Summary of Indications for Commonly Used Diabetes Drugs in Clinical Practice
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Diabetes is a group of metabolic diseases characterized by hyperglycemia. Poor long-term control of hyperglycemia can lead to damage to multiple organ tissues, accompanied by cardiovascular and cerebrovascular, eye, kidney, limbs, and other organ lesions. In addition to exercise and dietary intervention, medication intervention is also key to controlling blood sugar. Diabetes treatment drugs mainly include oral hypoglycemic agents and injectable hypoglycemic agents.
Oral Hypoglycemic Agents
Based on their effects, they can be divided into drugs that primarily promote insulin secretion and those that lower blood sugar through other mechanisms. The former mainly includes sulfonylureas and glinides, while the latter mainly includes biguanides, thiazolidinediones (TZDs), α-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 inhibitors (SGLT-2i). Different types of drugs vary in their hypoglycemic effect, risk of hypoglycemia, weight loss, and impact on the heart and kidneys, and they are not suitable for the same populations.
Sulfonylureas include glibenclamide (Glibenclamide), glipizide (Glipizide), glipizide (Glipizide), glipizide (Glipizide), and glimepiride (Glimepiride).
Sulfonylureas belong to insulin secretagogues, which mainly lower blood sugar by stimulating the secretion of insulin from pancreatic B cells and increasing the level of insulin in the body. Sulfonylureas can promote the production of endogenous insulin, so there is a certain risk of hypoglycemia, especially in elderly patients and patients with combined liver or kidney dysfunction.
Long-term use of sulfonylureas may lead to secondary failure of sulfonylureas, mainly due to pancreatic B cell function failure or insulin resistance that is difficult to alleviate. First-generation sulfonylureas such as tolbutamide and chlorpropamide have been phased out due to strong adverse reactions; second-generation include glibenclamide, glipizide, glipizide, and glimepiride; third-generation glimepiride has both insulin secretagogue and sensitization functions, is long-acting, and causes less hypoglycemia. Patients with mild to moderate renal insufficiency can use glimepiride, which is mainly excreted in feces via bile along with its metabolites.
Glinides include repaglinide (Repaglinide), nateglinide (Nateglinide), and mitiglinide. They can directly improve the early phase secretion defect of insulin and have a unique advantage in reducing postprandial blood sugar. Repaglinide can also restore pulsatile insulin secretion and improve insulin sensitivity to a certain extent. These drugs should be taken before meals and can be used alone or in combination with other hypoglycemic drugs (except sulfonylureas).
Common adverse reactions of glinides are hypoglycemia and weight gain, but the risk and degree of hypoglycemia are lighter than those of sulfonylureas. Glinides can be used in patients with renal insufficiency.
Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the inactivation of GLP-1 in the body by inhibiting DPP-4, thereby increasing the level of endogenous GLP-1. Blood GLP-1 increases insulin secretion in a glucose concentration-dependent manner and inhibits glucagon secretion. Currently, DPP-4 inhibitors marketed in China include sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin.
The use of DPP-4 inhibitors alone does not increase the risk of hypoglycemia.
The effect of DPP-4 inhibitors on body weight is neutral. Linagliptin does not increase the risk of composite renal outcomes (renal death, progression to end-stage renal disease, or persistent eGFR decline of 40%).
When using sitagliptin, saxagliptin, alogliptin, and vildagliptin in patients with renal insufficiency, attention should be paid to reducing the drug dose according to the drug instructions. There is no need to adjust the dose when using linagliptin in patients with liver or renal insufficiency.
Biguanides include metformin (Metformin). Metformin is the first choice of medication for type 2 diabetes patients and the basic medication in combination therapy. It lowers blood sugar by reducing hepatic glucose output, increasing muscle glucose uptake, and improving peripheral insulin resistance. The hypoglycemic effect is strong, and the use of metformin alone does not increase the risk of hypoglycemia, but the combination of metformin with insulin or insulin secretagogues may increase the risk of hypoglycemia. Whether it is the "Chinese Type 2 Diabetes Prevention and Treatment Guidelines (2020 Edition)" released by the Chinese Diabetes Society or the "Diabetes Medical Diagnosis and Treatment Standards (2021 Edition)" issued by the American Diabetes Association, metformin is recommended as the preferred initial treatment drug for type 2 diabetes. Once treatment is initiated, if the patient can tolerate it and there are no contraindications, metformin should always be retained in the treatment plan.
Thiazolidinediones include rosiglitazone (Rosiglitazone) and pioglitazone (Pioglitazone). TZDs mainly lower blood sugar by increasing the sensitivity of target cells to insulin. Since the main pathogenesis of type 2 diabetes is insulin resistance and relative insulin secretion deficiency, and thiazolidinediones have a good effect on these two causes, they were highly regarded by clinicians at the beginning of marketing.
