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Introduction
Diabetes mellitus type 2 is currently a public health problem, its incidence and prevalence are increasing around the world hand in hand with obesity, especially in developing countries. Diabetes and obesity are components of the metabolic syndrome, its impact on health is substantial and include long-term complications such as cardiovascular-cerebrovascular events, renal disease and reduced expectancy and quality of life 1.
The pathophysiology includes multiple alterations and one of them is the attenuation of incretin effect that is accompanied by inappropriate levels of glucagon which contributes to chronic hyperglycemia with two different incretins: the insulinotropic polypeptide glucose-dependent (GIP) and glucagon-like peptide 1 (GLP-1), strongly involved with the glycemic balance 2.
GIP is synthesized in the duodenum and jejunum in K cells, while GLP-1 is synthesized in the L cells, in the distal ileum and the colon. After food intake, GIP and GLP-1 values increase; however, these post-prandial concentrations rapidly diminished by the enzymatic inactivation of dipeptidyl peptidase 4 (DPP4). Fasting, GLP-1 levels are between 5-10 pmol / L, reaching levels of 5-50 pmol / L during food intake 3.
Intact plasma GLP-1 and biologically active represents only 10-20% of the total 9, for this reason different strategies have been developed to overcome the barrier that involves the instantaneous inactivation of GLP-1 by the DPP-4 enzyme, as the DPP-4 inhibitors and GLP-1 receptor agonists (AR-GLP1) 4.
GLP-1 receptor is expressed in alpha islets, beta cells and peripheral tissues, including central and peripheral nervous system, heart, kidneys, lungs and gastrointestinal tract. According to its distribution and expression, GLP-1 inhibits glucose-dependent glucagon secretion, decreases emptying gastric, reduces food intake and contributes to the regulation of glucose and satiety through neural mechanisms 5.
The AR-GLP-1 are part of the glucose reducing agents associated with reduction of body weight, in addition to inhibitors of the sodium-glucose cotransporter type 2; its therapy is based on the administration of doses applied by subcutaneous injection, among which are: exenatide, LAR exenatide, lixisenatide, liraglutide and albiglutide 6.
The objective of this review is to describe the main characteristics of agonists of GLP-1 receptor in diabetes, weight control and adverse effects profile.
Methodology
A review was made about the pharmacology of peptide receptor agonists 1 like glucagon liraglutide, lixisenatide, albiglutide, exenatide, exenatide LAR in humans, in PubMed / Medline, of articles published in English or Spanish, up to January 2016. The search was made with the following MeSH terms: Diabetes, Mellitus, Type 2, Obesity. The inclusion criteria were: to describe in the title or summary pharmacology information of the peptide 1 receptor agonists and access to the full text. We excluded articles without any relation to the objectives of the review and articles without information on the pharmacology of AR-GLP1 agonists.
The identified articles were independently reviewed by two investigators. Considering the CONSORT checklist for clinical trials, the titles and abstracts of all the publications identified were reviewed, to decide their eligibility. Selected articles were analyzed jointly, and, by consensus, their inclusion was defined or not.
Generalities
The human GLP-1 receptor is a receptor coupled to G proteins, composed of 463 amino acids (7). GLP-1 stimulates adenylate cyclase and phospholipase C and, subsequently, activation of protein kinase A (PKA) and protein kinase C (PKC) that induce the proliferation of beta cells; in addition to increasing free calcium Ca2 + in pancreatic islets and cell lines 8.
To stimulate insulin secretion, GLP-1 has a synergistic action with glucose through mechanisms that involve the closure of potassium channels (K +) sensitive to ATP, resulting in depolarization of the cell membrane and increase of the intracellular Ca2 + levels. The insulinotropic effects of GLP-1 are dependent on plasma glucose concentrations 9.
The AR-GLP1 drugs impact differently the components of the dyusglycemia according to their half-life: the long-acting ones produce changes in fasting blood glucose levels with minimal or no impact on postprandial blood glucose levels; while short-acting ones have a predominant effect on the postprandial glycemia.
Exenatide
It is a synthetic analogue of exendin-4 obtained initially from saliva the Heloderma suspectum or Gila monster 11. It is composed of a chain of 39 amino acids of which 53% share with human GLP-1 12; Average life is from is 1.5 to two hours, with a duration of action of six to eight hours after of a subcutaneous injection; its administration must be twice a day 13 and it is undetectable in blood after 15 hours of administration 12.
A dose of 10 μg twice a day reduces glycosylated A hemoglobin (HbA1c) between 0.8-1.5% 14. As monotherapy achieves a reduction in weight of 3 kg at 24 weeks of treatment. In uncontrolled type 2 diabetic patients with metformin or sulfonylureas, the addition of exenatide for a period of 3 to 18 months induces a weight reduction of 1.6 to 5.3 kg. The most frequent adverse effects associated are: nausea (36 - 45%), diarrhea (12 - 16%), upper respiratory pathway infection (10 - 14%%), vomiting (11 - 12%), dizziness (4 - 9%), sinusitis (5-6%), hypoglycemia (5%) and back pain (3-6%) for doses of 5 and 10 μg 15.
