Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

Abstract

Objective:Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.Design:A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.Subjects:A total of 564 adults (n=90–98 per group; body mass index 30–40 kg m−2) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90–95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007–April 2009 and is registered with Clinicaltrials.gov, number NCT00480909.Results:From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7–8.0) more weight than those on placebo and 3.8 kg (1.6–6.0) more than those on orlistat (P⩽0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3–4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids.Conclusion:Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

“…Prior studies have shown that administration of GLP‐1 agonists has an impact on lipid homeostasis 72, 73, 74, 75. Liraglutide administration appears to have beneficial effects on plasma lipids and lipoproteins, including a reduction in total cholesterol, triglycerides, and low‐density lipoprotein cholesterol, and an increase in high‐density lipoprotein cholesterol 76, 77, 78. Moreover, we have demonstrated that intravenous lipid infusion induces ER stress in endothelial cells 41.…”

Food preferences and underlying mechanisms after bariatric surgery

“…The exaggerated release of gut hormones post RYGB has been implicated as a potential mediator of the observed changes in food preferences and weight loss. Their anorexigenic properties are already being exploited to treat obesity and gut hormones analogues are showing great promise (72)(73)(74)(75) , for example, Liraglutide 3 mg, a GLP-1 agonist, has recently been approved as an antiobesity drug in the USA and Europe. Perhaps the key to a 'medical bypass' relies on successfully mimicking the hormonal milieu of RYGB with the additive or even synergistic effects of combination gut hormones.…”

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

“…Monotherapy with liraglutide at a higher dose of 2.4-3.0 mg once a day induced significant and sustained weight loss, improved certain obesityrelated risk factors (especially blood pressure), and reduced the incidence of prediabetes and metabolic syndrome over 1-2 years 85,86 . Of interest, results were more favourable with liraglutide than with orlistat (120 mg three times a day orally) used as an active comparator.…”

“…Liraglutide 85,86 appears also to have promising effects on bodyweight in overweight/obese adults without T2DM. Monotherapy with liraglutide at a higher dose of 2.4-3.0 mg once a day induced significant and sustained weight loss, improved certain obesityrelated risk factors (especially blood pressure), and reduced the incidence of prediabetes and metabolic syndrome over 1-2 years 85,86 .…”