However, in May 2007, a meta-analysis published in the top medical journal "The New England Journal of Medicine" showed that rosiglitazone might increase the risk of myocardial infarction and cardiac death in patients. In August of the same year, the FDA's Advisory Committee reviewed the safety issues of rosiglitazone and decided to add a black box warning about heart failure to all drug labels in this category. In November, the FDA announced again that it would add the potential increased risk of heart attacks to the existing warnings. In addition to cardiovascular risks, TZDs do not increase the risk of hypoglycemia when used alone, but may increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues.
Weight gain and edema are common adverse reactions of TZDs, which are more pronounced when used in combination with insulin. Therefore, patients with heart failure (New York Heart Association Class II or higher), active liver disease, or aminotransferase levels more than 2.5 times the upper limit of normal, severe osteoporosis, or a history of fractures are contraindicated for this class of drugs.
Common therapeutic drugs for diabetes in clinical practice mainly include oral hypoglycemic agents and injectable hypoglycemic agents.
Oral Hypoglycemic Agents
α-Glucosidase Inhibitors include acarbose, voglibose, and miglitol. α-Glucosidase inhibitors lower blood sugar by inhibiting the absorption of carbohydrates in the intestines, mainly reducing postprandial blood sugar in diabetic patients. Due to differences in dietary structure among different races, the main sales targets of α-glucosidase inhibitors are Asian populations that mainly consume carbohydrates. Common adverse reactions of α-glucosidase inhibitors are gastrointestinal reactions (such as bloating, flatulence, etc.). Starting with a small dose and gradually increasing the dose is an effective method to reduce adverse reactions. Usually, hypoglycemia does not occur when taking this class of drugs alone. If hypoglycemia occurs in patients taking α-glucosidase inhibitors, treatment requires the use of glucose or honey, while the effect of correcting hypoglycemia with sucrose or starchy foods is poor.
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors include dapagliflozin, empagliflozin, and canagliflozin, etc., which are a new type of oral hypoglycemic drugs. It has been proven to have a protective effect on the kidneys, can inhibit the reabsorption of glucose by the kidneys, lower the renal threshold for glucose, thereby promoting the excretion of urinary glucose, bringing new hope for the treatment of diabetic nephropathy.
Studies have shown that this class of drugs can reduce the risk of composite renal endpoints by up to 30%, while reducing the risk of cardiovascular events, and has good safety. The occurrence and development of diabetic nephropathy are related to many factors, and hyperglycemia is not the only cause. Its pathogenesis involves disorders of carbohydrate metabolism, hemodynamic changes, inflammation, oxidative stress, and many other aspects.
The renoprotective mechanism of SGLT-2 inhibitors mainly includes lowering blood sugar, improving renal hyperfiltration, reducing proteinuria, improving renal hypoxia, reducing weight, lowering blood pressure, lowering uric acid, and alleviating inflammation and oxidative stress, which can act on various links of diabetic nephropathy.
Injectable Hypoglycemic Agents
Including insulin and glucagon-like peptide-1 (GLP-1) receptor agonists.
Insulin can be divided into animal insulin, human insulin, and insulin analogs based on different sources and chemical structures. Depending on the characteristics of their action, insulin can be divided into ultra-short-acting insulin analogs, regular (short-acting) insulin, intermediate-acting insulin, long-acting insulin, long-acting insulin analogs, premixed insulin, premixed insulin analogs, and dual insulin analogs.
Selection of insulin preparations at the start of insulin therapy: According to the specific situation of the patient, basal insulin, premixed insulin, or dual insulin analogs can be selected to initiate insulin therapy; on the basis of initiating insulin therapy and after adequate dose adjustment, if the patient's blood sugar level is still not up to standard or repeated hypoglycemia occurs, the treatment plan needs to be further optimized. Intensive insulin therapy can be carried out using mealtime plus basal insulin (2-4 times/day) or 2-3 times/day premixed insulin analogs.
Type 1 diabetic patients depend on insulin to maintain life, while type 2 diabetic patients do not need insulin to maintain life, but when oral hypoglycemic drugs are ineffective or there are contraindications to oral drugs, insulin is still needed to control hyperglycemia and reduce the risk of diabetic complications. At some point, especially when the course of the disease is longer, insulin therapy may be the most important, or even necessary, measure to control blood sugar.
GLP-1 receptor agonists can be divided into short-acting ones such as benaglutide, exenatide, and lixisenatide, and long-acting ones such as liraglutide, exenatide weekly formulation, dulaglutide, loxenatide, and semaglutide based on pharmacokinetics. GLP-1 receptor agonists stimulate insulin secretion, inhibit glucagon secretion in a glucose concentration-dependent manner, increase glucose uptake in muscle and adipose tissue, and inhibit hepatic glucose production to play a hypoglycemic role, and can inhibit gastric emptying, reducing food intake through central appetite suppression.
