Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue with a 97% sequence identity to the endogenous GLP-1 molecule, and a half-life of about 13 hours making it suitable for use in a once-daily treatment regimen;1 an added benefit is that administration does not need to be restricted to mealtimes. Dose adjustment is not required for patients with mild renal impairment as it is degraded by endogenous peptidases, rather than by renal elimination. Liraglutide received market authorisation in Europe in July 2009.2
Mode of action
Liraglutide is a GLP-1 receptor agonist or incretin mimetic—in the 1960s, the observation was made that the insulin response to an oral glucose load was greater than that seen with an intravenous glucose infusion; this was labelled the ‘incretin effect’ and is due to the secretion of hormones such as GLP-1 and gastric inhibitory polypeptide (GIP). Glucagon-like peptide-1 is secreted by L cells in the ileum in response to food intake. It has multiple actions:3,4
- Stimulates glucose-sensitive insulin release
- Stimulates glucose-sensitive glucagon suppression
- Delays gastric emptying
- Promotes satiety
- Proven to improve myocardial contractivity.5
The incretin system is impaired in individuals with type 2 diabetes, and GLP-1 therefore represents an important therapeutic target. However, endogenous GLP-1 has a very short half-life (less than 2 minutes) as it is broken down by an enzyme know as dipeptidyl peptidase-4 (DPP-4).1,3 Therapeutic efforts have relied on the development of stable variants of GLP-1 that are resistant to DPP-4 action (GLP-1 receptor agonists or incretin mimetics) or on the development of DPP-4 inhibitors.
The first GLP-1 receptor agonist to be developed was exenatide, a synthetic version of exendin-4. Exenatide has a 53% sequence identity with native GLP-1 and is given by twice-daily injections.3 The use of exenatide is covered by NICE Clinical Guideline 87 (2009).6
In clinical use, both exenatide and liraglutide have demonstrated improved glycaemic control in association with weight loss, which in some individuals, can be significant.4,6
NICE Technology Appraisal (TA) 203,4 which was published in October 2010, recommends the use of liraglutide 1.2 mg daily in triple therapy regimens (in combination with metformin and a sulfonylurea, or metformin and a thiazolidinedione) for the treatment of people with type 2 diabetes when control of blood glucose remains or becomes inadequate: this is defined as glycated haemoglobin (HbA1c) of ?7.5% (or other higher level agreed with the individual). To fulfil the criteria specified by NICE, individuals must have a body mass index (BMI) ?35 kg/m2 (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight.4
Individuals with a BMI <35 kg/m2 may also qualify for treatment if therapy with insulin would have significant occupational implications or where weight loss would benefit other significant obesity related co-morbidities.4
So far, this mirrors exactly the advice given in relation to exenatide in NICE Clinical Guideline 87.6 Where TA203 goes further is in recommending liraglutide 1.2 mg in dual therapy regimens but only if:4
- the patient is unable to tolerate either metformin or a sulfonylurea, or treatment with metformin or a sulfonylurea is contraindicated
- the patient is unable to tolerate thiazolidinediones and DPP-4 inhibitors or treatment with thiazolidinediones and DPP-4 inhibitors is contraindicated.
However, the limitations imposed on using liraglutide in this way are so strict that it renders this option almost unusable in common clinical practice, and I can only foresee this therapy being used in this context by specialists.
It should be noted that the higher dose of liraglutide (1.8 mg daily) is not recommended by NICE for the treatment of people with type 2 diabetes.4 This is despite there being the capacity to dial up to this dose in the currently available preparations and the fact that this is the dose quoted in many of the clinical trials, such as LEAD 5 (Liraglutide Effect and Action in Diabetes 5).1
Implications for primary care
Who is eligible?
When incretin mimetics were first introduced, there was a perception that they would be for secondary care use only. This perception was to some extent encouraged by those who were concerned about the cost implications of using either exenatide or liraglutide in common clinical practice. What has become clear is that both of these agents are ideally positioned for use in primary care and this has been endorsed by NICE. A closer look at the recommendations brings the realisation of how broadly the guidance can be interpreted:4
- Individuals must have ‘... specific psychological or medical problems associated with high body weight ...’ —presumably this includes anxiety, depression, low self-esteem, shyness, and embarrassment?
- And what of people with a BMI <35 kg/m2: ‘... therapy with insulin would have significant occupational implications ...’—so this would include occupational drivers, people who work at heights, work in or near water, work with gas, electricity, or hazardous substances; even people who have to drive to work
- ‘... or where weight loss would benefit other significant obesity related co-morbidities ...’ —we know that weight loss leads to reduction in blood pressure, improved glycaemic control, reduction in total cholesterol, reduction in the risk of certain cancers, and improved fitness levels. It is difficult to think of a situation where weight loss would not benefit an individual with diabetes and a co-morbidity such as hypertension, dyslipidaemia, or obstructive sleep apnoea.
Taken together, the above recommendations throw the net ever wider for which patients may receive liraglutide.
The monitoring requirements for prescribing of liraglutide (and exenatide) are a tall order: the need for a 3% weight loss and a reduction of at least 1 percentage point in HbA1c at 6 months.4 Those of us with extensive experience of liraglutide and exenatide will know that to achieve either of these requirements is perfectly possible, but that attaining both can be more problematical. Thankfully, increasing numbers of medical advisers and prescribing regulators seem to be taking a more relaxed attitude, and would be unlikely to pull the plug on a patient with a 3% weight loss and a 0.8% reduction in HbA1c, for example.
Incretin therapies are going to have a profound impact on the management of type 2 diabetes over the next few years. Longer-acting GLP-1 agonists are on the way, together with more DPP-4 inhibitors. The NICE technology appraisal on liraglutide has facilitated a practical and pragmatic approach to its use.
- Russell-Jones D, Vaag A, Schmitz O et al; on behalf of the Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met and SU study group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulphonylurea therapy in type 2 diabetes mellitus; a randomised controlled trial. Diabetologia 2009; 52 (10): 2046–2055.
- European Medicines Agency website. Victoza: liraglutide. Available at: www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001026/human_med_001137.jsp&murl=menus
/medicines/medicines.jsp&mid=WC0b01ac058001d125&jsenabled=true (accessed 10 March 2011).
- Holst J. Pharmacology of GLP-1-based therapies. Br J Diabetes Vasc Dis 2008; 8 (suppl 2): S10–S18.
- National Institute for Health and Care Excellence. Liraglutide for the treatment of type 2 diabetes mellitus. Technology Appraisal 203. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA203
- Nyström T, Gutniak M, Zhang Q et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 2004; 287 (6): E1209–E1215.
- National Institute for Health and Care Excellence. Type 2 diabetes: the management of type 2 diabetes (partial update). Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87 G