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【经验】2型糖尿病合并慢性肾脏病患者服用二甲双胍的治疗方案

MY APPROACH to Use of Metformin in Patients With CKD

发布者:PracticeUpdate 发布时间:2014-8-13

 Clifford J. Bailey博士,英国爱丁堡皇家内科医师学会会员FRCP(Edin)

大多数国际指南对于2型糖尿病患者高血糖的管理都建议把二甲双胍患者的首选初始治疗药物,而且,由于二甲双胍除血糖控制以外的其他益处,其治疗时间应尽可能长。但是,肾功能受损的患者避免使用二甲双胍,20%-40%的2型糖尿病患者存在肾功能损伤(肾小球滤过率GFR<60 mL/min)。因此,对于CKD患者,二甲双胍的起始用药以及如何继续用药就成为一个老生常谈的话题。

益处与风险

二甲双胍增加胰岛素依赖和非胰岛素依赖效用从而可以减轻胰岛素抵抗、降低高血糖且不会引发低血糖症和体重增加。二甲双胍还可以降低心血管风险,且其独立与降血糖效应之外。前瞻性研究和回顾性研究证明二甲双胍对改善微血管和大血管功能具有长期效用。另外,有限证据表明,二甲双胍可能有助治疗多囊卵巢综合征以及减少某些癌症的发病风险。

进入血液循环的二甲双胍大约20%经过肾小球过滤,80%由肾小管分泌,最终几乎全部以原型从尿液排泄。肾功能正常者血浆中二甲双胍的半衰期大约为6-7小时,GFR下降者半衰期延长。二甲双胍在体内蓄积会增加乳酸酸中毒风险,据报道大约3-6例/10万患者-年,但是,发生二甲双胍乳酸酸中毒者约有一半会导致死亡。虽然对于二甲双胍导致2型糖尿病患者乳酸酸中毒的程度一直存在争议,但值得关注的是大多数这些案例都发生在肾衰竭的患者。这些服用二甲双胍的患者可能合并有慢性肾脏病但未注意药物禁忌症,或者是急性肾衰竭患者。

美国对二甲双胍禁忌症的描述

美国于1995年推出的二甲双胍药品说明书中提出了安全界限以防药物蓄积,并提示在开始服用二甲双胍前以及用药后至少每年检查肾功能,如果已经出现肾功能损伤或预期发生进一步恶化,则需进行更频繁地监测。建议80岁以上的患者需提高警惕并且重新调整二甲双胍剂量。

美国二甲双胍药品说明书的禁忌症为血肌酐水平男性>1.5 mg/dL、女性>1.4 mg/dL。然而,有些研究发现血肌酐超出此界限的患者服用二甲双胍是个普遍现象,但是乳酸酸中毒的发生率并无明显上升。这或许可以体现药品说明书中血肌酐安全界限值的作用。但是,依据数十年来的经验,下面两个问题还有待解答:重新定义二甲双胍的安全界限是否存在一定程度的自由度;以及当前禁忌服用二甲双胍的患者是否能够从该药中获得潜在的益处。

估算肾小球滤过率是一种评估肾功能的方法,在调整了性别、年龄和体表面积等因素,估算肾小球滤过率(eGFR)是一种常用评估肾功能的方法。那么,CKD患者是否应该根据eGFR值来重新制定二甲双胍的使用呢?

已修改禁忌症的临床指南

英国国家卫生与临床优化研究所(NICE) 建议:在没有其他禁忌症且监测良好的情况下,患者可以继续接受二甲双胍治疗直至eGFR低于45mL/min/1.73m2或血肌酐高于1.5mg/dL;而eGFR低于45mL/min/1.73m2者不宜把二甲双胍作为起始用药;已经接受二甲双胍治疗的患者可以继续用药,但要重新评估用药剂量(通常可能需要减量)和检测肾功能;如果eGFR低于30mL/min/1.73m2或血肌酐高于1.7mg/dL,则必须停用二甲双胍。

此外,加拿大和澳大利亚的指南也给出了类似的建议。

CKD患者服用二甲双胍的剂量调整

随着逐渐增加到每日最大剂量的2000 mg/天,二甲双胍的降糖效果也达到极限。在肾功能尚可的情况下,所谓典型的“治疗性”二甲双胍循环浓度为1-2μg/mL,最高不超过5μg/mL。

虽然二甲双胍的消除在很大程度上赖于肾小管的分泌能力,但肾小球滤过率(GFR)仍然是一个重要指标:肾脏对二甲双胍的清除能力随GFR的降低而近乎呈线性下降。因此,当肾功能下降时,应调整二甲双胍剂量以使循环浓度控制在治疗范围之内。短期内人体可耐受二甲双胍的蓄积,但长期是无法承受的。

除了当前的eGFR指标,其他禁忌症也对二甲双胍的剂量调整有影响,尤其是血氧不足。当eGFR接近45mL/min/1.73 m2时,二甲双胍剂量可以适当减少;当eGFR<45mL/min/1.73 m2时,二甲双胍剂量应减半;而在eGFR<30mL/min/1.73 m2前需停用二甲双胍。当出现急性肾功能恶化、脱水、严重肝病、严重感染或心脏、呼吸功能异常所致的血氧不足时,也应注意停用二甲双胍。

免责声明,要强调的是,以上建议来源于NICE,与二甲双胍美国处方无相关责任。

Clifford J. Bailey PhD, FRCP(Edin), FRCPath

Most international guidelines for the management of hyperglycemia in patients with type 2 diabetes suggest metformin as the initial preferred pharmacotherapy. Treatment with metformin is usually continued for as long as possible because the beneficial effects of this agent extend beyond glycemic control. However, metformin is contraindicated in patients with impaired renal function, and 20% to 40% of patients with type 2 diabetes are reported to incur impaired renal function (as indicated by a glomerular filtration rate [GFR] <60 mL/min). Thus, questions are often raised about the initiation or continued use of metformin in type 2 diabetes patients who develop chronic kidney disease (CKD).

