23 cases of Metformin-induced Metabolic Lactic Acidosis in Patients treated with Metformin
Authors:
K. Kubát 1; M. Zbořil 1; M. Semrádová 1; V. Kaňák 2
Authors‘ workplace:
Interní oddělení, Městská nemocnice v Litoměřicích
1; OKL, Městská nemocnice v Litoměřicích
2
Published in:
Klin. Biochem. Metab., 25, 2017, No. 2, p. 77-85
Overview
Metformin is currently the cornerstone of treatment of Type-2 diabetes mellitus with obesity (DM2). Its most serious side effect is metabolic acidosis referred to as metformin-induced lactic acidosis (MILA). The aim of our paper was to provide an overview of patients with MILA treated in a hospital serving a catchment area of 90 000.
Overall, 23 cases of MILA were identified over a period of 18 years (0.2 a year per 1000 patients). Most patients were shown to have developed a mixed disturbance of acid-base balance (with other acidifying but, also, alkalizing disorders). Blood pH was on average low (pH 7.13), with the lowest and highest values being 6.81 and 7.47, respectively. Significant hypocapnia was present (average pCO2, 2.80 kPa), Lactate levels were 10.10 mmol/l (max. 19.8 mmol/l). Levels of BE were on average lowered (-19.25 mmol/l) as were bicarbonate levels (10.10 mmol/l). Levels of AG were high: 36.55 mmol/l. Patients’ partial pressure of oxygen was relatively high (pO2, 13.25 kPa). Patients were usually diagnosed to have pre-renal acute renal failure (ARF), whose causes were later fully corrected in most survivors. In 17 patients, we were able to track down their creatinine levels before the pre-renal ARF, which were significantly higher in two cases only. Levels of glycemia were on average higher (15.85 mmol/l), with hypoglycemia detected in only three cases.
The first significant disturbance and, probably, also the cause of MILA development in our patients was gastrointestinal tract involvement. While common infection – or the effect of metformin itself – caused vomiting and diarrhea, subsequent hypovolemia resulted in pre-renal ARF, which in turn led to an increase in metformin levels up to toxic values. Development of kidney failure was often unexpected and fast. The prognosis of patients with MILA was rather grim, with death rates reaching 48%. Administration of bicarbonates failed to improve the clinical status of most patients. The prognosis was poor in ventilated patients, with a 75 % death rate. Hypercapnia seems to be the underlying mechanism preventing the development of critical intracellular acidosis in MILA. The low respiratory volumes limiting hypocapnia appear to pose a risk in MILA patients. The most effective therapeutic option in our group of patient was elimination of metformin from the body (using hemodialysis or CVVHD).
Limitation of aerobic metabolism is likely not only to be an undesirable but, also, the main therapeutic effect of metformin. Decreased energy income, ATP deficiency affect the underlying mechanisms determining basic mechanism of cells. The resultant effect is increased influx of glucose into the cell enabling ATP formation (via anaerobic glycolysis). This mechanism explains why metformin decreases production of glucose by liver cells and restores glucose consumption by muscle cells from blood, even if not responding adequately to insulin-stimulated impulses. The unique kinetics of metformin enables limited auto regulation. At present, metformin belongs to the safest medications of its class. Nevertheless - if we are forced to take medication that reduces the effect of unwanted chronic energy surplus in T2DM treatment, the risk of development of the MILA persists.
Keywords:
lactic acidosis; metformin; T2DM; Type-2 diabetes mellitus; AMPK, AMP-activated protein kinase; respiratory complex I.
Sources
1. Standards of Medical Care in Diabetes – 2011. Diabetes Care January 2011, vol. 34, no. Supplement 1, p. 11-61.
2. Prospective Diabetes Study Group. Effective intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998, 352, p. 854-865.
3. Rosival, V., Tibenský, T., Dečkov, J. Fatálna metabolická acidóza u diabetičky liečenej buforminom. Prakt. Lék., 1985, 65(17), p. 634-636.
4. Kubát, K., Zbořil, M. Undesirable effect of biguanides: 31 cases of lactic acidosis in patients treated with buformin in the course of 10 years. Klin. Biochem. Metab., 2000, 8(29), No 2, p. 103-107.
5. Vambera, M., Čížková, M., Petr, P. Laktátová acidóza jako komplikace léčby biguanidy Čas. Lék. Čes., 1990, 129(18).
6. Musil, F., Šmahelová, A., Zajíc, J., Maňák, J., Mádlová, E., Sobotka, L. Závažná laktátová acidóza provázená akutním renálním selháním u diabetičky léčené metforminem. Praktický lékař, 2006, 86(12), p. 707-709.
7. ÚZIS ČR, Informace ze zdravotnictví Ústeckého kraje č. 1/2010, 2014.