This class of drugs has the effect of reducing weight and may have a good prospect in reducing blood pressure and other aspects. It is suitable for type 2 diabetic patients who cannot fully control blood sugar with metformin, sulfonylureas, and other combination therapies.
Oral Hypoglycemic Agents
Based on their effects, they can be divided into drugs that primarily promote insulin secretion and those that lower blood sugar through other mechanisms. The former mainly includes sulfonylureas and glinides, while the latter mainly includes biguanides, thiazolidinediones (TZDs), α-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 inhibitors (SGLT-2i). Different types of drugs vary in their hypoglycemic effect, risk of hypoglycemia, weight loss, and impact on the heart and kidneys, and they are not suitable for the same populations.
Sulfonylureas include glibenclamide (Glibenclamide), glipizide (Glipizide), glipizide (Glipizide), glipizide (Glipizide), and glimepiride (Glimepiride).
Sulfonylureas belong to insulin secretagogues, which mainly lower blood sugar by stimulating the secretion of insulin from pancreatic B cells and increasing the level of insulin in the body. Sulfonylureas can promote the production of endogenous insulin, so there is a certain risk of hypoglycemia, especially in elderly patients and patients with combined liver or kidney dysfunction.
Long-term use of sulfonylureas may lead to secondary failure of sulfonylureas, mainly due to pancreatic B cell function failure or insulin resistance that is difficult to alleviate. First-generation sulfonylureas such as tolbutamide and chlorpropamide have been phased out due to strong adverse reactions; second-generation include glibenclamide, glipizide, glipizide, and glimepiride; third-generation glimepiride has both insulin secretagogue and sensitization functions, is long-acting, and causes less hypoglycemia. Patients with mild to moderate renal insufficiency can use glimepiride, which is mainly excreted in feces via bile along with its metabolites.
Glinides include repaglinide (Repaglinide), nateglinide (Nateglinide), and mitiglinide. They can directly improve the early phase secretion defect of insulin and have a unique advantage in reducing postprandial blood sugar. Repaglinide can also restore pulsatile insulin secretion and improve insulin sensitivity to a certain extent. These drugs should be taken before meals and can be used alone or in combination with other hypoglycemic drugs (except sulfonylureas).
Common adverse reactions of glinides are hypoglycemia and weight gain, but the risk and degree of hypoglycemia are lighter than those of sulfonylureas. Glinides can be used in patients with renal insufficiency.
Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the inactivation of GLP-1 in the body by inhibiting DPP-4, thereby increasing the level of endogenous GLP-1. Blood GLP-1 increases insulin secretion in a glucose concentration-dependent manner and inhibits glucagon secretion. Currently, DPP-4 inhibitors marketed in China include sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin.
The use of DPP-4 inhibitors alone does not increase the risk of hypoglycemia.
The effect of DPP-4 inhibitors on body weight is neutral. Linagliptin does not increase the risk of composite renal outcomes (renal death, progression to end-stage renal disease, or persistent eGFR decline of 40%).
When using sitagliptin, saxagliptin, alogliptin, and vildagliptin in patients with renal insufficiency, attention should be paid to reducing the drug dose according to the drug instructions. There is no need to adjust the dose when using linagliptin in patients with liver or renal insufficiency.
Biguanides include metformin (Metformin). Metformin is the first choice of medication for type 2 diabetes patients and the basic medication in combination therapy. It lowers blood sugar by reducing hepatic glucose output, increasing muscle glucose uptake, and improving peripheral insulin resistance. The hypoglycemic effect is strong, and the use of metformin alone does not increase the risk of hypoglycemia, but the combination of metformin with insulin or insulin secretagogues may increase the risk of hypoglycemia. Whether it is the "Chinese Type 2 Diabetes Prevention and Treatment Guidelines (2020 Edition)" released by the Chinese Diabetes Society or the "Diabetes Medical Diagnosis and Treatment Standards (2021 Edition)" issued by the American Diabetes Association, metformin is recommended as the preferred initial treatment drug for type 2 diabetes. Once treatment is initiated, if the patient can tolerate it and there are no contraindications, metformin should always be retained in the treatment plan.
Thiazolidinediones include rosiglitazone (Rosiglitazone) and pioglitazone (Pioglitazone). TZDs mainly lower blood sugar by increasing the sensitivity of target cells to insulin. Since the main pathogenesis of type 2 diabetes is insulin resistance and relative insulin secretion deficiency, and thiazolidinediones have a good effect on these two causes, they were highly regarded by clinicians at the beginning of marketing.
However, in May 2007, a meta-analysis published in the top medical journal "The New England Journal of Medicine" showed that rosiglitazone might increase the risk of myocardial infarction and cardiac death in patients. In August of the same year, the FDA's Advisory Committee reviewed the safety issues of rosiglitazone and decided to add a black box warning about heart failure to all drug labels in this category. In November, the FDA announced again that it would add the potential increased risk of heart attacks to the existing warnings. In addition to cardiovascular risks, TZDs do not increase the risk of hypoglycemia when used alone, but may increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues.
