Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes.
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SUBMITTER: Ott C
PROVIDER: S-EPMC3897922 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes.
Ott Christian C Raff Ulrike U Schmidt Stephanie S Kistner Iris I Friedrich Stefanie S Bramlage Peter P Harazny Joanna M JM Schmieder Roland E RE
Cardiovascular diabetology 20140114
<h4>Background</h4>Patients with diabetes mellitus are at increased risk for microvascular complications. Early changes in microcirculation are characterized by hyperperfusion (e.g. in the retina and kidney) and increased pulse wave reflection leading to increased aortic pressure. We investigated the effects of the DPP-4-inhibitor saxagliptin on early retinal microvascular changes.<h4>Methods</h4>In this double-blind, controlled, cross-over trial 50 patients (without clinical signs of microvascu ...[more]
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Project description:Aims/hypothesisThe study aimed to assess the usefulness of capillaroscopy and photoplethysmography in the search for early vascular anomalies in children with type 1 diabetes.MethodsOne hundred sixty children and adolescents aged 6-18, 125 patients with type 1 diabetes, and 35 healthy volunteers were enrolled in the study. We performed a detailed clinical evaluation, anthropometric measurements, nailfold capillaroscopy, and photoplethysmography.ResultsPatients with diabetes had more often abnormal morphology in capillaroscopy (68.60%, p = 0.019), enlarged capillaries (32.6%, p = 0.006), and more often more over five meandering capillaries (20.90%, p = 0.026) compared to healthy controls. Meandering capillaries correlated with higher parameters of nutritional status. In a photoplethysmography, patients with diagnosed neuropathy had a higher percentage of flow disturbance curves (p < 0.001) with a reduced frequency of normal curves (p = 0.050).ConclusionsCapillaroscopic and photoplethysmographic examinations are non-invasive, painless, fast, and inexpensive. They are devoid of side effects, and there are no limitations in the frequency of their use and repetition. The usefulness of capillaroscopy and photoplethysmography in the study of microcirculation in diabetic patients indicates the vast application possibilities of these methods in clinical practice.
| S-EPMC10590527 | biostudies-literature
Project description:Saxagliptin (Onglyza™) is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D). By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower blood glucose. In controlled clinical trials, saxagliptin administered as monotherapy or in combination with metformin, glyburide, or a thiazolidinedione improved glycemic control in a clinically significant manner, reflected by significant decreases in glycated hemoglobin (monotherapy, -0.5%; add-on to metformin, thiazolidinedione, or sulfonylurea, -0.6% to 0.9%; initial combination with metformin, -2.5%), fasting plasma glucose, and postprandial glucose compared with controls. Additionally, saxagliptin improved ?-cell function, reflected as increases in homeostasis model assessment (HOMA)-2?. Saxagliptin was generally well tolerated; it did not increase hypoglycemia compared with controls, and was weight neutral. A meta-analysis of Phase II and III trials showed that saxagliptin did not increase the risk of major cardiovascular events. Professional organizations have updated their guidelines for T2D to include a DPP-4 inhibitor as an early treatment option-either as initial therapy in combination with metformin, or as add-on therapy for patients whose glycemia is inadequately controlled by a single oral antidiabetic drug.
| S-EPMC3047974 | biostudies-other
Project description:AIMS:Type 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients. METHODS:In 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1-2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40-70 years with diabetes for <?10 years, with no known cardiovascular disease, BMI 25-39.9, HbA1C 6-9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p?<?0.05). RESULTS:Although there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1?) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p?<?0.05) and a downregulation in CD34- cells for IL-6 (p?<?0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p?<?0.05). CONCLUSION:Saxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear. Trial registration Trial is registered under clinicaltrials.gov, NCT02024477.
| S-EPMC5934787 | biostudies-literature
Project description: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 m(2).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.
| S-EPMC5014790 | biostudies-literature
Project description:Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.
| S-EPMC4103926 | biostudies-literature
Project description:IntroductionSaxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes.MethodsThis was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18-65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period.ResultsMean (range) baseline HbA1C was 7.4% (6.4-9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity.ConclusionOnce daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.
| S-EPMC3889317 | biostudies-literature
Project description: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.
