Understanding "GLP-1 Receptor Agonists"

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Clinical examples

Sugar patient Li, male, 50 years old, height 172cm, weight 100kg, body mass index (BMI) 33.
8kg/m^2
.
Treatment regimen: insulin glargine 26 U, iH, qn, metformin 1000 mg 2 times / day, acarbose 50 mg 3 times / day
.
Fasting blood glucose (FPG) 9.
2mmol/L, postprandial blood glucose (PPG) 14.
8mmol/L, glycated hemoglobin (HbA1c) 8.
7%, poor glycemic control
.
After that, on the basis of the original treatment plan, add semeglutide, 0.
5mg, iH, 1 time / week, according to the patient's tolerance, the dose is adjusted to 1mg, iH, 1 time / week after two weeks, and re-examination after 1 month, the patient's fasting and postprandial blood glucose are generally normal, glycated hemoglobin (HbA1c) 6.
8%, and the weight is reduced by 8 kg
compared with before the drug adjustment.

GLP-1 receptor agonist (GLP-1RA) has become a remarkable and sought after hypoglycemic rookie
in recent years with its excellent hypoglycemic and weight-reducing effects and cardiorenal protective effects.
As a new drug, many sugar friends, even some grassroots doctors, generally lack understanding
of the drug.
Because these drugs are also injections, some patients often confuse them with insulin, and even some people with type 1 diabetes want to stop insulin and switch to a weekly preparation of GLP-1RA.

Below, the author answers some representative questions frequently consulted by GLP-1RA patients
.

First, the life history of glucagon-like peptide-1 (GLP-1).

As early as the 60s of the 20th century, foreign scholars found in the study of diabetes that the insulin secretion effect of oral glucose was significantly stronger than that of intravenous glucose, suggesting that there may be a substance in the intestine that can promote insulin secretion, and then found that this mysterious substance is a hypoglycemic hormone secreted by L cells in small intestinal epithelial cells (i.
e.
"incretin"), the main component of which is glucagon-like peptide-1 (GLP-1), The amount of insulin secretion it stimulates accounts for about 50%~70%
of the total insulin secretion.

Regarding the pathogenesis of type 2 diabetes, in addition to the well-known "insufficient insulin secretion" and "insulin resistance (IR)", it is currently believed that the decrease in intestinal GLP-1 production and the resulting weakening of incretin effect is also a very important cause
.

Because the GLP-1 secreted by its own physiology exists in the body for a short time, it will be degraded and inactivated by an enzyme (dipeptidyl peptidase) within a few minutes, so natural GLP-1 is not suitable for direct clinical treatment, but the discovery of GLP-1 provides a new idea
for the treatment of type 2 diabetes.

Second, how do GLP-1 receptor agonists lower glucose?

After unremitting efforts, researchers finally developed a glucagon-like polypeptide-1 receptor agonist (GLP-1RA)
for clinical use at the beginning of this century.
As a new hypoglycemic drug, GLP-1RA is partially or completely homologous to the amino acid sequence of GLP-1 in vivo, and has the same biological activity, but it is not easily degraded by enzymes and the maintenance time is significantly prolonged, so it can better meet the needs
of clinical treatment.

GLP-1RA mainly exerts hypoglycemic effects
by stimulating insulin secretion by pancreatic islet β cells, inhibiting islet α cells from secreting glucagon, suppressing appetite, and delaying gastric emptying.

Happily, because the hypoglycemic effect of GLP-1RA is glucose-dependent, when the blood glucose concentration is lower than 4~5mmol/L, it no longer plays a role, therefore, the application alone generally does not cause hypoglycemia, in other words, it only reduces hyperglycemia but does not increase the risk of hypoglycemia, so it is known as "intelligent" hypoglycemic drugs
.

Fig.
1 Mechanism of action and multiple efficacy of GLP-1RA

What is the difference between GLP-1 receptor agonists and insulin? Can it replace insulin?

First of all, the two sources are different, natural GLP-1 is secreted by intestinal L cells after food stimulation, while insulin is secreted by human islet β cells; Secondly, the mechanism of action of the two is not exactly the same, GLP-1RA can not only stimulate the islet β cells to secrete insulin, but also inhibit the secretion of glucagon by pancreatic α cells, in addition to other multiple benefits, such as blood pressure, lipid reduction, weight loss, cardiorenal protection, etc.
; The biggest advantage of insulin is that it has excellent hypoglycemic effect, and the disadvantage is that it can cause weight gain and the risk of hypoglycemia is relatively high; Third, because GLP-1RA mainly lowers glucose by stimulating insulin secretion, it is not suitable for diabetics with complete loss of islet function (such as type 1 diabetes), while insulin is suitable for all types of diabetic patients, including type 1 diabetes patients
.

