- dipeptidyl peptidase-IV (DPP-IV)
- exenatide
- glucagon-like peptide-1 (GLP-1) analogues
- glycaemic control
- liraglutide
- obesity
- type 2 diabetes mellitus
Key Points
Glucagon-like peptide-1 (GLP-1) levels are low in patients with type 2 diabetes mellitus (T2DM)
GLP-1 administration improves insulin secretion, reduces glucagon secretion, promotes satiety and delays gastric emptying
GLP-1 mimetics are efficacious in the treatment of T2DM; currently available agents include exenatide and liraglutide
Inhibitors of enzyme dipeptidyl peptidase-IV are available as oral agents for the treatment of T2DM
Type 2 diabetes mellitus (T2DM) is a progressive disease characterised by a variable degree of β-cell dysfunction, insulin resistance and hyperglycaemia. Recently there has been enormous interest in developing pharmacological agents which modulate the incretin system. These therapeutic agents improve glycaemic control through multiple mechanisms similar to the endogenous incretin hormone glucagon-like peptide-1 (GLP-1).1–3
The incretin effect
The incretin effect is a phenomenon by which oral glucose ingestion elicits a much higher insulin secretory response than intravenous glucose.1,4 Following an oral glucose load, GLP-1 is secreted from the intestinal mucosa and augments the insulin response to hyperglycaemia. Plasma levels of GLP-1 increase six- to eightfold after a carbohydrate meal.5 The action of GLP-1 is therefore dependent on residual insulin secretory capacity. GLP-1 is released in response to nutrient ingestion from L-cells distributed throughout the intestine, but preferentially located in the distal gut.6 It is of interest that plasma levels of GLP-1 increase within minutes of food consumption, suggesting that a combination of endocrine and neural signals promotes early GLP-1 secretion before digested food passes through the gut to directly engage the L-cells.1
In addition to its insulinotropic effect, GLP-1 inhibits glucagon release,6 prolongs gastric emptying and leads to a decrease in body weight, all of which explain the ‘antidiabetic’ effect of this incretin hormone.7 Endogenous GLP-1 undergoes rapid inactivation by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in a plasma half-life of 1–2 min. Therefore, the therapeutic potential of endogenous GLP-1 would be limited without attempts to prolong its duration of action.
The therapeutic potential of the incretin system in type 2 diabetes mellitus
There is a moderate degree of GLP-1 hyposecretion in subjects with T2DM. The typical phenotype of T2DM consists of a heterogeneous picture of diminished insulin secretion, excess glucagon secretion relative to the plasma glucose, and increased body weight with associated insulin resistance. Rodent and in vitro studies have shown an increase in β-cell mass following long-term administration of GLP-1. An improvement in β-cell function has been observed in humans, with increased insulin secretory capacity in response to GLP-1.8 Infusion of GLP-1 results in the suppression of glucagon secretion and normalisation of fasting plasma glucose.8 Importantly, GLP-1 administration does not impair the glucagon counter-regulatory response to hypoglycaemia since glucagon secretion is glucose-dependent.9 GLP-1 has a direct action on the hypothalamus to induce satiety10 and also delays gastric emptying.11 Both these factors induce a feeling of postprandial ‘fullness’.
The physiological effects of GLP-1 in improving β-cell function, reducing glucagon secretion and gastric emptying, inducing satiety and facilitating weight loss would be ideal in the therapy of a typical subject with T2DM.
Therapeutic strategies based on the incretin system
The main challenge in using GLP-1 to treat T2DM relates to its rapid metabolism by plasma DPP-IV. Initial interest in the use of GLP-1 based therapies for T2DM focused on DPP-IV resistant peptides that bound to the GLP-1 receptor (GLP-1 agonists) or substances inhibiting DPP-IV which would increase endogenous levels of GLP-1.12 This led first to the development of incretin mimetics and subsequently of DPP-IV inhibitors.
GLP-1 mimetics
Two GLP-1 mimetics (also known as GLP-1 receptor agonists) are currently available in clinical practice: exenatide and liraglutide. They are DPP-IV resistant analogues of human GLP-1 that improve glycaemic control through multiple mechanisms similar to the endogenous incretin hormone GLP-1.1,2 The efficacy of both these agents has been established in phase III clinical trials.
Exenatide
The first product licensed was exenatide, a synthetic analogue of a 39-amino acid peptide (exendin-4) originally found in the saliva of the lizard Heloderma suspectum. It is a functional, partly DPP-IV-resistant analogue of human GLP-1.13 Studies have examined the efficacy of adding exenatide to concurrent oral therapy (metformin,14 sulphonylureas,15a combination of both16 or thiazolidinediones17) in patients with suboptimal glycaemic control. The starting dose of exenatide is 5 μg twice daily for four weeks followed by 10 μg twice daily thereafter.
Exenatide was associated with a mean reduction in HbA1c of 0.8–1.0% during 30 weeks of treatment, with a weight loss of 1.5–3.0 kg.14–16 Patients continuing in an open-label extension lost as much as 4–5 kg after 80 weeks.18,19 Furthermore, in a 26-week comparator study against insulin-glargine20 there was a similar overall improvement in glycaemic control (−1.1% reduction in HbA1c) with the additional benefit of sustained weight reduction (−2.3 kg with exenatide, +1.8 kg with insulin glargine).
