Effect of the glucagon‐like peptide‐1 analogue liraglutide versus placebo treatment on circulating proglucagon‐derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial

Abstract

Aim To examine how circulating glucagon‐like peptide‐1 (GLP‐1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon‐derived peptides (PGDPs), including endogenous GLP‐1, glucagon‐like peptide‐2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control. Materials and Methods Adults who were overweight/obese (body mass index 27‐40 kg/m2) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP‐1 agonist [GLP‐1A]) and endogenous (GLP‐1E) GLP‐1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady‐state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area‐under‐the‐curve (AUC) was calculated for ISR, glucose and levels of PGDPs. Results Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean −3.6%, 95% CI [−5.2% to −2.1%]), SSPG (−32% [−43% to −22%]) and glucose AUC (−7.0% [−11.5% to −2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP‐1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = −0.54) and SSPG (r = −0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP‐1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP‐1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP‐1 receptor agonists to decrease their endogenous production in contrast to weight loss‐dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells. Conclusions Circulating GLP‐1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.

Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in the Weight Loss Among Obese Individuals: A Systematic Review

“…These side effects included nausea and vomiting [26]. Likewsie, another trial conducted by Kim et al on 35 patients for 14 weeks found the similar results in terms of weight loss [27]. More precisely, authors found that subjects randomized to intervention arm (liraglutide 1.8 mg/day) were found to have a significant reduction in mean weight: -3.6% with 95% CI of -5.2% to -2.1% when compared to the placebo [27].…”

“…The sample size of all included research studies varied between 9 and 564 with an equal distribution between patients who were and were not randomized to different treatment modalities under the umbrella of GLP-1 agonists in the RCTs. The studies were conducted mostly in developed countries such as USA (n = 4), Japan (n = 1, Europe (n = 1), Italy (n = 2), China (n = 2), Korea (n = 1), UK (n = 1), and Denmark (n = 1) (Table 3 [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]).…”

Liraglutide changes postprandial responses of gut hormones involved in the regulation of gallbladder motility

“…Other potential causes of the hormonal changes could be changes in bile acids, as both CCK and FGF19 secretion is regulated by bile acids in the intestines. Finally, GLP‐1 is shown to exercise negative feedback on secretion of GLP‐1 from the L cell, this negative feedback might also affect other products from the L cell, including GLP‐2 25,26 . We cannot exclude that liraglutide‐induced weight loss may have contributed to the changes in postprandial plasma responses of CCK, GLP‐2 and FGF19 observed in the liraglutide‐treated as compared with the placebo‐treated subjects during the meal test at steady state.…”

The molecular signaling of exercise and obesity in the microbiota-gut-brain axis

“…It was recently identified that applying subcutaneous injections of GLP-1 receptor agonist exenatide 2 mg (ExQW) once a week and over 36 weeks leads to a reduction in the total adipose tissue waist circumference of obese individuals ( 82 ). In this context, the pharmacological manipulation of GLP-1 receptor agonists as a target in taste perception and weight loss has recently emerged ( 47 , 83 ). PYY and cholecystokinin (CCK) peptides are also related to appetite control and decreased gastric secretion ( 84 , 85 ).…”