Liraglutide in the management of type 2 diabetes

Drug Design, Development and Therapy Dovepress open access to scientific and medical research Review Open Access Full Text Article Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Liraglutide in the management of type 2 diabetes This article was published in the following Dove Press journal: Drug Design, Development and Therapy 21 October 2010 Number of times this article has been viewed Estela Wajcberg Amatur Amarah Premier Nephrology and Hypertension, Internal Medicine Department, Trinitas Regional Medical Center, Elizabeth, New Jersey, USA Introduction Correspondence: Estela Wajcberg Premier Nephrology and Hypertension, Internal Medicine Department, Trinitas Regional Medical Center, 240 Williamson Street Suite 405, Elizabeth, NJ 07202, USA Tel +1 908 353 2064 Fax +1 908 353 5052 Email submit your manuscript | www.dovepress.com Dovepress DOI: 10.2147/DDDT.S10180 Powered by TCPDF (www.tcpdf.org) Abstract: The pathophysiology of type 2 diabetes has been attributed to the classic triad of decreased insulin secretion, increased insulin resistance, and elevated hepatic glucose production. Research has shown additional mechanisms, including incretin deficiency or resistance in the gastrointestinal tract. Liraglutide is a modified form of human glucagon-like peptide-1. Liraglutide was obtained by substitution of lysine 34 for arginine near the NH2 terminus, and by addition of a C16 fatty acid at the ε-amino group of lysine (at position 26) using a γ-glutamic acid spacer. Liraglutide has demonstrated glucose-dependent insulin secretion, improvements in β-cell function, deceleration of gastric emptying, and promotion of early satiety leading to weight loss. Liraglutide has the potential to acquire an important role, not only in the treatment of type 2 diabetes, but also in preservation of β-cell function, weight loss, and prevention of chronic diabetic complications. Keywords: diabetes mellitus, incretin, glucagon-like peptide, insulin resistance Type 2 diabetes mellitus (T2DM) is a major public health burden that poses management challenges in clinical practice.1 The core pathophysiology of T2DM has been attributed to the classic triad of decreased insulin secretion, increased insulin resistance, and elevated hepatic glucose production. Research has shown that additional mechanisms, including those related to the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and the brain (insulin resistance), referred to as the “ominous octet”,2 are also involved. Overt T2DM occurs only when β-cells fail (due to decreased mass or their failure to recognize the hyperglycemic signal) and can no longer compensate for the increased insulin secretion required to maintain normoglycemia.3 Amelioration of the decline in β-cell function must be addressed to alter the progressive nature of the disease.4,5 Agents that may prevent deterioration of β-cell function or enhance endogenous insulin concentrations are much needed for the management of T2DM. Other pathophysiologic defects of T2DM that current therapeutic agents do not address include hyperglucagonemia, accelerated gastric emptying, and decrease or loss of the incretin effect. It had been demonstrated that glucagon secretion in T2DM is not suppressed after a carbohydrate-rich meal.6,7 This results in an inability to suppress postprandial hepatic glucose production and excessive plasma glucose excursions. The rate of Drug Design, Development and Therapy 2010:4 279–290 279 © 2010 Wajcberg and Amarah, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Dovepress Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Wajcberg and Amarah gastric emptying is a key determinant of postprandial glucose excursions and is often accelerated in people with diabetes.8,9 In T2DM, glucagon-like peptide-1 (GLP-1) concentrations are reduced in response to a meal, whereas glucose-dependent insulinotropic polypeptide concentrations are normal or increased. This observation suggests resistance to the actions of glucose-dependent insulinotropic polypeptide, making GLP-1 the favored potential therapeutic target.10,11 Many of the pathophysiologic disturbances that are present in T2DM can be corrected by incretin replacement with GLP-1. In response to the physiologic loss of incretin activity associated with T2DM, administration of exogenous GLP-1 has been shown to lower both fasting and postprandial plasma glucose significantly.12,13 The main limitation in developing GLP-1 for the treatment of T2DM is its short half-life of less than two minutes. By removing two N-terminal amino acids, dipeptidyl peptidase-4 (DPP-4) rapidly inactivates GLP-1.14 The development of the GLP-1 receptor agonists offers incretin-based therapies with built-in modifications to provide resistance to DPP-4 degradation. Pharmacokinetics and pharmacology Liraglutide (Victoza ®; Novo Nordisk Inc, Bagsvaerd, Denmark) is a modified form of human GLP-1 (γ-Lglutamyl[N-α-hexadenoyl]-Lys,26 Arg34-GLP-1 [7–37]). Native GLP-1 is a 30-amino acid peptide produced by cleavage of the transcription product of the preproglucagon gene.15 Liraglutide was obtained by substitution of lysine 34 to arginine near the NH2 terminus, and by addition of a C16 fatty acid at the ε-amino group of lysine (at position 26) using a γ-glutamic acid spacer, which allows noncovalent binding to albumin (see Figure 1).16 The resultant molecule shares 97% (36/37 amino acids) sequence identity with native human GLP-1.17 The high degree of homology of liraglutide to GLP-1 may in part explain the relatively low levels of His Ala Glu Gly Thr Phe Thr Ser Asp C-16 fatty acid (palmitoyl) Glu Glu Ile Ala Trp Leu Val Arg Gly Arg Gly Figure 1 Liraglutide structure. Powered by TCPDF (www.tcpdf.org) Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Phe 280 Val submit your manuscript | www.dovepress.com Dovepress antibodies produced in response to liraglutide. However, the clinical relevance of antibodies is not yet known. Pharmacokinetic studies show that liraglutide, after subcutaneous injection, has a time to maximum plasma concentration (Tmax) of 9–13 hours and a half-life (T1/2) of 13 hours. The structural modifications of liraglutide are responsible for the prolonged half-life. Indeed, following subcutaneous injection, the fatty acid chain allows liraglutide to self-associate and form heptamers at the injection site depot. It is thought that the size of the heptamer and strong self-association are the most likely mechanisms by which delayed absorption of liraglutide from the subcutis is facilitated.18 Once in the bloodstream, the (...truncated)