A more recent study21 compared exenatide with biphasic insulin aspart as additional therapy in patients already receiving metformin and a sulphonylurea over a 52-week period. The HbA1c reduction was similar (−1% reduction) but weight loss was observed in the exenatide treated participants (−2.5 kg with exenatide, +2.9 kg with biphasic insulin). Favourable reports have also been obtained with exenatide in the routine clinical setting.22
Liraglutide
Liraglutide is a long-acting GLP-1 analogue with 97% sequence homology to human GLP-1 but with structural modifications that result in reversible albumin binding, resistance to GLP-1 inactivation by DPP-IV, and prolonged duration of action.23 The starting dose of liraglutide is 0.6 mg once a day increased weekly to a maximum of 1.8 mg daily.
The results of phase III clinical studies (Liraglutide Effects and Action in Diabetes (LEAD)) demonstrate the efficacy of liraglutide in reducing HbA1c and also show beneficial effects on body weight. The LEAD programme comprised six randomised controlled, double-blind studies examining the effect of liraglutide directly against commonly used therapies in T2DM. As shown in Table 1, HbA1c reduction is typical and weight loss was observed in all the studies except LEAD-1.17,24–28
Summary of changes in HbA1c, body weight and systolic blood pressure (BP) in the Liraglutide Effects and Action in Diabetes (LEAD) studies.
It is of interest that a recent placebo-controlled study in obese individuals without T2DM demonstrated a significant weight reduction associated with liraglutide at 20 weeks.29 The mean weight loss observed with liraglutide doses of 1.2 mg, 1.8 mg, 2.4 mg and 3.0 mg were −4.8 kg, −5.5 kg, −6.3 kg and −7.2 kg, respectively, compared with −2.8 kg with placebo. At present, liraglutide is not licensed for use as a weight reducing agent.
In the LEAD-6 study24 the efficacy of liraglutide was compared with exenatide as add-on therapy to metformin and/or sulphonylurea. There was greater improvement in glycaemic control with once daily liraglutide compared with twice a day exenatide (reduction in mean HbA1c, −1.12% with liraglutide, 0.7% with exenatide).
Adverse effects
Table 2 summarises the main adverse effects associated with GLP-1 mimetics. Essentially, these are gastrointestinal (GI) disturbances and risk of hypoglycaemia. The former include nausea, vomiting and diarrhoea. Typically, these adverse events, which are dose-dependent,17 are often mild and diminish within a few days or weeks on continued therapy. Patients should be counselled with regard to the GI adverse effects to prevent unnecessary discontinuation and improve compliance.
Summary of common adverse effects associated with incretin-based therapy.
The frequency of hypoglycaemia depends on the oral hypoglycaemic agents co-administered.22 Importantly, the incidence of minor hypoglycaemia with liraglutide was comparable (3%) with that on placebo and 17% lower than with sulphonylurea.25,27 Similarly, exenatide is also associated with an increased risk of hypoglycaemia when co-administered with a sulphonylurea.16,20 Patients should exercise increased vigilance with regard to this potential adverse effect, particularly when using a combination of liraglutide and a sulphonylurea.
DPP-IV inhibitors
An alternative approach to the use of GLP-1 mimetics is to inhibit the breakdown of endogenous GLP-1. DPP-IV inhibitors mimic many actions of the GLP-1 mimetics, including the stimulation of insulin, inhibition of glucagon secretion and preservation of β-cell mass.30 DPP-IV inhibitors are not typically associated with decreased gastric emptying or clinically significant weight loss.
Several DPP-IV inhibitors are in development and have the advantage of oral administration. Currently licensed available agents include sitagliptin, vildagliptin and saxagliptin. Clinical studies have shown that vildagliptin is associated with a −0.8% change in HbA1c when combined with metformin therapy.31 As a monotherapy, similar reductions in HbA1c are seen compared with metformin32 and rosiglitazone.33 Clinical studies with sitagliptin have shown a −0.65% change in HbA1c when combined with metformin therapy.34 Monotherapy at a dose of 100 mg/day is associated with a −0.79% change in HbA1c.35
Adverse effects
The main adverse effect associated with DPP-IV inhibitors is hypoglycaemia, apparent on combination with sulphonylurea. For this reason, dose reduction and caution are advised when commenced in addition to these agents. The other main adverse effects associated with DPP-IV inhibitors are shown in Table 2.
Conclusions
The use of therapeutic agents that enhance the incretin effect is an important and rapidly developing area of interest within diabetic medicine. Prior to their advent all traditional available therapies apart from metformin were associated with weight gain. Furthermore, sulphonylureas and insulin are associated with the further risk of hypoglycaemia. Newer GLP-1 mimetics are in development and phase III trials well underway with long-acting preparations such as exenatide LAR which is administered once weekly. This promising agent has shown a reduction in HbA1c of 1.4–1.7% and weight reductions up to 3.8 kg over a 15-week period.36 Incretin-based therapies offer great potential, but further experience with routine clinical practice is required and long-term evidence on benefit with regard to the micro- and macrovascular complications of T2DM.
Conflict of interest
Dr Stephens has received speaker fees from Lilly and research grant support from Novonordisk.
- © 2010 Royal College of Physicians
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