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Endocrine Disorders, Contraception, and Hormone Therapy during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
No controlled trials in pregnant women are published, and clinical experience with this drug in pregnancy has not been reported. Based solely upon animal studies in rats and rabbits that were negative, the FDA pregnancy risk category assigned is B. Placental transfer of saxagliptin has not been studied, but based upon its molecular weight, lack of protein binding and terminal half-life, it is expected to cross the placenta. First trimester exposure to saxagliptin was reported in 15 pregnancies, but outcomes were available for only two infants (Benhalima et al., 2018); one elective termination and one healthy infant, who were normal.
Athletes with Chronic Conditions
Published in Flavia Meyer, Zbigniew Szygula, Boguslaw Wilk, Fluid Balance, Hydration, and Athletic Performance, 2016
Jane E. Yardley, Michael C. Riddell
Several medications prescribed for type 2 diabetes have side effects that may interfere with hydration and electrolyte balance. Metformin, a common oral antidiabetic drug that interferes with gluconeogenesis, has been associated with gastrointestinal upset and diarrhea (Rx files 2013), which can lead to dehydration and potentially a depletion in potassium levels. Acarbose, another antidiabetic drug, decreases the rate of absorption of glucose from the intestines, but is also associated with a risk of diarrhea and subsequently dehydration when taken at higher dosages (Rx files 2013). Pioglitozone, an antihyperglycemic drug often prescribed to individuals with type 2 diabetes, is associated with a dose-related risk of peripheral edema (Rx files 2013). Similarly, the antidiabetic drugs sitagliptin and saxagliptin have an associated risk of diarrhea and vomiting which can negatively impact hydration and increase the risk of hypokalemia (Rx files 2013).
Managing Diabetes without Weight Gain
Published in David Heber, Zhaoping Li, Primary Care Nutrition, 2017
Glucagon-like peptide 1 (GLP-1) and its analogs reduce glucose levels via a glucose-linked enhancement of insulin secretion; this was first observed when it was noted that oral glucose stimulated insulin secretion to a greater extent than intravenous insulin due to gastrointestinal hormones called incretins. The short half-life of 1–2 minutes of native GLP-1 due to rapid degradation by the enzyme dipeptidyl peptidase 4 (DPP-4) led to the search for GLP-1 analogs and DPP-4 inhibitors. Exendin-4 was isolated from the salivary gland venom of the Gila monster reptile (Heloderma suspectum). Xenatide, a synthetically produced form of exendin-4, was the first GLP-1, in 2005. A second GLP-1 receptor agonist, liraglutide, was approved in 2010, which is modified to be long acting. In 2012, a long-acting form of exenatide that could be administered weekly was approved. Weight loss is one advantage of treatment with incretin-based agents. However, these compounds can cause significant gastrointestinal side effects, particularly early in therapy, and concerns about associations between GLP-1 receptor agonists and pancreatitis are ongoing. They are also expensive and injectable. The first DPP-4 inhibitor, called sitagliptin, could be taken orally and acted by prolonging the circulating half-life of GLP-1. It was approved in 2006 and followed by the release of saxagliptin and linagliptin. Alogliptin was approved by the Food and Drug Administration (FDA) in 2013. Vildagliptin has been approved for use in Europe but is not available in the United States. DPP-4 inhibitors are weight neutral and do not tend to cause hypoglycemia (White 2014). However, pancreatitis has been reported in patients treated with DPP-4 inhibitors (Quianzon and Cheikh 2012).
