Diabetes is a chronic metabolic disease that seriously endangers human health and has a high prevalence in China. In the 10 years from 2001 to 2010, the prevalence of diabetes has more than tripled, with an overall prevalence of 9.7% among people over 20 years of age; the number of people with diabetes has exceeded 92 million, which has become a serious public health problem. As a chronic disease, diabetes mellitus is a lifelong disease, and the main harm to human body is its various chronic complications, and the most fundamental measure to prevent complications and slow down their development is to control blood sugar. The majority of diabetic patients do not know about various hypoglycemic drugs, and there are even many misunderstandings. Just like in a war, only a good understanding of the characteristics of the weapons in their hands and the defects of the enemy, in order to more effectively destroy the enemy, know yourself and your enemy, a hundred battles will not be lost.
In order to better understand the characteristics of the role of hypoglycemic drugs, we first briefly review the basic pathological characteristics of diabetes
The basic pathological characteristics of diabetes mellitus
There is only one hormone in the human body that has a hypoglycemic effect, which is insulin, so the abnormal increase of blood sugar in diabetes is mainly due to the abnormality of insulin. The main treatment method for type 2 diabetes is insulin resistance in the early stage, and as the disease progresses, insulin secretion deficiency gradually becomes the main conflict.
The physiological secretion of human insulin is mainly divided into basal secretion and high-dose secretion during meals. Basal secretion means that when the body does not eat, the pancreatic islet cells maintain a continuous secretion of insulin in small doses, which works together with other glucose-raising hormones in the body to maintain basal blood glucose within a narrow range, and the source of fasting blood glucose is mainly the liver’s output of glucose through gluconeogenesis and glycogenolysis, which will cause a rise in basal blood glucose or fasting blood glucose when basal insulin secretion is insufficient or other glucose-raising hormones are secreted more. When the secretion of basal insulin or other glucose-raising hormones is insufficient, it will cause the increase of basal or fasting blood sugar. After meal, due to the stimulation of glucose, islet cells have a large secretion, and the peak of this large secretion occurs 10-30 minutes after meal, and gradually decreases to the basal level after 2-3 hours, when the body insulin secretion is delayed and the total amount is insufficient, it will cause the abnormal increase of postprandial blood glucose, and the delay of secretion makes insulin cannot decrease to the basal level 2-3 hours after meal This will cause hypoglycemia before the next meal.
It is based on the above mechanism that various hypoglycemic drugs target various aspects of hyperglycemia through different mechanisms to exert hypoglycemic effects, which can be basically divided into two categories, namely oral hypoglycemic drugs and insulin.
Oral hypoglycemic drugs
Oral hypoglycemic drugs can be divided into two categories, namely, non-insulin-promoting drugs and insulin-promoting drugs
Non-insulin-promoting drugs. The common features of these drugs are 1. They do not cause hypoglycemia when used alone. Repeated hypoglycemia can induce cardiovascular events, damage the central nervous system, a serious hypoglycemia may be life-threatening and can ruin the benefits of a patient’s long-term ideal glycemic control; 2. These drugs can be used in combination with each other or with pro-secretory drugs or insulin; 3. They can be used in all stages of diabetes (except for those with severe liver and kidney impairment). It can be used in all stages of diabetes (except for those with severe hepatic and renal impairment). 4. It can be used to intervene in pre-diabetes to delay the transformation of low glucose tolerance into diabetes. The following is a detailed description of the characteristics of the role of this class of drugs.
1.Biguanide: the most commonly used is metformin, generally as the first choice for first-onset type 2 diabetes, especially with obese, overweight patients, the main mechanism of action is to inhibit the production and output of liver glucose, the role of reducing fasting blood sugar is obvious. It can also suppress appetite, and is one of the few drugs that can reduce body weight among glucose-lowering drugs.
The main side effects are reversible gastrointestinal reactions, such as abdominal pain, diarrhea, nausea, vomiting, etc. It can be started in small doses, 250mg, twice a day, during or after meals, or the use of enteric soluble tablets or extended release tablets can significantly reduce gastrointestinal discomfort. Gradually increase the dose to 500mg 2-3 times a day or 850mg twice a day, and do not exceed the maximum dose of 2000mg a day.
The most serious side effect is lactic acidosis, this complication has a high mortality rate, but at the same time the incidence is also very low, the annual incidence of patients using metformin is less than 1 in 100,000, and mostly occurs in patients with contraindications to metformin, in the past the commonly used phenelzine (hypoglycemia) is relatively high, and now many countries have stopped using it.
