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Endocrine Disorders, Contraception, and Hormone Therapy during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Studies in women who used alogliptin during first or subsequent trimesters of pregnancy have not been published. The manufacturer reported placental transfer of alogliptin in pregnant rats. Offspring of pregnant rabbits and rats given alogliptin during the period of organogenesis alogliptin at 149 times and 180 times the usual human dose, respectively, did not have an increased frequency of congenital anomalies. Pregnant rats given up to 95 times the usual human dose reportedly did not affect embryo-fetal or postnatal development. The manufacturer also reports that this drug is classified as a pregnancy risk category B drug, but other sources quote a C risk category. The manufacturer reports alogliptin crosses the placenta. One of 18 infants born after exposure to alogliptin during the first trimester had a congenital anomaly (Benhalima et al., 2018). Notably, this birth defect was an enlarged kidney.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Alogliptin does not undergo extensive metabolism. Two minor metabolites were detected following administration of an oral dose of [14C]-alogliptin, N-demethylated alogliptin, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is a highly selective inhibitor of DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
Diabetes in Older Adults and Its Management
Published in K. Rao Poduri, Geriatric Rehabilitation, 2017
Susanne U. Miedlich, Steven D. Wittlin
A long-term study (up to 4 years) does not suggest a hazardous effect on cardiovascular outcomes, including CHF in patients treated with sitagliptin compared to placebo (98). The authors do mention a trend toward a slightly higher occurrence of pancreatitis in the sitagliptin arm, though the difference was not statistically significant (n = 23 in sitagliptin arm, n = 12 in placebo arm, p = 0.07 (98)). Another study with alogliptin reports no change in cardiovascular outcomes during follow-up of up to 2.5 years with a similar risk of hypoglycemia compared to the placebo group; no pancreatitis cases were reported (102). Further studies are underway (reviewed in Reference 103).
Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: a novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade
Published in Drug and Chemical Toxicology, 2022
Rania M. Salama, Merihane M. Nasr, Jannatullah I. Abdelhakeem, Omar K. Roshdy, Mohamed A. ElGamal
Alogliptin (Alo) is a dipeptidyl peptidase 4 (DPP-IV) inhibitor that is booming as an antidiabetic agent (Marino and Cole 2015). The enzyme, DPP-IV inactivates the incretin hormone, glucagon-like peptide 1 (GLP-1), and thus, inhibition of DPP-IV leads to enhanced and prolonged effect of GLP-1 (Sangle et al.2012). This effect is beneficial in type 2 diabetes mellitus as GLP-1 enhances insulin secretion in a glucose-dependent manner, thus avoiding hypoglycemia (Muller et al.2019). Interestingly, increased levels of GLP-1 were shown to exert counter-regulatory effects against oxidative stress and kidney inflammation (Chang et al.2015). One of the signaling cascades involved in the beneficial effect of GLP-1 was its ability to inhibit the mitogen-activated protein kinase (MAPK)/JNK pathway (Laviola et al.2012). Therefore, inhibiting this cascade through increased GLP-1 levels via gliptins can mitigate SMAD3 and c-Jun phosphorylation and activity, which may result in decreased expression of pro-fibrotic and pro-inflammatory mediators, and consequently apoptosis. However, the possible ameliorative effect of Alo against CP-induced renal inflammation has not been previously elucidated. Thus, the present research is designed to explore, for the first time, the possible therapeutic benefit of Alo against CP-induced acute kidney injury via targeting the MAP3K/JNK/SMAD3 signaling cascade, and the influence on kidney function, renal inflammation, as well as the kidney histological structure.
The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Mieke Steenbeke, Sander De Bruyne, Marc De Buyzere, Bruno Lapauw, Reinhart Speeckaert, Mirko Petrovic, Joris R. Delanghe, Marijn M. Speeckaert
In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, a case-cohort study with 3763 participants with type 2 diabetes, an independent association was found between increased plasma sRAGE concentrations and both new or worsening kidney disease and mortality over the next 5 years [141]. A Chinese study with 318 diabetic subjects and 150 healthy controls found that the highest serum sRAGE levels occurred in type 2 diabetic patients with proteinuria and observed an association between sRAGE and the severity of nephropathy. A positive correlation was seen between serum sRAGE and AGEs, although it was not known if AGEs could also directly influence sRAGE expression by alternative splicing [142]. A positive correlation was observed between plasma sRAGE concentrations and 24-h albumin excretion [143,144]. Treatment of Japanese type 2 diabetic patients with alogliptin (a dipeptidyl peptidase-4 inhibitor, 25 mg daily over 12 weeks) resulted in changes in sRAGE concentrations that were associated with changes in 1,5-anhydroglucitol, HbAlc concentrations and a reduction in albuminuria. The underlying mechanisms are still unclear. The pleiotropic effects of alogliptin may decrease serum sRAGE concentrations by improving postprandial glucose fluctuation and cumulative hyperglycemia [145].
Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan
Published in Expert Opinion on Drug Safety, 2020
Yosuke Ishida, Hiroki Murayama, Yohei Shinfuku, Tomoko Taniguchi, Takayoshi Sasajima, Naotsugu Oyama
These concerns regarding CV events were initially evaluated in the SAVOR-TIMI 53 (saxagliptin) and EXAMINE (alogliptin) trials in 2008, and then more recently in the TECOS (sitagliptin) trial [14–16]. In the SAVOR-TIMI 53 study, it was estimated that the rate of a CV event with saxagliptin treatment was similar to placebo (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.89–1.12) [14]. In the EXAMINE trial, alogliptin treatment was assessed in T2DM patients who had a high CV event risk [15]. In this study, alogliptin was not associated with an increased risk of a CV event compared with placebo (HR 0.96, 95% CI upper boundary ≤1.16). Similarly, in the TECOS trial there was no significant difference in CV event endpoints between patients receiving placebo or the DPP-4 inhibitor sitagliptin (HR 0.98, 95% CI 0.88–1.09) [16].