The Experts below are selected from a list of 4557 Experts worldwide ranked by ideXlab platform
Boaz Hirshberg - One of the best experts on this subject based on the ideXlab platform.
-
Nonclinical and clinical pharmacology evidence for cardiovascular safety of Saxagliptin
Cardiovascular diabetology, 2017Co-Authors: Pia S. Pollack, Boaz Hirshberg, Nayyar Iqbal, Kristina D. Chadwick, David M. Smith, Martin Billger, David W. BoultonAbstract:In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, Saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with Saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of Saxagliptin with the aim of identifying any potential signals of myocardial injury. In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of Saxagliptin and its major active metabolite, 5-hydroxy Saxagliptin, on the CV system are reviewed. In addition, results from Saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). Neither Saxagliptin nor 5-hydroxy Saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with Saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. The Saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.
-
Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials
Diabetes Therapy, 2017Co-Authors: Mikaela Sjostrand, William Cook, Cheryl Wei, Pia S. Pollack, Christina Stahre, Kristina Johnsson, Boaz HirshbergAbstract:Introduction This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies ( N = 4632) summarizes Saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens. Methods Patients received Saxagliptin 5 mg/d or control as either monotherapy ( n = 1196 vs placebo), add-on therapy ( n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy ( n = 619 vs control monotherapy). Patients with renal impairment received Saxagliptin 2.5 mg/d or placebo ( n = 164). Results Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the Saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with Saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: –0.55% [–0.63%, –0.47%]) and when used as monotherapy (–0.52% [–0.63, –0.40%]), add-on (–0.55% [–0.69%, –0.40%] vs placebo; –0.72% [–0.88%, –0.56%] vs uptitrated sulfonylurea), initial combination therapy (–0.54% [–0.73%, –0.35%] vs control monotherapy), and in patients with renal impairment (–0.42% [–0.75%, –0.09%]). Similar reductions in A1C versus control were noted for patients
-
Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial.
Diabetes care, 2016Co-Authors: Ofri Mosenzon, Boaz Hirshberg, Gil Leibowitz, Cheryl Wei, Avivit Cahn, Ilan Yanuv, Aliza Rozenberg, Deepak L Bhatt, Christina StahreAbstract:OBJECTIVE Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy. RESEARCH DESIGN AND METHODS We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to Saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESULTS At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] 300 mg/g). Treatment with Saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P 50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR 6.0 mg/dL, were similar as well. CONCLUSIONS Treatment with Saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of Saxagliptin on albuminuria could not be explained by its effect on glycemic control.
-
predisposing factors for any and major hypoglycemia with Saxagliptin versus placebo and overall analysis from the savor timi 53 trial
Diabetes Care, 2016Co-Authors: Avivit Cahn, Boaz Hirshberg, Gil Leibowitz, Nayyar Iqbal, Itamar Raz, Ofri Mosenzon, Ilan Yanuv, Aliza Rozenberg, Mikaela Sjostrand, Christina StahreAbstract:OBJECTIVE To analyze the impact of adding Saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes ( n = 16,492) were randomized to Saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement RESULTS At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to Saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with Saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with Saxagliptin in those with baseline HbA 1c ≤7.0% and not in those with baseline HbA 1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to Saxagliptin, long duration of diabetes, increased updated HbA 1c , macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to Saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.
-
Saxagliptin Responder Analysis: A Pooled Analysis of 5 Clinical Trials
Journal of Diabetes & Metabolism, 2016Co-Authors: Mikaela Sjostr, Gil Leibowitz, Nayyar Iqbal, William Cook, Cheryl Wei, Boaz HirshbergAbstract:Objective: To assess the treatment response of patients with T2DM to Saxagliptin at 24 weeks based on their initial response to Saxagliptin at 12 weeks. Methods: Data were pooled from five 24-week, randomized, placebo-controlled trials of Saxagliptin. Patients (N=1994) were categorized by change in glycated hemoglobin (HbA1c) after 12 weeks of Saxagliptin treatment as responders (HbA1c decrease ≥ 0.5%; 61% of Saxagliptin-treated patients), intermediate responders (HbA1c decrease ≥ 0.2% and
David W. Boulton - One of the best experts on this subject based on the ideXlab platform.
-
Nonclinical and clinical pharmacology evidence for cardiovascular safety of Saxagliptin
Cardiovascular diabetology, 2017Co-Authors: Pia S. Pollack, Boaz Hirshberg, Nayyar Iqbal, Kristina D. Chadwick, David M. Smith, Martin Billger, David W. BoultonAbstract:In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, Saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with Saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of Saxagliptin with the aim of identifying any potential signals of myocardial injury. In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of Saxagliptin and its major active metabolite, 5-hydroxy Saxagliptin, on the CV system are reviewed. In addition, results from Saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). Neither Saxagliptin nor 5-hydroxy Saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with Saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. The Saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.
