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Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin.

ABSTRACT:

Introduction

Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes.

Methods

This was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18-65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period.

Results

Mean (range) baseline HbA1C was 7.4% (6.4-9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity.

Conclusion

Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.

SUBMITTER: Tatosian DA

PROVIDER: S-EPMC3889317 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:We previously reported the effect of sitagliptin or glimepiride treatment for 24 weeks on body composition in Japanese overweight and obese patients with type 2 diabetes. Although the degree of HbA1c reduction was similar between the two groups, significant reduction of intrahepatic lipid (IHL), determined by proton magnetic resonance spectroscopy (1H-MRCP), and fat mass (FM), determined by dual-energy X-ray absorptiometry (DXA), was observed in the sitagliptin group but not in the glimepiride group. As both IHL and FM are known as associating factors of insulin resistance, these reductions may lead to improvement of insulin sensitivity, which in turn may contribute to sitagliptin-induced amelioration of glycemic control. On the other hand, muscle and muscle/fat ratio were also reported to be positively correlated with insulin sensitivity, but we did not evaluate these factors. Methods:DXA separates the whole body into three major components, bone mass (BM), FM and fat and bone-free mass (FBFM), and measures the weight of each component. FBFM is normally used as a good marker of muscle mass; therefore, in this post-hoc analysis, we investigated whether sitagliptin treatment for 24 weeks influenced the FBFM and FBFM/FM ratio. Results:After 24 weeks, the FBFM and FBFM/FM ratio significantly increased in the sitagliptin group (47.6 ± 10.3 to 48.8 ± 11.0 kg, P < 0.05 and 2.0 ± 0.8 to 2.1 ± 0.8, P < 0.05), but not in the glimepiride group (49.7 ± 10.6 to 49.3 ± 9.9, P = 0.655 and 2.1 ± 0.9 to 2.0 ± 0.7, P = 0.855). The mean change of FBFM and FBFM/FM ratio from baseline to 24 weeks in the sitagliptin and glimepiride groups was 1.24 ± 2.01 (sitagliptin group) vs. -0.34 ± 2.63 kg (glimepiride group) (P = 0.074) and 0.13 ± 0.17 (sitagliptin group) vs. -0.11 ± 0.30 (glimepiride group) (P < 0.05), respectively. Conclusions:Sitagliptin 24-week treatment demonstrated not only reduction of body fat and liver fat but also an increase of muscle and muscle/fat ratio. These changes may partly explain the mechanism underlining sitagliptin-induced improvement of glycemic control.

Project description:Activation of the renin-angiotensin-aldosterone system is common in hypertension and obesity and contributes to cardiac diastolic dysfunction, a condition for which no treatment currently exists. In light of recent reports that antihyperglycemia incretin enhancing dipeptidyl peptidase (DPP)-4 inhibitors exert cardioprotective effects, we examined the hypothesis that DPP-4 inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)-induced cardiac diastolic dysfunction. Male C57BL/6J mice were infused with either Ang II (500 ng/kg/min) or vehicle for 3 weeks receiving either Saxa (10 mg/kg/d) or placebo during the final 2 weeks. Echocardiography revealed Ang II-induced diastolic dysfunction, evidenced by impaired septal wall motion and prolonged isovolumic relaxation, coincident with aortic stiffening. Ang II induced cardiac hypertrophy, coronary periarterial fibrosis, TRAF3-interacting protein 2 (TRAF3IP2)-dependent proinflammatory signaling [p-p65, p-c-Jun, interleukin (IL)-17, IL-18] associated with increased cardiac macrophage, but not T cell, gene expression. Flow cytometry revealed Ang II-induced increases of cardiac CD45+F4/80+CD11b+ and CD45+F4/80+CD11c+ macrophages and CD45+CD4+ lymphocytes. Treatment with Saxa reduced plasma DPP-4 activity and abrogated Ang II-induced cardiac diastolic dysfunction independent of aortic stiffening or blood pressure. Furthermore, Saxa attenuated Ang II-induced periarterial fibrosis and cardiac inflammation, but not hypertrophy or cardiac macrophage infiltration. Analysis of Saxa-induced changes in cardiac leukocytes revealed Saxa-dependent reduction of the Ang II-mediated increase of cardiac CD11c messenger RNA and increased cardiac CD8 gene expression and memory CD45+CD8+CD44+ lymphocytes. In summary, these results demonstrate that DPP-4 inhibition with Saxa prevents Ang II-induced cardiac diastolic dysfunction, fibrosis, and inflammation associated with unique shifts in CD11c-expressing leukocytes and CD8+ lymphocytes.