The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

Abstract

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM-exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m(2) , and patients with a BMI <35 kg/m(2) who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m(2) ) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin.

Figure 1

LEAD-5 trial: mean HbA1c change (%) from baseline over time (last observation carried forward, intention-to-treat population). *p<0.05 for liraglutide vs. insulin glargine and placebo. LEAD, liraglutide effect and action in diabetes. Reprinted with permission from Springer .

Figure 2

LEAD-5 trial: change in (A) body weight over time, and (B) body weight from baseline [mean (SD)]. Data are last observation carried forward, intent-to-treat population; *Liraglutide vs. insulin glargine (p<0.0001) and placebo (p=0.0001). SD, standard deviation; LEAD, liraglutide effect and action in diabetes. Reprinted with permission from Springer .

Figure 3

A strong relationship is evident between HbA1c and FPG reductions in clinical trials with insulin glargine [,–39].

Figure 4

LEAD-5 trial: Mean change from baseline in HbA1c (%) at Week 26 by baseline body mass index category . Subgroup analysis of the intent-to-treat, last observation carried forward population. LEAD, liraglutide effect and action in diabetes.