PharmacotherapyReview articleSaxagliptin: A Clinical Review in the Treatment of Type 2 Diabetes Mellitus
Introduction
According to the Centers for Disease Control and Prevention,1 8% of the US population has diabetes, and in 2006, diabetes was listed as the 7th leading cause of death. In 2007, the economic cost burden of diabetes in the United States was conservatively estimated at >$174 billion.2 Poorly treated hyperglycemia can lead to microvascular and macrovascular complications, including retinopathy, nephropathy, neuropathy, and cardiovascular disease. It is increasingly essential for health care providers to have an understanding of all diabetes treatment options to provide optimal care for the growing population of diabetic patients.
Unfortunately, only ∼50% of diabetic patients in the United States meet the American Diabetes Association's recommended goal for glycosylated hemoglobin (HbA1c), <7.0%.3 Conventional treatment options help to improve insulin secretion, insulin sensitivity, and excess production of hepatic glucose, yet some do not maintain normoglycemia over time when used as monotherapy.4 Some conventional therapies fail to address the progressive nature of diabetes and the pathophysiologic deterioration in β-cell function.5, 6 In addition, these therapies have been associated with an increased risk for hypoglycemia (sulfonylureas and insulin), weight gain (sulfonylureas, insulin, and thiazolidinediones [TZDs]), and gastrointestinal intolerance (metformin and α-glucosidase inhibitors), which may limit glycemic control.7
Over the past decade, antihyperglycemic therapies have been developed to target incretin hormones and their pathways. In individuals without diabetes, incretin hormones, such as glucagon-like peptide (GLP)-1, are released from the small intestine after the ingestion of a meal. In a glucose-dependent manner, GLP-1 causes insulin release from the β cells of the pancreas, decreases glucagon secretion from the α cells of the pancreas, and reduces hepatic glucose production. GLP-1 also slows gastric emptying and induces satiety.8, 9 Incretin analogues, specifically GLP-1, and agents that delay their degradation, the dipeptidyl peptidase (DPP)-4 inhibitors, offer mechanisms of action that may improve overall type 2 diabetes mellitus (T2DM) management.10, 11, 12 Much interest has also been devoted to the effects of DPP-4 inhibitors on the preservation of β-cell function.13
In May 2009, the National Institute for Health and Clinical Excellence recommended DPP-4 inhibitors for use as second-line therapy behind metformin for patients at significant risk for hypoglycemia or if a sulfonylurea is not tolerated or is contraindicated.14 Initially, the place of DPP-4 inhibitors in therapy is likely to parallel that of GLP-1 agonists (eg, exenatide, liraglutide) until more research on the potential benefits is available.7
The use of saxagliptin as monotherapy or in combination with other oral antihyperglycemic medications was approved by the US Food and Drug Administration (FDA) in July 2009 and by the European Medicines Evaluation Agency in October 2009 for the treatment of diabetes. Sitagliptin was the first agent in this class of medications to be approved by the FDA (October 2006). The combination product of sitagliptin/metformin was subsequently approved in March 2007. In November 2010, the combination product of saxagliptin/metformin was approved, and a third DPP-4 inhibitor, linagliptin, was approved in May 2011.15 Vildagliptin and alogliptin are 2 DPP-4 inhibitors that have not been approved for use in the United States.16 The use of saxagliptin in combination with insulin has not been extensively studied.17
The purpose of this review article was to discuss the mechanism of action, pharmacology, clinical efficacy, and tolerability associated with the use of saxagliptin in patients with T2DM. The potential place in therapy for saxagliptin among other oral antihyperglycemics and DPP-4 inhibitors is also discussed.
Section snippets
Materials and Methods
MEDLINE, BIOSIS, International Pharmaceutical Abstracts, and Google Scholar were searched for English-only clinical trials and therapeutic reviews published between 1966 and June 15, 2011, using the search term saxagliptin. Additional trials and reviews were identified from the reference lists of published articles.
Results
Sixty-one clinical trials and review articles were identified. Efficacy and tolerability results were obtained from 11 clinical trials of saxagliptin. Two of the 11 trials were extension studies, 1 of which was presented in abstract form.
Discussion
The DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) offer a treatment option in patients with T2DM. DPP-4 inhibitors have been reported to be efficacious when used as monotherapy and in combination with metformin, sulfonylureas, and thiazolidinediones.35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 The lack of an increased risk for hypoglycemia from the glucose-dependent mechanism of action, a generally good AE
Conclusions
Based on the findings from the studies in this review, saxagliptin is a potent and highly selective DPP-4 inhibitor associated with significant reductions in HbA1c, FPG, and PPG and with significant increases the proportions of patients achieving an HbA1c <7.0% when used as monotherapy and in combination regimens in patients with T2DM. Compared with conventional therapies, saxagliptin has been reported to be well tolerated, with a minimal risk for hypoglycemia and a neutral effect on weight.
Acknowledgments
The authors have indicated that they have no conflicts of interest with regard to the content of this article.
Ms. Kania was responsible for the abstract, clinical efficacy, discussion, and conclusions. Ms. Gonzalvo was responsible for the introduction, materials and methods, and mechanism of action. Mr. Weber was responsible for the pharmacokinetics and pharmacodynamics, special populations, drug-drug interactions, and tolerability. All authors helped with the literature search and in writing
References (73)
Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective
Metab Clin Exp
(2006)Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors
J Am Pharm Assoc
(2009)- et al.
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
Lancet
(2006) - et al.
Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?
Trends Pharmacol Sci
(2009) - et al.
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study
Clin Ther
(2006) - et al.
Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel of type 2 diabetes mellitus: an algorithm for glycemic control
Endocr Pract
(2009) DPP-4 inhibitors: what may be the clinical differentiators?
