The prevalence of type 2 diabetes mellitus (T2DM) in the world continues to rise, leading to a continuous increase in diabetes treatment needs and medical burden. With the progress of science and technology, social needs, hypoglycemic drugs continue to change, hypoglycemic programs become more diverse.
“Classic” traditional hypoglycemic drugs, such as sulfonylureas, metformin α- Glucosidase inhibitors and insulin still occupy half of the hypoglycemic world; However, the rise of new hypoglycemic drugs, such as dipeptidyl peptidase IV inhibitor (dpp-4i), glucagon like peptide-1 receptor agonist (glp-1ra), sodium glucose transporter 2 inhibitor (sglt2i), set off a new trend of hypoglycemic “popularity”“ How to treat and choose “classic” and “popular”?
Break the inherent impression and understand the characteristics of drugs from multiple dimensions
Compared with traditional oral hypoglycemic drugs, new hypoglycemic drugs have different hypoglycemic mechanisms and sites. At present, most people think that the new hypoglycemic drugs have good hypoglycemic safety and low risk of hypoglycemia. Besides hypoglycemia, they can also obtain multiple benefits such as heart and kidney, blood pressure control and weight control. However, the hypoglycemic effect is not strong enough and it is not suitable for patients with poor islet function. So far, insulin therapy is still an important means to control blood glucose.
The majority of diabetic patients’ understanding of insulin is that they are suitable for patients with long course of T2DM and poor function of islets. They have strong hypoglycemic effect and wide indications, but insulin can increase body weight and increase side effects such as low blood sugar risk. At the same time, insulin needs to be refrigerated and stored. Before injection, it needs to be disinfected and the needle needs to be replaced, which brings inconvenience to life. The research on insulin and new hypoglycemic drugs is constantly in-depth exploration and progress, in order to meet the needs of patients with good curative effect, convenient use and high safety.
Popularity ≠ flash in the pan
Representatives of new hypoglycemic drugs include dpp-4i, glp-1ra and sglt2i. Dpp-4i reduces the inactivation of endogenous GLP-1 by inhibiting DPP-4; Glp-1ra can reduce blood glucose by activating GLP-1 receptor. Sglt2i can reduce renal glucose threshold and promote urine glucose excretion by inhibiting SGLT2, which is responsible for reabsorption of sodium and glucose from urine. Some new drugs can reduce blood glucose, maintain or reduce weight, control blood pressure, protect heart and kidney, etc.
Because cardiovascular disease (CVD) is easily associated with diabetes mellitus, which seriously affects the quality of life and life expectancy of patients, cardiovascular benefits of new drugs have attracted much attention and favor. Cardiovascular outcome trails (cvot) of new drugs have emerged one after another. Table 1 shows the completed cvot outcomes.
Table 1 cvot outcomes of completed dpp-4i, glp-1ra and sglt2i
In terms of cardiovascular outcome, the main evaluation criteria were composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3p-mace), which was the combination of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. Renal outcomes, including proteinuria progression, end-point events. Some sglt2i and glp-1ra have significant cardiovascular protection and renal endpoint benefit. This suggests that some new drugs have multiple benefits while lowering blood glucose, and can delay the occurrence of cardiovascular, cerebrovascular and vascular complications in diabetic patients.
Classic ≠ invariable
The development of insulin has experienced a long time, and constantly updated. In early twentieth Century, Banting and his assistant successfully extracted animal insulin from the pancreas of dogs and used it for the treatment of diabetes. In the 1980s, with the breakthrough of genetic engineering / recombinant DNA technology, human insulin began to be widely used in clinic because of its high homology, less adverse reactions such as allergy and less daily insulin consumption.
In the 1990s, insulin analogues came out, which are highly homologous with physiological insulin secretion, with rapid onset and metabolism, higher safety, flexible administration mode, and better simulation of physiological insulin secretion mode. After the 21st century, a new generation of insulin analogues was born. The use of fast acting insulin (such as insulin aspart and insulin lispro) during meals makes the injection time more free and convenient, and can be injected before or during meals; The drug release of super long acting insulin (specific hexamer structure, such as degulin, etc.) is slower, which can further reduce the risk of hypoglycemia.
At present, there are three kinds of insulin, which are basal insulin, postprandial insulin and premixed insulin. Basic insulin is injected once a day to control basic blood glucose. Insulin was injected before meals to control postprandial blood glucose. Premixed insulin can give attention to both basic blood glucose and postprandial blood glucose. In addition to the innovative structure of insulin, the current technological innovation is also reflected in the dosage form and administration mode.
The innovative dosage form has to be insulin tigro / insulin aspart, which is a combination of 70% insulin tigro and 30% insulin aspart. After one injection, it works independently and complements each other. It is injected once or twice a day with the main meal, while taking into account the basic blood glucose and postprandial blood glucose. Compared with the traditional basic postprandial scheme, the injection times and dose are improved. The current research direction focuses on insulin weekly preparation, intelligent insulin patch, oral insulin capsule, etc., which are all in the clinical research stage. The progress of these studies is bound to bring more convenient, safe and efficient treatment experience to diabetic patients.
