|Year : 2014 | Volume
| Issue : 2 | Page : 85-88
Glucagon - like peptide-1 receptor agonists in obesity management
Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India
|Date of Submission||20-Jan-2014|
|Date of Decision||12-Mar-2014|
|Date of Acceptance||01-Apr-2014|
|Date of Web Publication||12-Jun-2014|
Department of Endocrinology, Bharti Hospital Karnal 132 001, Haryana
Source of Support: None, Conflict of Interest: None
Obesity is a fast growing pandemic, for which there are limited pharmacological options. This review describes the functional impairment of glucagon-like peptide (GLP-1) observed in obesity, and assesses the impact of the novel class of glucagon-like peptide-1 receptor agonists (GLP-1- RA) on weight. It discusses weight loss observed with GLP-1- RA use in subjects with and without diabetes, and assesses their safety and tolerability
Keywords: Diabesity, diabetes, incretins, overweight
|How to cite this article:|
Kalra S. Glucagon - like peptide-1 receptor agonists in obesity management. J Obes Metab Res 2014;1:85-8
| Introduction|| |
Obesity is a major public health challenge across the globe. Though not listed as a non-communicable disease (NCD) per se, overweight and obesity directly influence NCDs.  Diabetes mellitus, cardiovascular disease, stroke and cancer, listed as major NCDs by international and national organisations, are more common in overweight and obese, especially in South Asians.  The World Health Organisation estimates that 44% of global diabetes burden, 23% of ischemic heart disease burden, and 7-41% of certain cancers are due to overweight and obesity. 
Modest weight loss, that is 5-10% weight loss, improves metabolic function and reduces the risk of comorbid disease.  However, this is easier said than done. Limited therapeutic options are available today for obesity management; however, they have limited efficacy and/or tolerability profiles. This makes it difficult to meet the health challenge that obesity poses.
Thus, there is certainly a need to develop newer anti-obesity drugs that are safe, well-tolerated, effective, and have sustained capabilities.
| Glucagon-Like Peptide -1|| |
In recent decades, many hormones have been discovered, and implicated in the pathogenesis of obesity.  These include products of two main organ systems: The adipose tissue; and the gastrointestinal (GI) tract. One such GI hormone is glucagon-like peptide-1 (GLP-1). GLP-1 is a polypeptide which is released from the L-cells of the small intestine, in response to food intake. It acts as a satiety hormone, as well as a glucose-dependent insulinotropic agent. Since, it increases insulin secretion from the beta cells only in response to oral ingestion of meals, but not to intravenous calorie intake, it is known as an incretin hormone.
Glucagon-like peptide-1 is derived from proglucagon, which is present in the brain, pancreas and intestine. In the intestine, proglucagon is broken down by peptidase prohormone convertase (PC) 1/3, which produces GLP-1, GLP-2, and oxyntomodulin. In the central nervous system, specifically hypothalamus and caudal brain system, glycentin, oxyntomodulin, GLP-1, GLP-2, and intervening peptide-2 are produced from proglucagon, by PC 2, and PC 1/3 enzymes. The pancreas contains mainly PC 2 enzyme, which converts proglucagon to glucagon.
In the GI tract, food intake triggers a biphasic release of GLP-1. Early-phase GLP-1 secretion occurs within 10-15 min of food ingestion, and is mediated by the autonomic nervous system (parasympathetic) as well as transmitters such as gastrin-releasing peptide. Second-phase GLP-1 secretion lasts longer, peaks at 30-60 min, and is mediated through physical contact of nutrients with L-cells in the ileum and colon.
Glucagon-like peptide-1 has a very short plasma half-life of <2 min, as it is degraded by dipeptidyl peptidase-4. Majority of GLP-1 is inactivated in the intestine, portal vein and liver and only 10-15% is able to reach the pancreas. GLP-1 acts through the GLP-1 receptor, which has been found in various tissue across the body; GLP-1 receptor is a member of the B1 seven-trans-membrane G-protein-coupled receptor. 
| Weight-Related Effects Of Glucagon-Like Peptide -1|| |
Glucagon-like peptide-1 is involved in the regulation of weight by a number of mechanisms - listed in [Table 1]. While conclusive opinion may not be available for some postulated mechanisms - such as the effect of GLP-1 on resting energy expenditure and fat oxidation - the bulk of evidence clearly establishes GLP-1 as an important player in energy homeostasis.  This fact, in isolation, is not enough; however, to suggest GLP-1-mediated therapy for the management of obesity.
| Glucagon-Like Peptide-1 Functional Impairment In Obesity|| |
The preceding paragraphs have demonstrated the role of GLP-1 in energy homeostasis. Is this function impaired in obesity?
