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Glucagon-like peptide-1 in the treatment of type 2 diabetes

John Laverty
Lead Diabetes Nurse
Diabetes Therapy Service

The plethora of oral agents available can certainly help accomplish manageable glycaemia, but they also carry disadvantages for the patient. This article explains these new therapies, how they work and how to manage their initiation

The management of type 2 diabetes has not changed significantly since the introduction of the first oral hypoglycaemic agent, metformin, back in 1957.1 There has been an overwhelming drive to delay or prevent diabetes-related complications by attempting to ensure that glycaemic control remains well managed. The plethora of oral agents currently available can certainly help accomplish manageable glycaemia, but they also carry additional disadvantages for the patient.

Weight management is an ongoing issue for the vast majority of patients with type 2 diabetes, yet few, if any, of the current oral hypoglycaemic agents can help address this concern.2,3

In 2006, Eli Lilly introduced the European healthcare community to exenatide, a twice-daily injectable therapy that could not only help with improving glycaemic control, but that also seemed to provide a means of losing weight. Novo Nordisk introduced a similar product in 2009.

What is GLP-1?
GLP-1 is one of the incretin hormones released by the L-cells of the intestine following the ingestion of a meal. GLP-1, along with another incretin hormone (glucose-dependent insulinotrophic polypeptide - GIP) is thought to be responsible for up to 70% of postprandial insulin secretion. The half-life of native GLP-1 is short, estimated to range from one to five minutes, so its impact on postprandial blood glucose levels is somewhat limited.4 One of the objectives of research into the incretin system was to prolong the period of activity of GLP-1, thereby enhancing the impact on postprandial insulin production, which in turn would improve overall blood glucose control.

How does GLP-1 work?
What are the options?
The first GLP-1 substitute was exenatide (Byetta), which has been derived from exendin-4, a substance found in the saliva of the Gila monster (heloderma suspectum), a small venomous lizard found in south-west US. Eli Lilly produced a derivative of exendin-4 and named it exenatide and, although not strictly speaking a GLP-1, it has a similar binding affinity at the GLP-1 receptor in vitro and, as such, can bestow benefits on many of those who use it. It was granted a licence for use in type 2 diabetes in 2006.5 It is licenced for use with metformin alone, sulphonylureas (SU) alone or with a combination of both, in patients who have failed to achieve adequate control on maximum tolerated doses of the aforementioned therapies.

In July 2009, Novo Nordisk launched their GLP-1. Named liraglutide (Victoza), this is a laboratory manufactured product, which is remarkably similar to native GLP-1 both in structure and action. It is a once-daily, human GLP-1 analogue, which was launched in the UK in 2009 having been granted a licence for use in type 2 diabetes in combination with metformin alone, an SU alone, metformin plus SU combination and with a metformin plus thiazolidinedione (TZD) combination, where patients have failed to achieve adequate control on maximum tolerated doses of the aforementioned therapies.

The differences between the two options
Exenatide is not strictly speaking a GLP-1, given that it is derived from exendin-4, which is not known to exist naturally within the human system. It is 53% homologous with native GLP-1 and this affords it the benefit of being protected against the action of dipeptidyl peptidase IV (DPP-IV), which is secreted by the body and causes degradation of GLP-1. It is administered twice daily via subcutaneous injection, taken up to one hour before breakfast and one hour before evening meal (though generally speaking 20-30 minutes before breakfast and evening meal tends to be as effective). The initiation dose is 5 µg twice daily for one month, after which time the dosage is increased to 10 µg twice daily (the maintenance dosage).

Liraglutide is 97% homologous with native GLP-1 so is very much at risk of the action of DPP-IV, but the dosage administered and the mode of action can protect the product from adverse impact. Liraglutide is administered by subcutaneous injection once daily and at a time of the patient's choosing, as it is not meal specific. The patient must ensure they are consistent with the timing (ie, at around the same time every day to ensure consistent levels are maintained within the blood stream). The initiation dosage is 0.6 mg daily for one week, rising to 1.2 mg thereafter. New NICE guidelines suggest that 1.8 mg should not be used in the management of diabetes.

