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

Although metformin has been used for over 60 years, the balance between the drug's 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.

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

AIMS: 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. RESEARCH DESIGN AND METHODS: We systematically searched two data sources for information on mortality in cases recorded as MALA: (i) series in the scientific literature containing over 20 case reports and (ii) a large pharmacovigilance database (containing 869 reports logged between 1995 and 2010). RESULTS: We identified 12 series published between the 1960s and 2013 (mean ± SD [range] number of case reports per series: 51.4 ± 24.7) [23-110]) and 722 case reports with a specified outcome in the pharmacovigilance database. None of the sources specified all three criteria for determining MALA (i.e., the pH level, blood lactate concentration, and blood metformin concentration). The mortality rate in the literature series ranged from 3% to 61%. The value was 47% in the earliest series (1960-1993) and below 25% in the last series. The mean pH per literature series varied widely (from 6.89 to 7.20). The mortality rates in the pharmacovigilance database fell from around 50% to 25% over the study period, while the pH remained in a narrow range (6.94-7.07). CONCLUSIONS: The overall mortality rate for MALA was around 50% during the period 1960-2000 but has since fallen to around 25%.

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

OBJECTIVE: 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. METHODS: We performed a systematic research for metformin contraindications in: (i) official documents from the world's 20 most populated countries and the 20 most scientifically productive countries in the field of diabetology and (ii) publications referenced in electronic databases from 1990 onwards. RESULTS: We identified three international guidelines, 31 national guidelines, and 20 proposals in the scientific literature. The criteria for metformin withdrawal were (i) mainly qualitative in the most populated countries; (ii) mainly quantitative in the most scientifically productive countries (with, in all cases, a suggested threshold for withdrawing metformin); and (iii) quantitative in all, but one of the literature proposals, with a threshold for withdrawal in most cases (n = 17) and/or adjustment of the metformin dose as a function of renal status (n = 8). There was a good degree of consensus on serum creatinine thresholds; whereas guidelines based on estimated glomerular filtration rate thresholds varied from 60 mL/minute/1.73 m(2) up to stage 5 CKD. Only one of the proposals has been tested in a prospective study. CONCLUSIONS: In general, proposals for continuing or stopping metformin therapy in CKD involve a threshold (whether based on serum creatinine or estimated glomerular filtration rate) rather than the dose adjustment as a function of renal status (in stable patients) performed for other drugs excreted by the kidney.

How does blood glucose control with metformin influence intensive insulin protocols? Evidence for involvement of oxidative stress and inflammatory cytokines.

INTRODUCTION: Recent investigations have revealed that control of hyperglycaemia with insulin improves outcomes. The cornerstone of hyperglycaemia in critically ill patients is insulin resistance and it remains refractory to intensive insulin protocols. We designed this study to evaluate the efficacy and safety of a new intensive insulin therapy (IIT) protocol combined with metformin. METHODS: Twenty-one patients with systemic inflammatory response syndrome and a blood glucose level of >120 mg/dl admitted to an intensive care unit (ICU) were randomised to receive either intravenous infusion of IIT alone (n=11) or combined with metformin (IIT+MET; n=10) to maintain a blood glucose level (BGL) of 80-120 mg/dl. Blood samples were obtained at baseline and at 48 hours, 96 hours and 7 days after initiation of the study. Samples were analysed for interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and nitric oxide (NO) as inflammatory mediators; plasminogen activation inhibitor-1 (PAI-1) as a coagulation mediator; and thiobarbituric reactive substances (TBARS), total antioxidant power (TAP) and total thiol molecules (TTM) as oxidative stress parameters. RESULTS: The addition of metformin to the IIT protocol decreased insulin requirement and concentration of insulin and C-peptide. With both treatments at most time points, the mean plasma levels of IL-6, TNF-alpha, NO, PAI-1 and TBARS were found to be significantly lower compared with baseline. Antioxidant activity was increased in both arms with increasing TAP and TTM (P<0.05). There was no significant difference between the two groups regarding reported beneficial effects on these parameters. Therapeutic Intervention Scoring System-28 (TISS-28) score, an index of nursing workload and number of therapeutic interventions, decreased in the IIT+MET group (P<0.01). We did not observe any occurrence of hyperlactataemia or acidosis in the IIT+MET group. CONCLUSION: Metformin plus insulin appears to lower the incidence of insulin resistance, lower insulin requirement while maintaining blood glucose level control, and consequently lower the incidence of adverse effects related to high-dose insulin therapy, particularly hypoglycaemia, and also declined nursing workload. Both treatment protocols showed improvements in inflammatory cytokine levels. Further studies with larger sample sizes are warranted to determine the undiscovered facts of insulin-sensitising agents in critically ill patients.

