Exetide, liraglutide, duraglutide.. What is the difference between various GLP-1 receptor agonists? How to choose? What to pay attention to?

Glucose homeostasis depends on a complex hormonal Interactions: Insulin, glucagon, and gastrointestinal peptides, including GlP-1 and GLP. In recent years, GLP-1 receptor agonists (GLP-1RA) have been continuously developed and marketed for clinical application. This article summarizes the mechanism of action, clinical application, adverse reactions and use of GLP-1RA in special populations.


Generation of human GLP-1

Released after meal intake and absorption of glucose, protein, and fat.


GLP-1 receptors and their corresponding effects

GLP-1 is released from the small intestine The gene encoding for proglucagon in cells. GLP-1 binds to specific receptors, GLP-1 receptors are expressed in various groups. includespancreasislets β cells, gastric mucosa, intestine, lung, brain, Kidneys, hypothalamus, cardiovascular system, etc.

  • Actions on pancreatic β-cells: GLP-1 receptor activation in a glucose concentration-dependent manner .
  • acts on the gastrointestinal tract, delaying gastric emptying and intestinal peristalsis. Inhibits gastric acid and pentagastrin secretion, thereby reducing postprandial blood sugar fluctuations and weight loss.
  • acts on the central nervous system, inhibiting appetite, increasing satiety, etc. span> in order to achieve the purpose of reducing food intake.
  • acts on the liver, inhibits hepatic glucose production, , Lower blood lipids, improve liver function.
  • acts on the kidney to increase sodium excretion, reduce H+ secretion, span>Reduces glomerular hyperfiltration, which may protect the kidneys.
  • acting on the cardiovascular system, reducing systolic blood pressure, improving myocardial ischemia and myocardial contractile function.
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    < span>What are the approved GLP-1RAs in my country?  

    The GLP‑1RA approved in my country is mainly used for the treatment of T2DM, and its specific See Table 1 for usage, dosage and indications. ▼Table 1: Specific usage, dosage and indications of GLP‑1RA▲img><640" width="600" /span>


    < strong>What should I do if I have adverse reactions when using GLP-1RA?  

    The adverse reactions of GLP-1RA mainly include gastrointestinal reactions, hypoglycemia and acute pancreatitis.

    • Gastrointestinal reactionsGastrointestinal reactions such as nausea, vomiting, and diarrhea It is the most common adverse reaction of GLP-1RA, which generally decreases with the prolongation of treatment time. Coping methods:Clinical use can start with a small dose and gradually increase the dose. Those who are intolerant should stop the drug and change to other treatment plans in time. GLP-1RA-induced gastrointestinal reactions may exacerbate gastrointestinal discomfort in patients with T2DM and severe gastrointestinal diseases (eg, severe gastroparesis, inflammatory bowel disease), so it is not recommended for such patients.
    • HypoglycemiaGLP‑1RA alone Hypoglycemia is rare with use, but the risk of hypoglycemia is increased when combined with other antidiabetic drugs (eg, sulfonylureas, insulin). Coping methods: When GLP-1RA is combined with other antidiabetic drugs, the dose of other drugs needs to be adjusted.
    • Acute pancreatitisGLP‑1RA treatment did not increase the risk of acute pancreatitis in a large clinical study , but adverse events of acute pancreatitis associated with GLP-1RA treatment have been reported in clinical use. Response:For safety reasons, GLP‑1RA is not recommended for T2DM patients with a history of pancreatitis or high risk.


    Which patients cannot use GLP-1RA?  

    • History of pancreatitis< /strong>A warning about pancreatitis is included in the package insert for all GLP-1 receptor agonists. In large clinical studies, GLP-1RA treatment did not increase the risk of acute pancreatitis, but adverse events of acute pancreatitis associated with GLP-1RA treatment have been reported in clinical use. For safety reasons, GLP-1 receptor agonists are not recommended in patients with a history of pancreatitis.
    • Type 1 Diabetes However, until more clinical data are available, the use of GLP-1 receptor agonists in patients with type 1 diabetes is not recommended.. Although some of the beneficial effects of drugs such as GLP-1RA are not related to islet cell function (insulin sensitivity, glucagon reduction, weight loss), they may benefit selected patients with type 1 diabetes.
    • Patients with medullary thyroid carcinoma, multiple endocrine neoplasia type 2Most experts do not use any GLP-1 receptor agonists in these patients. Liraglutide, dulaglutide, once-weekly exenatide, and semaglutide should not be used in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2A/2B.
    • Severe gastroparesis< strong>Exenatide (short-acting) and lixisenatide delay gastric emptying and should not be used in patients with severe gastrointestinal diseases (eg gastroparesis). Long-acting GLP-1 receptor agonists (liraglutide, dulaglutide, once-weekly exenatide, semaglutide) should be used with caution in patients with severe gastroparesis.
    • Allergic to the active ingredients or any other excipients of this type of product .


    < span>Which is suitable for people with impaired renal function GLP-1RA?  

    • mild renal impairment various GLP-1RA use Unrestricted.
    • Moderate renal impairment: exenatide, liraglutide, lixisenatide, duraglutide, etc.;
    • Severe renal impairment: liraglutide and dulaglutide may be used with caution.

    The pharmacokinetic characteristics of various GLP‑1RAs are quite different, and their use in patients with hepatic and renal insufficiency is shown in Table 2 . Table 2: Application of GLP‑1RA in patients with hepatic and renal insufficiency


    Which GLP-1RA is suitable for patients with clinical ASCVD?

    for patients with clinical ASCVD (eg, previous myocardial infarction, stroke), we suggest usingliraglutide, semaglutide (subcutaneous), or dulaglutide, based on Corresponding cardiovascular outcome study results. GLP-1RAs with clear evidence of cardiovascular benefit include liraglutide, dulaglutide, and semaglutide, which are interestingly associated with human GLP-1 The amino acid sequence homology is high. GLP-1RAs with different molecular characteristics and different molecular characteristics are shown in Table 3. ▼ Table 3: GLP-1RAs with different molecular characteristics ▲ Click to enlarge It is worth noting that DMT2LP‑1 is added, Resting-state heart rate,significantly elevated (>70 beats/min) is associated with poor clinical outcomes in patients with chronic heart failure. Therefore, GLP-1RA should be used with caution in decompensated T2DM patients with reduced ejection fraction and heart failure, but it can still be used in T2DM patients at risk for heart failure.

    Part of GLP-1RA can bring cardiovascular protection to T2DM patients with cardiovascular disease. A meta-analysis of 7 large clinical studies including 56,004 patients worldwide showed that GLP-1RA reduced 3P-MACE (a composite event of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke) by 12% and reduced the risk of cardiovascular death by 12% , reduced fatal and non-fatal strokes by 16%, reduced fatal or non-fatal myocardial infarction by 9%, reduced the risk of all-cause mortality by 12%, and reduced hospitalizations for heart failure by 9%.


    Which GLP-1RA is suitable for patients without clinical ASCVD?

    without ASCVD, should be selected according to the patient’s blood glucose characteristics. short-acting GLP-1RA versus postprandialblood sugar is better than that of long-acting GLP-1RA, and long-acting GLP-1RA has advantages in controllingfastingblood sugar. If the patient’s primary concern is weight loss, semaglutide or liraglutide are preferred. If long-acting GLP-1 receptor agonists (liraglutide, Once a week exenatide, degreelaglutide, semaglutide), the need for drug preparation (subcutaneous preparation) and the patient’s wishes should also be considered.

    ▼ Long-acting, short-acting GLP-1RA classification


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