二甲双胍是ckd最好的降糖药Hypoglycaemic Agent in Chronic Kidney Disease

Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com The Opposite View Nephron Clin Pract 2011;118:c380–c383 DOI: 10.1159/000323739 Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? Helen J. Nye   a William G. Herrington   b a   North Bristol NHS Trust, Bristol , and b   Oxford Kidney Unit, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxford , UK Introduction Metformin is a highly effective agent in the treatment of type 2 diabetes. In addition to controlling blood sugar, it has been shown to reduce the long-term complications of diabetes, including macrovascular disease. The long- standing and now entrenched anxiety over the prescrip- tion of metformin in patients with chronic renal impair- ment has arisen from a theoretical risk of lactic acidosis arising from reduced clearance and consequent accumu- lation of the drug. However, critical analysis of the avail- able literature suggests that the contribution of metfor- min to lactic acidosis is minimal, with tissue hypoxia be- ing the most significant risk factor. Background Metformin is a biguanide which acts independently of insulin to lower blood glucose levels primarily through the inhibition of hepatic gluconeogenesis. It is the first- line oral agent in the treatment of type 2 diabetes melli- tus, and there is growing interest in its potential in type 1 diabetes. Extensive clinical experience has been com- plemented by favourable results from the UK-PDS, in which metformin was shown to reduce the incidence of macrovascular complications (myocardial infarction, angina, sudden death, stroke and peripheral vascular Key Words Metformin � Lactic acidosis � Renal impairment Abstract Metformin is the first-line oral agent in the treatment of type 2 diabetes and has many established benefits, including the reduction of macrovascular complications of diabetes. Its prescription in patients with renal impairment is limited by concerns relating to the theoretical risk of lactic acidosis, a fear which is perpetuated by numerous case reports in which it is implicated. Critical review of this literature calls into question the validity of these claims, with metformin usually acting as an ‘innocent bystander’ in acutely unwell patients with conditions well recognised to precipitate lactic acidosis such as sepsis or hypovolaemia. In fact, the evidence sup- ports the safe use of appropriate doses of metformin in patients with chronic stable renal impairment, and high- lights the important possible greater risks of the alternatives, most notably severe hypoglycaemia in patients taking sul- phonylureas and/or insulin and fluid retention in patients taking a thiazolidinedione. Other traditional contraindica- tions to metformin use such as heart failure are also being re-evaluated, as the benefits of metformin in these patients are increasingly recognised. Physicians should weigh this ev- idence carefully before deciding to withdraw metformin therapy in their patients with stable chronic kidney disease. Copyright © 2011 S. Karger AG, Basel Published online: February 16, 2011 Dr. William G. Herrington Oxford Kidney Unit, The Churchill Hospital Oxford Radcliffe Hospitals NHS Trust Old Road, Headington, Oxford OX3 7LE (UK) Tel. +44 186 574 3926, E-Mail w.herrington   @   doctors.org.uk © 2011 S. Karger AG, Basel 1660–2110/11/1184–0380$38.00/0 Accessible online at: www.karger.com/nec Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? Nephron Clin Pract 2011;118:c380–c383 c381 disease) in overweight patients with type 2 diabetes. This benefit was independent of glycaemic control and other traditional cardiovascular risk factors [1] . In contrast to the oral alternatives and insulin, metformin is not asso- ciated with a risk of hypoglycaemia, nor does it cause weight gain [2] . In addition, recent observational data suggests that, when compared to sulphonylureas and in- sulin, metformin is associated with a reduced risk of de- veloping solid organ cancer (after cardiovascular dis- ease, the second largest cause of death in patients with diabetes) [3] . Between 20 and 40% of patients with diabetes ulti- mately develop diabetic nephropathy. As a result of the combination of chronic kidney disease, diabetes and, in most cases, other traditional risk factors, these patients are at particularly high risk of cardiovascular events. However, in this group, prescription of metformin has been limited by a concern that its accumulation may be associated with lactic acidosis. Metformin is eliminated unchanged by the kidney, and would be expected to ac- cumulate as the glomerular filtration rate (GFR) falls, in- creasing the theoretical risk of lactic acidosis. Current NICE guidelines [4] recommend that the dose of metfor- min should be reviewed if the serum creatinine exceeds 130 � mol/l (or estimated GFR is ! 