Research Is Always Trending
Background: Metformin is one of the principal treatments in type 2 diabetes mellitus (T2DM) because of his benefits in cardiovascular system, cancer incidence or diabetes prevention.
In cases of advanced chronic kidney disease (ACKD) or acute renal failure may lead to a severe type B lactic acidosis with high rates of mortality restricting its use in these patients and depriving them of these important beneficial effects.
Summary: A systematic review, compiling recent and more relevant papers: systematic reviews, observational studies, original research, pharmacokinetic and pharmacodynamic studies and expert opinions about the current state and safety of metformin in advanced CKD. The analysis has been structured about pharmacokinetic and pharmacodynamic data, potential benefits, mortality and rate of metformin-associated metabolic acidosis (MALA).
Key Messages: Several papers described interesting pharmacokinetic and pharmacodynamic data of metformin behavior in advanced CKD. The dose-dependent toxicity, among other modifiable factors, with a low rate of MALA has been a strong finding. There is enough evidence to believe that a daily dose of 500mg with some medical advices seems safety and appropriate. A pilot clinical trial is imperative
Metformin is one of the principal treatments in type 2 diabetes mellitus (T2DM) and one of the three biguanide compounds: phenformin, buformin and metformin. Metformin has a renal elimination, being contraindicated in patients with advanced chronic kidney disease (CKD) (glomerular filtration less than 30mL/min,) and a very low rate of acidosis compared to the other family compounds, especially phenformine, the first approved for human use [1,2]
The benefits of Metformin on glycemic control, cardiovascular morbidity and mortality in relation to other diabetic drugs are now widely known [3-7]. An important analysis from the UKPDS study concluded that the cardiovascular outcomes may be independent of dose . A urinary albumin excretion reduction in obesity and a reduction in micro-vascular and macro-vascular complications independent of glycemic control with a lower incidence of renal cancer and others have been another important finding [9-12]. Metformin withdrawal often induces a poor glycemic control and the loss of these cardiovascular benefits in a high-risk population .
Metformin clearance depends on factors like kidney disease or low-function of his Organic Cation Transporters (OCT) variants . Metformin induce inhibition of the hepatocyte mitochondria cycle leading to a gluconeogenesis and glycogenolysis reduction, a glycolysis increased and an activation of intestinal anaerobic metabolism [1,2,14]. Lactic acidosis risk factors are: tissue hypoxia, overdose, sepsis, shock, myocardial infarction, renal, cardiac, respiratory or hepatic failure. Acidosis could have fatal repercussions in form of ventricular dysfunction, pulmonary edema or coma. [1,2].
Metformin associated lactic acidosis (MALA) has a frequency ranging from 1 to 47 cases per 100,000 person-years, the mortality rate is around 50%, the use of metformin worldwide in relation to the number of MALA reports seems to be not much significant . There are epidemiological controversial data about an increased MALA risk versus others studies with a no positive association even in CKD patients. The additional risk factors are largely present [1, 2].
The pharmacokinetics data of metformin in CKD come from hemodialysis, hemodiafiltration or in overdose and lactic acidosis contexts [15,16]. The therapeutic plasma range of metformin concentration is controversial but levels greater than 5 mg/L are considered high and potentially dangerous. .
This review consist of a recent and most impact papers analysis, including systematic reviews, retrospective observational studies, original research, pharmacokinetic and pharmacodynamic data and current opinions about the possibility of metformin employment on advanced CKD.
A pharmacokinetic model of metformin developed by K. Duong et al.  describes the variability factors between healthy subjects and (T2DM) patients as well as drug concentrations in renal patients. They grouped metformin plasma data from 3 studies: study A (2 DM patients, n=120), study B (healthy Caucasian subjects, n = 16) and study
C (n = 169, healthy Malaysia subjects). In the A study 52 patients (43%) had creatinine clearance (CrCl) below 60mL/min, including 13 patients (11%) with advanced CKD (CrCl below 30mL/min). In the (T2DM) group approximately 50% of patients were taking metformin plus another oral anti-diabetic drug, mainly sulfonylureas. Pharmacokinetics were developed for metformin Immediate Release (IR) and prolonged release (XR) formulations. The variables investigated were CrCl between others (total and lean body weight, 57 polymorphisms of metformin transporters). This model allow simulate 1,000 concentration time profiles to evaluate metformin dose ranges (500, 1,000, 2,000 and 3,000 mg) at different levels of CrCl (CrCl: 15, 30, 60 and 120 mL/min) to ensure that Cmax 95th percentile was kept below 5 mg/L.