Many patients worry that metformin will damage the kidney function, this understanding is wrong, metformin itself will not damage the kidney function, but it is mainly in the excretion through the kidneys, if there are patients with renal insufficiency, may cause the accumulation of drugs and lead to increased lactic acid.
Contraindications: ① patients with liver and kidney function damage; ② patients in a state of hypoxia, such as those with chronic cardiac insufficiency, heart failure, chronic obstructive pulmonary disease, peripheral vascular disease; ③ those with chronic and serious gastrointestinal diseases and alcoholics; ④ poor general condition, severe malnutrition and wasting, etc.
Also note that the drug should be stopped for 48 hours before surgical procedures requiring fasting, general anesthesia and radiological examinations with iodine-containing contrast agents. Age is not a factor to consider whether to stop the drug, as long as there are no contraindications, the elderly can also be used effectively and safely.
2.α-glucosidase inhibitors
The main drugs are acarbose (Bactrim, Carboplatin), voglibose (Bexin), etc. The dosing method should be taken immediately before meals or chewed with the first bite of food. The mechanism of action is to delay the degradation and absorption of carbohydrates, thus delaying the rise of blood glucose after meals and reducing the magnitude, and also making the trough after the peak of blood glucose insignificant, which can also avoid the occurrence of hypoglycemia. Simply put, it is the slowing down of the rise of blood glucose in diabetic patients in line with the delayed secretion of their own insulin, thus lowering blood glucose. So these drugs mainly lower the blood sugar level after meals.
The main side effects are gastrointestinal symptoms such as bloating, diarrhea and abdominal pain, although most of them can be relieved with continued use of the drug. Bactrim is hardly absorbed into the blood circulation, so there are no systemic side effects, but if the dose is too high, such as 300mg three times a day, it can also lead to abnormal liver function.
Contraindications: Chronic intestinal dysfunction with significant digestive and absorption disorders; organic intestinal lesions such as severe hernia and intestinal obstruction are contraindicated.
Note: If hypoglycemia occurs when combining bactrim with other hypoglycemic drugs or insulin, glucose, milk or honey should be taken, such as sucrose or general sweets can not make the blood sugar rise rapidly.
3.Gliadin class
The main ones are rosiglitazone (Vindial, Tylenol), pioglitazone (Ekotuo, Riton), etc., which are taken once a day, 1-2 tablets at a time. The mechanism of action is to reduce insulin resistance and improve the body’s insulin sensitivity, which can slow down the decline of islet cell function.
However, the controversy over the increased cardiovascular risk of rosiglitazone in recent years has raised concerns about the application of rosiglitazone among the majority of diabetic patients and some clinicians. However, subsequent clinical evidence has shown that the rational application of rosiglitazone can avoid or reduce the occurrence of cardiovascular-related events. The main side effects of rosiglitazone are increased water and sodium retention, which can lead to exacerbation of heart failure, and in addition this class of drugs can increase the risk of fracture. Therefore, the current clinical principle of use is not to use rosiglitazone drugs in patients with existing heart failure, and it is not recommended for patients with significant edema, renal lesions, elderly patients, those with long disease duration, or those applying insulin or nitrates. Therefore, the use of this class of drugs should be reasonably applied under the guidance of clinicians.
Drugs that promote insulin secretion. They include sulfonylurea, glinepiride, and the drugs based on intestinal insulinotropic hormone that have been marketed in recent years.
1. Sulfonylureas
Clinically used mainly include glibenclamide (euglycemia), glipizide (mepyridamole, disulfiram), gliclazide (DAMAC), glipizide (glucophage) and glipizide controlled-release tablets (Ruiyin), gliclazide extended-release tablets (DAMAC extended-release tablets) and the third-generation sulfonylurea glimepiride (Amoxicillin). For non-obese type 2 diabetes and obese type 2 diabetes who cannot be controlled with other oral hypoglycemic drugs, or cannot tolerate them
First of all, in terms of glucose-lowering intensity, glibenclamide and glimepiride have stronger effects, and glipizide is weaker, but because it is only 5%; excreted from the kidney, it is suitable for mild to moderate renal insufficiency or elderly patients, while glipizide has the highest chance of hypoglycemia among sulfonylureas because of its binding to the point of action of the pancreas and its long duration of action, and is prone to severe hypoglycemia, which is not easily corrected. The hypoglycemic effect of glimepiride has a powerful extrapancreatic effect, improving insulin sensitivity in addition to promoting insulin secretion, and its fast binding to receptors on pancreatic islet cells, fast onset of action and fast dissociation, so hypoglycemia is less frequent.
