1. Warning hydrochloric acid: metformin lactate poisoning: lactic acidosis is a rare but serious metabolic disease, and metformin may accumulate in the body when this product is given. The mortality rate of this disease is about 50%. The occurrence of lactic acidosis may also be related to a variety of pathophysiological conditions, including diabetes and when there is obvious tissue perfusion insufficiency and blood oxygen deficiency. Lactic acidosis is characterized by the increase of blood lactic acid level (>: 5mmol/L), the decrease of blood pH value, electrolyte disorder, anion gap and the increase of lactic acid/pyruvate ratio. If metformin may be the cause of lactic acidosis, the plasma concentration level of metformin is usually >: 5μg/ml. It is reported that the probability of lactic acidosis in patients treated with metformin hydrochloride is very low (about 0.03/ 1000 patients per year, about 0.0 15 deaths per year/1000 patients). Reported cases mainly occur in diabetic patients with obvious renal insufficiency, including patients with endogenous nephropathy and renal hypoperfusion, which usually occur at the same time. Patients with congestive heart failure who must be treated with drugs, especially patients with unstable or acute heart failure, are prone to the risk of hypoperfusion and insufficient blood oxygen, and are high-risk groups of lactic acidosis. The risk of lactic acidosis increases with the degree of renal insufficiency and the age of patients. The risk of lactic acidosis can be significantly reduced by regularly monitoring the renal function of patients receiving metformin and giving the minimum effective dose of metformin. The renal function of elderly patients receiving treatment should be closely monitored. For patients over 80 years old, this product can only be given after creatinine clearance rate shows that renal function has not decreased, because such patients are more prone to lactic acidosis. Stop using this product immediately when there are any symptoms related to hypoxemia, dehydration and septicemia. Because impaired liver function will obviously limit its ability to clear lactic acid, patients with clinical or laboratory liver disease symptoms should avoid using this product. Patients taking this product should pay attention to the intake of acute or chronic excessive alcohol, because alcohol can enhance the metabolism of lactic acid by metformin. In addition, the use of this product should be temporarily stopped before undergoing angiography or any surgery. Lactic acidosis is usually mild, with only nonspecific symptoms, such as discomfort, myalgia, poor breathing, drowsiness and nonspecific abdominal discomfort. Related hypothermia, hypotension and intractable chronic arrhythmia with more obvious signs of acidosis may occur. Both patients and doctors should be fully aware of the possible significance of these symptoms, and should instruct patients to inform doctors immediately when these symptoms appear, and stop using the product until the situation is clear. Serum electrolytes, ketones, blood sugar, especially blood pH value, lactic acid level and even blood metformin level have great reference value. If patients use a certain dose of this product steadily, the common gastrointestinal symptoms in the initial treatment of metformin may not be related to the drug. The gastrointestinal symptoms that followed may be caused by serious diseases such as lactic acidosis. Lactic acidosis may not be indicated when the lactic acid level in venous plasma of patients receiving this product exceeds the upper limit of normal value but is lower than 5 mmol/L. This situation can be explained by other mechanisms, such as failure to control diabetes or obesity, strenuous exercise or technical problems in sample handling (see also precautions). Lactic acidosis can be suspected in diabetic patients who lack the signs of ketoacidosis (ketonuria and ketonemia) but are accompanied by metabolic acidosis. Lactic acidosis is a serious emergency, and patients must be hospitalized. Patients with lactic acidosis who are taking this product should stop using this product immediately and conduct routine supportive tests quickly. Because metformin can be removed by dialysis (the clearance rate can reach 170ml/min under the condition of good hemodynamics), it is suggested to perform dialysis immediately to correct excessive acid and remove accumulated metformin. This treatment can quickly improve symptoms and restore the disease. 2. Special warning to increase the risk of cardiovascular death It is reported that oral hypoglycemic drugs are associated with an increase in cardiovascular mortality compared with diet alone or diet plus insulin treatment. This warning is based on the results of a long-term prospective study conducted by the University Joint Diabetes Activity (UGDP), which aims to evaluate the role of hypoglycemic agents in preventing and delaying the onset of vascular diseases in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly divided into 4 groups. According to UGDP, the cardiovascular mortality of patients treated with diet plus fixed dose of tolbutamide (1.5g/ day) for 5-8 years is about 2.5 times that of patients treated with diet alone, and the overall mortality has not increased significantly. However, due to the increase of cardiovascular mortality, tolbutamide was stopped, which limited the study on whether the overall mortality increased. Although the explanation of these results is still controversial, the research of UGDP provides sufficient basis for this warning. Patients should be informed of the potential risks and benefits of using glipizide and other alternative therapies. Although only one sulfonylurea drug (tolbutamide) was included in this study, from the perspective of safety, this warning can also be applied to other hypoglycemic drugs in this kind of drugs because of their similar action mode and chemical structure. 