scholarly journals Decrease in the efficacy of glucagon-like peptide-1 receptor agonists: what is the reason?

2021 ◽  
Vol 17 (8) ◽  
pp. 637-645
Author(s):  
N.M. Kushnarova ◽  
O.V. Zinych ◽  
V.V. Korpavchev ◽  
A.V. Kovalchuk ◽  
O.V. Prybyla ◽  
...  
Keyword(s):  
Glycemic Control ◽  
Cardiovascular Effects ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Incretin Mimetics ◽  
Gastrointestinal Side Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

The review deals with the drugs of a group of glucagon-like peptide-1 receptors agonists (GLP-1RA) the action of which is based on the incretin effect. In addition to insulinotropic and glucagonostatic action, GLP-1RA contributes to the improvement of glycemic control, a decrease in body weight, and also reduces cardiovascular effects in diabetic patients. The members of this group are divided into short- and long-acting preparations that is determined by their pharmacodynamic properties. Studies have shown that the long-acting GLP-1RA, which are administered once a week, demonstrate better glycemic control with a similar or less risk of the hypoglycemia and gastrointestinal side effects than their short-acting analogues. However, with long-term use of GLP-1RA, there is a reduction in the hypoglycemic action associated with a decrease in the inhibition of intestinal motility due to the phenomenon of tachyphylaxis (desensitization) of the GLP-1 receptors as a result of the vagus nerve activation. Promising means to overcome this shortcoming are considered, such as the development of modified and combined coagonists of dipeptidyl peptidase 1 receptors, as well as oral forms of GLP-1RA. In addition, we have described possible mechanisms influencing the effectiveness of GLP-1RA due to the production of antibodies to various drugs in this group, and the relationship between the effects of incretin mimetics with the state of the intestinal microbiota. In conclusion, the group of incretin-based drugs provides broad perspectives for use in type 2 diabetic patients, with the possibility of correction of both basal and prandial glycemia, and new efficient and safe forms of drugs of this group are actively creating.

scholarly journals Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients

2001 ◽  
Vol 86 (8) ◽  
pp. 3717-3723 ◽  
Author(s):  
Mai-Britt Toft-Nielsen ◽  
Mette B. Damholt ◽  
Sten Madsbad ◽  
Linda M. Hilsted ◽  
Thomas E. Hughes ◽  
...  
Keyword(s):  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Type 2 Diabetic

scholarly journals Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials

2009 ◽  
Vol 160 (6) ◽  
pp. 909-917 ◽  
Author(s):  
Matteo Monami ◽  
Niccolò Marchionni ◽  
Edoardo Mannucci
Keyword(s):  
Type 2 Diabetes ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Relevant Information ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

ObjectiveThe role of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information.Design and methodsAll available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with GLP-1 receptor agonists (exenatide and liraglutide), with a duration>12 weeks were meta-analysed for HbA1c, body mass index, hypoglycaemia and other adverse events.Results and conclusionsA total of 21 RCTs (six of which unpublished), enrolling 5429 and 3053 patients (with GLP-1 receptor agonists and active comparator or placebo respectively), was retrieved and included in the analysis. GLP-1 receptor agonists determine a significant improvement of HbA1c in comparison with placebo (−1.0 (−1.1, −0.8),P<0.001), with a low risk of hypoglycaemia. There is no evidence of increased cardiovascular risk with the use of GLP-1 receptor agonists. GLP-1 receptor agonists, which induce weight loss, are associated with gastrointestinal side effects. GLP-1 receptor agonists are effective in reducing HbA1c and postprandial glucose. In patients failing to sulphonylureas and/or metformin, GLP-1 receptor agonists are similarly effective as insulin. Available data suggest that the efficacy and tolerability of the novel agent, liraglutide, which is adequate for once-a-day administration, are comparable with those of exenatide bis in die.

Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans

1997 ◽  
Vol 273 (5) ◽  
pp. E981-E988 ◽  
Author(s):  
Michael A. Nauck ◽  
Ulrich Niedereichholz ◽  
Rainer Ettler ◽  
Jens Juul Holst ◽  
Cathrine Ørskov ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Normal Subjects ◽  
Diabetic Patients ◽  
Phenol Red ◽  
Type 2 Diabetic Patients ◽  
Liquid Meal ◽  
Healthy Humans ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulin Responses

Glucagon-like peptide 1 (GLP-1) has been shown to inhibit gastric emptying of liquid meals in type 2 diabetic patients. It was the aim of the present study to compare the action of physiological and pharmacological doses of intravenous GLP-1-(7—36) amide and GLP-1-(7—37) on gastric emptying in normal volunteers. Nine healthy subjects participated (26 ± 3 yr; body mass index 22.9 ± 1.6 kg/m2; hemoglobin A1C 5.0 ± 0.2%) in five experiments on separate occasions after an overnight fast. A nasogastric tube was positioned for the determination of gastric volume by use of a dye-dilution technique (phenol red). GLP-1-(7—36) amide (0.4, 0.8, or 1.2 pmol ⋅ kg−1 ⋅ min−1), GLP-1-(7—37) (1.2 pmol ⋅ kg−1 ⋅ min−1), or placebo was infused intravenously from −30 to 240 min. A liquid meal (50 g sucrose, 8% amino acids, 440 ml, 327 kcal) was administered at 0 min. Glucose, insulin, and C-peptide were measured over 240 min. Gastric emptying was dose dependently slowed by GLP-1-(7—36) amide ( P < 0.0001). Effects of GLP-1-(7—37) at 1.2 pmol ⋅ kg−1 ⋅ min−1were virtually identical. GLP-1 dose dependently stimulated fasting insulin secretion (−30 to 0 min) and slightly reduced glucose concentrations. After the meal (0–240 min), integrated incremental glucose ( P < 0.0001) and insulin responses ( P = 0.01) were reduced (dose dependently) rather than enhanced. In conclusion, 1) GLP-1-(7—36) amide or -(7—37) inhibits gastric emptying also in normal subjects, 2) physiological doses (0.4 pmol ⋅ kg−1 ⋅ min−1) still have a significant effect, 3) despite the known insulinotropic actions of GLP-1-(7—36) amide and -(7—37), the net effect of administering GLP-1 with a meal is no change or a reduction in meal-related insulin responses. These findings suggest a primarily inhibitory function for GLP-1 (ileal brake mechanisms).

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