Initiation of therapy: what the patient needs to know
Local guidelines and policies dictate which product is used and how its initiation should be managed. Given that GLP-1 can be administered alongside a range of oral hypoglycaemic agents, it is commonplace for it to be used as an added therapy rather than a replacement one. It should be noted that as a stand-alone therapy or when taken with metformin, hypoglycaemia is unlikely to occur. Taken with either an SU or a TZD, hypoglycaemia is a real risk and the dosage of said oral medications will need to be reduced. It may be practical to discontinue said therapies and persevere with just the GLP-1 and metformin (if tolerated). It is imperative that the patient understands the possible side-effects of GLP-1 treatment (see Table 1).

[[Tab 1 therapy]]

Perhaps the most important point to stress is the reduction in appetite experienced by patients who use a GLP-1, as it is this combined with the initial experiences of nausea which can impede the patient's determination to persevere with the therapy. From the author's own experience, many patients complain of a lack of appetite accompanied by a change in food choices. As appetite suppression occurs, patients generally lose weight. A smaller body mass requires less insulin to meet energy needs and in many cases the body is able to manage glycaemia more effectively.

A recent audit of patients in Wolverhampton, where GLP-1 use per capita is the greatest in the UK, patients lost on average 12 kg over the first 12 months from initiation - it should be remembered that weight loss is relative to starting weight (the heavier the patient, the greater the propensity to lose weight).

Patients managed on a GLP-1 with an SU or TZD, require regular initial follow-up in order to monitor them for the possible hypoglycaemic effects of combined therapy. Once control has been established, the patient can be discharged back into the care of the primary care team - requiring only HbA1c monitoring at three or four monthly intervals.

For individuals on metformin and a GLP-1, care can be provided by the primary care team from the outset, although it is common for patients to be monitored within the acute sector until there is evidence that the therapy is having effect. It is appropriate to monitor the weight of the patient and the HbA1c, along with the blood pressure (as GLP-1 can have a beneficial effect on this).

For patients on metformin, it is important to monitor serum B12 folate levels, as metformin can interfere with vitamin B12 absorption and when taken with a GLP-1, this impact is exaggerated in certain patients. There have been reports of hair loss among patients taking a GLP-1, though both companies are keen to stress that interference with B12 absorption is attributed to metformin rather than their product.

The management of type 2 diabetes has followed a well defined pathway for a number of decades. The use of oral hypoglycaemic agents can help with HbA1c management, which, in turn, can help prevent or delay the onset of diabetes related complications. Unfortunately, none of the oral agents currently being used can help significantly with weight loss, which is a necessity for the vast majority of type 2 patients. Metformin can help maintain weight, but weight gain is inevitable when used with additional therapies, SUs, as we know contribute to weight gain, as do TZDs.6

The newer medications - DPP-IV inhibitors - are weight neutral and as such do little to tackle the issue of excess weight. Patients seeking/needing to lose weight are often considered for bariatric surgery, though this is not without risk. GLP-1s can offer the benefit of potential weight loss and improved glycaemic control at a time when insulin therapy might be considered the only viable alternative. It should be remembered that GLP-1 therapy is licenced for use as a means to improve HbA1c, not as a weight loss therapy; it just happens to be that many who use it do lose weight.

Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711-21.
UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
Keiffer TJ, McIntosh Ch, Pederson RA. Degradation of glucose-dependent insulinotrophic polypeptide and truncated glucagon-like peptide-1 in vitro and in vivo by Dipeptidyl peptidase I. Endocrinology 1995;136:3585-96.
Drucker DJ, Nauck M. The incretin system: glucagon-like peptide -1 receptor agonists and Dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-705.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in Type 2 diabetes. New Engl J Med 2008; 359(15):1576-89.