alogliptin and pioglitazone combination therapy improves beta-cell function in patients with recent-onset type 2 diabetes ChaPTeR 6

Context Type 2 diabetes (T2DM) management requires continuous treatment intensification due to progressive beta-cell function decline in insulin resistant individuals. Initial combination therapy of a dipeptidyl peptidase (DPP)-4 inhibitor with a thiazolidinedione (TZD) to improve both beta-cell function and insulin sensitivity may be rational. objective To assess the effects of the DPP-4 inhibitor alogliptin (ALO) combined with the TZD pioglitazone (PIO), versus ALO monotherapy or placebo (PBO), on beta-cell function and glycemic control in T2DM. Design, setting, Patients A 16-week two-center, randomized, double-blind, placebo-controlled, parallel-arm intervention study in 71 patients with well-controlled T2DM (age 59.1±6.3 years; A1C 6.7±0.1%) treated with metformin, sulfonylurea or glinide monotherapy was conducted. Intervention Combined ALO 25 mg and PIO 30 mg daily or ALO 25 mg daily monotherapy or PBO. Main outcome measures Change in A1C and fasting plasma glucose (FPG) from baseline to week 16. In addition change in parameters beta-cell function parameters obtained from standardized meal tests at baseline and week 16. Results ALO/PIO and ALO decreased A1C from baseline by 0.9±0.1% and 0.4±0.2% respectively (both P<0.001 vs PBO). FPG was decreased to a greater extent by ALO/PIO compared to ALO monotherapy (P<0.01). ALO/PIO treatment improved beta-cell glucose sensitivity (vs. PBO; P<0.001) and fasting secretory tone (vs. PBO; P=0.001), while ALO monotherapy did not change beta-cell function parameters. All treatments were well tolerated. Conclusion Short-term treatment with ALO/PIO or ALO improved glycemic control in well-controlled T2DM patients, but only combined ALO/PIO improved beta-cell function. These data support that initial combination therapy with a DPP-4 inhibitor and TZD to address multiple core defects in T2DM may be a sensible approach. Alogliptin/pioglitAzone improves betA-cell function 125 6 Type 2 diabetes mellitus (T2DM) is characterized by beta-cell dysfunction against a background of reduced insulin sensitivity (1, 2). These defects are usually present long before the presence of overt hyperglycemia (3). Over time, T2DM patients require repetitive therapy intensification as the disease progresses due to the relentless decline of beta cell function. The optimal management for hyperglycemia in T2DM patients is still under debate. Despite the availability of novel therapeutic agents, optimal glycemic control is achieved only in a minority of patients and is often of short duration (4). This may in part be due to the currently advocated treatment paradigm, which is characterized by a stepwise approach (5). After initiation of lifestyle interventions and metformin treatment, another hypoglycemic agent, classically sulfonylurea, or basal insulin is added (1). The recent position statement for hyperglycemia treatment of the ADA and EASD, however, recommends a more individualized approach after metformin failure (5). Accordingly, the current position statement allows early introduction of recently developed drugs, i.e. the thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1RA) or dipeptidyl peptidase-4 (DPP-4) inhibitors, based on assessment of individuals patientand disease characteristics in association with drugrelated properties (5). Despite this broadening of treatment options, the stepwise approach may be ineffective due to the fact that intensification is often delayed (6) and serial failures are frequently observed due to modest A1C reductions following introduction of glucose-lowering therapies after metformin therapy (7). In addition, the current treatment strategy does not address the multiple core defects of T2DM at the same time, i.e. islet-cell dysfunction, insulin resistance, impaired incretin effect and a state of low-grade inflammation. Another regimen that was proposed, but for which to date evidence is scarce, is to start aggressively, using initial combinations of different agents that address the core defects of T2DM at the same time (1, 6, 8). In this regard, combination therapy with incretin-based therapies, i.e. either GLP-1 RA or DPP-4 inhibitor, agents that were shown to improve alphaand beta-cell function in humans (9, 10), 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, DPP-4 inhibitors are weight-neutral and their use is associated with low hypoglycemia rates (11). TZDs not only enhance hepatic and peripheral insulin sensitivity, but were also shown to improve beta-cell function (12). Indeed, TZDs uniquely were shown to durably lower A1C in several studies in T2DM up to several years of treatment (1). Previously, combined DPP-4 inhibitor and TZD treatment improved glycemic control in T2DM, when used as add-on therapy (13, 14) or initial combination therapy (15, 16). However, the effects on beta-cell function of initial combined DPP-4/TZD therapy in T2DM patients have currently not been studied. In the present study we investigated the effects of initial combination therapy with the DPP4 inhibitor alogliptin (ALO) (17) and the TZD pioglitazone (PIO) on model-derived parameters of beta-