8. Bailey, C. J., Wilcock, C., Scarpello, J. H. Metformin and the intestine. Diabetologia, 2008, 51, p. 1552-1553.
9. Bailey, C. J., Wilcock, C., Day, C. Effect of metformin on glucose metabolism in the splanchnic bed. Br. J. Pharmacol., 1992, 105(4), p. 1009–1013.
10. Zhou, M., Xia, L., Wang, J. Metformin Transport by a Newly Cloned Proton-Stimulated Organic Cation Transporter (Plasma Membrane Monoamine Transpor-ter) Expressed in Human Intestine. Drug Metabolism and Disposition, 2007, 35, p. 1956–1962.
11. Páleníčková, E., Cahová, M., Drahota, Z., Kazdová, L., Kalous, M. Inhibitory effect of metformin on oxidation of NADH-dependent substrates in rat liver homogenate. Physiol. Res., 2011, 60(5), p. 835-839.
12. Owen, M. R., Doran, E., Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J., 2000, 348, p. 607–614.
13. El-Mir, M. Y., Nogueira, V., Fontaine, E., Averet, N., Rigoulet, M., Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem., 2000, 275, p. 223–228.
14. Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhausl, W. et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes, 2004, 53, p. 1052–1059.
15. Nosadini, R., Avogaro, A., Trevisan, R., Valerio, A., Tessari, P., Duner, E., Tiengo, A., Velussi, M., Del Prato, S., De Kreutzenberg, S., Muggeo, M., Crepaldi, G. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care, 1987, 10, p. 62-67.
16. Nagi, D. K., Yudkin, J. S. Effects of Metformin on Insulin Resistance, Risk Factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care, 1993, 16, P. 621–629.
17. Collier, C. A., Bruce, C. R., Smith, A. C., Lopaschuk, G., Dyck, D. J. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol. Endocrinol. Metab., 2006, 291(1), p. 182-189.
18. Suchard, J. R., Grotsky, T. A. Fatal metformin overdose presenting with progressive hperglycemia. West J. Emerg. Med., 2008, 9(3), p. 160-164.
19. Gura, M., Devrim, S., Sagirogluy, A. E., Orhon, Z., Sen, B. Severe Metformin Intoxication With Lactic Acidosis in An Adolescent: A Case Report. The Internet Journal of Anesthesiology, 2010, Vol. 27, No 2.
20. Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108, p. 1167–1174.
21. Fryer, L. G., Parbu-Patel, A., Carling, D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J. Biol. Chem., 2002, 277, p. 25226–25232.
22. Stephenne, X., Foretz, M., Taleux, N., van der Zon, G. C., Sokal, E., Hue, L., Viollet, B., Guigas, B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia, 2011, 54(12), p. 3101-10. doi: 10.1007/s00125-011-2311-5.
23. Ouyang, J., Parakhia, R. A., Ochs, R. S. Metformin activates AMP-Kinase through inhibition of AMP deaminase. J. Biol. Chem., 2010, 286, p. 1-11.
24. Anedda, A., Rial, E., Gonzalez-Barroso, M. M. Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels. J. Endocrinol., 2008, 199, p. 33–40.
25. Hawley, S. A., Gadalla, A. E., Olsen, G. S., Hardie, D. G. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes, 2002, 51, p. 2420–2425.
26. Ferrannini, E. The Target of Metformin in Type 2 Diabetes. New Engl. J. Med., 2014, 371(16), p. 1547-1548.
27. Bridges, H. R., Jones, A. J. Y., Pollak, M. N., Hirst, J. Effects of Metformin and other Biguanides on Oxidative Phosphorylation in Mitochondria. Biochem. J., 2014, 462, p. 475-487.
28. Protti, A., Russo, R., Tagliabue, P., Vecchio, S., Singer, M., Rudiger, A., Foti, G., Rossi, A., Mistraletti, G., Gattinoni, L. Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication. Crit. Care, 2010, 14(1), R22. Epub Feb. 19.
29. Kubát, K. Model of Diabetes Mellitus Type 2, T2DM. J Nutr. Food Sci., 2015, 5, p. 344. doi:10.4172/2155-9600.1000344
30. Kazda, A., Jabor, A. Hodnocení vztahů mezi ionty natria a chloridů při posuzování nálezů acidobazické rovnováhy. Klin. Biochem. Metab., 2001, 9(30), No 4, p. 199-201.
31. Salpeter, S. R., Greyber, E., Pasternak, G. A. et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch. Intern. Med., 2003, 163, p. 2594–602.
Labels
Clinical biochemistry Nuclear medicine Nutritive therapistArticle was published in
Clinical Biochemistry and Metabolism
2017 Issue 2
Most read in this issue
- Exercise-induced rhabdomyolysis – frequent cause of false diagnosis
- 23 cases of Metformin-induced Metabolic Lactic Acidosis in Patients treated with Metformin
- MedPed project in Czech Republic
- Interpretation difficulties in electrophoresis and immunofixation findings in patients with multiple myeloma after autologous transplantation