Weight gain and edema are common adverse reactions of TZDs, which are more pronounced when used in combination with insulin. Therefore, patients with heart failure (New York Heart Association Class II or higher), active liver disease, or aminotransferase levels more than 2.5 times the upper limit of normal, severe osteoporosis, or a history of fractures are contraindicated for this class of drugs.
Common therapeutic drugs for diabetes in clinical practice mainly include oral hypoglycemic agents and injectable hypoglycemic agents.
Oral Hypoglycemic Agents
α-Glucosidase Inhibitors include acarbose, voglibose, and miglitol. α-Glucosidase inhibitors lower blood sugar by inhibiting the absorption of carbohydrates in the intestines, mainly reducing postprandial blood sugar in diabetic patients. Due to differences in dietary structure among different races, the main sales targets of α-glucosidase inhibitors are Asian populations that mainly consume carbohydrates. Common adverse reactions of α-glucosidase inhibitors are gastrointestinal reactions (such as bloating, flatulence, etc.). Starting with a small dose and gradually increasing the dose is an effective method to reduce adverse reactions. Usually, hypoglycemia does not occur when taking this class of drugs alone. If hypoglycemia occurs in patients taking α-glucosidase inhibitors, treatment requires the use of glucose or honey, while the effect of correcting hypoglycemia with sucrose or starchy foods is poor.
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors include dapagliflozin, empagliflozin, and canagliflozin, etc., which are a new type of oral hypoglycemic drugs. It has been proven to have a protective effect on the kidneys, can inhibit the reabsorption of glucose by the kidneys, lower the renal threshold for glucose, thereby promoting the excretion of urinary glucose, bringing new hope for the treatment of diabetic nephropathy.
Studies have shown that this class of drugs can reduce the risk of composite renal endpoints by up to 30%, while reducing the risk of cardiovascular events, and has good safety. The occurrence and development of diabetic nephropathy are related to many factors, and hyperglycemia is not the only cause. Its pathogenesis involves disorders of carbohydrate metabolism, hemodynamic changes, inflammation, oxidative stress, and many other aspects.
The renoprotective mechanism of SGLT-2 inhibitors mainly includes lowering blood sugar, improving renal hyperfiltration, reducing proteinuria, improving renal hypoxia, reducing weight, lowering blood pressure, lowering uric acid, and alleviating inflammation and oxidative stress, which can act on various links of diabetic nephropathy.
Injectable Hypoglycemic Agents
Including insulin and glucagon-like peptide-1 (GLP-1) receptor agonists.
Insulin can be divided into animal insulin, human insulin, and insulin analogs based on different sources and chemical structures. Depending on the characteristics of their action, insulin can be divided into ultra-short-acting insulin analogs, regular (short-acting) insulin, intermediate-acting insulin, long-acting insulin, long-acting insulin analogs, premixed insulin, premixed insulin analogs, and dual insulin analogs.
Selection of insulin preparations at the start of insulin therapy: According to the specific situation of the patient, basal insulin, premixed insulin, or dual insulin analogs can be selected to initiate insulin therapy; on the basis of initiating insulin therapy and after adequate dose adjustment, if the patient's blood sugar level is still not up to standard or repeated hypoglycemia occurs, the treatment plan needs to be further optimized. Intensive insulin therapy can be carried out using mealtime plus basal insulin (2-4 times/day) or 2-3 times/day premixed insulin analogs.
Type 1 diabetic patients depend on insulin to maintain life, while type 2 diabetic patients do not need insulin to maintain life, but when oral hypoglycemic drugs are ineffective or there are contraindications to oral drugs, insulin is still needed to control hyperglycemia and reduce the risk of diabetic complications. At some point, especially when the course of the disease is longer, insulin therapy may be the most important, or even necessary, measure to control blood sugar.
GLP-1 receptor agonists can be divided into short-acting ones such as benaglutide, exenatide, and lixisenatide, and long-acting ones such as liraglutide, exenatide weekly formulation, dulaglutide, loxenatide, and semaglutide based on pharmacokinetics. GLP-1 receptor agonists stimulate insulin secretion, inhibit glucagon secretion in a glucose concentration-dependent manner, increase glucose uptake in muscle and adipose tissue, and inhibit hepatic glucose production to play a hypoglycemic role, and can inhibit gastric emptying, reducing food intake through central appetite suppression.
This class of drugs has the effect of reducing weight and may have a good prospect in reducing blood pressure and other aspects. It is suitable for type 2 diabetic patients who cannot fully control blood sugar with metformin, sulfonylureas, and other combination therapies.