The incidence of diabetes, one of the most dangerous and costly chronic diseases with significant complications, is growing rapidly worldwide, and recent studies show that the incidence of diabetes in some areas of China has tripled in the past 20 years and is expected to reach 38 million people by 2025. The fear of diabetes is not the disease itself, but the complications that arise from it. type 2 diabetes complications are harmful to long-term health, affect quality of life and life expectancy, and have a significant impact on the morbidity and mortality of some diseases. The results of many large-scale clinical studies suggest that early diagnosis and early treatment can help control the occurrence and development of diabetes complications. A large clinical study conducted in the UK confirmed that microvascular complications in diabetic patients can be reduced if blood glucose is controlled at near normal levels. Glycosylated hemoglobin HbA1c is an indicator of longer-term glycemic control in diabetic patients, and is generally normal at 6.5% or less. The American Diabetes Association requires physicians to take appropriate action when a patient’s HbA1c >8% indicates poor glycemic control. However, a large body of literature also shows that diabetic patients are not being treated appropriately. Some data show that less than 10% of patients in China are currently receiving treatment, and less than 30% of them are well controlled.
The conventional treatment pattern for type 2 diabetes is lifestyle modification followed by the use of oral hypoglycemic agents. A single drug is used first, then the dose is increased if glycemic control is poor, and if that does not work, a combination of two or more oral hypoglycemic agents is considered. The problem with the conventional model is that: after a period of “exploration”, the pancreatic β-cells continue to decline, and the excessive glucose level accelerates the development of atherosclerosis and the failure of the insulin-secreting β-cells of the pancreas, which eventually leads to an increase in the incidence of complications and mortality. The efficacy of monotherapy decreases year by year and the long-term effect is poor. In addition, the possibility of side effects increases. According to the current situation of diabetes in China, we recommend the early combination of oral hypoglycemic drugs for diabetic patients.
Why do you advocate combination therapy?
1.Improve glucose metabolism, long-term good blood sugar control.
2.Protect the function of beta cells and delay the decline of their function.
3.Reduce insulin resistance.
4.Delay, reduce the occurrence and development of complications.
The principles of combination therapy are as follows.
1, the common dose of a single drug can not satisfactorily control blood sugar. Should not wait until the maximum dose of a single drug is ineffective before considering the combination of drugs.
2. Drugs with different mechanisms of action can be combined to avoid shortcomings. Avoid the combination of similar drugs with the same mechanism of action.
3, the general application of the combination of two drugs, if necessary, three drugs.
4, in the combination of treatment to take into account the cost – effect factors.
Commonly used oral hypoglycemic drugs
I. Sulfonylureas
These drugs mainly stimulate insulin secretion by pancreatic beta cells. They can also increase the sensitivity of peripheral tissues and the liver to insulin.
At present, the commonly used sulfonylureas are D860 in the first generation, euglycemia, damacell, mepyridamole, glucagon and glucophage in the second generation, and glimepiride in the third generation. The above sulfonylureas have their own characteristics: 1) Eugenol has the strongest effect and a long half-life, and should be used with caution in elderly diabetic patients ≥70 years old to avoid serious hypoglycemia. 2) DAMECA also inhibits platelet aggregation, which is beneficial in preventing and treating vascular complications caused by diabetes at the same time. 3) Mepyridam is second only to Eugenol in terms of strength, but has a shorter half-life, and is a more potent and safe hypoglycemic agent. 4) 95% of glucophage is excreted by biliary tract, so glucophage can be used for diabetic patients with mild renal insufficiency. 5) Glimepiride is still effective for some type 2 diabetic patients with secondary sulfonylurea failure, especially when combined with insulin, which can reduce insulin dosage.
Precautions when applying sulfonylureas.
1) Sulfonylureas should be started in small doses, especially in elderly patients, along with close monitoring of blood glucose. Sulfonylureas are most effective when taken half an hour before meals.
2) The daily dosage of any sulfonylurea should not exceed its maximum dosage (euglycemia 15mg/day; Damacell 240mg/day; Mepyridamole 30mg/day).