The protective effects of saxagliptin against lipopolysaccharide (LPS)-induced inflammation and damage in human dental pulp cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Bacterial penetration has been reported as an important risk factor of pulp inflammation, necrosis and periapical pathosis [21]. LPS, the main component of the outer membrane of Gram-negative bacteria, plays a key role in bacteria-induced dental pulp inflammation and pulpitis [22]. Saxagliptin is an important DPP-4 inhibitor and an anti-diabetic agent approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of type 2 diabetes [23]. The effects of saxagliptin in pulpitis and HDPCs have not been reported before. In this study, we report, for the first time, that treatment with saxagliptin protected HDPCs against LPS-induced insults. First, we found that DPP-4 is expressed in HDPCs and the expression of which is upregulated in response to LPS treatment. Second, our results indicate that saxagliptin treatment ameliorated LPS induced oxidative stress and mitochondrial dysfunction. Third, our findings demonstrate that saxagliptin treatment attenuated LPS-induced cell death of HDPCs. Fourth, we show that saxagliptin treatment reduced LPS-induced production of TNF-α, IL-1β and IL-8. Mechanistically, we found that saxagliptin treatment inhibited the activation of p38 and NF-κB signalling pathway.
An update on therapies for the treatment of diabetes-induced osteoporosis
Published in Expert Opinion on Biological Therapy, 2019
Sahar Mohsin, May MYH Baniyas, Reem SMH AlDarmaki, Kornélia Tekes, Huba Kalász, Ernest A. Adeghate
Dipeptidyl peptidase 4 (DPP-4), a ubiquitous enzyme, located on the plasma membrane of osteoblast, osteoclast and osteocyte, has been implicated in the regulation of collagen synthesis [114]. The conclusion on the effect of DPP4 inhibitors on osteoporosis has not been conclusive. Some reports have indicated that vildaglitin has no effects whatsoever on bone structure and function in osteoporosis after one year of treatment [115]. In contrast, a meta-analysis of 28 clinical trials showed that DPP-4 inhibitors improve bone health [116]. Since DPP-4 inhibitors increase the pool of incretins, which has an anabolic effect of bone, it is possible that DPP-4 inhibitors, when used in the right form, dosage and duration, would promote bone health in osteoporotic patients. In fact, in a meta-analysis of 28 clinical trials involving a cohort of 11,880 patients with more than 9,000 on DPP-4 inhibitors, it was concluded that DPP-4 inhibitors could be associated with a reduced bone fracture risk [116]. The authors, however, agreed that the conclusion has to be treated carefully because of the short duration (~24 weeks) of most of the trials. In contrast to some beneficial effect of DPP-4 on bone health, saxaglitpin reduced osteoblast number and osteocytic density in metaphyseal trabecular bone of rats [117]. Overall, many reports showed that the majority of DPP‐4 inhibitors have neutral and/or beneficial effects on skeletal bone. However, a large variety of effects were reported for sitagliptin and saxagliptin. For example, saxagliptin has a harmful effect on bone health [118] (Table 5).
Concordance with prescribing information dosage recommendations for dipeptidyl-peptidase-4 inhibitors among type 2 diabetes mellitus patients with moderate to severe chronic kidney disease
Published in Current Medical Research and Opinion, 2018
Huan Huang, Sharash Shetty, Elise Bauer, Kathleen Lang
Dipeptidyl-peptidase-4 inhibitors (DPP4-is) have become an important drug class in their oral dosage form for the treatment of T2DM as second-line therapy after metformin failure or as monotherapy or combination therapy with other drugs when metformin is not tolerated or is contraindicated8,9. Some DPP4-i medications require dosage adjustments with declining renal function. Metabolism is a minor elimination pathway of sitagliptin, as almost 80% of an administered dose is eliminated unchanged in the urine10. The elimination half-life (t1/2) of sitagliptin progressively increases as renal function declines10. Therefore, sitagliptin dose adjustments are recommended for patients with moderate CKD (50 mg daily, defined in the prescribing information [label] as creatinine clearance [CrCl] ≥ 30 to <50 ml/min) or severe CKD or end stage renal disease (ESRD) (25 mg daily, CrCl <30 ml/min) to provide plasma sitagliptin exposure comparable to that of patients with normal renal function (100 mg daily)10. Similarly, t1/2 of saxagliptin progressively increases as renal function declines. Consequently, one half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate or severe CKD or ESRD on haemodialysis10. In contrast, linagliptin is predominantly eliminated by a hepatobiliary route. Therefore, it can be used in all stages of CKD without dose adjustment10.