Dipeptidyl Peptidase-4 Inhibitors Saxagliptin Research Articles

DPP-4 Inhibitor Improved the Cognitive Function in Diabetic Rats.

Diabetes-associated cognitive dysfunction is a major problem of the international community. Dipeptidyl peptidase-4 (DPP-4) inhibitors are drugs with hypoglycemic effect widely used in diabetic treatment in clinic. In this article, we studied the effect of the DPP-4 inhibitor saxagliptin on cognitive function in diabetic rats. Firstly, to observe cognitive dysfunction caused by diabetes, we built the diabetic rat model. Subsequently, the effect of diabetes on cognitive function was evaluated by Morris Water Maze Task. Thirdly, the mechanism of the alleviation effect of DPP-4 inhibitor on cognitive dysfunction was investigated. Specifically, (1) the anti-inflammation mechanism was revealed by quantifying the accumulation of the inflammatory factor interleukin-1β (IL-1β) in the hippocampus area by western blotting and the glial fibrillary acidic protein (GFAP) by immunohistochemistry; (2) the anti-tau phosphorylation mechanism was revealed by quantifying phosphorylated tau by western blotting. This work represents the first study demonstrating the alleviation effect of DPP-4 inhibitor on cognitive dysfunction caused by diabetes. Results obtained here could be useful to seeking for a medical solution with high efficacy to the diabetes-associated cognitive dysfunction.

Glucagon-like peptide-1 attenuates diabetes-associated osteoporosis in ZDF rat, possibly through the RAGE pathway

BackgroundDiabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs.MethodsIn the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway.ResultsLiraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage .ConclusionsAltogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor.

From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management.

Aims Despite the very clear association between polycystic ovary syndrome (PCOS) and dysglycemia, few studies have explored the continuum of glycemic alterations leading from minor glucose abnormalities to overt diabetes. The purpose of this review is to trace the natural history of glycemic alteration in women with PCOS. Methods We performed a literature review without time limit until August 2019. Inclusion criteria were studies addressing the association between impaired glucose tolerance or impaired fasting glucose or type 2 diabetes (T2D) and PCOS with at least an English abstract. The exclusion criteria were no PCOS or impaired glucose tolerance or impaired fasting glucose or T2D as outcome. The outcomes of interest were the onset of impaired glucose tolerance, impaired fasting glucose, T2D, and the progression from impaired glucose tolerance or impaired fasting glucose to T2D. Results Healthy diet and physical activity are the first-line therapy for PCOS. Treatment with metformin was associated with significant lower 2-hour postload glucose levels and with reduction in fasting glucose when compared to placebo. Thiazolidinediones were more effective in reducing fasting glucose levels compared to placebo. Metformin and pioglitazone treatments showed similar effects on fasting glucose levels. The sodium-glucose cotransporter-2 inhibitor empagliflozin did not show differences in metabolic parameters when compared to metformin. The combination therapy with metformin plus the glucagon-like peptide-1 receptor agonist liraglutide was associated with significant improvements in basal and postload glucose levels compared with only liraglutide. Likewise, a combination therapy with the dipeptidyl peptidase-4 inhibitor saxagliptin and metformin demonstrated superiority versus metformin in fasting glucose and oral glucose tolerance test normalization. Myo-inositol supplementation was associated with lower insulin levels, glucose levels, and insulin resistance when compared with placebo, metformin, or estrogen treatments. Conclusions The use of insulin-sensitizing agents, such as metformin and inositols, along with lifestyle interventions may improve the metabolic profile in PCOS women.

Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes: A Prospective Multicenter Study

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function.

SAT-300 EFFECTS OF DAPAGLIFLOZIN AND DAPAGLIFLOZIN PLUS SAXAGLIPTIN ON HbA1c AND ALBUMINURIA IN PATIENTS WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE: PHASE II/III DELIGHT STUDY

Suboptimal glycemic control is often associated with albuminuria and decline in estimated GFR (eGFR) in patients with diabetic kidney disease (DKD). Sodium-glucose linked transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors have individually been shown to exert benefit on glycemic control and/or albuminuria in patients with DKD. We assessed the effects of the SGLT2 inhibitor dapagliflozin (dapa) alone and in combination with the DPP4 inhibitor saxagliptin (saxa) on albuminuria and HbA1c in patients with Type 2 diabetes and DKD.

Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial

In patients with type 2 diabetes, intensive glucose control can be renoprotective and albuminuria-lowering treatments can slow the deterioration of kidney function. We assessed the albuminuria-lowering effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin with and without the dipeptidyl peptidase-4 inhibitor saxagliptin, and the effect of dapagliflozin-saxagliptin on glycaemic control in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. In this double-blind, placebo-controlled trial (DELIGHT), we enrolled patients at 116 research centres in Australia, Canada, Japan, South Korea, Mexico, South Africa, Spain, Taiwan, and the USA. We included patients with a known history of type 2 diabetes, increased albuminuria (urine albumin-to-creatinine ratio [UACR] 30-3500 mg/g), an estimated glomerular filtration rate of 25-75 mL/min per 1·73 m2, and an HbA1c of 7·0-11·0% (53-97 mmol/mol), who had been receiving stable doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy and glucose-lowering treatment for at least 12 weeks. After a 4-week, single-blind placebo run-in period, participants were randomly assigned (1:1:1; via an interactive voice-web response system) to receive dapagliflozin (10 mg) only, dapagliflozin (10 mg) and saxagliptin (2·5 mg), or placebo once-daily for 24 weeks. Primary endpoints were change from baseline in UACR (dapagliflozin and dapagliflozin-saxagliptin groups) and HbA1c (dapagliflozin-saxagliptin group) at week 24 in all randomly allocated patients with available data (full analysis set). This study is registered with ClinicalTrials.gov, number NCT02547935 and is completed. The study took place between July 14, 2015, and May 18, 2018. 1187 patients were screened, of whom 461 were randomly assigned: 145 to the dapagliflozin group, 155 to the dapagliflozin-saxagliptin group, and 148 to the placebo group (13 patients were excluded because of data integrity issues). Dapagliflozin and dapagliflozin-saxagliptin reduced UACR versus placebo throughout the study period. At week 24, the difference (vs placebo; n=134 patients with available data) in mean UACR change from baseline was -21·0% (95% CI -34·1 to -5·2; p=0·011) for dapagliflozin (n=132) and -38·0% (-48·2 to -25·8; p<0·0001) for dapagliflozin-saxagliptin (n=139). HbA1c was reduced in the dapagliflozin-saxagliptin group (n=137) compared with the placebo group (n=118) at week 24 (-0·58% [-0·80 to -0·37; p<0·0001]). The numbers of patients with adverse events (79 [54%] in the dapagliflozin group, 104 [68%] in the dapagliflozin-saxagliptin group, and 81 [55%] in the placebo group) or serious adverse events (12 [8%], 12 [8%], and 16 [11%], respectively) were similar across groups. There were no new drug-related safety signals. Dapagliflozin with or without saxagliptin, given in addition to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, is a potentially attractive option to slow the progression of kidney disease in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. AstraZeneca.

Effects of saxagliptin on adipose tissue inflammation and vascular function in overweight and obese people: a placebo-controlled study.

To test the effect of the dipeptidyl peptidase-4 inhibitor saxagliptin on adipose tissue inflammation and microvascular function, and whole-body postprandial endothelial function. A randomized, double-blind, placebo-controlled, parallel study was conducted between June 2013 and November 2016 in 44 overweight or obese people without diabetes (saxagliptin, n=28; placebo, n=16). Subcutaneous abdominal adipose tissue biopsies, a 4-h fat-enriched meal test and peripheral arterial tonometry for measurement of endothelial function were performed at baseline and after 6 weeks of treatment with saxagliptin (5 mg/day) or matching placebo. Forty participants were analysed (saxagliptin, n=26; placebo, n=14). Secretion of interleukin-8 from adipose tissue explants was reduced after saxagliptin (median fold-change from baseline: 0.8 saxagliptin vs 3.3 placebo; P=0.02). Adipose tissue expression of thioredoxin-inhibitory protein (TxNIP) was lower after saxagliptin (0.75 vs 1.0; P=0.02), while there were no significant differences in adipose tissue secretion of interleukin-1b, interleukin-6 or macrophage chemoattractant protein 1 (MCP-1), adipose tissue macrophage content, adipose tissue mRNA levels of mcp1, cd36, cd68, il6, il8, txnip and adpq, and activation of adipose tissue inflammatory pathways [extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF- κB)] or insulin-induced vasodilation of adipose tissue arterioles. Postprandial plasma glucose was slightly lower (by an estimated 0.3 mmol/l; P=0.01), while postprandial insulin, triglyceride levels and endothelial function were unchanged after saxagliptin. The effect of saxagliptin on adipose tissue inflammation was relatively modest, with many inflammatory markers unchanged. We also found no evidence that saxagliptin therapy improved adipose tissue arteriole vasodilation or postprandial endothelial function.

