The progression of Type 2 diabetes is driven by progressive β-cell dysfunction and increased insulin resistance, which results in hypoglycaemia due to difficulty of achieving glycaemic control. Typically, lifestyle modifications such as diet and exercise fail to achieve and give way to the administration of oral hypoglycaemic agents (OHAs) in order to maintain glucose control. In addition to tolerability issues for patients, the inability of OHAs to stem the decline in β-cell function  commonly lead to the introduction of exogenous basal insulin to maintain normoglycaemia . Traditionally regarded as a drastic measure in Type 2 diabetes, physicians are increasingly favouring earlier introduction of basal insulin to control hyperglycaemia and minimise the associated micro- and macrovascular complications of diabetes [3, 4]. Whilst undoubtedly clinically effective, use of insulin regimens also carries some problems, namely:
an inability to control mealtime glucose excursion ,
increased risk of severe hypoglycaemia [6, 7],
the need for complicated dose-titration , and
weight gain .
Hypoglycaemia of any severity has a profound effect on patients' quality of life  and is regarded as the single greatest obstacle to achieving normoglycaemia . In addition to reduced quality of life, hypoglycaemia results in substantial direct medical cost and lost productivity .
Insulin glargine (Lantus™) is an analogue of human insulin with a prolonged duration of action and once-daily dosing. In Type 2 diabetes, the principal emergent benefit is significantly reduced risk of all forms of hypoglycaemia over Neutral Protamine Hagedorn (NPH) . However, initiation of insulin glargine still requires careful dose titration to an appropriate level over a period of time. This is essential for successful treatment of diabetes and the avoidance of hypoglycaemia . However, recent trial evidence has suggested that insulin glargine could be introduced earlier to achieve glycaemic goals  and a further study showed that adding insulin glargine to OHA therapy had a positive effect on treatment satisfaction and quality of life (QoL) without complaints related to hypoglycaemia . Insulin glargine is currently not recommended by the National Institute for Health and Clinical Excellence (NICE) for routine use for people with Type 2 diabetes, but can be considered for people with Type 2 diabetes who require assistance from a third party to administer their insulin injections, who have recurrent symptomatic hypoglycaemic episodes or who would otherwise need twice-daily basal insulin injections in combination with oral antidiabetic drugs. Using their own model (based on United Kingdom Prospective Diabetes Study (UKPDS) 68 ), NICE concluded that human insulin analogues are the most cost-effective option and glargine was estimated to be cost-effective in Type 2 diabetes patients at increased risk of hypoglycaemia ; the NICE guidelines are due to be reviewed and republished in early 2009.
The incretin mimetics are emerging as a significant new class of hypoglycaemic agents that regulate glucose homeostasis similarly to endogenous glucagon-like peptide-1 (GLP-1). Exenatide (Byetta™), the first such compound to be licensed by the European Medicine Agency (EMEA) , enhances glucose-dependent insulin secretion, regulates glucagon release, and delays gastric emptying thereby reducing hyperglycaemia in a similar manner to GLP-1. Unlike the short-lived GLP-1, exenatide resists metabolism by dipeptidyl peptidase-IV giving it a pharmacokinetic profile suitable for chronic administration . Exenatide is recommended for use in the treatment of Type 2 diabetes in combination with metformin, and/or sulphonylureas in patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies and is given twice daily by subcutaneous injection. Exenatide was approved by the Scottish Medicines Consortium (SMC) in June 2007, as an adjunct therapy to patients with Type 2 diabetes who, despite currently taking metformin and/or a sulphonylurea either singly or in combination, fail to achieve adequate glycaemic control . Exenatide, however, is not currently recommended by NICE for routine use for people with Type 2 diabetes  and should only be considered for people with Type 2 diabetes, who have a body mass index (BMI) over 35 kg/m2, specific problems arising from high weight, inadequate blood glucose control (glycosylated haemoglobin (HbA1c) >7.5 %), prescribed conventional oral therapy and where other high cost therapies would otherwise be commenced. Using their own model (based on UKPDS 68 ), NICE estimated that exenatide was not cost-effective in any scenario  and, furthermore, exenatide has been linked with occurrences of acute pancreatitis .
The only published head-to-head randomised controlled trial (RCT)  of exenatide versus glargine, reported similar improvements in the overall glycaemic control in patients with Type 2 diabetes sub-optimally controlled with combination OHAs at maximal doses. For secondary endpoints, patients treated with exenatide experienced significantly fewer nocturnal hypoglycaemic events (0.9 vs. 2.4 events per patient per year; a 63% reduction), but higher incidence of daytime hypoglycaemia (6.6 vs. 3.9 events per patient per year; a 69% increase) and achieved significant weight loss from baseline (Δ -2.3 kg), whereas insulin glargine-treated subjects gained weight of a similar magnitude (Δ +1.8 kg) by the study endpoint. The principal drawback reported in exenatide treated patients was nausea (in 57.1% of subjects) and vomiting (in 17.4%), which led to withdrawal of almost 10% of exenatide-treated patients from the study protocol. This finding is consistent with evidence from other published phase 3 placebo-controlled trials . By comparison, less than 1% of those exposed to insulin glargine withdrew due to adverse events. The most common adverse event reported with insulin glargine was nasopharyngitis (in 9.0%). Within this trial setting, however, the dosage of glargine was very low with an average of 25 international units (IU)/day. This does not reflect clinical practise, where the dosage is typically 42 IU/KG . A higher dose with glargine will lead to better glycaemic control, but also more weight gain and will have an effect on hypoglycaemic events [25, 26]. Regarding patient reported outcomes, Boye and colleagues published the patient reported outcomes measured from the same head-to-head trial  and showed no significant difference in improvement of health utility or quality of life .
The increasing global financial burden of chronic health conditions is fuelling a rising demand for value for money when introducing new health technologies. In line with many other countries, in the United Kingdom (UK), NICE currently accepts as cost-effective, "those interventions with an incremental cost-effectiveness ratio of less than £20,000 per QALY (quality adjusted life year) and that there should be increasingly strong reasons for accepting as cost effective interventions with an incremental cost-effectiveness ratio of over £30,000 per QALY ." A recently published study of Ray et al.  showed exenatide to have a cost-effectiveness ratio of £22,420 vs. insulin glargine; however, a major limitation of this study was that it used an estimated UK cost of exenatide based on the US price. The study reported exenatide as dominant (less costly and more effective) when marketed at 20% of the US price in the UK. The study of Ray et al. used cohort details from the Heine trial  that were then applied to a previously published cost effectiveness model , the CORE Model.
The objective of this analysis was to prospectively evaluate the cost-effectiveness of exenatide from a UK NHS perspective, using insulin glargine as a comparator and the current UK NHS price for exenatide and also applying the cohort profiles and published data from the Heine trial . The model, which has been previously published , used to evaluate the cost-effectiveness was a discrete event simulation (DES) model for patients with Type 2 diabetes using UKPDS-derived risk functions  and a multivariate regression model for the utility associated with hypoglycaemia .