45 ml/min/1.73 m 2 ) and that metformin should be stopped in patients in whom the creatinine rises above 150 � mol/l or eGFR falls to ! 30 ml/min/1.73 m 2 . Evidence from the Literature Predictably for such a rare event, the evidence for metformin-associated lactic acidosis is derived mainly from case reports or physician reports to drug safety committees. While metformin overdose can certainly cause lactic acidosis, analysis of all case reports has re- peatedly undermined the notion of a simple causal rela- tionship between metformin use and lactic acidosis in patients with diabetes [5, 6] . Particular criticisms have included: inadequate, or poor quality of information in reports, failure to measure metformin concentrations, and a normal metformin concentration at the time of lactic acidosis. In the majority of cases, other insults in- cluding sepsis, hypovolaemia, ischaemic events or he- patic failure are the prime cause of the lactic acidosis, with metformin merely an ‘innocent bystander’. The conclusion of the most recent Cochrane review [7] is clear: there is no evidence from prospective compara- tive trials or from observational cohort studies that met- formin is associated with an increased risk of lactic aci- dosis, or with increased levels of lactate, compared with other oral hypoglycaemic treatments. Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or non-fatal lactic acidosis in 70,490 patient- years of metformin use or in 55,451 patient-years in the non-metformin group. This implies an upper limit for true incidence of lactic acidosis of 5 per 100,000 patient- years. Although individual creatinine concentrations were not available in the meta-analysis, 45% of the studies reviewed did not exclude patients with a creatinine 1 133 � mol/l. This equates to 37,360 patient-years of metfor- min use in studies including chronic kidney disease pa- tients with no episodes of lactic acidosis. A recent nested case-control study using the UK- based General Practice Research Database (GPRD) iden- tified over 50,000 patients with type 2 diabetes taking oral anti-diabetes drugs with or without concomitant in- sulin use [8] . All cases of lactic acidosis occurring after first prescription of an oral anti-diabetic drug were re- viewed. The crude incidence rate of lactic acidosis was calculated as � 3.3 per 100,000 patient-years in metfor- min users, and � 4.8 per 100,000 patient-years in sulpho- nylurea users. The incidence of lactic acidosis in patients with diabetes does not appear to be influenced by the use of metformin. This study also investigated the incidence of hypo- glycaemia presenting to a physician within the same pa- tient population. It revealed that the crude incidence of hypoglycaemia for those patients prescribed sulphonyl- ureas was 110 per 100,000 patient-years and for metfor- min users (usually prescribed in combination with oth- er hypoglycaemic agents) 60 per 100,000 patient-years. Of the 73 cases of severe hypoglycaemia (3.6% of the to- tal events) that resulted in hospitalisation or death, only 3 patients were on metformin alone. Compared to pa- tients taking metformin alone the adjusted odds ratios for severe hypoglycaemia with sulphonylureas, insulin and the two in combination were 2.8, 16.5 and 39.9, re- spectively. Renal failure was the only co-morbidity that was significantly associated with an increased risk of hypoglycaemia. It has therefore been suggested that the risk of death as a result of sulphonylurea- (or insulin-) induced hypoglycaemia in CKD patients is likely to be greater than the risk of death due to metformin-associ- ated lactic acidosis. Metformin has other potential advantages: a recent letter from a nephrologist in India [9] , where in the year 2000 there were 31.7 million people with diabetes, ex- pands on the particular advantages of metformin over Nye   /Herrington   Nephron Clin Pract 2011;118:c380–c383 c382 insulin therapy in the developing world. Metformin is much cheaper than insulin, and avoids the infection risk associated with subcutaneous injections and invasive glucose monitoring. The stated contraindications to metformin include: hypoxic conditions (respiratory failure and heart fail- ure), impaired lactate clearance (liver failure) and im- paired metformin clearance (renal failure). However, the degree of impairment (of any organ) that should pre- clude metformin use has not been well-defined. Indeed, in a meta-analysis of retrospective cohort studies of pa- tients with both diabetes mellitus and heart failure (once believed to be a contraindication to metformin use), metformin was associated with reduced rates of hospi- talisation and death and was the only anti-diabetic drug that emerged without evidence of any associated harm. In contrast, thiazolidinediones cause fluid retention and are associated with an increased risk of hospitalisa- tion with symptomatic heart failure [10] . Rosiglitazone is also associated with an increased risk of cardiovascu- lar events. It has recently been suspended by European drug regulatory agencies, and in the USA new FDA re- strictions advise its prescription only in patients whose diabetes cannot be controlled on other medications. Thiazolidinediones are thus unlikely to benefit diabetic patients with a reduced GFR who already have both im- paired handling of salt and water and a higher baseline risk of cardiovascular events. Pharmacokinetic studies of metformin are in small numbers of subjects, and suggest that metformin doses should be reduced by one third in patients with eGFRs of ! 