MY APPROACH to Use of Metformin in Patients With CKD
Clifford J. Bailey博士，英国爱丁堡皇家内科医师学会会员FRCP(Edin)
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。
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。
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.