Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity

Abstract

The dramatic rise of the twin epidemics, type 2 diabetes and obesity is associated with increased mortality and morbidity worldwide. Based on this global development there is clinical need for anti-diabetic therapies with accompanied weight reduction. From the approved therapies, the injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only class of agents which are associated with a modest weight reduction. Physiological effects of the gastro-intestinal hormone GLP-1 are improvement of glycemic control as well as a reduction in appetite and food intake. Different approaches are currently under clinical evaluation to optimize the therapeutic potential of GLP-1 RAs directed to once-weekly up to once-monthly administration. The next generation of peptidic co-agonists comprises the activity of GLP-1 plus additional gastro-intestinal hormones with the potential for increased therapeutic benefits compared to GLP-1 RAs.

Intestinal permeation enhancers for oral peptide delivery

“…improved absorption of heparin following jejunal delivery in rats in vivo [279]. These data are not surprising as the most effective non-ionic surfactants tested in oral peptide delivery have similar hydrocarbon (C 8 -12 ) and ethoxylate ( [8][9][10][11][12][13][14][15][16][17][18][19][20] ) chain length [280]. Not all ethoxylated lipoidal vehicles alter intestinal permeability, for example, Kolliphor® EL (BASF, Germany) [281] and Cremophor® RH60 [282] are poor PEs.…”

Weight Loss Pharmacotherapy of Obese Non-Diabetic and Type 2 Diabetic Patients

“…Currently we have exenatide (exenatide and exenatide sustained release-EQW), liraglutide and lixisenatid, GLP-1 RA (except for the effect on glycaemia control also act centrally (stimulation of the nerve plexus in the digestive tract) thereby reducing partly appetite followed by reduction of the weight [17].…”

“…Both groups of anti-diabetic agents (GLP-1 RA, DPP-4 inhibitors) are very promising therapy in type 2 overweight or obese diabetic patients [17][18][19].…”

“…Addition of lixisenatide leads to improving of glycemic control and to the decrease the projected weight gain in subjects treated in combination with SU or in combination with insulin), without the risk of hypoglycemia [17].…”

Liraglutide-loaded multivesicular liposome as a sustained-delivery reduces blood glucose in SD rats with diabetes

“…Fortunately, liraglutide (a subcutaneous, once-daily GLP-1 agonist formed by adding a 16-carbon fatty acid at position 26 and replacing lysine 34 with arginine on GLP-1) was approved for clinical use in the European Union on July 2009 and in the United States on January 2010 (Russell-Jones, 2009;Ryan et al, 2011;Lorenz et al, 2013). As it is one of the latest and the most advanced drug for treating diabetes, liraglutide not only corrects the glucose metabolism disorder but also reduces the most common complications of diabetes (Astrup et al, 2009;Schwasinger-Schmidt et al, 2013;Tashiro et al,2014).…”