Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus—use which, in most reports, has not been associated with increased rates of lactic acidosis.

Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. Conclusions and Relevance Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

Inzucchi SE , Lipska KJ , Mayo H , Bailey CJ , McGuire DK. Metformin in Patients With Type 2 Diabetes and Kidney Disease : A Systematic Review. Artificial Intelligence Resource Center. Featured Clinical Reviews Screening for Atrial Fibrillation: US Preventive Services Task Force Recommendation Statement JAMA.

X Facebook LinkedIn. This Issue. Views 34, Citations View Metrics. Share X Facebook Email LinkedIn. Silvio E. Inzucchi, MD 1 ; Kasia J. Lipska, MD, MHS 1 ; Helen Mayo, MLS 2 ; et al Clifford J. Bailey, PhD 3 ; Darren K. However, after considering the scientific literature, clinical data, epidemiological studies and clinical guidelines from medical bodies, EMA concluded that the large patient population with moderately reduced kidney function can benefit from use of metformin.

Clear dosing recommendations and monitoring before and during treatment aim to minimise any possible increased risk in these patients. Companies marketing metformin-containing medicines will be requested to closely monitor and analyse future lactic acidosis cases and report these during upcoming periodic safety reviews in order to follow up on any changes in the frequency of this side effect.

The product information for metformin-containing medicines will be updated to reflect the new recommendations and to ensure that the same advice is given to all patients in the EU.

Ekström, N. et al. Eppenga, W. Inzucchi, S. Richy, F. Roussel, R. Salpeter, S. Solini, A. Metformin is a medicine used on its own or in combination with other medicines for the treatment of type 2 diabetes. Metformin is used together with diet and exercise to improve control of blood glucose sugar levels.

Medicines containing metformin alone have been authorised nationally in the EU since the s, marketed as Glucophage and other tradenames. The review has been carried out by the Committee for Medicinal Products for Human Use CHMP , responsible for questions concerning medicines for human use, which has adopted the Agency's opinion.

For all three dose levels, there was a significant, inverse relationship between eGFR and metformin concentrations 12 h after the last dose after 1 week of treatment. Hence, the elimination of metformin by tubular secretion tends toward a constant. At increasing doses and plasma concentrations, tubular secretion becomes saturated and thus has a progressively less important role in the renal elimination of metformin We expected that this dose regimen would be safe but still pharmacologically efficacious in a context of moderate-to-severe kidney failure.

The blood metformin concentrations were remarkably stable. The absence of any upward trend over the study period thus validated our chosen metformin regimens. However, the question of what constitutes a stable but overly low blood metformin concentration i.

In fact, major methodological and conceptual errors have confounded the literature studies of so-called therapeutic concentrations for a review, see Kajbaf et al. A dose-efficacy study that relates blood glucose control to the plasma metformin concentration during chronic treatment is therefore still lacking.

With regard to high metformin levels, it should be borne in mind that massive metformin intake may induce hyperlactatemia 18 — Caution is therefore recommended when trying to link metformin to lactic acidosis 10 , Another important issue concerns the need or not to monitor metformin concentrations, given that metformin assays are costly and not always readily available.

Based on the present results, we do not recommend the monitoring of metformin levels in plasma or erythrocytes. Indeed, these levels can be predicted in patients with a stable eGFR once the metformin dose has been adjusted to the renal function.

In fact, the main question is whether or not metformin treatment is metabolically tolerated i. In this respect, 6 of the 46 patients displayed a lactate value above the upper normal limit i.

In each CKD stage, the mean lactate values did not rise from 1 monthly measurement to another. There was no correlation between the lactate concentration and the plasma or erythrocyte metformin concentration. The highest metformin concentrations were not accompanied by high lactate values, and vice versa, the highest lactate values were not observed in patients displaying high metformin concentrations.

There are a few PK studies of metformin in patients with CKD 25 , Based on a population with various dosing regimens, dose formulations, and degrees of renal function, Duong et al.

However, PK parameters have never been assessed in CKD in a steady state. Our results highlighted marked interindividual variations in metformin concentrations in the various CKD groups. These variations are mainly due to large differences in metformin bioavailability, genetic variability in metformin transporters, and renal clearance The three CKD groups did not differ significantly with regard to any of the PK parameters or the metformin concentrations.

The C avss measurements in plasma and erythrocytes providing a better idea of total drug exposure than the trough level alone were below the value of 2.

These results demonstrate that the metformin dose had been correctly adjusted for each of the three CKD stages studied here. Concerning safety, the variation in lactate levels in CKD stage 3—4 patients receiving chronic metformin treatment could have been compared with that of patients with normal renal function or CKD stage 2.

The classic parameter of HbA 1c was used as an index of the efficacy of metformin treatment; however, a further analysis after 3—4 months would have strengthened our observations.

Indeed, our satisfactory results do not constitute a direct call for the use of metformin in those patients but rather provide a solid basis for a larger, longer-term prospective study.

The suggested daily adjusted doses of metformin in CKD stages 3A and 3B are 1. Metformin should be withdrawn in patients likely to experience acute kidney injury in the context of severe pathologies. Lactate should be measured in fragile patients, particularly in the context of intercurrent disease.

The present studies are the first to have validated a metformin dose adjustment as a function of the eGFR in CKD patients. Our results support recent guidelines on metformin treatment in moderate-to-severe CKD and open the way for the initiation of metformin treatment in severe CKD, providing that the metformin dose is adjusted to the eGFR.

The authors thank Erik Snelders for editorial assistance. Dirk De Weerdt helped to draw the many figures in the manuscript. The insightful comments of Kerstin Brand and Ulrike Gottwald-Hostalek Merck KGaA, Darmstadt, Germany were much appreciated.

These studies were funded through an unrestricted grant by Merck KGaA Darmstadt, Germany and were conducted with Glucophage IR tablets. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. obtained extramural funding and contributed to the literature search, study design, data interpretation, and writing.

contributed to the literature search, study design, cohort development, and data coding and interpretation. and A. contributed to data measurement and interpretation. contributed to the interpretation of PK data and writing. contributed to the literature search, study design, data interpretation, and writing.

is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Sign In or Create an Account.

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Previous Article Next Article. Research Design and Methods. Article Information. Article Navigation. Emerging Technologies and Therapeutics January 05 Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4 Jean-Daniel Lalau Jean-Daniel Lalau.

Corresponding authors: Jean-Daniel Lalau, lalau. jean-daniel chu-amiens. fr , and Marc E. De Broe, marc. debroe uantwerpen. This Site.

Google Scholar. Farshad Kajbaf ; Farshad Kajbaf. Youssef Bennis ; Youssef Bennis. Anne-Sophie Hurtel-Lemaire ; Anne-Sophie Hurtel-Lemaire. Frans Belpaire ; Frans Belpaire. Marc E. De Broe Marc E. De Broe.