星期一22血糖控制0510158.7FBG (mmol/l)05107.7HbA1C (%) 6.1 18.4%6.1 mmol/l最佳血糖控制的亞洲標準6.5%6 mmol/l6.1 mmol/lFBG血糖控制：FBG達到并發(fā)癥風(fēng)險水平的病人 020406080100748382占總病人數(shù)比例 (%)ADAEUAP平均= 8.7 3.2 mmol/l76%的病人評估了FBGn = 17116.7 mmol/l6.0 mmol/l6.1 mmol/l2021/7/19 星期一24血糖控制：HbA1c達到并發(fā)癥風(fēng)險的病人020406080100

17、607284占總病人數(shù)比例 (%) 7%6.5%6.2%HbA1cADAEUAPn = 2243均數(shù) = 7.8 0.6%2021/7/19 星期一25Source: DCCT Intensive Therapy Group; NEJM; 329, 14, 977-986 (1993)不同HbA1c均值發(fā)生嚴重低血糖的頻率2021/7/19 星期一26血糖監(jiān)測與血糖控制的關(guān)系Kaiser Permanente of Northern California 24312 adult patients with diabetesFound a direct relationship between

18、frequency of testing and glucose controlEven those without pharmacologic treatment had better glucose control with more monitoring.Monitoring 3 times daily or more was associated with 1% lower HbA1c in insulin treated patients and 0.6% in those on oral agents2021/7/19 星期一27血糖監(jiān)測與HbA1c的關(guān)系Karter AJ et al. Am J Med 111:1-9, 20012021/7/19 星期一28血糖監(jiān)測與HbA1c的關(guān)系 Karter AJ et al. Am J Med 111:1-9, 20012021/7/19 星期一29血糖監(jiān)測頻率與HbA1c的關(guān)系 F( 2型糖尿病患者)HbA1c 8.0%HbA1c 8.0%定期監(jiān)測 (21%)70%30%不定期監(jiān)測 (42%)18%82%