| S-EPMC6629702 | biostudies-literature
Project description:OBJECTIVE:To evaluate the comparative efficacy and safety of saxagliptin for type 2 diabetes (T2D). METHODS:A systematic search of PubMed, Embase, the Cochrane Library, Web of Science, ClinicalTrials.gov and two Chinese databases for randomized controlled trials (RCTs) comparing saxagliptin with placebo or active comparators was performed up to July 2017. A complementary search was done to cover literature until March 2018. For continuous data, estimates were pooled using inverse variance methodology to calculate weighted mean differences (WMDs). Dichotomous data were presented as Mantel-Haenzel risk ratios (RRs). RESULTS:Thirty-nine references of 30 RCTs involving 29,938 patients were analyzed. Compared with placebo, saxagliptin significantly reduced glycated hemoglobin (HbA1c, WMD -0.52%, 95% CI -0.60 to -0.44) and fasting plasma glucose (WMD -13.78 mg/dL, 95% CI -15.31 to -12.25), and increased the proportion of patients achieving HbA1c <7% (RR 1.64, 95% CI 1.53 to 1.75). When combined with submaximal-dose metformin, saxagliptin significantly increased the proportion of patients achieving HbA1c <7% compared with acarbose (RR 2.38, 95% CI 1.17 to 4.83) and uptitrated metformin (RR 1.30, 95% CI 1.04 to 1.63). Saxagliptin was similar to other DPP-4 inhibitors but inferior to liraglutide and dapagliflozin on glycemic control. Saxagliptin significantly decreased the incidences of overall adverse events compared with acarbose (RR 0.71, 95% CI 0.57 to 0.89) and liraglutide (RR 0.41, 95% CI 0.24 to 0.71) when added to metformin. Weight gain and hypoglycemia with saxagliptin was slightly but significantly higher than placebo and lower than sulfonylureas. Saxagliptin did not increase the risk of arthralgia, heart failure, pancreatitis and other adverse events. CONCLUSIONS:Generally, saxagliptin has similar efficacy compared with most oral antidiabetic drugs and may be more effective than acarbose, while having a better safety profile than both acarbose and sulfonylureas.
| S-EPMC5963790 | biostudies-literature
Project description:BackgroundThe patterns and determinants of saxagliptin use among patients with type 2 diabetes mellitus (T2DM) are unknown in real-world settings. We compared the characteristics of T2DM patients who were new initiators of saxagliptin to those who were new initiators of non-dipeptidyl peptidase-4 (DPP-4) inhibitor oral anti-diabetic drugs (OADs) and identified factors associated with saxagliptin use.MethodsWe conducted a cross-sectional study within the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), US Medicare, and the HealthCore Integrated Research Database (HIRD(SM)) across the first 36 months of saxagliptin availability (29 months for US Medicare). Patients were included if they were: 1) ≥18 years old, 2) newly prescribed saxagliptin or a non-DPP-4 inhibitor OAD, and 3) enrolled in their respective database for 180 days. For each saxagliptin initiator, we randomly selected up to ten non-DPP-4 inhibitor OAD initiators matched on age, sex, and geographic region. Conditional logistic regression was used to identify determinants of saxagliptin use.ResultsWe identified 64,079 saxagliptin initiators (CPRD: 1,962; THIN: 2,084; US Medicare: 51,976; HIRD(SM): 8,057) and 610,660 non-DPP-4 inhibitor OAD initiators (CPRD: 19,484; THIN: 19,936; US Medicare: 493,432; HIRD(SM): 77,808). Across all four data sources, prior OAD use, hypertension, and hyperlipidemia were associated with saxagliptin use. Saxagliptin initiation was also associated with hemoglobin A1c results >8% within the UK data sources, and a greater number of hemoglobin A1c measurements in the US data sources.ConclusionsIn these UK and US data sources, initiation of saxagliptin was associated with prior poor glycemic control, prior OAD use, and diagnoses of hypertension and hyperlipidemia.Trial registrationClinicalTrials.gov identifiers NCT01086280 , NCT01086293 , NCT01086319 , NCT01086306 , and NCT01377935.
| S-EPMC4404079 | biostudies-literature
Project description:Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.
| S-EPMC3277488 | biostudies-literature