Drug Profile Insulin degludec/liraglutide (IDegLira) for the treatment of type 2 diabetes Expert Rev. Endocrinol. Metab. 11(1), 7–18 (2016) Stephen CL Gough*1, The progressive nature of type 2 diabetes necessitates that treatment is intensified as the disease Rajeev Jain2 and advances. Several studies have shown that basal insulin and glucagon-like peptide-1 receptor Vincent C Woo3 agonists (GLP-1RAs) can be used in combination to successfully improve glycemic control and this combination is increasingly being considered as an alternative to intensification with prandial insulin. 1Oxford Centre for Diabetes Endocrinology and Metabolism, NIHR Insulin degludec/liraglutide (IDegLira) is the first fixed-ratio combination of a basal insulin and a GLP- Oxford Biomedical Research Centre, 1RA in a single formulation. Here we consider the benefits and potential limitations of such a Churchill Hospital, Headington, combination, focusing on the unique modes of action of insulin degludec and the once-daily GLP- Oxford, UK 2 1RA liraglutide. IDegLira offers an efficacious combination therapy (mean end-of-trial HbA1c was Endocrinology, Aurora Advanced – Healthcare, Milwaukee, WI, USA 6.4 6.9% across the five completed Phase 3 trials), which was well-tolerated in clinical trials. The 3Department of Endocrinology and complementary modes of action resulted in a low rate of hypoglycemia and no weight gain in Metabolism, University of Manitoba, insulin-treated patients. As a once-daily injection with effects on both fasting and post prandial Winnipeg, MB, Canada hyperglycemia, IDegLira has the potential to help many patients reach glycemic target (60–81% of *Author for correspondence: Tel.: +44 1865 857 560 patients achieved HbA1c <7% in clinical trials). Fax: +44 1865 857 213 [email protected] KEYWORDS: type 2 diabetes ● glucagon-like peptide-1 receptor agonist ● IDegLira ● insulin The complex pathophysiology of type 2 diabetes is the numerous options available, data from obser- characterized by declining β-cell function resulting vational studies suggest many patients with dia- in reduced insulin secretion in response to glucose, betes do not have adequate glycemic control.[3,4] hypersecretion of glucagon from pancreatic α-cells Clinical inertia with respect to intensifying and insulin resistance in the muscle and liver. This treatment when HbA1c remains above target favors a strategic approach involving combination is also a contributing factor. For example, the therapy that can address the full spectrum of Study of Once Daily Levemir (SOLVE) study underlying abnormalities and maximize the showed that mean HbA1c in patients from 10 chance of treatment success. Metformin is recom- countries was 8.9% prior to insulin initiation. mended as first-line therapy in most patients with [3] Similarly, a UK-based retrospective cohort type 2 diabetes, and it is recommended that an study showed that the median time to treat- additional therapy be added if a patient is not at ment intensification for those taking one, two target after 3–6monthstreatment.[1,2]Options or three oral antidiabetes drugs (OADs) when for second-line therapy include sulfonylureas, thia- HbA1c was over 7.0% exceeded the maximum zolidinediones (TZD), dipeptidyl peptidase 4 follow-up time of 7.2 years.[5] Patients and (DPP-4) inhibitors, glucagon-like peptide-1 recep- physicians may be reluctant to intensify treat- tor agonists (GLP-1RA), basal insulin, acarbose ment as it often leads to increased risk of and sodium-glucose transport protein 2 inhibitors. hypoglycemia and weight gain.[6,7] However, despite recent treatment advances and This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial- NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, dis- tribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. www.tandfonline.com 10.1586/17446651.2016.1113129 © 2015 The Author(s). Published by Taylor & Francis. ISSN 1744-6651 7 Drug Profile Gough, Jain & Woo Therefore, there is still a need for new and innovative Rationale for combining a GLP-1RA and a basal insulin therapies that will enable patients to attain glycemic targets analog easily with minimal side effects. Furthermore, there is an Incretin and insulin therapies are both efficacious blood glucose- awareness that the control of diabetes needs to involve a lowering therapies, but with different mechanisms of action. GLP- combination of lifestyle measures and pharmacological inter- 1RAs increase insulin secretion by β-cells and decrease glucagon ventions, as well as addressing comorbidities such as dyslipide- secretion by α-cells, both in a glucose-dependent manner. mia and hypertension while minimizing weight gain.