The Holy Grail of Type II Diabetes Therapy

Type II diabetes or non-insulin dependent diabetes mellitus (NIDDM)  is a metabolic disease which is characterized by hyperglycemia resulting from insulin resistance. The incidence of Type II diabetes has risen steadily since 1960 and parallels the increase of obesity in the world population. As Type II diabetes is a metabolic disorder, it can be initially controlled by changes in diet and exercise. However, other treatment options which lower the blood sugar levels (typically by measuring the hemoglobin A1C glycation levels) are needed when this regimen is not successful. Treatment then turns to metformin as well as insulin. More recently, treatment options have increased with DPP-IV inhibitors, sulfonylureas, meglitinides and GLP-1 agonists. One of the benefits that GLP-1 agonists have over these other drugs is a lower risk of hypoglycemia.

Glucagon Like Peptide Receptor Agonists have been a hot area of research for the treatment for Type II diabetes. The first treatment approved by the FDA was for a novel peptide originally isolated from venom derived from the modified salivary glands of the Gila monster (Heloderma suspectum). This peptide, known as Exendin-4, was discovered and brought to the market by Amylin Pharmaceuticals in 2005 as Exenatide under the brand name Byetta. A longer acting form of this medication has also been approved  in 2012 called Bydureon. Both of these products are now owned and marketed  by Astra-Zeneca.

Since these initial medications, a host of other GLP-1 agonists have also been approved including Liraglutide (Victoza by Novo Nordisk) in 2010, Lixisenatide (Lyxumia by Sanofi) a hexaLys extended version of Exendin-4) in the EU in 2013, Albiglutide (Eperzam or Tanzeum by GSK) in 2014 and dulaglutide (Trulicity by Eli Lilly) also in 2014. Each of these new variants of GLP have components which extend their serum half-life by increasing their binding with human serum albumin (HSA) either directly via conjugation with HSA (dulaglutide) and albiglutide or through noncovalent means via fatty acylation (Liraglutide) or electrostatic interaction (Lixisenatide). The albumin conjugates have weekly dosing regimens versus daily injections for LiraglutideLixisenatide and Exenatide

In another interesting report, Potts, et al. (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126769) show the benefits of taking GLP-receptor agonists (Exenatide and Liraglutide)  for Type-II diabetes was also observed to have achieved significant reduction in body weight over the course of a 6 month treatment when compared to a placebo control group. In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; Exenatide 2mg/week: -1.62kg (95% CrI: -2.95kg, -0.30kg), Exenatide 20μg: -1.37kg (95% CI: -222kg, -0.52kg), Liraglutide 1.2mg: -1.01kg (95%CrI: -2.41kg, 0.38kg) and Liraglutide 1.8mg: -1.51 kg (95% CI: -2.67kg, -0.37kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.

 More recently, Novo Nordisk has published their work on refining Liraglutide into semaglutide (http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00726)   which will have weekly dosing similar to these albumin conjugates. This report describes the improvement of metabolic stability against DPP-IV as well as increasing the HSA association by development of the slightly longer fatty diacid and specialized linkage chemistry. Furthermore, they are also actively engaged in a phase III trial using an oral form of this semaglutide (http://www.reuters.com/article/2015/08/26/us-novo-nordisk-tablet-idUSKCN0QV1LA20150826). An oral GLP agonist is considered by many working in the field as the Holy Grail in this target space.

An even longer version for therapy is the recently reported trials going at Intarcia Therapeutics with ITCA-650 (http://www.intarcia.com/pipeline-technology/itca-650.html) an osmotic pump device which is implanted under the skin and delivers a constant dose of Exenatide for 1 year.

These are exciting times for those of us with expanding waist lines!

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