3. General precautions: Metformin and glipizide tablets have hypoglycemia. This product can cause hypoglycemia. Therefore, proper patient selection, dosage and guidance are very important to avoid the potential risk of hypoglycemia. When calorie intake is insufficient, calorie supplement after strenuous exercise is insufficient, or other hypoglycemic drugs or alcohol are used at the same time, the risk of hypoglycemia will increase. Renal insufficiency can lead to the increase of glipizide and metformin hydrochloride levels. Insufficient liver function can increase the drug level of glipizide and reduce gluconeogenesis, both of which can increase the risk of hypoglycemia. Old people, overworked people, malnourished people, people with insufficient secretion of adrenal gland or pituitary gland and alcoholics are particularly prone to hypoglycemia. In the elderly and people who use β -adrenergic blockers, hypoglycemia symptoms are usually difficult to identify. The metabolism and excretion rate of glipizide nephropathy and liver disease may slow down in patients with liver and/or renal function injury. If such patients have hypoglycemia, their attack period may be prolonged, and appropriate treatment measures should be taken. The renal function monitoring of metformin hydrochloride shows that metformin is mainly excreted through the kidney. With the aggravation of renal damage, the risk of metformin accumulation and lactic acidosis will increase. Therefore, patients whose serum creatinine level exceeds the upper limit of normal age should not use this product. For elderly patients, the dosage of this product should be carefully adjusted to achieve the lowest dosage that can fully control blood sugar. Because aging is related to the decline of renal function, elderly patients, especially those over 80 years old, should regularly monitor renal function. In general, this product should not be increased to the maximum dose (see warnings and usage). At the beginning of treatment with this product, and at least once a year thereafter, the patient's renal function was evaluated and confirmed to be normal. For patients with early renal insufficiency, the frequency of renal function evaluation should be increased, and if there are signs of renal function damage, this product should be stopped. Drugs that may affect renal function and the distribution of metformin, drugs that may affect renal function or cause obvious changes in hemodynamics, or drugs that may interfere with the distribution of metformin, such as cationic preparations excreted through renal tubules, should be used with caution (see drug interaction). Imaging studies using intravenous iodate contrast agents (for example, intravenous contrast agents, cholangiography, angiography and computed tomography) Intravascular iodate contrast agents can cause acute renal function changes, which are related to lactic acidosis in patients receiving metformin (see contraindications). Therefore, any patient who intends to carry out this study should temporarily stop using this product before, during and within 48 hours after the completion of the study, and can only use it again after the renal function is evaluated and considered normal. Cardiovascular failure (shock), acute congestive heart failure, acute myocardial infarction and other ischemic symptoms due to hypoxia are all related to lactic acidosis, and can also cause prerenal azotemia. When patients have such symptoms, they should stop using this product immediately. During the surgical operation, the treatment of this product should be temporarily stopped during any surgical operation (unless the operation is very small and does not restrict the intake of food and liquid), and this product can only be used again after the patient recovers the oral intake function and the renal function evaluation is normal. Alcohol intake It is known that alcohol can enhance the metabolism of lactic acid by metformin, so patients should be reminded not to take too much alcohol in an acute or chronic way when receiving metformin treatment. Alcohol may increase the risk of hypoglycemia attack because it affects liver gluconeogenesis. Because of liver function damage, liver function damage is related to some cases of lactic acidosis. Patients with clinical or laboratory liver diseases should usually avoid using this product. Vitamin B level In the 29-week clinical controlled trial of metformin, about 7% patients' previously normal serum dropped below normal level, but there was no clinical manifestation. This decline may be caused by interfering with the absorption of vitamin B by B- intrinsic factor complex, but it has little to do with anemia. It can be recovered quickly after stopping metformin or supplementing B. It is suggested that patients treated with metformin should measure hematological parameters once a year. If obvious abnormalities are found, the reasons should be investigated and appropriate treatment measures should be taken (see Precautions: Laboratory Testing). Some individuals (insufficient intake or absorption of vitamin B or calcium) seem to be more likely to form sub-normal levels of vitamin B. In such patients, routine serum vitamin B levels need to be determined every 2 to 3 years. Changes of clinical status in patients with previously controlled type 2 diabetes mellitus. For patients with type 2 diabetes who are well controlled with metformin but have abnormal laboratory examination or clinical conditions (especially diseases with vague or unclear definitions), it is necessary to immediately evaluate whether ketoacidosis or lactic acidosis occurs. When necessary, the assessment should include serum electrolyte and ketone, blood sugar, blood pH, lactate, pyruvate and metformin levels. If acidosis occurs in any form, stop using this product immediately and take appropriate corrective measures (see warning). 4. Patient information should inform patients of the potential risks and benefits of using this product and other alternative treatment methods. They should also be informed of the importance of adhering to diet therapy, regular exercise and regular detection of blood sugar, glycosylated hemoglobin, renal function and blood parameters. Patients should be explained the risks, symptoms and conditions of lactic acidosis related to metformin treatment. See the Precautions section. It is suggested that patients should stop using this product immediately and notify their doctors if they have nonspecific symptoms such as abnormal hyperventilation, myalgia, discomfort and drowsiness. If patients use a certain dose of this product steadily, the common gastrointestinal symptoms in the initial treatment of metformin may not be related to the drug. After that, gastrointestinal symptoms may be caused by serious diseases such as lactic acidosis. Patients and their families who are in charge of monitoring should understand the harm, symptoms, treatment methods and causes of hypoglycemia. Patients should be told to avoid excessive alcohol intake when using metformin and glipizide. 5. Laboratory examination should regularly detect fasting blood glucose and glycosylated hemoglobin (HbA) of patients to monitor the treatment response. Hematological parameters (such as hemoglobin/blood volume and red blood cell index) and renal function (serum creatinine) were monitored regularly during initial treatment, and then at least once a year. Macrocytic anemia is extremely rare when treated with metformin. If in doubt, vitamin B deficiency should be ruled out.