45 ml/min/1.73 m 2 [11] . Metformin is likely to be toler- ated at eGFRs of ! 30 ml/min/1.73 m 2 , particularly in pa- tients with stable CKD with no other significant hepatic or respiratory failure. However, more detailed pharmaco- kinetic investigation of metformin elimination in renal patients is required before current dosing guidelines can be changed. Metformin is removed by haemodialysis, but unlike drugs such as vancomycin, gentamicin and digox- in, plasma concentrations are not available in routine clinical practice. Increasing the availability of metformin assays would not only serve to reassure physicians that reducing metformin doses in renal impairment was safe and sufficient to preclude accumulation, but careful monitoring might even allow metformin to be adminis- tered three times weekly post-dialysis in patients with end-stage renal disease. Conclusions Lactic acidosis is rare and unpredictable. It is usually precipitated by an additional acute condition predispos- ing to tissue hypoxia. Metformin is an effective oral agent in the treatment of type 2 diabetes and in the prevention of its complications, particularly in overweight patients. Although a number of reports have been published sug- gesting that metformin is a cause of lactic acidosis, sys- tematic review of all the available trials and cohort stud- ies does not support this. In fact, the evidence suggests that type 2 diabetes mellitus itself may be associated with reduced lactate clearance and be a more important risk factor for lactic acidosis than metformin. Sulphonylureas, the major oral alternative, and of course insulin, are associated with weight gain and hypo- glycaemia (which is also more common in patients with renal impairment). They carry a more significant total morbidity and mortality than lactic acidosis. In spite of this, the majority of patients with chronic stable kidney disease (who stand to gain most from its cardiovascular benefits) are being denied metformin. Metformin will always be avoided in patients whose renal function is deteriorating acutely and in those pa- tients in whom oxygenation, tissue perfusion or liver function are severely compromised. However, in patients with type 2 diabetes and stable chronic kidney disease, clinicians are doing their patients a disservice by prema- turely and unnecessarily withdrawing metformin treat- ment. Acknowledgement Thanks to Dr. C.G. Winearls for his review of the manuscript. Conflicts of Interest None to declare. References 1 UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–856. 2 Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, Wiley C, Selvin E, Wil- son R, Bass EB, Brancati FL: Systematic re- view: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007; 147: 386–399. Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? Nephron Clin Pract 2011;118:c380–c383 c383 3 Currie CJ, Poole CD, Gale EA: The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766–1777. 4 NICE Clinical Guideline CG87 (May 2009): Type 2 diabetes – newer agents (a partial up- date of CG66). 5 Stades AM, Heikens JT, Erkelens DW, Holle- man F, Hoekstra JB: Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004; 255: 179–187. 6 Lalau JD, Race JM: Lactic acidosis and met- formin therapy: searching for a link with metformin in reports of ‘metformin-associ- ated lactic acidosis’. Diabetes Obes Metab 2001; 3: 195–201. 7 Salpeter SR, Greyber E, Pasternak GA, Sal- peter EE: Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 dia- betes. Cochrane Database Syst Rev 2010; 4: CD002967. 8 Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR: Metformin, sulfonylureas, or oth- er antidiabetes drugs and the risk of lactic acidosis or hypoglycaemia. Diabetes Care 2008; 31: 2086–2091. 9 Mani MK: Metformin in renal failure – weigh the evidence. Nephrol Dial Transplant 2009; 24: 2287–2288. 10 Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, John- son JA: Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007; 335: 497–506. 11 Sambol NC, Chiang J, Lin ET, Goodman AM, Liu CY, Benet LZ, Cogan MG: Kidney function and age are both predictors of phar- macokinetics of metformin. J Clin Pharma- col 1995; 35: 1094–1102.