Therapy in Practice Exenatide: role in management of Type 2 diabetes and associated cardiovascular risk factors Zin Z Htike1, Kamlesh Khunti2 & Melanie Davies* Practice Points Obesity in Type 2 diabetes poses a challenge in choosing the right combination of glucose-lowering agents, particularly due to the potential side effect of weight gain with many of the existing glucose-lowering medications. One of the incretin-based therapies, the glucagon-like peptide-1 analog, exenatide, is found to be a promising new agent that not only provides glucoregulatory effect in improving glycemic control without increase risk of hypoglycemia but also often results in weight loss. Treatment with exenatide results in reduction in HbA1c comparable to many of the existing glucose-lowering agents including basal insulin analog, galrgine or biphasic insulin aspart. Exenatide is of particular benefit in obese patients with Type 2 diabetes whose control in inadequate on a combination of oral glucose-lowering agents. To date, exenatide is not licensed for use in combination with insulin. SUMMARY Management of Type 2 diabetes, particularly in obese patients, is rather challenging as treatment with the majority of the available glucose-lowering t herapies is often associated with side effects of weight gain and hypoglycemia, in addition to failure to maintain durable glycemic control. The first available glucagon-like peptide-1 analog, exenatide, adds a new t herapeutic option to the currently available glucose-lowering agents for obese patients with Type 2 d iabetes. Both randomized controlled trials and retrospective observational s tudies have shown that treatment with exenatide not only improves glycemic control with a low risk of h ypoglycemia, but also results in concurrent weight loss with the additional benefit of i mprovement in cardiovascular risk factors of hypertension and hyperlipidemia. 1Department of Diabetes & Endocrinology, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK 2Department of Health Sciences, University of Leicester, Leicester, UK *Author for correspondence: Department of Cardiovascular Sciences, University of Leicester, UK; [email protected] part of 10.2217/CPR.11.132 © 2012 Future Medicine Ltd Clin. Pract. (2012) 9(1), 23–38 ISSN 2044-9038 23 Therapy in Practice | Htike, Khunti & Davies Background cardiovascular disease and mortality [9,11] . The The need for newer glucose-lowering availability of new glucose-lowering therapies therapies that can achieve or maintain acceptable gly- Type 2 diabetes (T2DM) is characterized by cemic control without weight gain is therefore multiple pathophysiological defects. Insulin highly desirable to clinicians [12] . The develop- resistance in multiorgans (liver, muscle, adipose ment of GLP-1 analogs, which not only improve tissue and brain), progressive decline in b-cell glycemic control but also results in weight loss, function of the pancreas, inappropriate hyper- is a welcome addition to the treatment options glucagonemia, increased glucose reabsorption in T2DM. from the kidney and reduced resistance to gas- trointestinal (GI) hormones termed incretins, all Background to incretin-based therapy interplay in the pathogenesis [1] . Physiologically, ingestion of glucose elicits a In practice, when lifestyle measures and met- greater insulin response than intravenous glu- formin therapy fails, many clinicians traditionally cose infusions. This phenomenon is known adopt a step-wise approach in adding other oral as the incretin effect [13] . Glucose-dependent glucose-lowering agents before initiation of insulin. insulinotropic peptide (GIP) and GLP-1 are However, with an improved understanding of the gut hormones produced in response to oral pathophysiology, there has been a shift in treat- glucose ingestion and are collectively known as ment paradigm with early insulin initiation recom- incretins. Their action is short-lived as a result mended as the first-tier approach in the consensus of rapid inactivation by the enzyme dipeptidyl statement by the American Diabetes Association peptidase-4 (DPP-4) [14,15] . The incretin effect is and European Association for the Study of Diabetes deemed to be impaired in T2DM [16] . Although after lifestyle modification and metformin therapy GLP-1 secretion and activity are maintained, a [2]. The UK Prospective Diabetes Study confirmed supraphysiological concentration is needed to that despite implementation of lifestyle and medi- compensate for the disease-associated impair- cal management with metformin or sulfonylurea ment of GIP activity [17] . Unlike GIP, GLP-1 (SU), or combination therapy, b-cell function con- is capable of stimulating both early- and late- tinues to decline with the resultant worsening