3) After the correction of hyperglycemia, the pancreatic beta cells may resume responsiveness to glucose stimulation, and the dose of sulfonylureas should be adjusted promptly to try to avoid hypoglycemia.
4) Two sulfonylureas are generally not combined at the same time in the same patient, but they can be combined with biguanides or α-glucosidase inhibitors to enhance their hypoglycemic effect, and also with insulin sensitizers, and insulin to avoid secondary failure.
Side effects: mainly hypoglycemia, uncooperative diet, excessive exercise, and overdose of drugs may induce hypoglycemic reactions, especially in the elderly. Digestive system side effects include dyspepsia, nausea, cholestatic jaundice and liver function impairment. Hematopoietic system is more common with leukopenia. Skin manifestations include pruritus and rash and other allergic reactions. The occurrence of severe hypoglycemia should be noted during combination therapy.
Second, the biguanide drugs
The mechanism of action of these drugs: improve the sensitivity of peripheral tissues and liver to insulin, reduce intestinal glucose absorption, inhibit hepatic glycogen isogenesis, and increase peripheral tissue anaerobic enzymes.
Commonly used biguanide hypoglycemic drugs include: phenelzine (hypoglycemia); metformin (hypoglycemic tablets, meticam, dioscorea, gevalt, etc.). Glucagon has the risk of causing lactic acidosis, and has been eliminated and discontinued in Europe and America. Metformin is less likely to accumulate in the body due to its increased water solubility, and the incidence and risk of lactic acidosis is greatly reduced. Now it has been widely accepted as the first choice anti-hyperglycemic drug for mild to moderate type 2 diabetic patients, especially obese patients.
Advantages of metformin.
1, the hypoglycemic effect is obvious, the effect and dose related, there is a dose-effect relationship, the minimum effective dose 0.5g, the best dose 2.0g, the maximum dose 2.5g. single use generally does not cause hypoglycemia.
2.If patients choose appropriate within the therapeutic dose metformin rarely induces lactic acidosis.
3, wide range of applications, obesity, insulin significantly high should be given priority.
4.Does not increase blood insulin level, does not increase body weight, can protect beta cell function.
5.For the stage before type 2 diabetes-IGT (reduced glucose tolerance), it has an intervention effect and can prevent or delay from IGT state into diabetes stage.
6.It has the effect of lowering cholesterol and triglyceride.
7.Metformin can be used in combination with sulfonylureas, alpha-glucosidase inhibitors, thiazolidinedione derivatives, proinsulin secretagogues, and insulin.
Side effects.
Adverse reactions occur in 30% of patients because the main site of action of metformin is in the intestinal tract and, therefore, the adverse reactions caused by it occur mainly in the intestinal tract. These reactions include: decreased appetite, metallic taste in the mouth, nausea, abdominal pain, bloating, diarrhea, which usually diminish on their own after a period of treatment and are gradually increased from low doses dose, as well as taking the drug after a meal or eating can reduce the symptoms. Lactic acidosis due to metformin is rare. However, metformin is contraindicated in hepatic and renal insufficiency, heart failure, severe anemia, and hypoxia.
III. α-glucosidase inhibitors
These drugs can competitively and reversibly inhibit mesenteric brush border alpha-glucosidase, slowing down the absorption of carbohydrates in the digestive tract and reducing the magnitude of postprandial blood glucose rise.
Currently, there are more clinically used drugs in this class, such as Bactrim, also known as acarbose (Bactrim), and Bexin. The characteristics of these drugs are that they do not stimulate insulin secretion when lowering blood glucose, and can also lower blood insulin, triglyceride and cholesterol levels. It is mainly used for type 2 diabetic patients with mainly elevated postprandial glucose, especially obese and elderly people. It does not cause hypoglycemia when used alone. It can be used in combination with sulfonylureas, biguanides or insulin. It can be used as interventional therapy for patients with IGT.
Side effects: Mainly GI reactions, unabsorbed carbohydrates are fermented by bacteria leading to abdominal distension, abdominal pain, diarrhea. Not easy to cause hypoglycemia, when the alpha glucosidase inhibitor and sulfonylurea hypoglycemic drugs or insulin combination, still can occur hypoglycemic reaction, once it occurs must be oral glucose, can not be oral other sugar and carbohydrate food.