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.

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.

Therapeutic Concentrations of Metformin: A Systematic Review.

BACKGROUND: Metformin has been available since 1957. Over 50 years later, one can legitimately question whether a clear definition of its "therapeutic concentrations" is available. OBJECTIVE: The objective of this systematic review was to establish whether or not there is a literature consensus on the "therapeutic concentrations" of metformin. METHODS: We systematically searched the scientific literature with the keywords "metformin", "therapeutic concentration", "therapeutic level", and "therapeutic range". When the suggested values were defined by citing a literature reference, the types of studies in cited references and the concordance of data between the citations and theirs sources were studied. RESULTS: We identified 120 documents that reported or cited 65 different "therapeutic" plasma metformin concentrations or ranges. The values ranged from 0.129 to 90 mg/L, and the lowest and highest boundaries were 0 and 1800 mg/L. Only four original research studies determined a "therapeutic concentration". Fifty-four publications cited previous studies as defining the therapeutic concentrations, whereas 62 publications mentioned "therapeutic concentrations" but did not even cite a supporting reference. The supporting references were mostly reviews, pharmacokinetic studies and in vitro studies. In the 54 publications that cited references, concordance between the wording of the citation and the true nature of the source data was observed in only 23 cases (42.6%). LIMITATIONS: Given the nature of a systematic literature search, the only possible limitation would be incomplete identification and retrieval of publications on therapeutic concentrations. An extensive study of the literature has, however, been performed by examining nearly 1000 potentially relevant publications. GUIDANCE FOR CLINICAL PRACTICE: The only valid way of defining the therapeutic concentration window for metformin would be to relate dose efficacy (in terms of blood glucose control) to the corresponding plasma concentration in long-term treated patients. CONCLUSIONS: Although metformin has been available for over 50 years and it is the key medication in first-line treatment of type 2 diabetes mellitus, major methodological and/or conceptual errors have confounded the literature on its therapeutic concentrations.

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 patient's lactic acidosis status will have changed by the time the metformin assay is performed, even though metformin accumulation may still be present.

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.

The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis.

AIMS: Analysis of the prognostic values of blood pH and lactate and plasma metformin concentrations in severe metformin-associated lactic acidosis may help to resolve the following paradox: metformin provides impressive, beneficial effects but is also associated with life-threatening adverse effects. RESEARCH DESIGN AND METHODS: On the basis of 869 pharmacovigilance reports on MALA with available data on arterial pH and lactate concentration, plasma metformin concentration and outcome, we selected cases with a pH < 7.0 and a lactate concentration >10 mmol/L. Outcomes were compared with those described for severe metformin-independent lactic acidosis. RESULTS: Fifty-six patients met the above-mentioned criteria. The mean arterial pH and lactate values were 6.75 ± 0.17 and 23.07 ± 6.94 mmol/L, respectively. The survival rate was 53%, even with pH values as low as 6.5 and lactate and metformin concentrations as high as 35.3 mmol/L and 160 mg/L (normal < 1 mg/L), respectively. Survivors and non-survivors did not differ significantly in terms of the mean arterial pH and lactate concentration. The mean metformin concentration was higher in patients who subsequently died but this difference was due to a very high value (188 mg/L) in one patient in this group, in whom several triggering factors were combined. Sepsis, multidrug overdoses and the presence of at least two triggering factors for lactic acidosis were observed significantly more frequently in non-survivors (p = 0.007, 0.04, and 0.005, respectively). This contrasts with a study of metformin-independent lactic acidosis in which there were no survivors, despite less severe acidosis on average (mean pH: 6.86). CONCLUSIONS: In 56 cases of severe metformin-associated lactic acidosis, blood pH and lactate did not have prognostic value. One can reasonably rule out the extent of metformin accumulation as a prognostic factor. Ultimately, the determinants of metformin-associated lactic acidosis appear to be the nature and number of triggering factors. Strikingly, most patients survived - despite a mean pH that is incompatible with a favorable outcome under other circumstances.