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Introduction
Alogliptin, a highly selective and potent non-covalent inhibitor of dipeptidyl peptidase-4 (DPP-4), was developed through the approach of structure-based drug design [1]. The ubiquitous presence of DPP-4 at various sites like monocytes, macrophages, intestinal cells, kidneys, liver, pancreas, lungs, epithelial and endothelial cells implicates its biological activity [2]. DPP-4 enzyme terminates the actions of gut hormones or incretins like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Deactivation of DPP-4 limits the incretin metabolism, to prolong its effects. This promotes insulin secretion and release and decreases glucagon secretion, which together regulates glucose metabolism [3, 4]. Alogliptin has a 14,000-fold higher selectivity for DPP-4 than other similar proteases such as DPP-8/DPP-9 [5]. It improves the β-cell functioning in type 2 diabetes mellitus (T2DM) [6]. The drug is approved in three different forms for treating T2DM by the US Food and Drug Administration (FDA). These forms include alogliptin alone, and in combination with pioglitazone or metformin. The available doses are 6.25 mg, 12.5 mg and 25 mg. A 0.4–1.0% reduction in HbA1c (glycosylated hemoglobin A1c) has been observed with monotherapy of alogliptin after 26 weeks of treatment [7]. The glucose regulatory effect of alogliptin is majorly via GLP-1. Alogliptin 0.03% in diet stimulated phosphorylation of CREB (cAMP-response element binding protein) in pancreatic β-cells. CREB signaling induces Bcl-2 (B- cell lymphoma) and BIRC3 (Baculoviral IAP repeat containing 3), a caspase protein, and exerts anti-apoptotic effects that in turn signal insulin receptors to release insulin [8].
Alogliptin affects several signaling mechanisms that enabled researchers to exploit its effects on pathologies related to other organ systems [9]. FDA adverse event reporting system (FAERS) reported that lesser side effects associated with alogliptin in comparison with other anti-diabetics between 2006 and 2020. Bullous pemphigoid, an autoimmune skin condition, is reported after long-term therapy in elderly patients [10]. FAERS algorithms for signal detection also documented concerns of pancreatic carcinoma with alogliptin [11]. Alogliptin therapy is cost-effective for the health care system as it minimizes cost and generates savings in patients with long-term use [12, 13].
In the present review, the recent advances in preclinical and clinical development of alogliptin are discussed. We put forward the beneficial role on other organ systems via several proteins and signaling mechanism as targets. The protective effects...