On the premise of “reaching the standard of blood glucose”, hypoglycemia is the last word
With the changes of the times, the concept of hypoglycemia is also evolving, but blood glucose control is still the core of many ideas. The guidelines for type 2 diabetes published by the Chinese Medical Association Diabetes Association in 2020 suggested that Glycated hemoglobin (HbA1c) determined by standardized testing can be used as a supplementary diagnostic standard for diabetes in laboratories with strict quality control. This is the first time that HbA1c has been included in the diagnosis of diabetes in China. At the same time, it is also proposed that controlling HbA1c is the first goal.
Figure 1 no matter how the guidelines change, controlling blood sugar is always the core
Among all kinds of drugs, insulin decreased HbA1c by 1.5-3.5%, with the most obvious effect, while dpp-4i, glp-1ra and sglt2i decreased HbA1c by 0.4-0.9%, 1.0-1.5% and 0.5-1.5%, respectively (Table 2). No matter which hypoglycemic regimen is chosen, blood glucose should be considered.
Table 2 Comparison of characteristics of various hypoglycemic drugs
Insulin can be combined with some new hypoglycemic drugs, and the combination of drugs with complementary mechanisms is more effective for blood glucose. Basic insulin and premixed insulin can be used in combination with the three new drugs. Adding dpp-4i, glp-1ra or sglt2i to hypoglycemic regimen can reduce insulin resistance, reduce insulin dosage, offset weight gain to a certain extent, and increase patient compliance. At present, there are compound preparations of glp-1ra and basic insulin, such as glargine insulin, lisnatide compound preparation, degu insulin, liraglutide injection, etc. when the dosage of insulin is the same or lower, the hypoglycemic effect is better than that of basic insulin, reducing the risk of hypoglycemia and weight gain.
Looking for a hypoglycemic method suitable for Chinese people
What kind of hypoglycemic method is suitable for Chinese people? The choice of treatment for diabetes patients will be considered in many ways. The efficacy, safety and convenience are essential. Patients’ willingness and economic cost are also important.
Figure 2 diabetes treatment options need multiple considerations.
According to the recommendation of the 2020 edition of China 2 diabetes guideline, when patients’ blood sugar is not well controlled or HbA1c is not up to standard, drug therapy can be started on the basis of lifestyle intervention. The first choice is oral metformin, if it is still not up to the standard, it can be combined according to the specific situation: glp-1ra or sglt2i is preferred for patients with atherosclerotic cardiovascular disease (ASCVD); Combined with chronic kidney disease, sglt2i is the first choice, glp-1ra is the second choice; Combined with heart failure, the first choice is combined with sglt2i, if not combined with the above diseases, other different types of hypoglycemic drugs can be selected for combination [1].
Insulin treatment can be divided into 2 cases, one is short-term intensive insulin treatment, usually for newly diagnosed type 2 diabetes patients, HbA1c or more than 9% or fasting blood glucose is more than 11.1 mmol/L, can be 2 weeks to 3 months of short-term intensive insulin treatment. The second is that HbA1c ≥ 7.0% after 3 months of conventional oral hypoglycemic drug treatment. If the oral hypoglycemic drug has poor blood glucose control, the first step is to start subcutaneous injection of basal insulin or premixed insulin for 1-2 times. If the blood glucose is still not up to the standard, the second step is to start multiple injections of basal + intraprandial insulin or premixed insulin [2].
Figure 3 hypoglycemic therapy in China’s type 2 diabetes
Insulin and new drugs can also be combined or combined. Studies have shown that insulin combined with dpp-4i can significantly reduce HbA1c and insulin dosage compared with insulin alone [3]. The mechanism of basal insulin combined with glp-1ra is complementary, which can control the blood glucose level of patients more comprehensively, significantly reduce HbA1c and weight, and reduce the incidence of hypoglycemia [5, 6]. In theory, the hypoglycemic mechanism of sglt2i is independent of insulin, and the combination of sglt2i and basal insulin is ideal, with less hypoglycemic events [7].
In terms of composition of compound preparation, degu insulin / liraglutide mixture is the first mixture product of basic insulin and glp-1ra. The latest research in Chinese population has confirmed that the mixture has more decrease in HbA1c, higher compliance rate and lower risk of hypoglycemia compared with insulin degu alone or liraglutide alone. Compared with the insulin degu group, the body weight gain was less and the daily insulin dose was less [8]. Premixed insulin, such as insulin aspart 30, can also be combined with new hypoglycemic drugs with definite curative effect. It can be used as both initial insulin therapy and intensive insulin therapy, with lower medical cost and better safety.
Summary
The incidence rate of type 2 diabetes is increasing, science and technology are progressively improving, and market and technology have been promoting the continuous updating of hypoglycemic drugs. Whether for insulin or new hypoglycemic drugs, we should understand it from multiple dimensions. In the selection of hypoglycemic program, we should consider the needs of Chinese people, take HbA1c standard as the core, make the program according to different people, and appropriately integrate the classic and popular.