[2] The Depending on their duration of action, they can decrease both fasting idea of combination therapies is not new – combination pro- plasma glucose (FPG) and postprandial glucose (PPG), with longer- ducts containing metformin with a number of oral agents, for acting GLP-1RAs having a greater effect on FPG and shorter acting example, sulfonylureas, TZDs and DPP-4 inhibitors, are avail- products having a greater effect on PPG.[13]GLP-1RAsalsoreduce able, offering a less complicated option for patients requiring satiety, delay gastric emptying, can reduce body weight and are more than one oral agent. associated with a low risk of hypoglycemia. However, GLP-1RAs GLP-1RAs are one of the newer classes of therapies that, along may not lead to sufficient insulin secretion from β-cells to achieve the with DPP-4 inhibitors, are classified as incretin-based therapies. desired glycemic control. Basal insulin therapy increases circulating GLP-1 is a natural hormone secreted from L-cells in the small insulin in a non-glucose-dependent manner and has been associated intestine and colon in response to caloric intake. GLP-1 stimu- with improved β-cell function. Basal insulin has a role in glucose lates insulin secretion, suppresses glucagon secretion when glu- regulation in the liver and peripheral tissues, and modulates hepatic cose levels are elevated, delays gastric emptying and reduces glucose production.[14] Basal insulin is very effective at lowering appetite.[8] GLP-1RAs activate a G-protein-coupled receptor; HbA1c and FPG, but has less of an effect on PPG. Insulin is in pancreatic β-cells this is coupled to adenylyl cyclase, increasing associated with an increase in body weight (due in part to increased cAMP levels and leading to the release of insulin.[8] Following appetite and food intake) and a risk of hypoglycemia. secretion, natural GLP-1 is rapidly degraded by DPP-4, resulting Therefore, the two mechanisms of action may complement each in a very short half-life of approximately 1.5 min. other, with the glucose-dependent effect of GLP-1RAs on pancreatic Studies have shown that the pancreatic β-cell response to islet function counterbalancing the risk of hypoglycemia observed GLP-1 is impaired in patients with type 2 diabetes.[9] with increasing doses of insulin. By reducing hunger and food Exogenous GLP-1 can augment the β-cell response to reach intake, GLP-1RAs can decrease the weight gain associated with similar levels to those of healthy individuals.[10]Thefirst insulin. The individual effects of basal insulin and GLP-1RAs marketed GLP-1RA, exenatide, is based on the structure of suggest a theoretical rationale for combination therapy with clinical exendin-4, a hormone with similar properties to GLP-1. benefits to be expected.[15] Exenatide has only 53% homology to native human GLP-1 and is available in twice-daily (approved in 2005) and once- weekly (approved in 2012) formulations. Liraglutide is a Introduction to the compounds liraglutide and insulin GLP-1 analog, sharing 97% amino acid homology with degludec: the components of IDegLira native human GLP-1. It was approved in 2009 for once- Liraglutide daily dosing. Since then several other GLP-1RAs have The structure of liraglutide is based on that of native human GLP-1 reached the market or are expected to gain approval in the (Figure 1).[16,17] The attachment of a C16 side chain allows near future. liraglutide to self-associate into heptamers, delaying absorption When added to OAD(s), GLP-1RAs can offer significant from the injection site. In the bloodstream, liraglutide binds rever- HbA1c reductions with a low risk of hypoglycemia and clinically sibly to albumin, providing stability and reducing metabolism by significant weight loss.[11] However, even with HbA1c reduc- DPP-4, resulting in a half-life of 13 h and making it suitable for tions of ~1–1.5% in clinical studies, many patients may require once-daily dosing.[18] A study in patients with type 2 diabetes basal insulin therapy in addition to a GLP-1RA in order to indicated that liraglutide can improve β-cell function, restoring achieve HbA1c target. insulin secretion in response to glucose to that of healthy indivi- The combination of insulin and an incretin therapy is men- duals.[19] However, a study in Japanese patients with type 2 diabetes tioned as a possibility in the European Association for the Study of suggests that caution should be taken with switching patients with Diabetes (EASD)/American Diabetes Association (ADA) guide- reduced insulin secretory capacity from insulin to liraglutide.[20] lines on the management of hyperglycemia in type 2 diabetes,[2] The liraglutide Phase 3