Diab Res Clin Pract
(2010)National diabetes fact sheet: general information and national estimates on diabetes in the United States
Economic costs of diabetes in 2007
Diabetes Care
(2008)- et al.
Achievement of American Diabetes Association clinical practice recommendations among US adults with diabetes, 1999–2002The National Health and Nutrition Examination Survey
Diabetes Care
(2006)
Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary report
Diabetes Care
Management of hyperglycemia in type 2 diabetes
BMJ
Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and European Association for the Study of Diabetes
Diabetes Care
DPP-4 inhibitors in clinical practice
Postgrad Med
Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes
Expert Opin Emerg Drugs
Incretin-based therapies for type 2 diabetes mellitus: current status and future prospects
Pharmacotherapy
Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus
Pharmacotherapy
Choosing among the incretin agents and why it matters
J Fam Pract
Changing the treatment paradigm for type 2 diabetes
Diabetes Care
Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes
Drug details
Onglyza (saxagliptin)
Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
J Med Chem
Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections
Drug Metab Dispos
Pharmacokinetics of dipeptidylpeptidase-4 inhibitors
Diabetes Obes Metab
Saxagliptin
Drugs
Safety, tolerability, pharmacokinetics and pharmacodynamics of once daily oral doses of saxagliptin for 2 weeks in type2 diabetic and healthy subjects
Diabetes
Saxagliptin: a new DPP-IV inhibitor for the treatment of type 2 diabetes
Adv Ther
DPP-IV Inhibitors in type 2 diabetes: importance of selective enzyme inhibition and implications for clinical use
Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidase 8 and 9
Diabetes
Effect of a high-fat meal on the pharmacokinetics of saxagliptin in healthy subjects
J Clin Pharmacol
Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin
Clin Pharmacokinet
The effects of age and gender on the single dose pharmacokinetics and safety of saxagliptin in healthy subjects
Diabetes
Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
Adv Ther
Dipeptidylpeptitase-4 inhibitors (gliptins): focus on drug-drug interactions
Clin Pharmacokinet
Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of 3 oral antidiabetic drugs (metformin, glyburide, or pioglitazone) in healthy subjects
Diabetes Obes Metab
Cited by (45)
Co-delivery of saxagliptin and dapagliflozin by electrosprayed trilayer poly (<inf>D</inf>, <inf>l</inf>-lactide-co-glycolide) nanoparticles for controlled drug delivery
2022, International Journal of PharmaceuticsSitagliptin's effects on bone tissue and osseointegration in diabetic rats
2019, Archives of Oral BiologyCitation Excerpt :Although several clinical studies found a positive influence of DPP-4 inhibition on bone fracture (Choi et al., 2016; Dombrowski, Kostev, & Jacob, 2017; Monami et al., 2011), a recent meta-analysis concluded that alogliptin may be the only drug associated with a lower risk of bone fracture among patients with type II DM when compared with placebo (Yang et al., 2017). These results show that while all DPP-4 inhibitors improve glycemic control, there may be some differences between the various drugs regarding their effects on other tissues (Evans & Bain, 2016; Kania, Gonzalvo, & Weber, 2011; Yang et al., 2017). We used the same dose (10 mg/kg) and administration period of sitagliptin from a previous study conducted by our group, in which the drug was used over a 28-day period in a periodontitis induction model in rats (Moraes et al., 2015).
Electrochemical determination of Saxagliptin hydrochloride with MWCNTs/CuO/4′aminobenzo-18-crown-6-ether composite modified carbon paste electrode
2019, Microchemical JournalCitation Excerpt :Saxagliptin (SXG) (1S,3S,5S)‑2‑[(2S)‑2‑amino‑2‑(3‑hydroxy‑1‑adamantly)acetyl]‑2‑azabicyclo [3.1.0] hexane‑3‑carbonitrile, Fig. 1 is an orally active, selective, long-acting and reversible dipeptidyl-peptidase 4 (DPP4) inhibitor that is used for the treatment of type 2 diabetes mellitus [1].
Investigation of medicinal plants from Madagascar against DPP-IV linked to type 2 diabetes
2018, South African Journal of BotanyCitation Excerpt :Incretin mimetics (exendin-4 and liraglutide) and DPP-IV inhibitors are two approaches for treatment of type 2 diabetes. Some examples of clinically used DPP-IV inhibitors are sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin (Villhauer et al., 2003; Augeri et al., 2005; Kim et al., 2005; Zerilli and Pyon, 2007; Gerich, 2010; Kania et al., 2011; Duez et al., 2012; Hung et al., 2012; Chang et al., 2013). A meta-analysis showed that DPP-IV inhibitors reduce the risk of cardiovascular diseases (Patil et al., 2012) and sitagliptin may decrease the risk of breast cancer in females with type 2 diabetes (Tseng, 2016).
Saxagliptin is similar in glycaemic variability more effective in metabolic control than acarbose in aged type 2 diabetes inadequately controlled with metformin
2015, Diabetes Research and Clinical PracticeSaxagliptin: A novel antiparkinsonian approach
2015, NeuropharmacologyCitation Excerpt :Moreover, the DPP-4 enzyme plays a pivotal role with respect to growth regulation and cytokine production (Ansorge et al., 2011). Saxagliptin (SAX), [(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile], a drug approved for the treatment of type-2 diabetes slows the rapid inactivation of GLP-1 through DPP-4 inhibition, extending the short half-life of the endogenous peptide due to the active metabolites of SAX (Kania et al., 2011). The neuroprotective effect afforded by SAX in Alzheimer's disease (AD) (Kosaraju et al., 2013) indicates that DPP-4 inhibition promises to be a novel approach for management of PD.