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Gump’s troubles

In 2013, Gump’s actor, the second American movie star Tom Hanks, who won the Oscar for Best Actor Award for two consecutive years, frankly told the hosts and viewers on a nighttime talk show: “When I went to see a doctor, he said to me, ‘Do you remember the high blood sugar that you have been trying to deal with since you were 36? Well, young people, you graduated! You got type 2 diabetes.’

The unfortunate “Gump” has become one of the more than 400 million diabetic patients in the world. In fact, according to the survey, half of the current global diabetes patients live in these five countries: China, India, the United States, Brazil and Indonesia. According to estimates by the Wall Street Journal, China’s annual expenditure on treating diabetes and related diseases has reached 13% of the national health care expenditure, and it has shown an accelerated upward trend, which has become one of the heaviest burdens of Chinese medical insurance. As the incidence of diabetes continues to increase, our need for effective, convenient, and economical diagnosis, care, and medications for diabetes becomes critical.

 

 

Insulin and incretin

When it comes to the treatment of diabetes, the first thing that everyone thinks of is insulin. Because type 1 diabetes is characterized by loss of insulin production, insulin injections can alleviate postprandial blood glucose elevations due to insulin deficiency, as well as other corresponding complications. Type 2 diabetes is caused by a decrease in the body’s sensitivity to insulin. In general, the patient’s pancreatic function begins to decline, but the function of synthesizing and secreting insulin and glucagon is not completely lost. Therefore, it is also possible to promote the synthesis and secretion of insulin through drug intervention, or slow down the synthesis and secretion of glucagon to achieve the effect of hypoglycemic.

 

In order to promote the synthesis and secretion of insulin, it is necessary to understand the regulation mechanism of insulin. Scientists have long discovered that in addition to insulin secretion directly caused by elevated blood glucose, oral glucose can also cause insulin secretion through another route. Oral glucose can cause the secretion of a group of peptide hormones in the gastrointestinal tract. These hormones act on their respective receptors to promote the synthesis and secretion of insulin. Therefore, scientists call these hormones “incretin hormones (Incretin). “,” and the insulin secretion caused by these hormones is called “Incretin Effect”.

You might say, “It sounds like incretin hormones can also alleviate postprandial blood glucose rise in patients with type 2 diabetes.” It sounds like this, and it turns out to be true.

By injecting drip, the scientist injected GLP-1 (Glucagon-like Peptide-1) into the vein of type 2 diabetic patients, artificially controlling this incretin hormone to a higher level. Effectively control the patient’s postprandial blood glucose. Why do you have to do some drip? Because GLP-1 has a half-life in human blood for only a few minutes, it will soon be degraded after a single injection and then excreted, which is not enough to show the effect of the drug. It can only be effective by continuous injection.

It is conceivable that prolonging the half-life of GLP-1 by various methods and making it suitable for clinical application is a hot topic in the development of diabetes drugs at the beginning of this century. But people are not as good as days. In the competition of the supernatural powers, the first GLP-1 analogue with sufficient half-life comes from the “Hand of God”, derived from an American lizard.

 

 

Poison lizard is a treasure

Known as the “Gila Monster”, this lizard lives in the deserts of the southwestern United States and northern Mexico. It grows 40 to 60 centimeters in adulthood and weighs 2 kilograms. It is the largest lizard in North America and the world. There are very few toxic lizards.

The Gila monster is a terrible monster in the minds of the early Western pioneers. It is said that the gas it exhales is very smelly and toxic, and it is fatal if it is bitten by it. In fact, the Gila monster is not so terrible, because it is slow to move, and it does not pose a threat to humans and animals. Although its saliva is toxic, it can cause severe symptoms such as severe pain, redness and weakness, but it is not enough to kill an adult.

After years of research, scientists have found many active substances in the venom of the Gila monster, including active substances that do not have a dozen peptides, some of which cause pain, some cause redness, and many of them act on blood vessels and gastrointestinal tracts. . From the active substances of these peptides, scientists not only found new compounds with anticancer effects, but also found several compounds similar to the above-mentioned gliotropin GLP-1.

One of the peptides, Exendin-4, has 50% amino acid sequence identical to GLP-1, which can cause GLP-1 hypoglycemic effect in humans and is less susceptible to degradation. Half-life (3~4 hours) It is much longer than GLP-1. In 2005, the synthetic Exendin-4 was marketed in the United States for the treatment of type 2 diabetes.

 

 

Lyxumia once a day

In addition to Exendin-4 from the “Hand of God”, there are several ways to artificially extend the half-life of a peptide drug, either as a sustained-release formulation or as a chemical structure modification. For example, Sanofi’s Lyxumia (Lyxumia) enhances its stability by chemically modifying GLP-1. The half-life of Lyxumia in the blood is also 3 to 4 hours. Although it is much higher than natural GLP-1, it seems to have no advantage compared with Exendin-4 from lizard toxin.

At the beginning of the clinical trial, the researchers deliberately arranged two groups of patients, one receiving Lyxumia twice a day and the other receiving treatment once a day. Although twice-daily treatments brought higher drug plasma exposure to patients, several key indicators related to efficacy, such as reduced glycated hemoglobin, did not improve compared to once-a-day treatment. What is going on here? The researchers made a possible explanation.

Through in vitro activity testing, we know that the binding of Lyxumia to the target (GLP-1 receptor) is very strong, and can occupy most of the target with a little bit. In this case (known to those familiar with the “titration curve”), increasing the blood concentration of Lyxumia beyond the critical point does not effectively increase the target occupancy. In addition, the speed at which Lyxumia dissociates from the target also affects the effective time of Lyxumia. If the dissociation rate is very slow, it can continue to occupy the target and play a role when the free drug content in the blood is already low.

In this way, rigorous scientific research has achieved unexpectedly good results, simplifying the original subcutaneous injection 60 minutes after each meal to once a day.

 

 

Gastric emptying and postprandial blood glucose

Targets of Lyxumia In addition to regulating insulin secretion, GLP-1 receptors have other biological regulatory functions, such as reducing glucagon secretion and slowing gastric emptying. These effects are also closely related to glycemic regulation. According to clinical results, the researchers believe that Lyxumia’s effect on pre-prandial blood glucose is mainly achieved by stimulating insulin secretion, while postprandial blood glucose is mainly achieved by delaying gastric emptying, which is a valuable choice for overall glycemic control.

Lyxumia was approved by the FDA for listing on the US market on July 28, 2016. To date, it is the only GLP-1 receptor agonist approved for basal insulin indications in China. Given the beneficial effects of Lyxumia on postprandial blood glucose levels and the control of basal insulin against fasting blood glucose, the mechanism of action of Lyxumia and basal insulin complement each other. Lyxumia should also be an effective treatment option for patients with type 2 diabetes who are not eligible for basal insulin therapy and may be the treatment of choice for basic intensive therapy.

The study showed that Lyxumia improved glycemic control in patients with various type 2 diabetes patients with different background therapies, showed good safety, had a low incidence of hypoglycemia, and did not increase the risk of cardiovascular events. .

As early as 2013, Lyxumia was approved by the EU regulatory authorities, but the listing process in the United States was a good thing. After 2008, the US FDA requires specific cardiovascular safety data for new antidiabetic drugs. Sanofi decided to cancel the listing application and plans to complete the clinical research results in 2015 and then re-declare. In September 2015, the FDA re-accepted Sanofi’s application and was finally approved.

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