Review of the Therapeutic Uses of Liraglutide

Abstract

Background

Glucagon-like peptide (GLP-1) is a neuroendocrine hormone that increases blood glucose and is a drug target for treatment of type 2 diabetes. Liraglutide, a subcutaneous, once-daily GLP-1 agonist, is approved for the treatment of type 2 diabetes in the United States and Europe. It also has been studied for weight loss.

Objective

The purpose of this article is to review all of the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions, cost, and place in therapy of liraglutide.

Methods

Literature searches of MEDLINE between 1969 and September 2010, International Pharmaceutical Abstracts between 1970 and September 2010, American Diabetes Association Meeting abstracts (2008–2010), and European Association for the Study of Diabetes abstracts (2008–2010) were performed using liraglutide, Victoza, and NN2211 as key terms.

Results

Thirteen randomized controlled trials were identified and summarized. Liraglutide has been shown to increase glucose-dependent insulin release by 34% to118% and reduce postprandial glucagon levels by 20%. Studies showed that liraglutide, as monotherapy and in combination with glimepiride, metformin, and/or rosiglitazone, lowers glycosylated hemoglobin (HbA_1c) between 0.84% and 1.5%. Transient nausea was reported by 7% to 40% of subjects. Severe hypoglycemia—glucose <55 mg/dL—was observed by 2.5% of subjects in 1 trial.

Conclusion

Liraglutide safely and effectively reduces HbA_1c in patients with type 2 diabetes. The most recent American Diabetes Association guidelines recommended a GLP-1 agonist along with metformin as a second-tier therapy for type 2 diabetes. Although the American Association of Clinical Endocrinologists/American College of Endocrinologists' guidelines recommended it for first-line monotherapy in patients with HbA_1c between 6.5% and 7.5% and with metformin if HbA_1c is between 7.6% and 8.5%, liraglutide should be considered for patients who cannot tolerate first-line agents or if an additional agent is needed to help reach target HbA_1c goals.

Introduction

The prevalence of diabetes continues to grow at an alarming rate. Comparison of the American Diabetes Association's (ADA) estimated economic cost of diabetes in 2002 and 2007 suggests that the number of people diagnosed with diabetes is rising by roughly 1 million per year.¹ This increase is attributed to several factors, including urbanization, population growth, increasing elderly population, decreased physical activity, and an increase in obesity worldwide.² Wild et al conclude that even if the proportion of patients with obesity remains the same, the prevalence of diabetes is still expected to double because of the aging population and urbanization.²

Although glycemic control is difficult to maintain, it prevents microvascular complications.3, 4, 5 β-cell dysfunction, insulin resistance, incretin hormone malfunction, disruption in renal reabsorption, malfunction in adipose tissues, and hypothalamic insensitivity to glucose all lead to hyperglycemia.⁶ The multifaceted nature of the pathophysiology of type 2 diabetes makes treatment difficult. Despite the plethora of drugs used for treating type 2 diabetes, few people are meeting the recommended glycemic targets.⁷ Many of the agents used for treating type 2 diabetes target insulin secretion, insulin sensitivity, hepatic glucose production, or a combination of these. Incretin-based therapies are a relatively new treatment strategy for patients with type 2 diabetes. Incretin hormones were discovered after researchers observed that oral ingestion of glucose stimulated a larger secretion of insulin than an intravenous infusion of the same quantity of glucose.8, 9 The 2 incretin hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(GLP-1), are responsible for up to 60% of the postprandial insulin released in normal glucose-tolerant subjects.¹⁰ GIP is released from the enteroendocrine K cells in the duodenum and jejunum and has a t_1/2 of 5 to 7 minutes.11, 12 Its mechanism of action involves the stimulation of glucose-dependent insulin release and the regulation of fat metabolism.13, 14 β Cells are the primary location of the GIP receptors. Others are located in the adipose tissue and the central nervous system. GLP-1 is a 31-amino-acid peptide that is released from the L cells in the colon and the ileum. GLP-1 has a t_1/2 of about 2 minutes¹⁵ with numerous physiologic effects. These effects include stimulating glucose-dependent insulin release, restoring first-phase insulin response, improving β-cell function, increasing β-cell mass, improving insulin sensitivity, delaying gastric emptying, and decreasing food intake.16, 17, 18 GLP-1 receptors are located in the hypothalamic nuclei, heart, β cells, lung, and kidney.16, 17, 19, 20 GIP and GLP-1 levels begin to rise after ingestion of a meal but before the food reaches the gastrointestinal tract. This finding suggests that incretins are regulated by neuronal stimuli.²¹

In patients with type 2 diabetes, the incretin effect is significantly diminished or eliminated.⁹ GIP levels are normal in type 2 diabetes, but the response is defective.9, 22, 23 In type 2 diabetes, GIP receptors are present on the β cells, but the insulintropic effect of GIP is not functioning.23, 24 Small amounts of insulin secretion are observed when high doses of GIP are infused in patients with type 2 diabetes.²⁵ Alternatively, GLP-1 levels are lower in patients with type 2 diabetes, and the insulinotropic activity is only reduced minimally rather than lost completely.24, 26

The physiologic activities of GLP-1 make it ideal for use in the treatment of type 2 diabetes. However, its physical properties limit its clinical utility. GLP-1, which only has a 2-minute t_1/2, is unsuitable for pharmacologic use because it is rapidly degraded by dipeptidyl-peptidase-4 (DPP-4).²⁷ For GLP-1 to exhibit effectiveness, DPP-4 must be inhibited or a GLP-1 agonist must be resistant to DPP-4 degradation. DPP-4 inhibitors and DPP-4–resistant GLP-1 agonists have recently been approved for the treatment of type 2 diabetes. Sitagliptin^⁎ and saxagliptin^† are the DPP-4 inhibitors available in the United States. Both of these agents and vildagliptin^‡ are available in the European Union. Vildagliptin and alogliptin^§ are currently under Food and Drug Administration (FDA) review for approval in the United States. The first GLP-1 agonist, exenatide,^∥ was approved in the United States in 2005. Liraglutide^¶ was approved for marketing in the European Union in July 2009 and in the United States in January 2010. A new drug review was previously published in this journal.²⁸ The current article reviews the published data on the chemistry, pharmacology, pharmacokinetics, clinical trials, drug interactions, safety, dosing, administration, pharmacoeconomics, and place in therapy of liraglutide in the treatment of type 2 diabetes and provides an update on more recently published trials.