Secondly, the common side effects of sulfonylureas are hypoglycemia and weight gain, but some long-acting dosage forms such as gliclazide extended-release tablets and glipizide controlled-release tablets have less chance of hypoglycemia, and also have less effect on weight. Moreover, in recent years, as the dangers of hyperinsulinemia have been gradually recognized, the ideal sulfonylurea is to minimize the total amount of insulin secretion stimulated throughout the day while ideally controlling blood glucose, which can “save insulin” and thus reduce the burden on pancreatic islet cells. In this regard, glipizide controlled-release tablets, glipizide extended-release tablets and glimepiride have certain advantages, and because of their once-a-day dosing method, compliance is higher, which is also more conducive to long-term blood glucose control.
Furthermore, ischemic preconditioning is a mechanism that dilates the blood vessels and protects the myocardium when ischemia and hypoxia occur in the heart, and sulfonylureas can diminish this protective mechanism and increase the mortality rate of heart attack. The latter drugs are appropriate for patients with high risk factors for cardiovascular disease or patients who have had previous myocardial infarction if they want to use sulfonylureas.
2.Glinide type pro-secretory agents
The latter is weaker than the former in terms of hypoglycemic intensity, but at the same time, hypoglycemia is also less frequent.
These drugs are similar to sulfonylureas in terms of mechanism of action, scope of application and side effects, and clinical observation shows that if sulfonylureas are ineffective, these drugs are also ineffective, but when these drugs cannot control blood sugar ideally, sulfonylureas can be used instead.
Its action is characterized by rapid onset of action and rapid metabolism, and its pro-secretory effect on pancreatic islet cells is glucose-dependent, and the higher the glucose level, the stronger its pro-secretory effect, so that hypoglycemia occurs less frequently, and it can promote the secretion of insulin in the first phase, which is more in line with physiology and better control of postprandial blood sugar.
Better safety, does not affect cardiac ischemic preconditioning; it is still safe to use in patients with mild to moderate renal insufficiency.
Higher flexibility, can be taken at meal time and no meal without medication, while traditional sulfonylureas (such as glipizide, glipizide, etc.) need to be taken 30 minutes before meal time, so glinides are more suitable for patients with irregular meal time.
However, clinical attention should be paid to the cautious use in patients with heart failure, unstable angina, severe arrhythmia, and myocardial infarction within the last 1 year.
3. Drugs based on intestinal insulin hormone
These drugs have been used in clinical practice in recent years, and have been marketed in the United States and the European Union for 4 years and in China for 1 year.
Intestinal glucagon hormone (glucagon-like peptide-1, GLP-1) is released by L-cells in ileum and colon after meal, stimulating β-cells to release insulin in a glucose-dependent manner, while it can inhibit α-cells to release glucagon, which can inhibit gastric emptying, reduce food intake and lower body weight, and preclinical models have confirmed its effect of promoting β-cell recovery.
However, this kind of hormone is degraded very fast in the body, so the drugs based on intestinal glucagon hormone are mainly two types, one is the analog of glucagon-like peptide-1, which can play the role of glucagon-like peptide-1 but is not easily degraded, there are exenatide and liraglutide, subcutaneous injection, fixed dose, 1-2 times a day; one is by inhibiting the enzyme that degrades glucagon-like peptide-1, so as to increase the The concentration in the body, currently used in China is sitagliptin phosphate (Genovent), oral formulation, once a day.
The action of these drugs is characterized by their glucose-dependent effect of promoting insulin secretion, which does not stimulate secretion when blood sugar is normal, so hypoglycemia occurs less frequently; they can inhibit glucagon secretion and are effective for patients with all stages of diabetes; they are the drugs that can be confirmed in animal experiments to have the effect of promoting islet cell recovery and increasing the number of islet cells.
The main side effects are gastrointestinal reactions, especially the first two injectable preparations, about 10%; of patients have nausea, while sitagliptin is less and better tolerated clinically, and the first two drugs are more costly.
However, after all, the clinical use of such drugs is relatively short, and their clinical efficacy and safety need to be further validated.
Insulin
Some patients have concerns about the use of insulin and worry about “addiction”, this idea is not correct, some diabetic patients need insulin therapy because their own islet function is basically exhausted, only then they need exogenous insulin supplementation to control blood sugar. 70-80% of type 2 diabetic patients with more than 8 years of disease need insulin therapy. However, the use of insulin is definitely more prone to hypoglycemia and weight gain than oral medications.