Obese subjects (with normal glucose tolerance) have been demonstrated to have a reduced incretin effect when compared with lean counterparts. They also have hyperglucagonemia, and this may be mediated through impairment of GLP-1 effect. Other researchers have calculated that incretin effect is inversely correlated with body mass index. ,
Although GLP-1 function is certainly impaired, there is inconsistency regarding GLP-1 serum concentrations in obesity. It has been suggested that L-cell responsiveness to carbohydrates is reduced in obesity; that high free fatty acids seen in obesity may inhibit GLP-1 secretion, and that leptin resistance may mediate GLP-1 penia in obesity.  Another postulate states that the impaired incretin effect noted in obesity is due to reduced GLP-1 levels, but because of impaired ί-cell sensitivity to GLP-1.  This sensing effect, in turn, may be linked with insulin resistance and lipotoxicity.  Indirect data also supports the concept of GLP-1 functional impairment as a consequence of obesity. GLP-1 levels increase following weight loss, and after bariatric surgery (Roux en-Y gastric bypass)  - this, however, may be due to altered transit of nutrients through the intestine.
In a nutshell, the impairment in GLP-1 concentrations and/or function in obesity provide a window of opportunity which can be used to create weight loss.
| Glucagon-Like Peptide-1 And Weight Loss|| |
The effects of GLP-1 infusion on appetite are well-known. Infusion of native GLP-1 causes a delay in gastric emptying, increase in the state of satiety, and reduction in postprandial glycaemia. This reduces food intake during the next meal. These effects are found in both lean and obese individuals. Therefore, GLP-1-based therapies have the potential to favourably influence weight homeostasis, and to help manage obesity. ,
| Glucagon-Like Peptide-1 Receptor Agonists|| |
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently used as drugs for the management of diabetes. They are injectable drugs that are administered subcutaneously. GLP-1- RAs can be classified according to the duration of action [Table 2].
| Glucagon-Like Peptide-1 Receptor Agonists And Weight In Diabetes|| |
Glucagon-like peptide-1 RAs are frequently used in the management of type 2 diabetes. Hence, the bulk of clinical trials using these molecules have been conducted in persons with diabetes. In two meta-analyses of GLP-1-based therapies, GLP-1- RAs was found to have beneficial effects on weight. , In one analysis of commercially available GLP-1- RAs, exenatide reduced weight by a mean of 2.03 kg, liraglutide by 2.29 kg, and exenatide extended release by 2.41 kg.  Various head-to-head studies have shown differing results in the comparative weight-lowering efficacies of liraglutide and exenatide when given once weekly. ,
Exenatide 10 mcg twice daily, in combination with lifestyle modification, has been studied in a 24-week long, randomised control trial in obese subjects without diabetes.  The exenatide group had a 1.6 kg greater weight loss than the placebo group (5.1 kg vs. 3.5 kg loss), and 32% of them were able to achieve a ≥5% weight loss, as compared with 17%, of placebo-treated subjects.
Liraglutide has been specifically studied in obese persons as a weight-reducing and weight-maintaining drug. In a 56-week long, randomised, double-blind, placebo-controlled trial, liraglutide was prescribed to persons who had achieved weight loss with a variable length (4-12 weeks) low calorie diet (1200-1400 Kcal/day) and regular exercise. Dose was up-titrated to a maximum of 3.0 mg/day. Treatment with this dose achieved an additional weight reduction of 6.1% when compared with placebo. Maintenance of a ≥5.0% weight loss was noted in 81.4% of liraglutide-treated subjects, as compared to 48.9% of placebo-treated peers. 
In another trial on obese individuals without diabetes, treatment with 3.0 mg liraglutide/day over 20 weeks resulted in greater weight loss than placebo (–4.4 kg) and orlistat (–3.0 kg). Weight loss was sustained over a period of 2 years, during which, liraglutide administration was maintained. , These data support, the use of liraglutide as an anti-obesity drug. It must be noted; however, that the maximum recommended daily dose of liraglutide is 1.8 mg as anti-diabetes drug, whereas the dose is being used as an anti-obesity intervention is 3.0 mg/day. ,, Currently, no GLP-1- RAs has regulatory approval as for management of obesity.
| Safety And Tolerability|| |
A prerequisite for any drug is that it must be safe and well-tolerated. No drug can be promoted for use if it causes unacceptable adverse effects. In general, the GLP-1- RAs are a well-tolerated class of drugs. The most frequent side-effects are GI in nature, including nausea and vomiting. These symptoms are usually mild and self-limiting, and should be explained to the patient while discussing the treatment option. Certain publications have reported that GLP-1 RAs could increase the incidence of pancreatitis, pancreatic cancer and medullary thyroid carcinoma. , However, the association seems to be unjustified or minimal. There are reports of natriuresis and renal failure with short-acting GLP-1- RAs. One should be cautious while prescribing these drugs in a setting of dehydration or renal insufficiency.
All currently available GLP-1- RAs are administered by subcutaneous injection. A different motivation strategy is required for these drugs when compared with insulin. This should include a detailed explanation of the mechanism of action, expected time frame for achievement of pre-set feasible goals, fore-warning of possible side-effects, and ways to minimize them.
| Conclusion|| |
Glucagon-like peptide-1 RAs are becoming more and more popular in diabetes management. Their use as off-label drugs for the management of obesity is already widespread, and is supported by observational studies as well as randomised controlled trials. There were concerns about their impact on pancreatic health, but these seem to have been addressed satisfactorily. The near future should see the results of large trials such as the SCALE trial,  being conducted to assess the effect of liraglutide on obesity.
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[Table 1], [Table 2]