The DPP-4 inhibitor saxagliptin ameliorates ox-LDL-induced endothelial dysfunction by regulating AP-1 and NF-κB

Diabetes-associated cardiovascular complications are the leading cause of death for diabetic patients. Dipeptidyl peptidase 4 (DPP-4) inhibitor agents, known as gliptins, are a class of potent anti-glycemic agents developed to treat diabetes. Recently, gliptins have been shown to have independent cardiovascular benefits. In this study, we revealed the protective role of saxagliptin in vascular endothelial cells. Our data show that saxagliptin suppresses oxidized low-density lipoprotein cholesterol (ox-LDL)-induced expression of its receptor lectin-like ox-LDL receptor-1 (LOX-1). Saxagliptin treatment reduces ox-LDL-induced production of cytokines and vascular adhesion molecules including tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), vascular cell adhesion molecule 1 (VCAM-1), and intercellular cell adhesion molecule-1 (ICAM-1). The presence of saxagliptin suppressed ox-LDL-induced adhesion of monocytes to endothelial cells in co-culture adhesion experiments. Moreover, saxagliptin mitigated ox-LDL-induced production of reactive oxygen species and suppressed elevated expression of endothelial nicotinamide adenine dinucleotide phosphate oxidase subunit (NOX-4) induced by ox-LDL. Mechanistically, saxagliptin exerted inhibitory effects against ox-LDL-induced phosphorylation of JNK kinase, expression of the activator protein 1 (AP-1) subunits c-Jun/c-fos, and AP-1 promoter activity. Saxagliptin also suppressed nuclear factor κB (NF-κB) p65 accumulation and inhibited its promoter activity. Our data elaborate the molecular mechanism of saxagliptin-mediated endothelial protection and indicate that saxagliptin could have vascular benefits independent on its anti-glycemic function.

Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases.

Nitrile group biotransformation is an unusual or minor metabolic pathway for most nitrile-containing drugs. However, for some cyanopyrrolidine dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, anagliptin, and besigliptin, but not saxagliptin), the conversion of nitrile group into carboxylic acid is their major metabolic pathway in vivo. DPP-4 was reported to be partly involved in the metabolism. In our pilot study, it was also observed that saxagliptin, a DPP-4 specific inhibitor, decreased the plasma exposures of besigliptin carboxylic acid in rats by only 20%. Therefore, it is speculated that some other enzymes may participate in nitrile group hydrolysis. After incubating gliptins with the cytosol, microsomes, and mitochondria of liver and kidney, carboxylic acid metabolites could all be formed. In recombinant DPP family such as DPP-4, DPP-2, DPP-8, DPP-9, and fibroblast activation protein-α, more hydrolytic metabolites were found. Among them, DPP-2 had the highest hydrolytic capacity besides DPP-4, and the DPP-4 inhibitor saxagliptin and DPP-2 inhibitor AX8819 can both inhibit the hydrolysis of gliptins. Western blot results showed that DPP-2 and DPP-4 existed in the aforementioned subcellular organelles at varying amounts. In rats, AX8819 decreased the plasma exposures of besigliptin carboxylic acid by 40%. The amide intermediates of gliptins were detected in vivo and in vitro. When the amide derivatives of gliptins were incubated with DPP-4, they were completely hydrolyzed at a rate far more than that from the parent drug, including saxagliptin-amide. Therefore, it was proposed that gliptins, except saxagliptin, were initially hydrolyzed to their amides by DPPs, which was the rate-limiting step in generating the carboxylic end product.

