Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus

Salpeter, Shelley R.; Greyber, Elizabeth; Pasternak, Gary A; Salpeter, E. E.

doi:10.1001/archinte.163.21.2594

Cited by 263 publications

(53 citation statements)

References 156 publications

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“…Systematic reviews and case series have shown a low incidence of metformin-associated lactic acidosis [8,9]. Salpeter et al [10] conducted a comparative review and found that lactic acidosis was present in 4.3 cases per 100,000 patient-years among metformin users and in 5.4 cases among non-metformin users. …”

Section: Introductionmentioning

confidence: 99%

Metformin Use in Kidney Transplant Recipients in the United States: An Observational Study

et al. 2014

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Background/Aims: Although metformin is contraindicated in patients with increased serum creatinine levels (≥1.5 mg/dl in men, ≥1.4 mg/dl in women) in the United States, its use has not been systematically examined in kidney transplant recipients. We aimed to determine the frequency of metformin use and its associations among kidney transplant recipients, and to assess allograft and patient survival associated with metformin use. Methods: In this retrospective cohort study, we linked Scientific Registry of Transplant Recipients data for all incident kidney transplants 2001-2012 and national pharmacy claims (n = 46,914). We compared recipients having one or more pharmacy claims for a metformin-containing product (n = 4,609) and recipients having one or more claims for a non-metformin glucose-lowering agent (n = 42,305). Results: On average, metformin claims were filled later after transplant and were associated with higher estimated glomerular filtration rates before the first claim. Median serum creatinine (mg/dl) levels before the first claim were lower in recipients with metformin claims than in those with non-metformin claims (1.3 [interquartile range 1.0-1.7] vs. 1.6 [1.2-2.5], respectively; p < 0.0001). Metformin was associated with lower adjusted hazards for living donor (0.55, 95% confidence interval 0.38-0.80; p = 0.002) and deceased donor (0.55, 0.44-0.70; p < 0.0001) allograft survival at 3 years posttransplant, and with lower mortality. Conclusions: Despite metformin being contraindicated in renal dysfunction, many kidney transplant recipients receive it, and it is not associated with worse patient or allograft survival.

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Section: Introductionmentioning

confidence: 99%

Metformin Use in Kidney Transplant Recipients in the United States: An Observational Study

et al. 2014

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“…The true incidence of metformin-associated lactic acidosis (MALA) remains unknown. 13 The average rate is estimated to be 0.03 cases per 1000 patient-years, with 50% of cases being fatal. 14 However, evidence linking elevated lactic acid levels to metformin use or metformin levels is poor.…”

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confidence: 99%

The Safety of Metformin in Heart Failure

Roberts

Ryan

2007

Ann Pharmacother

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“…15) To clarify the mechanism of this side effect, we have attempted to find genes whose expression changed by treatment with buformin through the screening of the subtraction cDNA library constructed by the suppression subtractive hybridization method. 9) We found that buformin suppressed expression of the GAPD gene in HepG2 cells and the suppression was dependent on the period of exposure.…”

Section: Discussionmentioning

confidence: 99%

Buformin Suppresses the Expression of Glyceraldehyde 3-Phosphate Dehydrogenase

Yano

Kubota

Iguchi

et al. 2006

Biological & Pharmaceutical Bulletin

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Three biguanides, phenformin, buformin, and metformin, were first used clinically for diabetes mellitus in the 1950s. Since phenformin was found to have a lethal side effect, lactic acidosis, in the late of 1970s, 1) its usage decreased rapidly in many countries and was finally withdrawn. Then use of other biguanides declined gradually because of their own adverse effects. Lactic acidosis, hypoglycemia, and digestive organ dysfunction have been found to be adverse effects of biguanides. Lactic acidosis caused by biguanides results in lethal metabolic acidosis, 2) so their use was stopped. Cohen and Woods 3) proposed a classification for lactic acidosis that consisted of types A, B 1 , B 2 , B 3 , and B 4 , and acidosis caused by biguanides belongs to type B 2 according to this classification. Type B is lactic acidosis occurring when clinical evidence of poor tissue perfusion or oxygenation is absent and type B 2 is due to drugs and toxins.Metformin was recently reported to decrease the risk of diabetes-related endpoints in overweight diabetic patients 4) and, therefore, has begun to be widely used again. The following mechanisms of action of biguanides have been proposed 5) : (i) suppression of glucose release from the liver, (ii) increase of glucose intake in peripheral tissues, (iii) decrease of glucose uptake in an alimentary tract, and (iv) suppression of b-oxidation. Metformin was found to improve resistance to insulin in type II diabetes. Zhou et al. 6) postulated that the suppression of SREBP-1 expression through the activation of AMPactivating protein kinase by metformin eliminated the insulin resistance.The following possible mechanism for the side effect of biguanides has been proposed. 7,8) The biguanide binds to the mitochondrial membrane and causes the disruption of oxidative phosphorylation in the mitochondria. This results in an increase in the NADH level, a decrease in pyruvate dehydrogenase activity, and deactivation of the TCA cycle. Furthermore, gluconeogenesis is suppressed and pyruvic acid accumulates in the liver. This leads to an increase in production of lactic acid. However, the molecular mechanisms of the side effects of biguanides are still unclear.When we researched which gene expressions underwent a change in order to clarify the mechanism of biguanides induced lactic acidosis, we found that the gene expression of glyceraldehyde 3-phosphate dehydrogenase (GAPD) in HepG2 cells decreases significantly by buformin treatment. Since GAPD is involved in the glucolytic pathway, we believe the decrease in GAPD may have caused the lactic acidosis. In this study, we demonstrate that expression of the gene for GAPD in HepG2 cells was suppressed by buformin treatment in a time-dependent manner. We also examined the effect of the biguanide on the protein expression of GAPD and determined the levels of NAD + and ATP in HepG2 cells treated with the biguanide to investigate the mechanism of the lactic acidosis side effect. . Therefore, the reaction equilibrium catalyzed by lactate dehydrogenase le...

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Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus

Abstract: There is no evidence to date that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of lactate compared with other antihyperglycemic treatments if the drugs are prescribed under study conditions, taking into account contraindications.

Cited by 263 publications

References 156 publications

Metformin Use in Kidney Transplant Recipients in the United States: An Observational Study

Metformin Use in Kidney Transplant Recipients in the United States: An Observational Study

The Safety of Metformin in Heart Failure

Buformin Suppresses the Expression of Glyceraldehyde 3-Phosphate Dehydrogenase

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