C. Smith et al. described his experience with four patients with (T2DM) in Hemodiafiltration (HDF) (18) three times per week during a 3-month follow-up period. The initial dose was 500 mg of IR metformin after each HDF session. Pre- HDF blood samples were taken at the end of weeks 1, 4, 8 and 12 respectively. To determine metformin clearance during the session pre and post filter, samples were collected in each procedure. Three venous blood samples were collected from 4 to 42 hours post dose 3 times to determine metformin concentrations between the HDF sessions. Metformin dose would be reduced if plasma concentrations are close to 5mg/L and/or if the lactate concentrations were close to 45mg/dL.
Mala (Metformin-Associated Metabolic Acidosis)
Inzucchi et al.  tired of determine the risk of MALA, they searching for articles between 1950 and June 2014. Of a total of 818 articles related to metformin, renal disease and metabolic acidosis, 65 were selected.
Hung et al.  using historical data from Taiwan, provide information with a unique insight: until 2009 metformin was prescribed in all patients irrespective of their renal function. They examined 12,350 stage 5 of CKD (T2DM) patients from the Taiwan National Health Insurance database between 1 January 2000 and 30 June 2009, with follow-up up to 31 December 2009. 1.005 patients were using metformin and 11.345 did not. All causes of mortality were the main objective.
Pharmacokinetics model results
In K. Duong et al. study, the mean daily metformin dose was 1,500mg. The mean clearance of metformin for studies A, B and C was 760mL/ min (156-2307mL/min), 1,201mL/min (800-1,762mL/min) and 1066 mL/min (564-3,048mL/min) respectively. The mean metformin concentration in A and B was 1.28mg/ L (0.2-7.7mg/l) and 0.9 (0.6- 1.1 mg/L), respectively. One patient with end-stage renal disease (CrCl =15 mL/min) presented the highest plasma metformin levels (7.7mg/L) with an oral dose of daily 2000mg. Dose simulations to ensure that the 95th percentile of metformin Cmax is less than risk levels (5mg/L), described a maximum daily doses of 500, 1,000, 2,000 and 3,000mg for a CrCl of 15, 30, 60 and 120mL/min respectively. The half-life was higher with lower CrCl (CrCl of 15, 30 and 60, mL/min, half-life of 13.8, 4.5 and 3 hours respectively) (Figure 3).
In hemodiafiltration patients study metformin pre-HDF concentrations approached 5mg/L at month in patients 1 and 2 so initial dose was reduced to 500mg once week. In patients 3 and 4 metformin dose was reduced to 250mg after each HDF. Metformin equilibrium or steady state was not possible to achieve. During HDF session metformin plasma concentrations were significantly reduced (52% -74%). Metformin plasma concentrations at 4 to 42 hours after dosing were generally constant, except in case of significant preserved residual renal function (patient 4) (Figure 1).
MALA studies results
Inzucchi et al.  described that metformin drug levels, therapeutic range and lactate concentrations do not increase significantly in situations of mild to moderate CKD. The overall incidence of MALA varies between studies (3 to 10 per 100,000 person-years) but is generally similar from the background rate in the population with diabetes. A. Frid et al. , showed that is indispensable high plasma concentrations of metformin to generate MALA. Other associated factors to MALA are sepsis, hepatic or renal insufficiency or heart attack or stroke. Metformin by itself was concomitant but not a clearly causal factor. Patients with (T2DM) have not an increase rate of MALA. Few studies also described a metformin a macro-vascular benefit, even in patients with renal failure. Lactate levels are not significantly increased in cases of reduced GFR and metformin use. (22-24). In a Swedish study, 51 675 men and women with (T2DM), not increased risk of MALA was described in eGFR of 30-45mL/min and metformin use ver us non-users .
In the Taiwan study they compared 813 patients with metformin versus 2,439 without it, no significant differences in variables analyzed between groups were found. The mean age was 67.2 years; the mean eGFR was 10 and 7 for 1.73 m² for men and women respectively. Allcause mortality was 53% (413 of 813) in the metformin group versus 41% (1012 of 2439) in the not metformin group. In the multivariate adjustment, metformin was described as an independent risk factor for mortality (adjusted risk ratio 1.35, 95% CI 1.20-1.51, p <0.0001). This risk of mortality was dose-dependent; those taking a dose of between 500-1000 mg/day did not present more risk of death than patients who did not take metformin. The MALA incidence was similar in both groups and without significant more risk (Figure 2). The metformin group was less susceptible to progression of CKD to dialysis.
