Dipeptidyl peptidase 4 inhibitor linagliptin can decrease the dosage of erythropoiesis-stimulating agents in patients on hemodialysis
DPP4 inhibitors selectively block DPP4, increase the activity of glucagon-like peptide-1 (GLP-1), stimulate insulin secretion, and inhibit glucagon secretion. The sole use of a DPP4 inhibitor is considered to rarely induce hypoglycemia because its plasma glucose-lowering effect is dependent on the plasma glucose level. Additionally, DPP4 inhibitors improve glycemic control without increasing body weight [1]. Based on these characteristics, a DPP4 inhibitor is very useful for diabetic patients on hemodialysis. Linagliptin is mainly excreted from the body unchanged via fecal and renal excretion [8]. Janet et al. reported that in patients with T2DM and severe renal impairment, linagliptin provided clinically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, stable body weight, and no drug-related renal failure [9]. Further, it has been reported that linagliptin can be used at a regular dose in patients on hemodialysis [10].
Recently the extra-pancreatic actions of DPP4 inhibitors were indicated by many reports, including kidney and cardiovascular protection, among other effects [2–5]. Our study showed that DPP4 inhibitor linagliptin significantly reduced the dosage of DA for T2DM patients on hemodialysis with renal anemia and significantly decreased ERI as well.
The resistance to ESAs might be caused by inflammation, which has a negative effect on erythropoietin receptors [11]. In our study hs-CRP, a marker of inflammation, did not change significantly before or after treatment. Additionally, insufficient iron metabolism can cause erythropoietin-resistant anemia. However, we also observed that TSAT and ferritin remained unchanged throughout the treatment. Thus, we concluded that DPP4 inhibitor linagliptin can reduce the dosage of ESA without affecting iron metabolism or inflammation.
A previous study by Broxmeyer showed that DPP4 cleaved within the N-termini of the CSFs, GM-CSF, G-CSF, interleukin-3, and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitro and in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization, and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4?/? mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising hematopoietic stem cell function, suggesting the potential clinical utility of this approach [7].
Heather O’Leary et al. [6] suggested that DPP4 is a protease that cleaves selected amino acids at the penultimate N-terminal position and has the potential to alter protein function. Recent reports on the number of proteins that have DPP4 sites, and on how DPP4 truncation may alter hematopoiesis based on the full protein length versus the truncated state, have shown that DPP4 truncation of CSFs alters their function and that the activity of these CSFs can be enhanced when DPP4 activity is inhibited. Thus, we speculate that the DPP4 inhibitor can increase the concentration of erythropoietin by inhibiting the action of DPP4 on erythropoietin.
In this study, the number of peripheral blood cells (WBC, platelet) did not increase, because blood cells tend to remain unchanged in hemodialysis patients. The level of G-CSFs did not decrease either. Thus, we presume that this was caused by the effect of the DPP4 inhibitor on erythropoietin. However, we did not measure the serum erythropoietin concentration because erythropoietin was administrated to patients at the hemodialysis session. Thus, we have merely speculated on the possible mechanism behind the effect of DPP4 inhibitor on erythropoietin.
Terawaki et al. reported that linagliptin can decrease serum levels of oxidized low-density lipoprotein in patients with T2DM undergoing hemodialysis independent of its glucose-lowering effect [3]. Additionally, the GLP-1 receptor agonist liraglutide has been demonstrated to decrease oxidative stress independent of its glucose-lowering effect [12]. We presume that as a result of the reduction of oxidative stress, red blood cell survival may have increased, thereby improving the ERI in our study.
Our study has some important limitations. This was merely a pilot study, and thus, our study population was small and the observation period was short. The patients were not randomized to treatment, and there was no blinding in place, which limits the strength of our results, but we found an association between the DPP4 inhibitor and erythropoietin. Confirmation of our findings is required in a large-cohort, randomized, double-blind study.