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      Recurrent lactic acidosis and hypoglycemia with inadvertent metformin use: a case of look-alike pills

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          Summary

          Metformin is recommended as the first-line agent for the treatment of type 2 diabetes. Although this drug has a generally good safety profile, rare but potentially serious adverse effects may occur. Metformin-associated lactic acidosis, although very uncommon, carries a significant risk of mortality. The relationship between metformin accumulation and lactic acidosis is complex and is affected by the presence of comorbid conditions such as renal and hepatic disease. Plasma metformin levels do not reliably correlate with the severity of lactic acidosis. We present a case of inadvertent metformin overdose in a patient with both renal failure and hepatic cirrhosis, leading to two episodes of lactic acidosis and hypoglycemia. The patient was successfully treated with hemodialysis both times and did not develop any further lactic acidosis or hypoglycemia, after the identification of metformin tablets accidentally mixed in with his supply of sevelamer tablets. Early initiation of renal replacement therapy is key in decreasing lactic acidosis-associated mortality.

          Learning points:
          • When a toxic ingestion is suspected, direct visualization of the patient’s pills is advised in order to rule out the possibility of patient- or pharmacist-related medication errors.

          • Though sending a specimen for determination of the plasma metformin concentration is important when a metformin-treated patient with diabetes presents with lactic acidosis, complex relationships exist between metformin accumulation, hyperlactatemia and acidosis, and the drug may not always be the precipitating factor.

          • Intermittent hemodialysis is recommended as the first-line treatment for metformin-associated lactic acidosis (MALA).

          • An investigational delayed-release form of metformin with reduced systemic absorption may carry a lower risk for MALA in patients with renal insufficiency, in whom metformin therapy may presently be contraindicated.

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          Most cited references11

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          Metformin.

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            Metformin in patients with type 2 diabetes and kidney disease: a systematic review.

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

              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. 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. 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. 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. 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. 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. 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.

                Author and article information

                Journal
                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                EDM
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                2052-0573
                5 January 2018
                2018
                : 2018
                : 17-0148
                Affiliations
                [1 ]Divisions of Endocrinology , Department of Medicine, Westchester Medical Center , Valhalla, New York, USA
                [2 ]Divisions of Nephrology , Department of Medicine, Westchester Medical Center , Valhalla, New York, USA
                Author notes
                Correspondence should be addressed to M D Goldberg; Email: Michael.Goldberg@ 123456wmchealth.org
                Article
                EDM-17-0148
                10.1530/EDM-17-0148
                5763280
                d4fdf194-e7f6-49fd-8faa-befbadc5067a
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

                History
                : 21 November 2017
                : 30 November 2017
                Categories
                Error in Diagnosis/Pitfalls and Caveats

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