2.5. Exenatide as an add-on treatment to insulin
A problem that is often encountered is a patient that is already on insulin and has poor glycaemic control, either due to problems with hypoglycaemia or weight gain with increasing doses of insulin, or simply due to failure of hefty doses of insulin to reduce the hyperglycaemia. One treatment option is to add a TZD, if this has not already been tried [11]. However, another exciting (but currently unlicensed) option is the addition of exenatide to insulin treatment. This was explored by several investigators. A retrospective study by Viswanathan et al. [28] examined the addition of exenatide to a group of 52 subjects with T2DM who were on insulin plus OHA. There was no significant improvement in HbA1c, but the reduction in weight and in total insulin daily requirement was significantly different after 26 weeks of therapy. Of those using exenatide, there was high dropout rate.
In another prospective study, Govindan et al. [29] studied patients with insulin treated diabetes who failed to achieve the HbA1c target and who also had problems with progressive weight gain. At the end of the study, the improvement in HbA1c was not significant, but patients were able to reduce the total daily dose of insulin, and they also managed to lose weight. The incidence of severe hypoglycemia was unchanged by the addition of exenatide.
In a retrospective study, the use of insulin and exenatide was assessed [30]. It showed weight loss of at least 1 kg in 78% of patients and a drop in HbA1c from 8.1% to 7.2% at 8 weeks. Mild hypoglycaemia occurred in only three patients. The study by Davis et al. [31] has suggested that patients with T2DM who have longer diabetes duration and those who are taking higher doses of insulin therapy may experience deterioration of their control if they substitute exenatide for insulin.
A further retrospective study of exenatide addition to insulin has also shown significant improvements in HbA1c and weight [32]. The mean total insulin daily dose was reduced in all patients in 6 and 12 months; when the total insulin dose was stratified between basal and prandial insulin, the reduction in insulin dose was significant for the prandial group only. This suggests that on introducing exenatide in addition to insulin we should perhaps be reducing the prandial insulin dose more than the basal dose.
To summarize, exenatide may prove to be an attractive agent to be used in insulin treated type 2 diabetic patients who are not achieving the adequate level of control. Benefits include in addition to perceived improved glycaemic control, a favorable impact on weight. Also, the potential of significant reduction in total insulin daily requirement and the prospect of stopping insulin all together are other benefits, but the preliminary evidence suggests that this may be confined to patients who have residual beta cell function. More research is certainly required for more rigid recommendations to be produced regarding if and when insulin should be concurrently used with exenatide, and at what doses. As exenatide is not currently licensed to be used in conjunction to insulin, this has to be relayed to the patient concerned, and consent obtained prior to any trial of combination therapy.
2.6. Exenatide compared to exenatide LAR
Exenatide LAR is not currently approved, but it is likely that it will become available in the near future [it is currently being assessed for approval by the US Food and Drug Administration (FDA)]. Although data are limited, current evidence indicates that exenatide LAR is an effective and safe antidiabetic agent [33,34]. A 15 week trial compared the effect of exenatide LAR with placebo in patients with suboptimal blood glucose control despite diet, exercise and metformin [33]. In this trial, exenatide LAR resulted in significant reduction in HbA1c of 1.7% and improvement of fasting blood glucose levels. A second trial compared the effect of exenatide LAR on blood glucose control with that of exenatide twice daily; at the end of 30 weeks, HbA1c decreased by 1.9% in exenatide LAR treated patients, compared to 1.5% in patients receiving exenatide twice daily. Treatment with exenatide LAR also resulted in significant lowering of fasting plasma glucose compared to exenatide. Both treatment modalities caused similar weight loss. Nausea was less common in the exenatide LAR group and no severe hypoglycaemia episodes were reported on either treatment arm [34]. Furthermore, exenatide LAR would be a real breakthrough in this area, as a one weekly injection will greatly boost compliance.