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Liraglutide

A Review of its Use in Type 2 Diabetes Mellitus

Summary

Abstract

Liraglutide (Victoza®) is an acylated analogue of glucagon-like peptide-1 (GLP-1) indicated for the treatment of type 2 diabetes mellitus. In phase III studies, once-daily subcutaneous liraglutide improved glycaemic control compared with placebo or active comparator in adult patients with type 2 diabetes, both as monotherapy and in combination with one or two oral antidiabetic drugs such as metformin, sulfonylureas or thiazolidinediones. Liraglutide provided significantly better glycaemic control than rosiglitazone or insulin glargine in combination trials. At appropriate dosages, liraglutide was noninferior to glimepiride with respect to glycaemic control in a combination trial, but provided significantly better control than glimepiride or glibenclamide in monotherapy trials. Liraglutide improved pancreatic b-cell function, generally led to weight loss, and was associated with a low risk of hypoglycaemia. Liraglutide was generally well tolerated, with the most common adverse events being gastrointestinal events, such as nausea, which decreased over time. Thus, liraglutide is an effective treatment option for use in patients with type 2 diabetes mellitus.

Pharmacological Properties

Liraglutide is an acylated GLP-1 analogue that shares 97% amino acid sequence identity with native GLP-1. Liraglutide reduces both fasting and postprandial plasma glucose levels, with its effect lasting throughout a 24-hour dosing interval. It increases insulin secretion, reduces postprandial glucagon secretion, delays gastric emptying and improves b-cell function. It is also associated with a reduction in bodyweight.

Liraglutide self-associates into a heptameric structure that delays absorption from the subcutaneous injection site and slows its metabolism, giving it a prolonged elimination half-life compared with native GLP-1. The resulting pharmacokinetic profile allows for once-daily administration. The delay in gastric emptying associated with liraglutide does not cause clinically significant changes in the overall exposure to coadministered oral drugs.

Therapeutic Efficacy

In a well designed, 52-week, monotherapy trial in 746 patients with early-stage type 2 diabetes (LEAD-3), subcutaneous liraglutide 1.2 or 1.8 mg once daily improved glycaemic control (in terms of reduction from baseline in glycosylated haemoglobin [HbAlc] level) to a significantly greater extent than seen with oral glimepiride 8 mg once daily. These improvements in glycaemic control were sustained after 2 years in a 1-year, open-label extension of LEAD-3, with liraglutide remaining more effective than glimepiride. Monotherapy with subcutaneous liraglutide 0.9 mg once daily was likewise significantly more effective than glibenclamide 1.25–2.5 mg/day in reducing HbAlc and fasting plasma glucose over 24 weeks in Japanese patients.

In four large (n = 533-1087), well designed, combination therapy trials (LEAD-1, -2, -4 and -5) of 26 weeks’duration in patients with type 2 diabetes inadequately controlled on one or two oral antidiabetic drugs (OADs; glimepiride, metformin, metformin plus rosiglitazone, or metformin plus glimepiride), adjunctive therapy with once-daily subcutaneous liraglutide provided significantly better glycaemic control (reduction from baseline in HbAlc level) than seen with the addition of placebo. The combination of liraglutide 1.2 or 1.8 mg plus glimepiride provided significantly better glycaemic control than rosiglitazone 4 mg plus glimepiride (LEAD-1), while the combination of liraglutide 1.2 or 1.8 mg plus metformin was noninferior to glimepiride 4 mg plus metformin (LEAD-2). Liraglutide 1.8 mg provided significantly better glycaemic control than insulin glargine when each was added to metformin plus glimepiride (LEAD-5).

In a 26-week, open-label trial (LEAD-6; n = 464), the addition of liraglutide 1.8 mg once daily to ongoing treatment with metformin and/or a sulfonylurea improved glycaemic control to a significantly greater extent than seen with the addition of exenatide 10 mg twice daily.

Reductions in fasting and postprandial plasma glucose levels were generally consistent with the reductions in HbAlc levels. The addition of liraglutide 1.2 or 1.8 mg to OAD therapy was associated with significantly greater improvements in the proinsulin-to-insulin ratio than seen with the addition of placebo or rosiglitazone; changes in the ratio with liraglutide were not significantly different from those seen with glimepiride in monotherapy and combination trials. Changes in the homeostasis model assessment of b-cell function generally followed a similar pattern.

Bodyweight decreased significantly after the addition of liraglutide 1.2 or 1.8 mg to OAD therapy compared with the addition of placebo (in three [LEAD-2, -4 and -5] of four trials), insulin glargine or glimepiride. Bodyweight also decreased significantly with liraglutide compared with glimepiride or glibenclamide in monotherapy trials; in LEAD-3, the weight loss was sustained for up to 2 years.

Tolerability

Subcutaneous liraglutide was generally well tolerated by patients with type 2 diabetes. The most frequent adverse events experienced with liraglutide were gastrointestinal, including nausea, vomiting and diarrhoea. Nausea was reported most often during the first few weeks and generally decreased over time.

The incidence of hypoglycaemia with liraglutide was generally low. Few patients experienced major hypoglycaemic episodes, and then only in combination with glimepiride. Minor hypoglycaemia was less frequent with liraglutide than with glimepiride when given as monotherapy (LEAD-3) or when added to metformin (LEAD-2), although it was more frequent with liraglutide 1.2 and 1.8 mg than with rosiglitazone when each was added to glimepiride (LEAD-1). The incidence of minor hypoglycaemia was not significantly different for liraglutide 1.8 mg and insulin glargine when each was given in combination with metformin and glimepiride (LEAD-5), and less frequent with liraglutide 1.8 mg than exenatide when given in combination with metformin and/or a sulfonylurea (LEAD-6).

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Author information

Correspondence to Paul L. McCormack.

Additional information

Various sections of the manuscript reviewed by: B.W. Bode, Atlanta Diabetes Associates, Atlanta, Georgia, USA; R.K. Campbell, College of Pharmacy, Washington State University, Pullman, Washington, USA; D. Hinnen, Mid America Diabetes Associates, Wichita, Kansas, USA; S. Madsbad, Department of Endocrinology, University of Copenhagen, Copenhagen and Hvidovre University Hospital, Hvidovre, Denmark; G. Sesti, Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy; B.B. Yeap, School of Medicine and Pharmacology, University of Western Australia, Department of Endocrinology and Diabetes, Fremantle Hospital, Fremantle, Western Australia, Australia.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘liraglutide’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘liraglutide’ and (‘type-2 diabetes mellitus’ or ‘diabetes mellitus type 2’ or ‘non insulin dependent diabetes mellitus’). Searches were last updated 25 August 2009.

Selection: Studies in patients with type 2 diabetes mellitus who received liraglutide. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Liraglutide, glucagon-like peptide 1 analogues, GLP-1, incretin therapies, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, weight loss.

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Croom, K.F., McCormack, P.L. Liraglutide. Drugs 69, 1985–2004 (2009). https://doi.org/10.2165/11201060-000000000-00000

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Keywords

  • Metformin
  • Rosiglitazone
  • Glycaemic Control
  • Sulfonylurea
  • Liraglutide