It can be seen that although GLP-1 receptor agonists (GLP-1RA) and insulin are both injections, they belong to two completely different classes of hypoglycemic drugs
.
Whether GLP-1RA can replace insulin cannot be generalized, and needs to be treated
on a case-by-case basis.
For those patients with type 2 diabetes who still retain some islet function, GLP-1RA can be tried instead of insulin according to the specific situation; A combination of the two may also be considered while reducing the original amount of
insulin.

4.
What are the outstanding advantages of GLP-1 receptor agonists?

The biggest highlight of GLP-1 receptor agonist is "one specialized, multi-functional", in addition to hypoglycemia, it can also reduce weight (especially visceral fat), lower blood pressure, improve blood lipid disorders, reduce fatty liver, especially for the heart and kidneys has a protective effect, can significantly reduce the risk of cardiovascular events, delay the progression of diabetic nephropathy, improve the long-term prognosis
of diabetic patients.

Data show that GLP-1 receptor agonists can reduce glycated hemoglobin (HbA1c) by 1.
0%~1.
5%, reduce body weight by 3~5kg on average, and reduce systolic blood pressure by 2~6mmHg
.

5.
What are the adverse reactions of GLP-1 receptor agonists?

The main adverse reactions of GLP-1 receptor agonists are:

1.
Gastrointestinal reactions
.
It is relatively common, including loss of appetite, nausea, vomiting, bloating, abdominal pain, diarrhea, etc.
, and is generally mild to moderate
.

2.
GLP-1RA alone generally does not cause hypoglycemia, but if combined with insulin secretagogues or insulin, hypoglycemia
may occur.

3.
Rare adverse reactions include pancreatitis, rash, etc
.

6.
How to deal with gastrointestinal reactions caused by GLP-1 receptor agonists?

GLP-1RA-induced gastrointestinal reactions are transient (usually disappear within 4 weeks) and usually lessen
with prolonged treatment.
At the same time, there are also dose-dependent characteristics, in order to reduce gastrointestinal reactions, small doses can be started, gradually increased, can enhance the patient's tolerance to the drug
.

7.
Who are GLP-1 receptor agonists suitable for?

It is suitable for adult patients with type 2 diabetes who are still poorly controlled with oral hypoglycemic agents alone or basal insulin
injections.
In view of its obvious weight loss effect and benefit the heart and kidneys, it is especially suitable for obese, combined with cardiovascular disease or chronic kidney disease type 2 diabetes patients, but also suitable for those who do not have cardiovascular disease but have cardiovascular risk factors, such as age ≥ 55 years old, hypertension, dyslipidemia, atherosclerosis (carotid artery, lower extremity artery, coronary artery, etc.
) and microalbuminuria
.

In addition, in view of the superior weight loss effect and good safety of GLP-1 receptor agonists, some of these products have been officially approved by the US FDA for weight management
in obese or overweight adults.

8.
The use of GLP-1RA is contraindicated

1.
GLP-1RA mainly plays a hypoglycemic effect by promoting insulin secretion, and cannot replace insulin, so type 1 diabetes, patients with type 2 diabetes with severe islet failure, and diabetic ketoacidosis patients are banned;

2.
Those with a history or family history of medullary thyroid cancer (MTC), or multiple endocrine tumor syndrome type 2 (MEN2);

3.
Diabetic patients with acute and chronic pancreatitis;

4.
Those who are allergic to the active ingredients or any other excipients of such products are banned;

5.
Severe renal insufficiency (creatinine clearance <30ml/min) is banned;

6
.
Due to the lack of relevant medication experience, it is currently not recommended for use in pregnancy, lactating women and people under 18 years old.

9.
Classification and use of GLP-1 receptor agonists

According to the duration of the action, GLP-1RA can be divided into:

1) Short-acting preparations: such as benaglutide (trade name: Yishengtai), exenatide (trade name: Baiyuda), etc.
, focusing on reducing postprandial blood sugar;

2) Medium-acting preparations: such as liraglutide (trade name: Novoliol), risnatide (trade name: Lexamine), etc.
;

3) Long-acting preparations, that is, weekly "weekly preparations", including semeglutide (trade name: Novotec), dulaglutide (Duyida), exenatide microspheres (trade name: Patek Yang), which are effective for fasting and postprandial blood sugar, and reduce fasting blood sugar more obviously
.