Predicting response to incretin-based therapy

Abstract

There are two important incretin hormones, glucose-dependent insulin tropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. GLP-1 appears to have a number of additional effects in the gastrointestinal tract and central nervous system. Incretin based therapy includes GLP-1 receptor agonists like human GLP-1 analogs (liraglutide) and exendin-4 based molecules (exenatide), as well as DPP-4 inhibitors like sitagliptin, vildagliptin and saxagliptin. Most of the published studies showed a significant reduction in HbA 1c using these drugs. A critical analysis of reported data shows that the response rate in terms of target achievers of these drugs is average. One of the first actions identified for GLP-1 was the glucose-dependent stimulation of insulin secretion from islet cell lines. Following the detection of GLP-1 receptors on islet beta cells, a large body of evidence has accumulated illustrating that GLP-1 exerts multiple actions on various signaling pathways and gene products in the β cell. GLP-1 controls glucose homeostasis through well-defined actions on the islet β cell via stimulation of insulin secretion and preservation and expansion of β cell mass. In summary, there are several factors determining the response rate to incretin therapy. Currently minimal clinical data is available to make a conclusion. Key factors appear to be duration of diabetes, obesity, presence of autonomic neuropathy, resting energy expenditure, plasma glucagon levels and plasma free fatty acid levels. More clinical evidence is required to identify the factors affecting response rate to incretin therapy.

The Difficulty of Diabetic Therapy: An Observational Retrospective Study from Actual Clinical Practice

“…The group of patients in therapy with GLP-1 RA was not below the target threshold for HbA1c, in contrast to other studies such as that of Pratley et al [25], in which exenatide and liraglutide improved more the glycemic control if compared to DPP-4is. In accord with Sanjay et al [26], it has revealed that the only group that achieved the therapeutic target was treated with DPP-4i but these patients presented also a significantly lower starting HbA1c than those of the other two groups. Contrarily patients treated with GLP-1 RA had the highest HbA1c mean value before treatment but they did have the best HbA1c reduction, probably because patients with a higher initial HbA1c seem to have a greater glycemic response to therapy [26][27][28].…”

“…In accord with Sanjay et al [26], it has revealed that the only group that achieved the therapeutic target was treated with DPP-4i but these patients presented also a significantly lower starting HbA1c than those of the other two groups. Contrarily patients treated with GLP-1 RA had the highest HbA1c mean value before treatment but they did have the best HbA1c reduction, probably because patients with a higher initial HbA1c seem to have a greater glycemic response to therapy [26][27][28]. Incretin-based therapy in general and GLP-1 RA in particular, are often used for obese patients, because their mechanism of action delays gastric emptying, suppresses appetite, and improves satiety.…”

The Insulin:Glucagon Ratio and the Choice of Glucose-Lowering Drugs

“…Within this group of patients, those with low glucagon values may respond better to SGLT2 inhibitors. Incretin-based therapy has been shown to be more effective in persons with high glucagon levels [ 32 ]. As these modes of treatment cause hyperinsulinemia, incretin-based therapy may prove more suitable for persons with a normal IGR.…”

Can cardiac autonomic neuropathy be a predictor of cardiovascular outcomes in diabetes?

“…This is especially true for trials involving incretin-based therapies, as their mechanism of action and response is closely linked with the autonomic nervous system. [ 16 ] This conjecture, however, is open to debate.…”