Fourth, thiazolidinedione derivatives
Thiazolidinediones are a new type of drugs to improve insulin resistance, which can increase the sensitivity of liver, muscle and adipose tissue to insulin, improve insulin activity, and achieve the effect of lowering blood sugar. It can also reduce triglyceride and LDL levels, increase HDL levels, and improve dyslipidemia in diabetic patients. It also has the effect of antioxidant, lowering diastolic blood pressure and reducing microalbuminuria.
It is now used clinically in preparations such as rosiglitazone, pioglitazone, troglitazone, and inglitazone. Hypoglycemia does not occur with this class of drugs alone. The combination with sulfonylureas can significantly improve the glycemic control of patients with sulfonylurea failure. The main side effects of this class of drugs are edema and increased blood volume, but they are generally mild. Regular observation of liver function is advisable for long-term use. Those with liver disease and cardiac insufficiency should not be used.
V. Insulin-producing agents
Also known as mealtime insulin secretagogue, this drug is a new type of hypoglycemic agent that mimics physiological insulin secretion. Repaglinide (Novaluron) belongs to this class of drugs. It is characterized by fast onset and fast clearance, and rarely causes hypoglycemia. Diabetic patients only need to take it before meals whenever they want to eat, and do not need to take it if they do not eat, so it has a high degree of flexibility. Between meals, it does not stimulate insulin release, which is important for controlling the average blood sugar level throughout the day, reducing complications and protecting the function of pancreatic β-cells. The drug has no liver or kidney function damage, so it is also suitable for elderly diabetic patients and those with mild diabetic nephropathy. It has a synergistic effect when combined with metformin, and its efficacy is enhanced when combined with insulin sensitizers. It is contraindicated in patients with severe hepatic and renal insufficiency. Adverse reactions include mild hypoglycemic reactions and gastrointestinal disorders.
Six, several hypoglycemic drugs in combination with the application of examples
1, sulfonylurea and biguanide combined use of the general principle is: obese people preferred to biguanide drugs, non-obese people preferred to sulfonylurea drugs. When the use of sulfonylureas fail, the addition of biguanides can make 1/2-1/3 of the patients in a few years of glycemic control is still satisfactory, but also reduce the weight gain caused by sulfonylureas. However, it should be noted that sulfonylureas can lead to higher insulin levels in obese patients.
2, sulfonylureas and α-glucosidase inhibitors combined use when the use of sulfonylureas unsatisfactory glycemic control or only high postprandial blood glucose, plus the use of α-glucosidase inhibitors taken at mealtime, can make postprandial blood glucose decreased by about 50%, the combination of the two can improve the function of pancreatic β cells. No effect on the pharmacokinetics of sulfonylureas was found.
3.Biguanide combined with α-glucosidase inhibitor this program is more suitable for obese diabetic patients, in addition to weight loss, can improve insulin resistance, but be aware that it may make the chance of gastrointestinal side effects increased.
The combination of sulfonylurea and thiazolidinedione derivatives can significantly improve the glycemic control of patients with sulfonylurea failure, and can also significantly reduce the plasma insulin level of patients, especially for patients with hyperinsulinemia. However, in the joint use should be noted that hypoglycemia may occur and the dose of sulfonylureas should be reduced.
5, the combined use of biguanides and thiazolidinedione derivatives research has confirmed that the use of metformin on top of rosiglitazone, its insulin sensitivity has also improved. It can reduce glycated hemoglobin by 1.2%.
6, the combined use of insulin secretagogues and biguanides insulin secretagogues have a more obvious effect on reducing blood glucose fluctuations during meal times, while biguanides have a greater effect on fasting blood glucose levels. Studies have shown that the combination of the two can significantly reduce blood glucose and no effect on body weight, the occurrence of hypoglycemic events and sulfonylureas and biguanides combined with less.
7. In addition, thiazolidinedione derivatives can be used in combination with α-glucosidase inhibitors, but they are not used as the main program because of the high cost required.