1. Types of insulin.
From the source classification there are animal insulin, human insulin and insulin analogues
From the classification of efficacy, there are rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, as well as rapid-acting, short-acting and intermediate-acting premixed insulin mixed in a certain ratio, such as Novolin 30R indicates 30%; the short-acting insulin and 70%; the intermediate-acting insulin mix, Novolac 30 indicates 30%; the rapid-acting insulin and 70%; the intermediate-acting insulin mix.
2. Indications for insulin.
Type 1 diabetic patients; diabetic patients with intensive treatment; type 2 diabetic patients with acute and chronic complications; diabetic patients in various emergency states (surgery, infection, trauma, etc.); patients with initial severe hyperglycemia (fasting blood glucose >;15mmol/L); patients whose blood glucose cannot reach the standard during non-pharmacological treatment and/or oral treatment; patients who cannot or should not adhere to the medication due to the side effects of oral medication; regular Glycosylated hemoglobin >;7%; after treatment and oral medication; diabetic patients who are wasting.
3.Insulin treatment plan.
①Insulin supplementation therapy
Continue to take oral hypoglycemic drugs, maintain the original dose unchanged, and add medium-acting or long-acting insulin before breakfast or bedtime. If the daily insulin dosage exceeds 30 units and blood glucose is still not ideally controlled, the oral drug needs to be stopped, and the treatment is insulin replacement therapy.
②Insulin replacement therapy
There are two common programs: one is to inject premixed insulin twice before breakfast and dinner, the advantage of this program is convenient and good compliance, the disadvantage is that blood sugar is not easy to control ideally, such as high blood sugar after fasting and lunch, while hypoglycemia is easy to occur before lunch and bedtime. The other is to inject short-acting insulin before three meals and medium- and long-acting insulin before bedtime. The advantage is that the insulin dosage is less, the adjustment is flexible, and the postprandial and fasting blood glucose can be controlled ideally.
If insulin use is large, insulin sensitizers, acarbose and metformin can also be used in combination.
If blood sugar fluctuates a lot and is prone to hypoglycemia, treatment with insulin analogues or insulin pumps can be considered.
The reason why blood glucose is prone to fluctuation with ordinary insulin is mainly determined by the absorption and action characteristics of exogenous insulin (short-acting insulin as mealtime insulin has slow onset and clearance, while medium-acting insulin as basal insulin has peak action), which is why insulin analogues and insulin pumps have emerged to make it closer to the secretion and action characteristics of a person’s own insulin.
Chinese medicine
Finally, I need to briefly mention the role of Chinese medicine in the treatment of diabetes. Chinese medicine has a better comprehensive therapeutic effect in relieving symptoms, reducing insulin resistance, improving physical fitness, playing a better role in lowering glucose in cooperation with western medicine and preventing chronic complications, but lowering glucose is not the advantage of Chinese medicine. However, the mechanism of action is not very clear and the effect of hypoglycemia is limited, so it is often difficult to rely on Chinese medicine or proprietary Chinese medicine alone to control blood glucose up to the standard, and less than 10% of patients in our clinic can use Chinese medicine or proprietary Chinese medicine alone to control blood glucose up to the standard, and most of them are patients with short duration of illness, good reserve of their own islet function and some elderly patients. Therefore, the treatment of diabetes mellitus should take the advantages and avoid the disadvantages of Chinese and Western medicine, and apply them reasonably for the best effect. There is no need for patients to worry about the burden on the liver and kidneys caused by western drugs and resist western hypoglycemic drugs, as all drugs are metabolized by the liver and kidneys, and none of the current hypoglycemic drugs have obvious liver and kidney toxicity. This mentality of patients is also easily deceived by some informal drugs or health care products on the market that are called “pure Chinese medicine” but have added glucose-lowering western medicine.
In conclusion, the principle of diabetes medication is, first of all, to control blood glucose up to the standard in order to reduce the appearance of chronic complications; then comes the fine selection of drugs, such as non-insulin secreting drugs or short-acting pro-secretory agents of glargine type are appropriate for early type 2 diabetes patients to reduce the burden on the pancreas islets, thus delaying the decline of islet function; individualized treatment plan should be emphasized, as each patient’s insulin sensitivity and islet function decline Since the insulin sensitivity and the degree and speed of islet function decline are different for each patient, patients should not adjust their own medication plan based on the medication experience of other patients, but should monitor their blood glucose well, understand their own disease characteristics, and cooperate with the specialist to develop a suitable treatment plan for themselves.