https://www.gastrojournal.org/article/S0016-5085(02)61906-7/pdf

Nonalcoholic fatty liver disease

Background Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. Objectives To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. Search strategy A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Selection criteria Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Data collection and analysis The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. Main results Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. Authors' conclusions There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

/pdf/risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-4ujte07kg8.pdf

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 1999 guidelines on contrast medium-induced nephropathy (CIN). Topics reviewed include the definition of CIN, the choice of contrast medium, the prophylactic measures used to reduce the incidence of CIN, and the management of patients receiving metformin. Key Points
 • Definition, risk factors and prevention of contrast medium induced nephropathy are reviewed.
 • CIN risk is lower with intravenous than intra-arterial iodinated contrast medium.
 • eGFR of 45 ml/min/1.73 m
 2
 is CIN risk threshold for intravenous contrast medium.
 • Hydration with either saline or sodium bicarbonate reduces CIN incidence.
 • Patients with eGFR ≥60 ml/min/1.73 m
 2
 receiving contrast medium can continue metformin normally.

Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines.

Cardiovascular Disease in Patients with Chronic Obstructive Pulmonary Disease, Saskatchewan Canada : Cardiovascular Disease in COPD Patients

Importance Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. Objective To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. Evidence Acquisition In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. Results Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m 2 ). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. 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.

/pdf/metformin-in-patients-with-type-2-diabetes-and-kidney-285c0t71xo.pdf

Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review

OBJECTIVE: The purpose of this study was to determine the incidence of lactic acidosis in a geographically defined population of metformin users. RESEARCH DESIGN AND METHODS: The study was based on a historical cohort from the Saskatchewan Health administrative databases. Individuals with a metformin prescription dispensed between 1980 and 1995 inclusive were eligible for the cohort. Person-years of exposure were calculated. Cases were defined by hospital discharge with a diagnosis of acidosis (International Classification of Diseases, Ninth Revision code: 276.2) and confirmation by chart review of a blood lactate level > or = 5 mmol/l. Death registrations of individuals dying within 120 days of a metformin prescription were also reviewed. RESULTS: During the study period, 11,797 residents received one or more metformin prescriptions, resulting in 22,296 person-years of exposure. There were 10 subjects who had hospital discharges with a diagnosis of acidosis. However, primary record review revealed only two cases with laboratory findings of elevated blood lactate levels, for an incidence rate of 9 cases per 100,000 person-years of metformin exposure. In both cases, other factors besides metformin could have contributed to the lactic acidosis. No additional cases were found on review of death registrations. CONCLUSIONS: From 1980 through 1995, the incidence rate of lactic acidosis was 9 per 100,000 person-years (95% CI 0-21) in patients dispensed metformin in Saskatchewan, Canada. This incidence rate was derived from a population with complete ascertainment of hospitalizations and deaths associated with lactic acidosis in metformin users. It is similar to previously published rates based on passive reporting of cases, and it is well below the lactic acidosis rate of 40-64 per 100,000 patient-years in patients prescribed phenformin.

D K Wysowski

Papers

Incidence of lactic acidosis in metformin users.