Farshad Kajbaf

Metformin therapy and kidney disease: a review of guidelines and proposals for metformin withdrawal around the world

We compared and contrasted guidelines on metformin treatment in patients with chronic kidney disease (CKD) around the world, with the aim of helping physicians to refine their analysis of the available evidence before deciding whether to continue or withdraw this drug.

Mortality rate in so-called "metformin-associated lactic acidosis": a review of the data since the 1960s.

The aim of this study is to study the mortality rate in so‐called “metformin‐associated lactic acidosis” (MALA) from the 1960s to date and to establish whether the rate has changed over time.

Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm

Although metformin has been used for over 60 years, the balance between the drugs beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so‐called “metformin‐associated lactic acidosis” (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin‐treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin‐unrelated lactic acidosis or metformin‐induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin‐treated patients. Accordingly, we propose a check‐list as a guide to clinical practice.

Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4

OBJECTIVE This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS Three complementary studies were performed: 1) a dose-finding study in CKD stages 1–5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. RESULTS First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. CONCLUSIONS Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.

Metformin accumulation without hyperlactataemia and metformin-induced hyperlactataemia without metformin accumulation

AIM These case reports demonstrate that, at the individual level, blood metformin concentrations and metformin effects on lactate do not always correlate. METHODS We report here on two unusual cases: metformin accumulation in the absence of hyperlactataemia; and metformin-induced hyperlactataemia with no metformin accumulation. RESULTS Patient #1 presented with severe kidney failure, severe acidosis (pH: 7.04), normal lactataemia (0.90 mmol/L) and marked metformin accumulation. Patient #2 presented with hyperlactataemia, even after dose reduction, during otherwise well-tolerated metformin treatment. Arterial lactate levels were 8.8, 8.2 and 4.7 mmol/L during metformin therapy with daily doses of 2550, 1700 and 850 mg, respectively. After withdrawal, metformin was reintroduced for 5-day periods at 500 mg/day up to 2000 mg/day with washout intervals. Lactate concentration, normal at baseline, rapidly exceeded 2 mmol/L after metformin administration. CONCLUSION These clinical data suggest a new concept for metformin therapy: there may be either resistance or, conversely, hypersensitivity to metformin effects on lactate generation according to the individual patient.

Unexpectedly long half-life of metformin elimination in cases of metformin accumulation.

In a study of the oral administration of a single dose of metformin to healthy participants, the estimated half‐life (t½) for the elimination of the drug from erythrocytes was found to be 23.4 h (compared with 2.7 h for metformin in plasma). However, these pharmacokinetic indices have not been well defined in metformin accumulation.

Interpreting the consequences of metformin accumulation in an emergency context: impact of the time frame on the blood metformin levels.

Objective. To clarify the link between metformin accumulation and its metabolic consequences by taking the time frame for metformin measurement into account. Research Design and Methods. Our database was studied for cases of metformin accumulation and lactic acidosis status available on admission, and then we selected patients in whom arterial pH, blood lactate, and plasma and erythrocyte metformin levels had been determined at the same time point. Results. Seventeen reports were studied on 16 patients, of whom 10 presented lactic acidosis. The time interval between admission and comprehensive testing ranged from 0 to 52 hours. The study parameters were determined simultaneously on admission in only 4 patients. In the 9 patients with lactic acidosis on admission and a delayed metformin assay, lactic acidosis persisted in 6 cases and had resolved in 3 cases by the time the blood sampling for metformin assay was performed. Conversely, lactic acidosis developed after admission in one case. Conclusions. Caution must be taken when interpreting the consequences of metformin accumulation in an emergency context: the patients lactic acidosis status will have changed by the time the metformin assay is performed, even though metformin accumulation may still be present.

Renoprotective Effects of Metformin

Background/Aims: It has become clear that metformin exerts pleiotropic actions beyond its glucose-lowering agent effect. In this review, we summarise the state of the art concerning the potential renoprotective effects of metformin in vitro, animal models and clinical nephrology. Methods: A literature search was performed in PUBMED, ScienceDirect, between January 1957 and March 2017 using the following keywords: “metformin,” “nephroprotection,” “renoprotection,” “survival,” “renal failure,” “chronic kidney diseases,” “fibrosis,” “polycystic kidney disease” and “microalbuminuria.” Results: A recent review of 17 observational studies concluded that metformin use appeared associated with reduced all-cause mortality in patients with CKD. Metformin has been shown to exert positive effects on the kidney in vitro and animal models representing different types of renal diseases, from acute kidney injury to chronic kidney disease. A retrospective cohort study from the Scientific Registry of Transplant Recipients indicated that metformin was associated with lower adjusted hazards for living donor and deceased donor allograft survival at 3 years posttransplant, and with lower mortality. Conclusion: Based on experimental evidence and some relevant clinical observations, metformin seems to be a promising drug in the treatment of progressive renal damage. RCT studies are the next essential step.

The Association between 25-Hydroxyvitamin D and Hemoglobin A1c Levels in Patients with Type 2 Diabetes and Stage 1–5 Chronic Kidney Disease

Aim. To examine the relationship between plasma 25-hydroxyvitamin D (25(OH)D) levels and blood hemoglobin A1c (HbA1c) levels in diabetic patients at various stages of chronic kidney disease (CKD). Methods. We screened for data collected between 2003 and 2012. The correlation between 25(OH)D and HbA1c levels was studied in patients categorized according to the severity of CKD and their vitamin D status. A multivariate linear regression model was used to determine whether 25(OH)D and HbA1c levels were independently associated after adjustment for a number of covariates (including erythrocyte metformin levels). Results. We identified 542 reports from 245 patients. The mean HbA1c value was 6.7 ± 1.0% in vitamin D sufficiency, 7.3 ± 1.5% in insufficiency, and 8.4 ± 2.0% in deficiency (P < 0.0001). There was a negative correlation between 25(OH)D and HbA1c levels for the population as a whole (r = −0.387, P < 0.0001) and in the CKD severity subgroups (r = −0.384, P < 0.0001 and r = −0.333, P < 0.0001 for CKD stages 1–3 and 4-5, resp.). In the multivariate analysis, the 25(OH)D level was the only factor associated with HbA1c (P < 0.0001). Conclusion. 25(OH)D levels were negatively correlated with HbA1c levels independently of study covariates.

Mortality and metformin use in patients with advanced chronic kidney disease

680 www.thelancet.com/diabetes-endocrinology Vol 3 September 2015 University of Warwick Medical School, Coventry and University Hospitals, Coventry and Warwickshire NHS Trust, Coventry CV4 7AL, UK (JPO’H); Royal Gwent Hospital and Oak Street Surgery, Cwmbran, UK (DM-J); University Hospital Birmingham, Birmingham, UK (WH); Barnet, Enfi eld and Harringey Mental Health Trust, London,UK (DH); Queen Mary, University of London, and St Bartholomews Hospital, London, UK (RDL); Swansea University and Abertawe Bro Morgannwg University Health Board, Swansea, UK (SCB); and University of Birmingham and Heart of England NHS Foundation Trust, Birmingham, UK (AHB)