Dr. Anant Patil details on classification and dosage of GLP-1 receptor agonists for the treatment of type 2 diabetes, also summarising the latest guidelines for the therapy from national and international associations.

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GLP-1 and GLP-1 receptor agonists

Type 2 diabetes mellitus is associated with abnormalities of the incretin axis. Glucagon-like peptide-1 (GLP-1) and gastro-inhibitory intestinal peptide (GIP) constitute most of the incretin functions. [1] GLP-1 is a hormone released by the intestine after detection of dietary glucose and other nutrients by the sensory receptors in the small intestine. [2] GLP-1 produces its effects through receptors of the G protein-coupled receptor family. [1] GLP-1 is a part of incretin effect which improves glucose-induced insulin secretion. [2,3]

Dipeptidyl peptidase-4 (DPP-4) is also involved in the incretin system. This enzyme inactivates GLP-1. [2] Considering these, incretin system is an important target in the management in type 2 diabetes mellitus. [4] GLP-1 receptor agonists are structurally related to GLP-1 and activate the GLP-1 receptors. [5]

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Classification of GLP-1 receptor agonists

GLP-1 receptor agonists are classified into short-acting, intermediate-acting and long-acting agents.

1. Short-acting agents include exenatide and lixisenatide. [6]
2. Liraglutide is an intermediate-acting GLP-1 receptor agonist. [6]
3. Long-acting agents include exenatide long acting release, albiglutide and semaglutide. [6]

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Important characteristics of GLP-1 receptor agonists

GLP-1 receptor agonists stimulate secretion of insulin while they inhibit the secretion of glucagon. [2,3,6] Inhibition of glucagon secretion results in the reduction in hepatic production of glucose and fasting blood sugar. [2] GLP-1 receptor agonists delay gastric emptying [2,3,6] which results in decrease of post-prandial blood glucose levels. They are also associated with suppression of appetite. [2] Thus, usage of GL-1 receptor agonists result in reduction of fasting blood glucose, post-prandial blood glucose and glycosylated haemoglobin (HbA1c). [5] GLP-1 receptor agonists are given by subcutaneous injection. [2,5] Semaglutide is given by oral route. [7]

GLP-1 receptor agonists have pharmacologically similar action but they differ in their frequency of administration. The original exenatide formulation is injected subcutaneously twice daily. [3,5] A longer acting formulation is prepared which can be given once weekly. Microspheres consisting of biodegradable polymers are slowly degraded which allows the drug to be slowly released and provide more stable concentration over a longer period of time. Lixisenatide is given once daily. [5] Liraglutaide is a GLP-1 analog which is also given once daily. [3,5] The longer action of this agent is due to delayed absorption and high binding to albumin. [5]

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Place of GLP-1 analogues in the management of type 2 diabetes

American Diabetic Association (2020)

GLP-1 receptor agonist is one of the recommended therapies for addition to metformin when HbA1c target is not achieved after about three months of starting metformin monotherapy. Most patients prefer to take oral therapy, but the need for more potent medication is common, especially in patients with diabetes with longer duration. In patients who need a combination of injectable therapy, basal insulin with GLP-1 receptor agonist provides potent effect on glucose reduction. The risk of hypoglycaemia with this is less common as compared to intensified insulin therapy. [7]

RSSDI-ESI Clinical Practice Recommendations (2020):

If glucose targets are not achieved with two oral drugs, GLP-1 receptor agonists are one of the recommended agents for addition as a third agent. GLP-1 receptor agonist may be considered in patients who do not achieve glucose targets with three oral agents.

GLP‑1 analogues with proven cardiovascular benefit should be considered to reduce the risk. These agents can be considered as a second-line option in overweight or obese patients without satisfactory response to metformin and as a first-line if metformin is not tolerated. When glycaemic control is not satisfactory with high doses of insulin, or if the patient experiences unacceptable weight gain or hypoglycaemia, GLP‑1 analogues can be added to basal insulin. [8]

European Society of Cardiology (ESC) guideline (2019) developed in collaboration with the European Association for the Study of Diabetes (EASD)

In drug-naive type 2 diabetes mellitus patients with atherosclerotic cardiovascular disease or high or very high cardiovascular risk, GLP-1 receptor agonist monotherapy (those with proven cardiovascular benefit) is recommended as first-line therapy. In other drug-naïve patients, metformin is recommended as first-line agent and GLP-1 receptor agonists are one of the recommended agents to add onto metformin if HbA1c target is not achieved. If the patient is already on metformin and has not achieved HbA1c target, GLP-1 receptor agonists can be added. [9]

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Advantages of GLP-1 analogues in the management of type 2 diabetes

GLP-1 analogues provide high efficacy in patients with type 2 diabetes mellitus. [7] Improvement in glycaemic control occurs by increase in glucose-dependent insulin secretion and reduction in glucagon levels. Use of GLP-1 receptor agonists result in reduction in fasting as well as postprandial glucose levels. [6] They also reduce post-prandial glucose excursions. [9] GLP-1 receptor agonists have beneficial effects on lipid profile and blood pressure. [6] GLP-1 analogues are associated non-glycaemic advantages, such as weight loss. [2,3,6] GLP-1 receptor agonists lower  bodyweight by about 1 to 5 kg. [5] Beneficial reports in the progression of diabetes kidney disease have been reported with liraglutide. [7]

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Dosages of GLP-1 analogues in patients with type 2 diabetes mellitus

The dosages of GLP-1 analogues are given in table below:

GLP-1 analogues	Dose
Liraglutide [10]	Starting dose: 0.6 mg/day (once daily) for 1 week then 1.2 mg Dose can be increased to 1.8 mg if glycaemic control is not adequate
Lixisenatide [11]	Starting dose: 10 mcg once daily for 14 days. On Day 15, increase dosage to 20 mcg once daily
Exenatide [12]	Starting dose: 5 mcg twice daily Increased to 10 mcg twice daily after 1 month depending on clinical response
Dulaglutide [13]	Staring dose: 0.75 mg once weekly Can be increased to 1.5 mg once weekly based on the clinical response
Albiglutide [14]	Starting dose: 30 mg once weekly Can be increased to 50 mg once weekly based on clinical response

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Important adverse events associated with GLP-1 analogues

Adverse events such as nausea or vomiting may be observed in some patients at the beginning of treatment. [3,5] These adverse events can be improved by proper dose adjustment. Risk of thyroid C cell tumours with GLP-1 receptor agonists (liraglutide, albiglutide, dulaglutide, exenatide extended release) is reported. Injection site reactions may be possible in some patients. Caution should be exercised when starting or increasing the dose considering possible risk of acute kidney injury. [7] Exenatide and lixisenatide are predominantly removed by the kidney; hence they should not be used in patients with eGFR less than 30 mL/min/1.73 m². [6] GLT-1 receptor agonists are associated with low risk of hypoglycaemia. [3,5]

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SGLT2 inhibitors in T2DM: 10 questions answered

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Disclaimer: The content is for educational purpose only. For agent specific information, healthcare providers are requested to refer the updated prescribing information.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anant Patil is Assistant Professor of Pharmacology.