GLP-1 drugs, the nemesis of obesity and diabetes, are becoming popular all over the world.

Introduction

Obesity is not only a personal struggle, it is also a public health crisis.

In recent years, a glucagon-like peptide-1, also known as GLP-1, has emerged. In addition to being highly effective in reducing weight and lowering blood sugar, it can also reduce stroke, heart failure, etc. In 2023, both Science and Nature magazines listed it as a "breakthrough of the year" or "important discovery". Next, we will unlock why GLP-1 is so magical.

Our guest today is Professor Guo Yifang, Vice President of Hebei Provincial People's Hospital. Professor Guo is a senior expert in cardiovascular disease and concurrently serves as a member of the Standing Committee of the Cardiovascular Medicine Branch of the Chinese Medical Doctor Association. He is also very enthusiastic about popular science and usually writes a large number of articles on cardiovascular diseases.

Guo Yifang (Deputy Director of Hebei Provincial People's Hospital) | Guest

Ye Shuisong | Interview

Is obesity a disease?

Q: Obesity is considered a major public health crisis. Currently, about 35% of people in my country are overweight or obese, and about 14% are obese. Do you think obesity itself is a disease?

Guo Yifang: Obesity itself is a disease. In fact, decades ago, the World Health Organization clearly classified obesity as a chronic metabolic disease. Although there is no controversy, many people do not realize that obesity is a disease and only classify obesity as an unsightly body shape. Therefore, we all need to pay attention to this issue in our minds.

Question: Taking my country as an example, what is the reason why more and more people are obese?

Guo Yifang: Obesity is a lifestyle disease. The main reason why there are more and more obese or overweight people is that the trend of unhealthy lifestyles is getting more and more serious. In particular, the calorie intake is increasing, and the food is very refined and fine, so the calorie ratio is very high.

Another reason is that we do less exercise. We take in more calories and burn less calories, so the excess calories are stored in the body as fat, which leads to obesity.

The harm caused by obesity

Q: Can you tell us what harm obesity can cause? What is the relationship between obesity and diabetes?

Guo Yifang: Obesity has many harmful effects, which can be divided into two categories: one is direct harm and the other is indirect harm.

We usually regard obesity as a "hotbed of multiple diseases", also known as "common soil". Many "poisonous weeds" grow on a piece of "toxic soil", such as a series of metabolic diseases such as hypertension, diabetes, hyperlipidemia, hyperuricemia, fatty liver, and atherosclerotic tracheal diseases, especially coronary heart disease, myocardial infarction and cerebral infarction, which are the most common and direct hazards.

In addition, obesity is more likely to cause osteoarthritis, tumors and even infertility and many other adverse consequences. The harm of obesity is very great.

Q: What harm does diabetes do to the human body?

Guo Yifang: There are four main aspects of harm to the body.

The first category is acute metabolic disorders, such as diabetic ketosis, hyperosmolar coma, etc. Such cases are becoming less and less common now, because there are many medical methods to control blood sugar, such as hypoglycemic drugs. Generally speaking, blood sugar is difficult to rise to a particularly serious level, so acute metabolic disorders are relatively rare.

The second category is microvascular complications. The so-called microvascular complications mainly refer to diabetic nephropathy, and even include renal failure, diabetic eye disease, fundus lesions, and blindness.

The third category is also the main cause of death and disability: macrovascular complications. The so-called macrovascular complications mainly refer to diseases such as coronary heart disease, myocardial infarction, and cerebral infarction. More than 70% of diabetic patients die from macrovascular complications, so this should be the focus of diabetes prevention and control.

The fourth category is other damages, such as diabetic neuropathy, diabetic foot and other damages.

Among these four major types of hazards, the most important is large vessel complications.

What are the challenges of treating diabetes?

Q: What challenges and difficulties are there in treating diabetes at present?

Guo Yifang: There are many challenges and difficulties. For patients with type 2 diabetes, although a small number of patients can reverse or alleviate their condition through intensive lifestyle intervention, the vast majority of diabetic patients need lifelong medication. In fact, there are many types of hypoglycemic drugs, such as traditional drugs such as insulin, metformin, sulfonylurea, glinide, thiazolidinedione and other drugs.

