In the 1950s, biguanide hypoglycemic agents were introduced and were soon used in the treatment of type 2 diabetes. over the past 50 years, it has seen its ups and downs. Due to the large chance of lactic acidosis from phenformin (>1/500 in previous studies), biguanide hypoglycemic agents always seem to be synonymous with lactic acidosis since the day they were used in clinical practice. Based on safety considerations, phenylethylguanidine has been banned in many countries such as the United States and the United Kingdom, while metformin has unfortunately been implicated and has been left unattended for a long time. However, with the unveiling of several evidence-based medical studies in recent years, people gradually realized that metformin has many benefits that other hypoglycemic drugs cannot match, and because of the difference in structure and mechanism of action between metformin and phenylethylguanidine, the chance of lactic acidosis due to metformin is much lower than that of phenylethylguanidine1. So people vindicated it and started to recognize metformin again, and it has been widely used, which has benefited many patients with type 2 diabetes. patients benefit greatly. However, because of the many contraindications of metformin application and the possibility of lactic acidosis, many clinicians are afraid of metformin and have many concerns about its clinical application, and even many patients who could benefit from metformin treatment have missed the opportunity to be treated. However, whether metformin can increase the risk of lactic acidosis is still a highly controversial issue. The author has read a lot of relevant literature and tried to sort out the relationship between metformin and lactic acidosis. Lactic acid production, metabolism and excretion Glucose glycolysis in hypoxia produces lactic acid, which can be converted to glucose in the liver and kidneys through gluconeogenesis to provide energy, and the hydrogen ions produced in this process can be neutralized by the body’s blood buffer system and excreted through the kidneys and lungs.2 Increased production of lactic acid during hypoxia or decreased metabolism and clearance of lactic acid during liver and kidney insufficiency can cause an increase in blood lactate concentration. The blood buffering system, the lungs, and the lungs are all responsible for the rise in lactate concentration. The body’s blood buffer system, lungs, kidneys, and intra- and extracellular ion exchange neutralize and excrete the excess acid produced to maintain the homeostasis of the internal environment. If excessive lactic acid production exceeds the body’s acid-base balance compensatory capacity and the blood PH value drops, lactic acidosis develops.3 The effect of metformin on lactic acid metabolism The glucose-lowering mechanism of metformin is still unknown, one of the mechanisms may be the inhibition of hepatic gluconeogenesis, that is, the inhibition of lactic acid isomerization into glucose, thus playing a glucose-lowering effect. However, this process can lead to lactate accumulation, which may be the main reason for the increase of blood lactate level and the development of lactic acidosis caused by metformin. However, some studies have shown that metformin does not affect the concentration of lactate in type 2 diabetic patients.4 Stumvoll et al. also showed that although metformin can cause lactate accumulation by inhibiting the conversion of lactate to glucose, it can also promote the oxidation of lactate to CO2 and then excrete it out of the body, thus reducing lactate levels, and the two effects counteract each other and do not cause lactic acidosis. The pharmacokinetics of metformin Metformin is structurally stable, almost does not bind with albumin, mainly excreted from the kidney in its original form, not through the liver metabolism and biliary excretion, short half-life, rapid clearance, about 90% can be excreted in 12 hours, the concentration of metformin in blood mainly depends on the state of renal function. Normal renal function will not cause the accumulation of metformin, unless renal function is seriously impaired, the excretion of metformin in the body will not be greatly affected, and the possibility of drug accumulation is very small.5 Some studies have confirmed that the average clearance of metformin in the kidney is 440.8 ml/min, which is 3.5 times of the clearance of creatinine, which should be the reason why metformin is not easy to accumulate in the body. Fourth, the odds of metformin causing lactic acidosis Salpeter et al. conducted a systematic review and meta-analysis of 194 studies on metformin. The results showed that lactic acidosis did not occur in 36,893 patients/year treated with metformin and in 30,109 patients/year not treated with metformin. The mean lactate level of patients during metformin treatment was 11.2 mg/dl, which was not significantly different from that of non-metformin drugs (P=0.07), suggesting that there is no evidence that metformin is associated with an increased risk of lactic acidosis.6 The results of the latest Cochrane study published in 2006 also showed that the incidence of lactic acidosis with metformin was 6.3 cases/100,000 patients Another study noted that in the United States, where metformin was not available before 1995, the incidence of lactic acidosis in type 2 diabetes was 0.169 cases/1000 patients/year, while in 1995-1996 the incidence dropped to 0.047 cases/1000 patients/year; The incidence of lactic acidosis has decreased rather than increased after metformin was marketed, as 0.032 cases/1000 patients/year in 1995-1997. V. Risk factors for lactic acidosis Although there is no clear correlation between metformin and increased risk of lactic acidosis, the application of metformin in some patients with high-risk factors may induce lactic acidosis. The high-risk factors are described as follows: 1. Renal failure: It is mostly considered as the first risk factor. Because of the accumulation of metformin in renal failure, it may increase lactic acid production, and at the same time, the kidney metabolism of lactic acid and hydrogen ion excretion is impaired, resulting in the rise of blood lactic acid level and lactic acidosis. 