Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control?

Abstract

Type 2 diabetes mellitus is associated with progressive decreases in pancreatic b-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet a-and b-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve b-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.European Journal of Endocrinology 158 773-784

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

“…In patients with T2DM not well controlled on oral glucose-lowering therapies (mainly metformin and/or sulfonylurea) and compared with insulin glargine 83 , the addition of GLP1RAs showed almost similar (or better) blood glucose control but with a lower incidence of hypoglycaemia and less weight gain (conversely a significant weight loss was recorded). The combination of a GLP-1RA (mainly targeting postprandial hyperglycaemia) and basal insulin (mainly targeting fasting hyperglycaemia) may also be highly effective for optimal glucose control, while limiting weight gain, an adverse effect typically associated with insulin therapy in patients with T2DM 84 .…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…Taspoglutide is a matrix-free sustained-release formulation usable as a water-soluble application once a Drucker and Nauck (2006), , Van Gaal et al (2008), and Ahrén et al (2009) (Wettergren et al, 1993;Nauck et al, 1997;Näslund et al, 1999b) 2Food intake, 2body weight (Flint et al, 1998;Näslund et al, 1999a;Verdich et al, 2001;Zander et al, 2002) (Nauck et al, 2011). c Only animal experiments; no clinical data yet available.…”

GLP-1 receptor agonists or DPP-4 inhibitors: How to guide the clinician?

“…Nous y avons particulièrement insisté sur le fait que tenter de répondre à la question de savoir si une classe des incrétines était supérieure à l'autre était probablement vain, tant il y avait des différences entre les deux approches et tant l'hétérogénéité marquée du DT2 offrait une place de choix à l'une ou l'autre approche thérapeutique, en fonction des particularités propres au patient. 6 26,64 Cette solution est sans doute plus efficace qu'une triple thérapie orale comprenant une gliptine, chez des patients présentant par ailleurs un DT2 déjà très évolué, même si cela reste à démontrer dans un essai clinique contrôlé comparatif direct (les essais disponibles jusqu'à présent concernent des patients uniquement traités par metformine) 52,53,55,56 (Tableau 2). Elle permet également d'espérer obtenir une perte pondérale, contrairement à la prise de poids généralement observée avec l'insuline ou une glitazone.…”