PDB15 - CARDIOVASCULAR SAFETY OF EMPAGLIFLOZIN VERSUS DIPEPTIDYL PEPTIDASE 4 (DPP-4) INHIBITORS: SYSTEMATIC LITERATURE REVIEW AND INDIRECT COMPARISONS

Clinical trials conducted in type 2 diabetes (T2DM) treated with glucose-lowering drugs and examining cardiovascular-related outcomes have yielded mixed results. In this work we aimed to assess the relative treatment effect of empagliflozin versus sitagliptin and saxagliptin (dipeptidyl peptidase 4 (DPP-4) inhibitors) on cardiovascular-related outcomes in patients with T2DM. We conducted a systematic literature review to identify clinical trials assessing cardiovascular-related outcomes for sitagliptin, saxagliptin and empagliflozin treated patients with T2DM. A network meta-analysis for indirect treatment comparison was conducted in a Bayesian framework. Hazard ratios were computed for six cardiovascular-related outcomes to estimate relative efficacy of these agents. Empagliflozin showed a statistically significant superiority over saxagliptin (HR: 0.60; 95% CrI 0.46-0.80), and sitagliptin (HR: 0.60; 95% CrI 0.46-0.79) to reduce the risk for cardiovascular-related mortality. Also for all-cause mortality, empagliflozin showed a statistically significant risk reduction compared to saxagliptin (HR: 0.61; 95% CrI 0.49-0.76), and sitagliptin (HR: 0.67; 95% CrI 0.54-0.83). A similar pattern was observed in the risk reduction for hospitalization due to hear failure, where empagliflozin was statistically significantly superior to saxagliptin (HR: 0.51; 95% CrI 0.37-0.70) and sitagliptin (HR: 0.65; 95% CrI 0.47-0.90). Empagliflozin was not statistically different to sitagliptin and saxagliptin with regard to the risk of a composite endpoint composed of death, stroke, or myocardial infarction. In this indirect comparison to the DPP-4 inhibitors saxagliptin and sitagliptin, empagliflozin significantly lowered the risk of cardiovascular-related mortality, all-cause mortality, and hospitalizations due to heart failure.

Cardiovascular Safety of Empagliflozin Versus Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in Type 2 Diabetes: Systematic Literature Review and Indirect Comparisons.

IntroductionClinical trials conducted in patients with type 2 diabetes (T2DM) treated with glucose-lowering drugs and examining cardiovascular-related outcomes have yielded mixed results. In this work, we aimed to assess the relative treatment effects of empagliflozin versus sitagliptin and saxagliptin (dipeptidyl peptidase-4 (DPP-4) inhibitors) on cardiovascular-related outcomes in patients with T2DM.MethodsWe conducted a systematic literature review to identify clinical trials assessing cardiovascular-related outcomes for sitagliptin-, saxagliptin-, and empagliflozin-treated patients with T2DM. A network meta-analysis of indirect treatment comparisons was conducted in a Bayesian framework. Hazard ratios (HR) and 95% credible intervals (CrI) were computed for six cardiovascular-related outcomes to estimate the relative efficacies of these agents.ResultsEmpagliflozin showed a statistically significant superiority over saxagliptin (HR 0.60; 95% CrI 0.46–0.80) and sitagliptin (HR 0.60; 95% CrI 0.46–0.79) to reduce the risk for cardiovascular-related mortality. For all-cause mortality, empagliflozin showed a statistically significant risk reduction compared to saxagliptin (HR 0.61; 95% CrI 0.49–0.76) and sitagliptin (HR 0.67; 95% CrI 0.54–0.83). A similar pattern was observed in the risk reduction for hospitalization due to heart failure, where empagliflozin was found to be statistically significantly superior to saxagliptin (HR 0.51; 95% CrI 0.37–0.70) and sitagliptin (HR 0.65; 95% CrI 0.47–0.90). Empagliflozin was not statistically significantly different to sitagliptin and saxagliptin with regard to the risk of a composite endpoint composed of death, stroke or myocardial infarction.ConclusionIn this indirect comparison to the DPP-4 inhibitors saxagliptin and sitagliptin, empagliflozin significantly lowered the risk of cardiovascular-related mortality, all-cause mortality and hospitalizations due to heart failure.FundingBoehringer Ingelheim GmbH.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0456-7) contains supplementary material, which is available to authorized users.

Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors.

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.

Engglis

Using the concept of inhibition of dipeptidyl peptidase-4 (DPP-4) as a new treatment for type 2 diabetes mellitus (T2DM) is based on the inhibition of bioactive peptide inactivation process. Most clinical trials on DPP-4 inhibition are based on vildagliptin, sitagliptin, saxagliptin, and linagliptin. The drugs may improve glycemic control when they are given as a combination with other oral hyperglycemic agents or when they are given to patients who received metformin and still had inadequate glycemic control. Studies showed that vildagliptin was well-tolerated if it was given as add-on treatment to metformin for 24 weeks duration. In addition, vildagliptin showed significant clinical improvement proven by the associated decrease in HbA1c and fasting glucose levels. Sitagliptin in initial combination therapy with metformin decreased HbA1c level by 2.1% after 24 weeks of treatment. It was reported that DPP-4 inhibitor saxagliptin increased glycemic control when it was added to metformin. The study included 743 patients with an average HbA1c level of 8.0% when they were treated with metformin alone. After 24 weeks of treatment, saxagliptin decreased HbA1c level by 0.7%. A multicenter, randomized, placebo-controlled, double-blind, parallel-group study examined the efficacy and tolerability of linagliptin as treatment adjunctive to metformin in patients T2DM. The primary end point was changed in HbA1c from baseline to 24 weeks of treatment. The mean adjusted change from baseline in HbA1c in the linagliptin group was 0.49% compared with an increase of 0.15% in the placebo group, with 26% and 9% of participants in the linagliptin and placebo groups, respectively, achieving an HbA1c 7.0% at 24 weeks. The combination of DPP-4 inhibitors and metformin has been shown to be well-tolerated with a very low risk of hypoglycemia. Therefore, DPP-4 inhibitors and metformin combination is an efficient, safe, and well-tolerated therapy for T2DM.

Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes

ObjectiveTo evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4)...

Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: a single-blind, randomized, pilot study

To evaluate efficacy with the dipeptidyl peptidase-4 inhibitor saxagliptin (SAXA), metformin extended release (MET), and combination (SAXA-MET) in patients with polycystic ovary syndrome (PCOS) and impaired glucose regulation. Prospective, randomized, single-blind drug study. Outpatient clinic. Patients (n = 38) with PCOS (aged 18-42years) and prediabetic hyperglycemia determined by a 75-gram oral glucose tolerance test. Patients were randomized to SAXA-MET (5mg/2,000mg), SAXA (5mg), or MET (2,000mg) for 16weeks. Fasting and mean blood glucose, insulin sensitivity, insulin secretion, and insulin secretion-sensitivity index (IS-SI) by oral glucose tolerance tests. Free androgen index and lipid levels, average menstrual interval, and anthropometric measurements (body mass index, waist circumference, and waist/height ratio). The study was completed by 34 patients. Nineteen patients had normal glucose tolerance: 3 of 12 (25%) on MET; 6 of 11 (55%) on SAXA; and 10 of 11 (91%) on SAXA-MET (SAXA-MET statistically superior to MET) at study completion. Body mass index, waist circumference, waist/height ratio, free androgen index, insulin sensitivity, IS-SI, and menses improved in all groups; however, IS-SI and menstrual regularity were significantly better with SAXA-MET vs. MET treatment. Triglyceride, triglyceride/high-density lipoprotein cholesterol ratio and mean blood glucose significantly declined in the SAXA-MET and SAXA groups only. This pilot work provides the first evidence regarding the effects of a dipeptidyl peptidase-4 inhibitor alone and in combination with MET in this patient population. Treatment with SAXA-MET was superior to either drug alone in terms of clinical and metabolic benefits in prediabetic patients with PCOS. NCT02022007.

