The therapeutic potential of a venomous lizard: the use of glucagon-like peptide-1 analogues in the critically ill

Abstract

Glucagon-like peptide-1 (GLP-1), a principal mediator of the postprandial insulinotropic response in health, has a half-life of minutes. The saliva of the Gila monster contains exendin-4, a structural analogue of human GLP-1, but with a much longer half-life. A synthetic preparation of exendin-4, exenatide, is suitable for human use and effectively lowers glucose in ambulant type 2 diabetic patients. When compared with insulin, exenatide therapy is associated with a reduction in hypoglycaemic episodes and postprandial glycaemic excursions in this group. Accordingly, GLP-1 analogues are appealing therapies for hyperglycaemia in the critically ill patient and warrant further study.

In the previous issue of Critical Care Mecott and colleagues report the effects of a glucagon-like peptide-1 (GLP-1) analogue, exenatide, on glycaemia in severely burned paediatric patients [1]. The incretin hormones, GLP-1 and glucose-dependent polypeptide (GIP), mediate ~70% of the insulin response to a meal [2]. While GIP is potently insulinotropic in health, its effect is markedly attenuated in type 2 diabetic patients, such that even pharmacological doses have little effect on glycaemia [3]. In contrast, physiological replacement or pharmaco-logical administration of GLP-1 lowers glycaemia substantially in this group [3]. Accordingly, studies in ambulant type 2 diabetic patients have focused on the therapeutic potential administration of GLP-1 rather than GIP. Significantly, the glucose-lowering effects of exogenous GLP-1 are glucose dependent, such that even pharmacological doses of GLP-1 are most unlikely to cause hypoglycaemia.

Native GLP-1 is not used as a glucose-lowering agent in ambulant type 2 diabetic patients because of the necessity for continuous administration [4]. Endogenous GLP-1 is metabolised rapidly to its so-called inactive metabolite by the ubiquitous enzyme dipeptyl-peptidase-4 (DPP-4), the half-life of native GLP-1 being ~1 to 2 minutes [5]. While this factor essentially precludes the use of exogenous GLP-1 in ambulant patients, rapid metabolism of an agent may be a desirable pharmacokinetic property in the hospitalised patient. Accordingly, our group and others have explored the effects of exogenous GLP-1 in a variety of hospitalised, adult patients [6–10].

Using a prospective, randomised, open-label, design, Mecott and colleagues compared an intervention (exenatide ± insulin) with a control (intensive insulin therapy) in patients receiving small intestinal nutrient. The authors report that the intervention decreased insulin requirements while comparable glycaemic control was achieved. The therapeutic use of GLP-1 in critically ill patients is inherently attractive as it does not substantially increase the risk of hypoglycaemia [11]. In addition, GLP-1 therapies show reduced glycaemic variability when compared with insulin in ambulant diabetic patients [11].

Strengths of the study are the evaluation of a GLP-1-based therapy in a new population (paediatric) that has suffered a specific insult (burns), and the prolonged duration of evaluation (up to 28 days). Finally, and perhaps most significantly, the investigators have elected to use a GLP-1 analogue (exenatide) rather than the synthetic peptide. The major advantages of exenatide when compared with GLP-1 are that it can be administered intermittently, as well as its cheaper price and ready availability (Table 1).

Table 1 Comparison between GLP-1, GLP-1 analogues and DPP-4 inhibitors

Limitations of the study, which are largely acknowledged by the authors, include its open-label design and the relatively small number of subjects studied, with the consequent potential for type 2 errors. The authors reported that the use of the GLP-1 analogue failed to reduce hypoglycaemic episodes and glycaemic variability. However, the lack of effect on variability and hypoglycaemia may reflect administration of exenatide ± insulin, rather than using exenatide as a single agent. Plasma exenatide concentrations were not reported, and it should be recognised that concentrations may not be predictable in these subjects - since, even in healthy subjects, exenatide has a biological half-life of ~3 hours and large fluctuations in plasma levels occur with twice-daily subcutaneous administration. Furthermore, given the limited information on the mechanisms of glucose-lowering in the critically ill patient, measurement of insulin and/or C-peptide, as well as glucagon, would have been valuable.

Exendin-4 was isolated originally from the saliva of the Gila monster (Heloderma suspectum), a slow-moving venomous lizard native to the United States and Mexico. The Gila monster eats only 5 to 10 times per year and a meal causes a substantial postprandial increase in plasma exendin-4 concentrations [12]. Exendin-4 shares ~50% amino acid sequence identity with human GLP-1 and binds to the pancreatic GLP-1 receptor in vitro. Importantly, exendin-4 is resistant to DPP-4 inactivation, thereby having a prolonged duration of action [12]. Exenatide, a synthetic form of exendin-4, has been shown to reduce fasting and postprandial glucose via glucose-dependent stimulation of insulin and suppression of glucagon secretion, as well as slowing gastric emptying [13]. The latter is probably the dominant mechanism to account for glucose lowering after oral or intragastric meals in healthy subjects, type 2 diabetic patients, and those critically ill patients in whom gastric emptying is normal [10, 13]. GLP-1 analogues with half-lives between 12 hours and 3 to 4 days have been recently developed. These analogues have less variation in plasma concentrations after once-daily (for example, liraglutide) or weekly (sustained release exenatide) administration than twice a day dosing (exenatide). Oral drugs that inactivate the DPP-4 enzyme (DPP-4 inhibitors) - thereby attenuating metabolism and increasing the availability of endogenous GLP-1 and GIP - have also entered the clinical domain (Table 1).

In the study of Mecott and colleagues, exenetide was well tolerated; but given the adverse effects associated with its use in ambulant diabetic patients, ongoing vigilance is warranted. These adverse effects include nausea and vomiting (usually transient) [14], as well as modest weight loss that occurs, and is frequently desirable, in ambulant type 2 diabetic patients [14], but may be detrimental in the critically ill patient. The potential association between GLP-1 analogues and pancreatitis remains uncertain [14]. Lastly, the investigators did not measure anti-exenatide antibodies or plasma calcitonin concentrations, but the significance of anti-exenatide antibiodies or mild increases in calcitonin concentrations is unclear [14].

Albeit preliminary, the present study represents part of a growing interest in the use of incretins, or incretin mimetics, for the management of hyperglycaemia in hospitalised patients [15]. The desirable blood glucose range in this group remains contentious, but, as with recent studies in ambulant type 2 diabetic patients, there seems to be minimal, or no, advantage in targeting glycaemia at the lower end of the fasting normal range. Rather, the latter may well be deleterious [16]. Because the glucose-lowering effect of GLP-1 is glucose dependent, there is likely to be a threshold - perhaps about 7 to 8 mmol/l - beyond which further reductions will only occur if exogenous insulin is co-administered. In addition to identifying the optimal glycaemic range, future studies should focus on the following: which of the incretin agents is most useful in the critically ill patient; whether these agents should be used in combination with insulin, or as single-agent therapy; and identification of the patient group most likely to benefit from administration of incretin mimetics.