Dipeptidyl peptidase‐4 inhibitors and preservation of pancreatic islet‐cell function: a critical appraisal of the evidence

Abstract

Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.

The effect of alogliptin and pioglitazone combination therapy on various aspects of β-cell function in patients with recent-onset type 2 diabetes

“…However, it should be noted that insulin levels were reduced by ALO/PIO treatment as well, therefore making the net effect on hepatic glucose production in this study uncertain. Lowering of postprandial glucagon levels has been extensively shown following short-term and longterm treatment with DPP4 inhibitors (8), which may be attributed to increased GLP1 levels (28). Indeed, active GLP1 levels were significantly increased by treatment with ALO/PIO as was reported elsewhere (17).…”

“…This improvement in b-cell function is likely a combined effect of both ALO and PIO. DPP4 inhibitors were extensively shown to enhance static and dynamic b-cell measures, the latter including the insulinogenic index, mathematical model-derived parameters b-cell glucose sensitivity and fasting insulin secretion, and hyperglycemic clamp-measured first-phase, second-phase, and arginine-induced insulin secretion (8,23). PIO was also shown to improve model-derived parameters of b-cell function in subjects with T2DM (24) and in patients at high risk to develop T2DM (25).…”

“…In this regard, combination therapy with incretin-based therapies, i.e. either GLP1RA or DPP4 inhibitors, agents that were shown to improve a-and b-cell function in humans (8,9), and insulin sensitizing agents, such as metformin or TZDs may have synergistic, more durable, and potentially disease-modifying effects. Beside their effects on islet cell function, DPP4 inhibitors are weight-neutral and their use is associated with low hypoglycemia rates (10).…”

Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

“…Indeed, both glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors mainly target postprandial hyperglycemia by stimulating insulin-and suppressing glucagon secretion in a glucosedependent manner (12). Moreover, compounds from both classes have shown to improve various aspects of pancreatic islet-cell function in humans with type 2 diabetes (13,14). In a proof-of-principle study, i.v.…”

Dipeptidyl peptidase-4 inhibitor sitagliptin improves pancreatic β-cell function in hypertensive diabetic patients treated with angiotensin receptor blockers

“…3,4 Recently, dipeptidyl peptidase (DPP)-4 inhibitors, a novel class of oral anti-diabetic agents, have been shown not only to exert antihyperglycemic effects, but also to preserve pancreatic β-cell function in animal experiments and clinical studies. [5][6][7][8][9] Hypertensive patients often have concomitant T2DM, and diabetic hypertensive patients are more susceptible to the development of cardiovascular diseases. 10,11 Accumulating evidence indicates that treatment with angiotensin receptor blockers (ARBs) prevents the new onset of T2DM, and that ARBs exert a protective role in the development of diabetic nephropathy.…”