of phase insulin secretion in T2DM. However, the glycemic control as the condition progresses [3,4]. exact mechanism remains debatable. Thus, the The use of metformin, SU or thiazolidinediones incretin effect could be potentially enhanced (TZDs), either as monotherapy or in combination, by either supplementing with incretin analogs, is limited by the inability to maintain durable gly- which mimic GLP-1 action such as exenatide cemic control [5]. Moreover, undesirable side effects, and liraglutide, or by preventing GLP-1 break- including weight gain, hypoglycemia, GI intoler- down by DDP-4 inhibitors, such as sitagliptin, ance, peripheral edema, fracture risk and suspected saxagliptin, linagliptin or vildagliptin, also risk of bladder cancer [6–8] lead to reduced patient termed incretin enhancers. adherence or physician reluctance to prescribe these medications. Intensifying therapy even with Role of the incretin mimetics modern insulin analog regimes invariably results Exenatide is the first synthetic GLP-1 analog, in weight gain [2,9]. originally isolated from the saliva of the des- In selected clinical settings, specifically when ert lizard, Gila monster (Heloderma suspectum). hypoglycemic or weight gain is particularly This synthetic peptide has 53% homology undesirable, addition of TZD (pioglitazone) or with the human GLP-1 amino acid sequence, newer agents, such as glucagon-like peptide-1 thus allowing it to bind avidly to the GLP-1 (GLP-1), may be considered as the second tier [2]. receptor but resist enzymatic degradation by Similarly, in the American Association Clinical DPP-4 [13,15] . Endocrinologists guidelines, early combination By mimicking GLP-1 action, exenatide of oral antidiabetic drugs (OADs) and treat- improves the glucoregulatory effect by enhancing ment with newer agents, such as incretin-based glucose-dependent insulin secretion, restoring t herapies are advocated at an earlier stage [10] . first-phase insulin response, suppressing inap- It is well established that poor glycemic con- propriate glucagon secretion [15,18,19] and thus has trol in T2DM and obesity, either in combination an effect on both fasting and postprandial glu- or independent of each other, increase the risk of cose levels [20,21]. It also delays gastric emptying 24 Clin. Pract. (2012) 9(1) future science group 0.85% and0.85% weight loss 1.5–3 of significantof approximately reduction in HbA1c exenatide unequivocally resulted in amodest but tion, hastion, been developed and tested in Phase mulation, exenatide once-weekly (Ex the Ex real-life settings from published data both for management in T2DM clinical of trials and safety and efficacyof using exenatide in the theby EMA clinical trials, and has recently been approved & bodyweight via the kidney g by ration is manufactured Eli by Lilly (Byetta asan adjunctive therapy recommended its use in patients with T2DM inthe UK since2009 and NICEhas recently ogy with human GLP amino acid substitution, sharing 97% homol recombinant DNA technology with only one GLP Exenatide: role in management of Type of management in role Exenatide: marized in lowering therapy various to OADs is sum The efficacyof adding exenatide as a glucose- co Ex controlled trials & real-life studies randomized from evidence Clinical leading weight to loss and decreases food intake promoting by satiety US Exendin-4) and was first the by approved therapy in T2DM updated guidelines in 2009 half-life 2–3 of 4–6 ger half-life 2.4 of resistant inactivation to has it alon DPP-4, by agement T2DM of as third-line second- a or agent the for man NICEmended by in the UK in 2008 be to used alone acombination or both. of These studies tolerated doses either metformin of an or SU optimal glycemic control using the maximum subjects with T2DM who wereunable achieve to addingof exenatide the to treatment regimens of AMIGO studies Effect of exenatide on glycemic control control glycemic on exenatide of Effect mbination of OADs The purpose this of article is review to the The exenatide twice daily (Ex Liraglutide (Victoza The pivotal clinical trials the were three b.i.d. as an add-on therapy to a single or or asingle to therapy add-on an as b.i.d. F h c - DA in 2005DA be to used as an adjunctive 1 a 1 b ompared with human GLP .i.d. and.i.d. the Ex nalog. Liraglutide is synthesized by Table [104] mi . n n 1 [23–25] h a . In all studies, addition of lo [22] [13,15] [101] merular filtration. nd adurationnd action of of [15,18,19] . It was. It originally recom ® - 1. I 1. , evaluating the effects , and then again in the ) is the second licensed . It is mainly It . e q [103] .w. preparation. .w. t has been available [102] . A long-acting. A for . Since exenatide is . k - g 1, w 1, b [23–26] .i.d.) prepa q li