In the past few decades of research, we have found that although these drugs can effectively control blood sugar, reduce acute hyperglycemia events and reduce the occurrence of microvascular complications, they cannot reduce the occurrence of macrovascular complications of diabetes.

This creates a very "awkward" situation because high blood sugar levels can cause cardiovascular and cerebrovascular diseases, which can lead to serious consequences or even death, but lowering blood sugar levels does not reduce the occurrence of complications.

Until 2015, a new drug research result came out - SGLT-2 inhibitor. In 2016, GLP-1 receptor agonist, which we are discussing today, came out. After these two types of new drugs came on the market, they brought us a new idea and brought the treatment of diabetes into a new stage.

GLP-1, a new drug that can both treat diseases and help lose weight

Q: After the emergence of GLP-1 drugs, there have been some very big breakthroughs in the treatment of diabetes. In the past two years, GLP-1 drugs have been very popular. Even Musk has used them and the effect seems to be very good. Science magazine also named it the "Top Scientific Breakthrough of the Year". It not only effectively lowers blood sugar, but also helps reduce weight and improve cardiovascular health. Can you explain what GLP-1 drugs are?

Guo Yifang: In recent years, there are more and more opportunities for the clinical use of GLP-1. Common varieties include semaglutide, liraglutide, dulaglutide and a similar new drug called GLP-1/GIP dual receptor agonist telpotide.

More and more studies have found that GLP-1 not only has a strong blood sugar lowering effect, but also can reduce the risk of cardiovascular and cerebrovascular diseases, and also has a significant weight loss effect.

Comparison before and after using GLP-1 drugs

Recent studies have found that in addition to treating diabetes, GLP-1 drugs can also reduce the incidence of adverse myocardial infarction events in obese patients without diabetes. Currently, there are several weight loss drugs approved for use on the market, but no weight loss drug can reduce the incidence of cardiovascular and cerebrovascular complications while reducing weight.

What are the dangers of obesity? The biggest danger of obesity is that it causes diabetes, high blood pressure, and high blood lipids. The more serious danger is that it increases the risk of cardiovascular and cerebrovascular diseases. However, before this, no weight loss drug of any type has been proven to reduce the risk of cardiovascular and cerebrovascular complications after losing weight.

After GLP-1 drugs were launched, especially semaglutide and liraglutide, they can not only significantly reduce body weight, but also reduce the risk of cardiovascular and cerebrovascular diseases in obese patients. Therefore, this drug is a revolutionary drug.

Q: Some people believe that GLP-1 has great application prospects in the treatment of obesity and metabolic syndrome. Can you explain how it works in the human body and what is the mechanism behind it?

Guo Yifang: The blood sugar lowering mechanism of GLP-1 is very clear, which is to increase insulin secretion.

It can increase insulin secretion through a glucose-dependent mechanism. Simply put, when the patient's blood sugar is high, the drug's effect on promoting insulin secretion is strong, and when the blood sugar is low, the effect on insulin secretion is small.

Insulin is the only hormone in the body that lowers blood sugar. GLP-1 drugs work by increasing insulin release to lower blood sugar.

Of course, in addition to this mechanism, the second mechanism of GLP-1 drugs is to inhibit the secretion of glucagon. Glucagon can increase blood sugar, it can increase the secretion of hormones that lower blood sugar and reduce the secretion of hormones that increase blood sugar, thus achieving the purpose of lowering blood sugar.

The third mechanism is to suppress appetite and delay gastric emptying. In simple terms, it makes people not want to eat, especially for people who have a large appetite. GLP-1 drugs can reduce the desire to eat and reduce food intake, which is also an important mechanism for its hypoglycemic effect.

The mechanism of GLP-1 drugs in lowering blood sugar is very clear. However, the mechanism of protecting cardiovascular and cerebrovascular vessels is still under research and discussion by experts, and this aspect has not been fully elucidated.

