A Randomized, Double-blinded, Placebo-controlled Trial of Sitagliptin for Reducing Inflammation and Immune Activation in Treated and Suppressed Human Immunodeficiency Virus Infection

Abstract

Background Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin. Methods Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/μL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15–16. Results Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/μL. At week 15–16, there was no difference in sCD14 change between the 2 arms (P = .69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, –57% to –35%) at week 15 (P < .001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated. Conclusions Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection. Clinical Trials Registration NCT01426438.

Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans

“…In contrast, administration of sitagliptin once daily for 24 weeks had no effect on numbers of CD4 + T cells, or plasma levels of RANTES and soluble TNF receptor II, despite reduction in glucose levels in HIV + subjects 57 . Similarly, 16 weeks of once daily sitagliptin therapy had no consistent effect on circulating markers of inflammation in non-diabetic subjects with HIV on stable antiretroviral therapy 58 .…”

“…DPP4 inhibitors reduce pro-inflammatory cytokine production and immune cell infiltration in multiple tissues in both animals and humans [21][22][23][24][25][26] . On the other hand, several studies failed to detect an anti-inflammatory effect of DPP4 inhibitors in animals 27 or humans 28,29 . Surprisingly, sustained inhibition of DPP4 activity in mice was associated with elevations in levels of circulating sDPP4, a molecule with proinflammatory activity 16 , without evidence for increased inflammation 17 , raising further questions about the relationships between DPP4 activity, sDPP4 and inflammation.…”

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation

“…Reproducible inflammatory phenotypes could inform clinical trials seeking to reverse chronic inflammation. To date, trials in this area of interventions such as statins, valganciclovir, dietary supplements, metformin and anti-inflammatory immunomodulatory agents have shown only modest effects [46][47][48][49][50]. One possibility is that the effects of interventions may have been limited by the heterogeneity of the patient populations, and would be enhanced when targeted towards a particular inflammatory phenotype.…”

The perceptions of natural compounds against dipeptidyl peptidase 4 in diabetes: from in silico to in vivo

“…illustrated that cardiovascular inflammation can be attenuated by DPP-4 inhibitor in the process of HIV treatment, and that leads to diminish cardiovascular morbidity of HIV treatment. 24 In T-cell activation, sDPP-4 can activate T-cell proliferation via co-stimulation with T-cell receptor (TCR) signaling and Toll-like receptor, whose activation is neither associated with its enzymatic activity nor with adenosine deaminase binding. 25–28 On the other hand, sDPP-4 can upregulate the expressions of IL-6 and TNF-α in monocyte through caveolin-1/ERK/NF-κB/c-Fos signaling, which is involved in monocyte proliferation.…”