Inside the body with Liraglutide

Native GLP-1 has a half-life of 1.5-2 minutes because of DPP-4 and neutral endopeptidase degradation. Liraglutide is stable against both enzymes. Its once-daily profile results from self-association that delays absorption, plasma protein binding above 98%, and enzymatic stability, giving a half-life of about 13 hours after subcutaneous administration. The palmitate-gamma-Glu side chain was selected as the optimal combination for protraction.[src][src]

Liraglutide binds and activates the GLP-1 receptor, a Gs-coupled receptor that activates adenylyl cyclase and raises cAMP. It stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner, which lowers blood glucose. Consistent with this, HbA1c fell in the LEAD trials, e.g. -1.12% with liraglutide vs -0.79% with exenatide in LEAD-6.[src][src]

In rodents, peripherally administered liraglutide reaches hypothalamic regions regulating appetite. Secher et al. found fluorescently labelled liraglutide in circumventricular organs and bound to neurons in the arcuate nucleus of mice, where it was internalised in POMC/CART neurons; uptake required GLP-1R (absent in Glp1r knockout mice). In mouse brain slices, GLP-1 directly stimulated POMC/CART neurons and indirectly inhibited NPY/AgRP neurons via GABA-dependent signalling. In rats, liraglutide-dependent weight loss did not require GLP-1 receptors in the vagus nerve, area postrema or paraventricular nucleus. The FDA label notes that in rats the specific regions mediating the appetite effect were not identified. Animal-only mechanistic evidence.[src][src]

The label states that liraglutide lowers body weight through decreased calorie intake and does not increase 24-hour energy expenditure. In a randomised crossover fMRI study of 20 adults with obesity and type 2 diabetes, 10 days of liraglutide reduced responses to food pictures in insula and putamen versus insulin glargine; no differences between liraglutide and insulin glargine were observed after 12 weeks. Imaging findings are correlational and small-sample.[src][src]

Liraglutide delays gastric emptying; the label advises caution with concomitant oral medicines whose absorption may be affected. In a post-hoc analysis (research letter) of a randomised placebo-controlled trial in 67 liraglutide-treated adults with obesity, 57% developed marked delay within 5 weeks; about half of those had persistent delay at week 16 while the rest normalised (tachyphylaxis), and delay persisted in 30% of the whole group.[src][src]

In SCALE Obesity and Prediabetes (n=3,731, 56 weeks), mean weight loss was 8.4 kg with liraglutide vs 2.8 kg with placebo (difference -5.6 kg; 95% CI -6.0 to -5.1); 63.2% vs 27.1% lost at least 5% of body weight. Weight loss follows reduced calorie intake rather than increased energy expenditure.[src][src]

In LEADER (9,340 participants, median follow-up 3.8 years), the primary composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 13.0% with liraglutide vs 14.9% with placebo (HR 0.87; 95% CI 0.78-0.97; P=0.01). Cardiovascular death was 4.7% vs 6.0% (HR 0.78). The trial was not designed to establish the mechanism.[src][src]