Saxagliptin Efficacy and Safety in Patients With Type 2 Diabetes and Moderate Renal Impairment.

IntroductionType 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). The recommended dose of the dipeptidyl peptidase-4 inhibitor saxagliptin is 2.5 mg in patients with moderate or severe renal impairment (creatinine clearance ≤50 mL/min). In this post hoc analysis, we assessed the effect of saxagliptin 2.5 and 5 mg/day versus placebo on glycemic measures in patients with T2D and estimated glomerular filtration rate 45–60 mL/min/1.73 m2.MethodsEfficacy and safety data were pooled from nine 24-week, randomized, placebo-controlled clinical trials.ResultsThe majority (56–61%) of patients were women aged <65 years with glycated hemoglobin (A1C) 8.1–8.2%; half of the patients had a T2D duration ≥5 years. Mean change from baseline in A1C was significantly greater with saxagliptin 2.5 (–0.6%, P = 0.036 vs placebo) and 5 mg/day (–0.9%, P < 0.001 vs placebo) compared with placebo (–0.2%). There were numerically greater reductions in fasting plasma glucose and 2-h postprandial glucose, and a significantly greater proportion of patients achieved A1C <7% with saxagliptin 5 mg/day (44.8%) compared with placebo (20.0%, P = 0.004 vs placebo). The incidence of hypoglycemia was not significantly different across groups (16.2% in the saxagliptin 5-mg/day, 12.2% in the saxagliptin 2.5-mg/day, and 11.3% in the placebo groups).ConclusionThese results suggest that saxagliptin 2.5 and 5 mg/day improve glycemic control and are generally well tolerated in patients with T2D and moderate CKD.Trial registrationClinicalTrials.gov identifier, NCT00121641, NCT00316082, NCT00698932, NCT00918879, NCT00121667, NCT00661362, NCT00313313, NCT00295633, NCT00757588.FundingAstraZeneca, Gaithersburg, MD, USA.

Glucose-independent renoprotective mechanisms of the tissue dipeptidyl peptidase-4 inhibitor, saxagliptin, in Dahl salt-sensitive hypertensive rats

Although previous studies have shown an important role of renal dipeptidyl peptidase-4 (DPP-4) inhibition in ameliorating kidney injury in hypertensive rats, the renal distribution of DPP-4 and mechanisms of renoprotective action of DPP-4 inhibition remain unclear. In this study, we examined the effects of the DPP-4 inhibitor saxagliptin on DPP-4 activity in renal cells (using in situ DPP-4 staining) and on renal gene expression related to inflammation and fibrosis in the renal injury in hypertensive Dahl salt-sensitive (Dahl-S) rats. Male rats fed a high-salt (8% NaCl) diet received vehicle (water) or saxagliptin (12.7mg/kg/day) for 4 weeks. Blood pressure (BP), serum glucose and 24-h urinary albumin and sodium excretions were measured, and renal histopathology was performed. High salt-diet increased BP and urinary albumin excretion, consequently resulting in glomerular sclerosis and tubulointerstitial fibrosis. Although saxagliptin did not affect BP and blood glucose levels, it significantly ameliorated urinary albumin excretion. In situ staining showed DPP-4 activity in glomerular and tubular cells. Saxagliptin significantly suppressed DPP-4 activity in renal tissue extracts and in glomerular and tubular cells. Saxagliptin also significantly attenuated the increase in inflammation and fibrosis-related gene expressions in the kidney. Our results demonstrate that saxagliptin inhibited the development of renal injury independent of its glucose-lowering effect. Glomerular and tubular DPP-4 inhibition by saxagliptin was associated with improvements in albuminuria and the suppression of inflammation and fibrosis-related genes. Thus, local glomerular and tubular DPP-4 inhibition by saxagliptin may play an important role in its renoprotective effects in Dahl-S rats.

Cardiovascular outcome clinical trials in type 2 diabetes mellitus: what are the epidemiological and methodological evidence and the first evaluations to date?

