This multicenter study compared the efficacy and safety of once-weekly exenatide and once-daily liraglutide in 912 patients with type 2 diabetes over 26 weeks. Liraglutide treatment resulted in greater reduction in HbA1c and more patients achieving HbA1c under 7% compared to exenatide. Common side effects like nausea and diarrhea were more frequent with liraglutide. Both medications similarly reduced other biomarkers. Adverse effects were generally mild and short-lived, with 5% of liraglutide patients and 3% of exenatide patients discontinuing treatment.

1. This multicenter study [ClinicalTrials.gov, number NCT01029886] evaluated the safety
and efficacy of once-weekly subcutaneous administration of exenatide (2 mg) and once-daily
subcutaneous administration of liraglutide (titrated to 1.8 mg) in 912 patients with type 2
diabetes. The primary endpoint of the study was change in HbA1c from baseline to week 26.
Once-daily liraglutide treatment resulted in greater reduction in HbA1c (-1.48%, SE 0.05;
n=386) than once-weekly exenatide (-1.28%, 0.05; n=390). The treatment difference did not
meet the predefined non-inferiority criteria. The most common adverse effects were nausea (21%
liraglutide / 9% exenatide), diarrehea (13% liraglutide / 6% exenatide) and vomitting (11%
liraglutide / 4% exenatide) with gastrointestinal adverse events decreasing in both groups over
the study duration.
Although once daily liraglutide treatment led to more frequent gastrointestinal adverse events, its
administration (1.8mg) resulted in greater reduction of glycated hemoglobin (HbA1c). Week 26
change in HbA1c was greater in patients taking liraglutide (p=0.0271). Overall, in patients
receiving liraglutide treatment 60% of patients achieved a HbA1cof less than 7% (53 mmol/mol;
p=0.0011), compared to 53% of patients receiving exenatide. Patients taking liraglutide lost more
weight irrespective of body-mass index. Decrease in blood pressure and other cardiovascular
biomarkers, including lipids, C-reactive protein, and brain natriuretic peptide, was comparable
for both treatment groups at endpoint. No difference was observed between liraglutide and
exenatide improvement of mean DMSAT and PHQ-8 total scores (p<0.0001). Adverse effects
were more frequent among patients in the liraglutide group, but subsided shortly after regiment
start resulting in 5% of liraglutide patients and 3% of exenatide patients discontinuing treatment.
Two patients from each treatment group died (suicide, cerebrovascular accident, pulmonary
embolism, and sudden death).
When type 2 diabetes patients do not achieve the desired clinical response with oral
antihyperglycemic drugs, differences between the clinical efficacy of injectable once-weekly
exenatide and once-daily liraglutide, together with adverse-event analysis, can be used by
clinicans during treatment decision-making. Both, exenatide and liraglutide (glucagon-like-1
receptor agonists / GLP-1) were previously reported to reduce bodyweight and improve glycemic
control. This class of antihyperglycemic drugs broadly affects glucoregulatory actions by
stimulating glucose-dependent insulin secretion, reducing glucagon secretion, controlling food
intake and slowing gastric emptying.
Both medications, exenatide and liraglutide have similar mechanisms of action. Exenatide is a
renal excreted synthetic form of exendin-4 capable of stimulating GLP-1 receptors, while
resisting degradation by dipeptidyl peptidase-4 (DPP-4). Exenatide, once released (median half-
life of 2-weeks), improves plasma glucose within 2 weeks and reaches steady-state
concentrations in 6-10 weeks. Liraglutide is a naturally metabolizable analogue of human
GLP-1 with a single amino acid substitution (Arg34Lys) and a C-16 palmitic acid side chain,
incorporated using a glutamyl spacer. Molecular modifications of this naturally occurring agonist
result in slow absorption and resistance to degradation by DDP-4. Liraglutide reaches maximum
concentration within 10-14 hours post administration with a median half-life of 13 hours.

2. All data was stratified by concomitant treatments (sulfonylurea), initial HbA1c screening (<9.0%
and ≥9.0%, [<75 mmol/mol and ≥75 mmol/mol]) and nationality. Resulting HbA1c stratum data
was analyzed using least-squares difference approach. Resulting continuous data was analyzed
using maximum likelihood- based mixed-model repeated measures (MMRM) statistical
approaches implemented in SAS and adjusted for treatment, baseline, HbA1cstratum, country,
oral antihyperglycaemic status and treatment date. Treatment-by-week interaction were treated as
fixed effects, and patient as a random effect. Incidence of adverse effects were summarized in
two week intervals.
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