2, impaired liver function: because metformin does not go through liver metabolism, so the application of metformin to lactic acidosis in patients with hepatic insufficiency may be the liver’s metabolism of lactic acid (gluconeogenesis) is restricted, causing lactic acid accumulation. 3, hypoxic state: (1) hypotonic hypoxia such as pulmonary ventilation, ventilatory dysfunction, presence of right-to-left cardiac shunt, etc.; (2) circulatory hypoxia such as shock, dehydration, heart failure, intraoperative hemorrhage, etc.; (3) hematologic hypoxia such as carbon monoxide poisoning, anemia, methemoglobinemia, etc.; (4) tissue hypoxia, i.e., cells cannot effectively use oxygen under the condition of normal tissue oxygen supply. In this state, glycolysis is enhanced and lactic acid production is increased, exceeding the compensatory capacity of acid-base balance of the body. 4. Alcoholism: Ethanol is mainly oxidized to acetaldehyde in cells catalyzed by ethanol dehydrogenase, and acetaldehyde is further oxidized to acetic acid catalyzed by aldehyde dehydrogenase, both of which produce NADH and H. This raises the intracellular NADH/NAD ratio, which facilitates the conversion of pyruvate to lactate; In addition, ethanol also inhibits the isomerization of pyruvate to glucose, and long-term chronic alcoholism can lead to vitamin deficiency and liver damage, which also reduces the oxidation of pyruvate and glycogen isomerization. Therefore, ethanol intoxication can directly lead to lactic acidosis by increasing lactic acid production and indirectly inhibiting lactic acid clearance. 5.Old age: Because of the gradual decline of renal function with age, it is easy to cause accumulation of metformin and lactic acid, plus the possible existence of cardiopulmonary disorders and hypoxic state resulting in excessive lactic acid production or decrease of renal capacity for acid excretion, causing the increase of blood lactic acid concentration and lactic acidosis. 6. Perioperative period: Most of the patients are in shock or dehydrated due to preoperative fasting, intraoperative or postoperative bleeding, and postoperative inability to eat normally, resulting in increased lactic acid production due to tissue ischemia and hypoxia. Foreign literature has reported one case each of postoperative patients who died from lactic acidosis caused by not stopping metformin at the time of surgery and stopping metformin on the day of surgery, suggesting that metformin should be stopped at least 48 hours before major surgery until the patient resumes normal diet after surgery and renal function returns, so as to prevent lactic acidosis.8 7. Intravenous application of contrast agent: renal vasodilation occurs first after the application of contrast agent. It can last for 20 minutes, followed by renal vasoconstriction, and this effect can last for 2 hours. The oxygen consumption and metabolic rate of the kidney increase after the application of contrast media. The above causes may lead to acute tubular necrosis. Direct nephrotoxicity and increased renal vascular resistance as well as renal ischemia eventually lead to tissue necrosis and acute renal impairment. Renal damage after causing metformin, lactate accumulation can increase the chance of lactic acidosis development. 8, overdose application: In the state of constant renal function, blood metformin concentration can increase when overdose application, which can increase the chance of causing lactic acidosis, especially in the elderly or renal impairment performance should be more prominent. 9, mitochondrial diabetes: is due to mitochondrial gene mutation caused by diabetes, TmaLeu (UUR) DNA gene mutation will affect the skeletal muscle oxidative phosphorylation, resulting in enhanced anaerobic enzymes, increased lactate production, lactic acidosis tendency 9. The above high risk factors of lactic acidosis, alone or a variety of co-existence, that may cause blood lactate levels rise, acidosis, and aggravate the This results in a very high mortality rate (up to 50%). The mere fact that a patient is taking metformin creates the illusion that metformin is the culprit. In fact, there is no evidence from national or international studies that it is associated with an increased risk of lactic acidosis, so can we blame all lactic acidosis on metformin? Probably based on medication safety considerations, there are many contraindications listed in the instructions for metformin. There is nothing wrong with clinicians who use the drug strictly according to the instructions, but it will certainly prevent many patients who should benefit from metformin use from doing so. In light of this, several studies have been conducted to apply metformin to the so-called contraindicated population under close monitoring.