Side effects of GLP-1 drugs

Q: The reason why GLP-1 drugs are so amazing is that they can not only help lose weight but also improve cardiovascular disease. Do these drugs have any side effects?

Guo Yifang: There are definitely side effects. There is an old saying that "all medicines are poisonous", as long as it is a drug that can treat diseases, there is a possibility of adverse reactions or side effects. The overall safety of GLP-1 drugs is very good, but side effects also exist. The most common is gastrointestinal discomfort. As I mentioned just now, this type of drug will delay gastric emptying and suppress appetite, so many people don't want to eat after taking the drug. This is both a mechanism for it to exert its hypoglycemic effect and its side effect.

In September 2023, the US FDA updated its review of semaglutide, noting that the drug may increase the risk of intestinal obstruction.

But I think this is a disadvantage that does not outweigh the advantages and will not affect the good clinical performance of GLP-1 drugs.

Question: A follow-up question is that the current price of GLP-1 drugs is relatively expensive. In addition, the celebrity effect has led to abuse among some young people. Will this also bring about some unnecessary impacts?

Guo Yifang: Indeed, overuse is quite common now, and there are many irregularities. For example, in our country, semaglutide is only approved for glucose reduction, and has not yet been approved for weight loss. Moreover, the glucose-lowering dose and weight-reducing dose of semaglutide are different. However, many people who do not have diabetes only get injections because they are fat or want to lose weight.

Strictly speaking, this is "off-label and off-instruction drug use" (beyond the indications approved by the Food and Drug Administration and beyond the approved user population), which is not compliant, but this situation is indeed common.

When taking medicine, people don't pay enough attention to some precautions in the use of convenient medicines. For example, the problems I mentioned just now, such as gastroparesis, gastric paralysis, intestinal obstruction, pancreatitis, etc. Many patients are unaware of the existence of these side effects, and do not know that they should seek medical treatment and treatment in time when related symptoms appear. There are potential risks here.

Although this type of drug is a good medicine, it must be used under the guidance of a doctor and according to the instructions, so as to obtain the greatest clinical benefits with the least adverse reactions.

Will GLP-1 drugs win the Nobel Prize in the future?

Q: Currently, both short-acting GLP-1 receptor agonists and long-acting GLP-1 receptor agonists are on the market. GLP-1 drugs have improved obesity or cardiovascular disease in billions of patients around the world. Do you think GLP-1 drugs will win the Nobel Prize in the future?

Guo Yifang: This possibility exists because this type of drug is epoch-making.

The reason why it is epoch-making is mainly reflected in two aspects. First, it puts an end to the history that blood sugar lowering cannot reduce macrovascular complications.

In the past, clinical use of drugs such as insulin, metformin, sulfonylurea, glinide, and thiazolidinedione, although they could lower blood sugar levels, did not reduce the occurrence of cardiovascular and cerebrovascular hypoxia. However, since the launch of SGLT-2 inhibitors and GLP-1 receptor agonists, treatment can reduce blood sugar while reducing the risk of cardiovascular and cerebrovascular diseases. This is the first epoch-making aspect.

The second is weight loss. There are many kinds of drugs for weight loss, but so far only GLP-1 and semaglutide have been proven to reduce cardiovascular complications while reducing weight in large clinical studies. These drugs can reduce the occurrence of serious events such as myocardial infarction and cerebral infarction while reducing weight, so these epoch-making drugs may win the Nobel Prize in the future.

In 2021, there is an award in the medical field called the Gairdner Award, which is considered by some scholars to be the "Nobel Prize in Medicine". Both semaglutide and the GLP-1/GIP dual receptor agonist telpotide won the award. This in itself reflects the importance that the medical community attaches to GLP-1 drugs.

From this perspective, I think that in the long process of research and exploration before GLP-1 was launched on the market, experts and scholars who made important contributions may be recommended for the Nobel Prize. This is something we are very much looking forward to.

This article is a work supported by Science Popularization China Starry Sky Project

Team/Author: Deep Science

Reviewer: Tang Qin, Director of the Science Popularization Department of the Chinese Medical Association

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.