Future perspectives for incretin therapy
Overall incretin-based therapy represents an important addition to the conventional antidiabetic treatments for type 2 diabetes. First, these drugs provide significant improvements in glycaemic parameters by improving the function of both beta cells and alpha cells in the pancreatic islets, that is, glucose-dependent insulin enhancement and glucagon suppression. Second, the wide distribution and pleiotropic effects of GLP-1 signalling generally confers favourable effects on several of the co-morbidities of type 2 diabetes and are expected to provide reduction in cardiovascular morbidity and mortality. Several large-scaled phase 4 trials of incretin-based therapy with cardiovascular disease endpoints are ongoing and hold the promise to convey a cardiovascular risk reduction. Third, the promising preclinical effects seen on beta cell proliferation and preservation could hold true to some extent in humans too, thereby offering the potential to improve the natural history of type 2 diabetes. Nonetheless, we still need the clinical evidence that long-term treatment with incretin-based therapy will indeed attenuate the progressive nature of diabetes in humans.
The emerging GLP-1 receptor agonists, to be introduced to the market in the next years, seem to be well tolerated (with some clinical relevant differences in head-to-head trials). Nevertheless, the general, and probably limiting issue, in regard to the treatment of patients with type 2 diabetes are the gastrointestinal side-effects (nausea and diarrhoea). In spite of these side-effects being mild to moderate, transient and probably less frequent with the once-weekly GLP-1 receptor agonists compared with the GLP-1 receptor agonists currently on the market (likely because of reduced peak concentrations with the once-weekly compounds), the use will still be limited in some patients. Furthermore, the importance of antibody formation is not fully known. So far, the available data do not indicate that moderate antibody formation attenuates the clinical efficacy of the GLP-1 receptor agonists. However, patients with high titres of antibodies seem to have less benefit of their GLP-1 receptor agonists’ treatment with regard to glycaemic control compared to patients who do not develop antibodies. It seems that compounds based on the exendin-4 backbone has a tendency to induce antibody formation at higher rates compared to the compounds build on the backbone of modified human GLP-1; plausible because of the closer resemblance to native GLP-1 of the latter. So far, no safety problems have been reported with the formation of antibodies against the GLP-1 receptor agonists.
Current treatment guidelines for type 2 diabetes favour initial therapy with metformin and lifestyle intervention. However, an emerging therapeutic trend towards initial or early combination therapy with metformin and incretin-based therapy could probably gain acceptance in the short-term future because it represents a more wide attempt to target the multiple pathophysiological features of type 2 diabetes that are thought to confer increased cardiovascular disease risk. The determination of which incretin-based therapy to choose necessitates a comparison not only between the various GLP-1 receptor agonists (exenatide, exenatide-once weekly, liraglutide) as a group weighted against DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin and linagliptin). Currently, the DPP-4 inhibitors are favoured by some as initial therapy because of their lower incidence of side effects (especially nausea) and oral route of administration. On the other hand, weight loss and larger HbA1c reductions than with DPP-4 inhibitors support GLP-1 receptor agonists as the initial combination therapy with metformin.
Within the next years, the comparable efficacy especially with regard to long-term safety and cardiovascular disease risk reduction of these drug classes are expected to be clarified further. The observations that GLP-1 might improve cardiovascular function and cardiovascular disease biomarkers in humans raise great expectations for the ongoing prospective trials. Furthermore, in the next years, some other indications for incretin-based therapy could also become relevant. Importantly, an expansion of the indication to the treatment of obesity could be within reach, as exemplified by recent trials with GLP-1 receptor agonists. Finally, because of the preserving effect on beta cells (so far only in preclinical studies), incretin-based therapy may prolong the remission, reduce insulin requirements and/or the risk of hypoglycaemia in patients with type 1 diabetes.
^ Lund A, Knop FK, Vilsbøll T. Emerging GLP-1 receptor agonists. Expert Opin Emerg Drugs. 2011 Dec;16(4):607–18.
^ Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean MEJ, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. International Journal of Obesity (2005) [Internet]. 2011 Aug 16 [cited 2011 Sep 5]