Exenatide with long-acting release (LAR)
It was the first one with a weekly dosage, it contains the original active principle of exenatide encapsulated in 0.06 mm diameter microspheres 16. It has a initial release period around the second week, followed by a gradual release that generates a second peak around 6-7 weeks; after this time the average plasma concentration is approximately 300 pg / mL and is maintained at weekly dose intervals 17.
Taylor et al. in a two-year follow-up study, observed that LAR exenatide is well tolerated, in addition to having a HbA1c reduction of 1.71 ±0.08%, the change in fasting plasma glucose level is -40.1 mg / dL and the weight reduction is from 1.58 to 3.64 kg 18. The most frequent adverse events in doses of 2 mg weekly were: upper respiratory tract infection (12.5%), diarrhea (8.6%), nausea (7%); vomit (6.3%) and no major hypoglycemia is reported 19,20.
Albiglutide
It is composed of the fusion of two sequences of 30 amino acids of human GLP-1 and recombinant human albumin 21. Presents substitution of the amino acid alanine in the second position for glycine, which is where the hydrolysis is carried out by of the enzyme DPP-4. This modification confers resistance to degradation; Besides, the fusion of amino acid sequences to human albumin prolongs its average life about 5-8 days, facilitating administration once a week 22,23.
In the study by Rosenstock et al. after 16 weeks of treatment is documented a decrease of HbA1c in -0.87, -0.79, and -0.87% for 30 mg weekly, 50 mg bi-weekly, and 100 mg monthly, respectively; the observed weight decrease was from -1.1 kg to -1.7 kg. Most frequent adverse reactions are: nausea (14.3 - 54%), diarrhea (14.3 - 20.6%), vomiting (8.6 - 41.2%), abdominal pain (3.0 - 5.9%), headache (11.4%) - 23.5%), dizziness (5.7 - 14.3%), hyperglycemia (5.7 - 17.1%), hypoglycemia (2.9 - 3.1%), nasopharyngitis (5.7 - 11.4%). There is a dependent dose relationship regarding gastrointestinal reactions, the percentage of at least one adverse event was found between 68.6% and 85.3% 24.
Weissman et al. in the Harmony 4 Study report a decrease in HbA1c of 0.66% and a decrease of 1.06 ± 3.80 kg after 52 weeks of treatment with a dose of 30 mg weekly 25.
Liraglutide
Long-acting AR-GLP1 shares 96% structural similarity with human GLP-1. It was obtained by replacing the amino acid lysine at position 34 with arginine at position 26 26. It contains a side chain of C16 fatty acid that allows to prolong the duration of its action more than 24 hours; this is achieved through the reversible binding to albumin, the increase in stability through the formation of the heptameter mediated by the fatty acid chain, aggregation at the injection site and lower susceptibility to degradation by DPP -4 26,27. The pharmacokinetics of liraglutide allow its administration once a day, with an average life time of 11-15 hours 27.
The series of papers called “Effect of liraglutide and action on diabetes” (LEAD) 28,29 show that Liraglutide has a significant reduction in blood glucose with a low incidence of hypoglycaemia, a HbA1c reduction between 0.8 - 1.5%, decrease in pre-prandial glycemia up to 39 mg / dL and induction of weight reduction from 2 to 3 kg when compared with placebo. Other clinical trials like LEAD 2 (30) reports frequent gastrointestinal disorders such as nausea (11 - 19%), vomiting (5 - 7%%) and diarrhea (10,8 - 15%%) as adverse events compared to treatment with glimepiride.
Liraglutide is administered as subcutaneous injection of 0.6 mg as a dose of starting during the first week with titration to 1.2 mg the following week and, if it is well tolerated, the dose can be increased up to 1.8 mg / day 31.
Lixisenatide
It is a synthetic analog of exendin-4 in which six residues of the lysine amino acid have been added to the amidated terminal chain and the proline amino acid has been removed from its terminal chain. These modifications result in a life average of approximately three hours in humans 32.
In patients with renal insufficiency its clearance is reduced by approximately 30% (glomerular filtration rate <30 mg / dL), so adjustment of the dose in this population is required 33. In the early phase it can restore the insulin response to intravenous glucose, decrease glucagon secretion, improve systemic glucose disposal and delay gastric emptying 34.
Its application once a day (20 μg dose) in patients poorly controlled with metformin demonstrates improvement in the efficacy and tolerability ratio 35. Clinical trials such as GetGoal 33,36 show a predominant effect on postprandial glycemia with 75% reduction of excursions in standard food tests compared with placebo. This effect is expected since lixisenatide reduces gastric emptying and with an impact on body weight with reductions of 1 to 3 kg in doses of 20 mg / day. Most frequent adverse events are gastrointestinal 37-40.
Conclusions
The improvement of glycemic control and weight loss have become one of the most important objectives for new therapies in diabetes. Current evidence suggests AR-GPL1 as a group of drugs that present an acceptable pharmacodynamic profile, significant effects in the reduction of glycaemia, inhibition of gastric emptying and discrete differences are observed regarding changes in weight. Its use in obesity requires the evaluation and approval of doses for this indication. Studies are still needed to assess their long-term safety.
