Lixisenatide: pharmacodynamics, pharmacokinetics and clinical applications

General Description

Lixisenatide is a synthetic GLP-1 receptor agonist used in the treatment of type 2 diabetes mellitus. It stimulates insulin secretion and suppresses glucagon secretion, improving glycemic control. It also slows gastric emptying, reducing postprandial glucose levels. Lixisenatide's pharmacokinetics show rapid absorption, with a median time to maximum plasma concentration of 1-3.5 hours. It has an apparent volume of distribution of approximately 100 L and is eliminated primarily via glomerular filtration. The mean half-life is around 3 hours, and clearance is approximately 35 L/h. Lixisenatide is suitable for once-daily administration and has minimal alterations in pharmacokinetics due to hepatic impairment, gender, age, bodyweight, or ethnic origin. Clinically, lixisenatide improves glycemic control, promotes weight loss, and has cardioprotective properties, making it beneficial for individuals with type 2 diabetes and cardiovascular comorbidities. Overall, lixisenatide offers multiple clinical benefits for type 2 diabetes management.

Figure 1. Lixisenatide

Pharmacodynamics

Lixisenatide is a synthetic GLP-1 receptor agonist that has been modified from exendin-4 and demonstrated high affinity and selectivity for the human GLP-1 receptor. It stimulates insulin secretion in response to increased blood glucose levels and suppresses glucagon secretion, which results in improved glycaemic control in patients with type 2 diabetes. Lixisenatide enhances first-phase insulin secretion to the level seen in nondiabetic subjects, and second-phase insulin secretion is elevated for up to two hours. In addition, lixisenatide slows gastric emptying, which contributes to the reduction in postprandial glucose. The once-daily administration of lixisenatide can effectively lower both post-prandial and fasting glucose levels. It also exhibited antiatherosclerotic activity and provided protection against myocardial ischemia/reperfusion-induced injury in preclinical studies. Overall, lixisenatide's pharmacodynamics demonstrate its potential as an effective treatment for type 2 diabetes with limited risk of hypoglycemia. ¹

Pharmacokinetics

Lixisenatide is rapidly absorbed following subcutaneous administration and has a median time to the maximum plasma concentration of 1-3.5 hours regardless of dose or administration site. It has an apparent volume of distribution of approximately 100 L and is approximately 55% bound to human proteins. Lixisenatide is eliminated via glomerular filtration, followed by tubular reabsorption and subsequent metabolic degradation. The mean terminal half-life of lixisenatide following repeated administration is approximately 3 hours, and the mean apparent clearance is approximately 35 L/h. The pharmacokinetics of lixisenatide are not expected to be altered by hepatic impairment, gender, age, bodyweight, or ethnic origin. However, in patients with moderate and severe renal impairment, the AUC was increased by 24% and 46%, respectively, compared to subjects with normal renal function. Overall, the pharmacokinetic profile of lixisenatide demonstrates its suitability for once-daily administration in patients with type 2 diabetes. ²

Clinical applications

Lixisenatide is a medication that belongs to the class of drugs known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs). It is primarily used in the management of type 2 diabetes mellitus. First and foremost, Lixisenatide helps to improve glycemic control in patients with type 2 diabetes. It stimulates the release of insulin from pancreatic beta cells, which leads to a reduction in blood glucose levels. Additionally, Lixisenatide slows down gastric emptying, which helps to regulate postprandial blood sugar levels. Furthermore, Lixisenatide has been shown to promote weight loss in individuals with type 2 diabetes. The medication suppresses appetite, leading to reduced food intake. This can be beneficial for patients who are overweight or obese, as weight loss can improve insulin sensitivity and overall metabolic health. In addition to its effects on glycemic control and weight management, Lixisenatide has also demonstrated cardioprotective properties. Studies have shown that it can reduce the risk of cardiovascular events, such as heart attack and stroke, in patients with type 2 diabetes who have a high risk of cardiovascular disease. This makes Lixisenatide a valuable treatment option for individuals with both diabetes and cardiovascular comorbidities. Overall, Lixisenatide offers several clinical benefits in the management of type 2 diabetes. It helps to improve glycemic control, promotes weight loss, and reduces the risk of cardiovascular events. These effects make it a valuable addition to the treatment regimen for individuals with type 2 diabetes, particularly those who are struggling to achieve adequate glycemic control or have concurrent cardiovascular risks. ³

Reference

1. Christensen M, Knop FK, Vilsbøll T. The GetGoal clinical trial program of lixisenatide, a once-daily GLP-1 receptor agonist. Expert Rev Endocrinol Metab. 2011;6(4):513–25.

2. European Medicines Agency. Lyxumia (lixisenatide): EU summary of product characteristics. 2013.

3. Elkinson S, Keating GM. Lixisenatide: first global approval. Drugs. 2013;73(4):383-391.