Benefits and risks

Metformin exerts insulin-dependent and insulin-independent effects that counter insulin resistance and reduce hyperglycemia without causing hypoglycemia and without causing weight gain. Metformin also reduces cardiovascular risk independently of its glucose-lowering effect, and there is prospective and retrospective evidence of improved long-term micro- and macrovascular outcomes with use of metformin. Additionally, there is limited evidence that metformin may be helpful in the treatment of polycystic ovary syndrome and may possibly reduce the risk for some cancers.

Almost all of the metformin that enters the circulation is eliminated unchanged in the urine, about 20% by glomerular filtration and 80% by tubular secretion. The plasma half-life is typically 6 to 7 hours in a person with normal renal function, increasing as the GFR declines. Accumulation of metformin is reported to carry a rare risk for lactic acidosis, which is estimated at 0.03 to 0.06 per 1000 patient years; but, around half of these cases can be fatal. Although there is on-going debate over the extent to which metformin has contributed to cases of lactic acidosis during treatment of type 2 diabetes, it is notable that most cases have occurred in patients with renal failure. These may have been patients with CKD who received the drug despite contraindications or patients who developed acute renal problems.

Prescribing contraindication in the US

The US product information for metformin (introduced in 1995) offers a safety margin against the accumulation of the drug. The product insert notes that renal function should be checked before starting metformin and at least annually thereafter, but more frequently if renal function is already reduced or deterioration is anticipated. Extra vigilance and reconsideration of dose titration are recommended for those aged >80 years.

In the US product information, the measure of renal function that contraindicates metformin is a serum creatinine >1.5 mg/dL for men and >1.4 mg/dL for women. However, several studies have found widespread use of metformin in patients with serum creatinine values above these boundaries, apparently without a noticeable increase in the incidence of lactic acidosis. This, of course, may vindicate the safety margin given by the serum creatinine boundaries in the product insert. However, it also raises the question of whether, in the light of decades of experience, there is any latitude to redefine these boundaries and offer the potential benefits of metformin to some of the patients in whom the drug is presently contraindicated.

Renal function is now more commonly assessed using an estimated GFR (eGFR) calculated by the MDRD method, which adjusts for gender, age, and body surface area. So, should a reconsideration of metformin use in CKD adopt eGFR as a measure of renal function?

Guidelines with revised contraindications

In the UK, the National Institute for Health and Care Excellence (NICE) recommends that, in the absence of other contraindications and with appropriate monitoring, patients can continue to receive metformin until the eGFR declines to 45 mL/min/1.73 m2 or the serum creatinine rises to 1.5 mg/dL (130 µmol/L). Metformin should not be started if the eGFR deteriorates below 45 mL/min/1.73 m2, but metformin can be continued for patients already receiving the drug, subject to careful review of the dose (which is likely to be reduced) and appropriate monitoring. If the eGFR declines to below 30 mL/min/1.73 m2 or the serum creatinine exceeds 1.7 mg/dL (150 µmol/L), then metformin should be stopped.

Similar guidelines in Canada and Australia also allow use of metformin, with appropriate caution, to an eGFR of 30 mL/min/1.73 m2.

Adjusting the metformin dose in CKD

Maximal glucose-lowering effects of metformin are usually achieved with dose escalation up to about 2000 mg/day (in divided doses with meals using the immediate-release formulation). With adequate renal function, this gives typical “therapeutic” circulating concentrations of metformin around 1 to 2 µg/mL and certainly below 5 µg/mL.

Although the elimination of metformin is largely dictated by the secretory capability of the renal tubules, GFR appears to be a useful surrogate for metformin elimination, and clearance of metformin declines approximately linearly with reduced GFR. Thus, as renal function declines, the dose of metformin should be adjusted to keep the circulating concentration within the therapeutic range. Some accumulation of metformin may be tolerated in the short term, but this is not acceptable in the long term.

In addition to the prevailing eGFR, dose adjustment for metformin will be influenced by the presence of other contraindications, particularly any conditions that predispose to hypoxemia. A typical dose reduction might see a modest reduction in dose as the eGFR approaches 45 mL/min/1.73 m2, and a half dose (ie, <1000 mg/day) if the eGFR is <45 mL/min/1.73 m2, before stopping metformin at an eGFR <30 mL/min/1.73 m2. Be prepared to withhold metformin if there is an acute renal deterioration, dehydration, severe liver disease, severe infection, or imminent risk for hypoxia with heart or respiratory conditions.

By way of a disclaimer, it is stressed that, while the suggestions above are supported by NICE in the UK, they do not obviate the responsibilities of prescribing within the US. 

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来源: PracticeUpdate
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