Figure 1: Average metformin plasma concentrations entering the hemodiafilter before and after dose changes in patient with T2DM receiving HDF. Samples were collected before the hemodiafilter at the start of the HDF session, during, and at the end of HDF for all patients (n=4 time points). All patients were initiated on 500mg of metformin after HDF (1500mg/wk). At the start of week 5 and 6, the metformin dose was decreased to 500mg once weekly for patients 1 and 2, respectively (taken after HDF), and to 250mg after HDF (750mg/wk) at week 7 and 8 for patients 3 and 4, respectively.
Figure 2: Cumulative incidence (A) all-cause mortality and (B) metabolic acidosis among matched Ptients with type 2 diabetes and advanced (approximately stage 5) chronic disease, according to metformin use.
Figure 3: Simulations of the plasma concentration at maximum doses of metformin for patients with varying degrees of renal function. The 5th, 50th and 95th percentilesof the simulated concentrations are shown. The maximum daily dose of metformin immediate (XR) that should be given to patients with creatinie clearances of 15, 30, 60 or 120 are 500, 1,000 2,000 or 3,000mg, respectively. The IR doses are reported as equal split doses.
Metformin contradictions in renal disease is an exciting challenge: mortality data versus cardiovascular benefits, including a possible slower progression of diabetic nephropathy Patients with advanced CKD are associated with very high cardiovascular risk but they currently do not benefit from this treatment, nevertheless there are plenty scientific data to consider the use of metformin in these patients.
In the simulation model related to the CrCl made by Duong et al. a promising metformin behavior in CrCl less than 30mL/min is described. The simulation model for a daily dose of 500mg at 1 mL/ min of CrCl is associated with the best stability versus the other situations, as never exceed the marked limits and present the greatest distance to the dangerous level. This behavior is not observed with higher doses and even with higher CrCl levels.
MALA incidence is very low, including patients with all degrees of chronic kidney disease. The Taiwanese population study has several interesting strengths: national representativeness, follow-up period, detailed clinical information...and describes how the risk of mortality is a dose dependence finding and also a no greater risk with doses of 500-1000mg/day in comparison with others. The incidence of MALA remains very low but presents with high mortality in glomerular filtrations around 10mL/min. It is mandatory not forget the other factors that contribute to Mala: dehydration, gastroenteritis, sepsis, hepatic and renal insufficiency, stroke, heart attack.
Metformin use in HDF situations is associated with high dose variability, it is necessary to reduce dose after a month approximately by the preserved residual renal function and also by the HDF dose. An individual and not fixed-dose behavior is intuited, it would be necessary establish a frequently monitoring blood levels in clinical practice. It is mandatory to note that metformin plasma levels do not correlate consistently with lactate levels because the necessary presence of others elements: infection, hypoperfusion, shock... We cannot adequately monitor metformin in a situation where drug levels are high variable and If we think in the high mortality rate associated with glomerular filtration rates around 10mL/min, we can concluded that the use of metformin in dialysis patients remain complex and prohibitive, it would be necessary continue expanding studies with a longer follow-up period but with an important difficult ethical approval. In conclusion we do not encourage further investigation on this ESRD population.
If we think in patients in stage 4 of CKD, they have enough renal function and why not they could use a demonstrated safe dose of 500 or even 250mg/day? this would be especially relevant in those who are stable for a considerable period of time. It would be mandatory to provide few important advices to diabetic patients: stop metformin during an inter current illness, dehydration risk or before a surgical operation, also it would be recommended to perform periodical studies of metformin plasma levels, this would be especially interesting in patients who are rapid progressors where it would be mandatory to withdrawn metformin as estimated GFR approaches to 15mL/min. The cardiovascular benefits are independent of the dose and in addition there also appears to lower the incidence of certain types of cancer [26-32]. We can also believe that diabetic nephropathy could be delayed, reduce the annual incidence of end stage renal disease (ESRD) and provide significant economic benefits for the health system.
Taking into account the number of people with CKD and type 2 DM, there should be thousands or millions patients without the drug and might benefit from its use.
This stage 4 of CKD population has more interesting field of applications rather than dialysis population.
We strongly believe that the contradictions of use of metformin should be taken under consideration. It is possible that an exhaustive and caution clinical follow up of these advanced CKD patients might allow so [32,33]. This fact should be sufficiently supported by well designed clinical trials.