Clinical trials of glucose-lowering strategies in patients with type 2 diabetes mellitus (T2DM) have shown a favorable effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular events. In 2008, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have required stringent criteria to approve new glucose-lowering drugs, demanding proof of cardiovascular safety. As a result of these regulatory requirements, a number of cardiovascular outcome trials in T2DM have been conducted examining the cardiovascular safety of novel glucose-lowering drugs. Dipeptidyl peptidase 4 (DPP4) inhibitors, analogs of glucagon-like peptide 1 (GLP-1), and inhibitors of the renal sodium-glucose linked transporter-2 (SGLT2) are new classes of glucose-lowering drugs for subjects with T2DM. The results of the cardiovascular outcome trials comparing the DPP4 inhibitors saxagliptin, alogliptin, and sitagliptin or the GLP-1 analog lixisenatide to placebo have demonstrated that these drugs are safe. The results of a cardiovascular outcome trial comparing the SGLT2 inhibitor empagliflozin to placebo have been published. Notably, empagliflozin treatment has been associated with a significant reduction in the primary composite cardiovascular outcome. Although the question regarding the positive effect of glycemic control on cardiovascular risk is still unanswered, current evidence suggests that a multifactorial approach aimed at treating not only hyperglycemia but also classical cardiovascular risk factors is necessary in order to reduce the risk of cardiovascular events in patients with T2DM.

Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes.

Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, improving glycaemic control alone has not decreased CV events. Therapies that improve glycaemic control, CV disease risk factors and CV function are more likely to be successful. Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent breakdown of incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide and improve glycaemic control in patients with T2DM. DPP-4 acts on other substrates, many associated with cardioprotection. Thus, inhibition of DPP-4 may lead to elevations in these potentially beneficial substrates. Data from animal studies and small observational studies in humans suggest that DPP-4 inhibitors may potentially reduce CV risk. However, recently completed CV outcome trials in patients with T2DM and CV disease or at high risk of adverse CV events have shown that the DPP-4 inhibitors saxagliptin and alogliptin neither increased nor decreased major adverse CV events.

Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin.

To determine the incidence of pancreatitis and pancreatic cancer in the SAVOR-TIMI 53 trial. A total of 16,492 type 2 diabetic patients ≥40 years old with established cardiovascular (CV) disease or CV risk factors were randomized to saxagliptin or placebo and followed for 2.1 years. Outcome measures were investigator reported with blinded expert adjudication of total pancreatitis (acute and chronic) and reported cases of pancreatic cancer. Trial investigators reported 35 events of pancreatitis in each treatment arm in 63 patients (33 [0.40%] in the saxagliptin arm and 30 [0.37%] in control arm), with a hazard ratio (HR) of 1.09 (95% CI 0.66-1.79, P = 0.80). Adjudication confirmed pancreatitis in 24 patients (26 events) in the saxagliptin arm (0.29%) and 21 patients (25 events) in placebo arm (0.26%), with an HR of 1.13 (0.63-2.06, P = 0.77). Cases of definite acute pancreatitis were confirmed in 17 (0.2%) vs. 9 (0.1%) (HR 1.88 [0.86-4.41], P = 0.17), definite plus possible pancreatitis in 22 vs. 16 (HR 1.36 [0.72-2.64], P = 0.42), and chronic pancreatitis in 2 vs. 6 (HR 0.33 [0.05-1.44], P = 0.18) in the saxagliptin and placebo arms, respectively. No differences in time to event onset, concomitant risk factors for pancreatitis, investigator-reported causality from study medication or disease severity, and outcome were found between treatment arms. The investigators reported 5 and 12 cases of pancreatic cancer in the saxagliptin and placebo arms, respectively (HR 0.42 [0.13-1.12], P = 0.09). In the SAVOR-TIMI 53 trial, within 2.1 years of follow-up, risk for pancreatitis in type 2 diabetic patients treated with saxagliptin was low and apparently similar to placebo, with no sign of increased risk for pancreatic cancer. Further studies are needed to completely resolve the pancreatic safety issues with incretin-based therapy.