-
Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor
Clinical Pharmacokinetics, 2017Co-Authors: David W. BoultonAbstract:Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type 2 diabetes mellitus at doses of 2.5 or 5 mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both Saxagliptin and its major active metabolite, 5-hydroxy Saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with Saxagliptin 5 mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in Saxagliptin or 5-hydroxy Saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in Saxagliptin or 5-hydroxy Saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration–time curve (AUC)] to Saxagliptin total active moieties. Clinically relevant drug–drug interactions have not been detected; however, limiting the dose to 2.5 mg once daily is recommended in the USA when Saxagliptin is coadministered with strong CYP inhibitors, because of increased Saxagliptin exposure. In summary, Saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.
-
Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study.
Clinical therapeutics, 2016Co-Authors: Blisse Vakkalagadda, Frank Lacreta, Susan Lubin, Laurie Reynolds, Dan Liang, Alan S. Marion, David W. BoultonAbstract:Abstract Purpose This single-dose, open-label, randomized, 3-period, 3-treatment crossover drug–drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of Saxagliptin and dapagliflozin when coadministered. Methods Healthy subjects (N = 42) were randomized to receive Saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or Saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of ≥6 days between treatments. Serial blood samples for determining Saxagliptin, 5-hydroxy Saxagliptin (5-OH Saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose. No interaction was to be concluded if the 90% CIs for the geometric mean ratios of the combination compared with each drug given alone for C max and AUC inf were within 0.80 to 1.25. Findings The results indicated that dapagliflozin had no effect on the pharmacokinetic properties of Saxagliptin, 5-OH Saxagliptin, or Saxagliptin total active moiety and vice versa. The 90% CIs for C max and AUC inf for all comparisons were contained entirely within the 0.80 to 1.25 equivalence intervals. Other pharmacokinetic parameters (apparent oral clearance or half-life) of Saxagliptin or dapagliflozin were similar when each medicine was administered alone or when coadministered. No safety profile or tolerability findings of concern were observed during the study. All adverse events were mild, and no serious adverse events were reported. Implications These data indicate that coadministration of Saxagliptin and dapagliflozin exhibits no pharmacokinetic interaction and is well tolerated. ClinicalTrials.gov identifier: NCT01662999.
-
Bioequivalence of Saxagliptin/dapagliflozin fixed-dose combination tablets compared with coadministration of the individual tablets to healthy subjects.
Pharmacology research & perspectives, 2016Co-Authors: Blisse Vakkalagadda, David W. Boulton, Charles H Smith, Jian Huang, Marion L. Vetter, Jignasa Rana, Jennifer Karkas, Frank LacretaAbstract:Saxagliptin and dapagliflozin are individually indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The bioequivalence of Saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg fixed-dose combination (FDC) tablets compared with coadministration of the individual tablets and the food effect on both strengths of Saxagliptin/dapagliflozin FDCs were evaluated in this open-label, randomized, single-dose crossover study. Healthy subjects were randomized to Saxagliptin 2.5 mg + dapagliflozin 5 mg fasted, 2.5/5 mg FDC fasted, 2.5/5 mg FDC fed (Cohort 1) or Saxagliptin 5 mg + dapagliflozin 10 mg fasted, 5/10 mg FDC fasted, 5/10 mg FDC fed (Cohort 2). Serial blood samples for pharmacokinetics of Saxagliptin and dapagliflozin were obtained predose and up to 60 h postdose. Bioequivalence of FDC tablets versus individual components was concluded if the 90% CIs for FDC to individual component geometric mean ratios of C max, AUC 0-T, and AUC inf of both analytes were between 0.80 and 1.25. Seventy-two subjects were randomized; 71 (98.6%) completed the study. Saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg FDC tablets were bioequivalent to the individual tablets administered concomitantly. Food had no clinically meaningful effect on Saxagliptin or dapagliflozin overall systemic exposure. Saxagliptin/dapagliflozin FDC tablets were bioequivalent to coadministration of the individual components in healthy subjects under fasted conditions and food had no clinically meaningful effect on bioavailability.
-
Bioequivalence of Saxagliptin/metformin immediate release (IR) fixed-dose combination tablets and single-component Saxagliptin and metformin IR tablets in healthy adult subjects.
Clinical drug investigation, 2013Co-Authors: Vijay V. Upreti, David W. Boulton, Angela Tang, Ernst U. Frevert, Chi-fung Keung, Ming Chang, Bonnie C Hsiang, Donette Quamina-edghill, Frank P LacretaAbstract:As compared with individual tablets, Saxagliptin/metformin immediate release (IR) fixed-dose combination (FDC) tablets offer the potential for increased convenience, compliance, and adherence for patients requiring combination therapy. Two bioequivalence studies assessed the fed-state and the fasted-state bioequivalence of Saxagliptin/metformin IR 2.5 mg/500 mg FDC (study 1) and Saxagliptin/metformin IR 2.5 mg/1,000 mg FDC (study 2) relative to the same dosage strengths of the individual component tablets [Saxagliptin (Onglyza™) and metformin IR (Glucophage(®))] administered concurrently. These were randomized, open-label, single-dose, four-period, four-treatment, crossover studies in healthy subjects (n = 24 in each study). The treatments in study 1 were a Saxagliptin/metformin IR 2.5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and Saxagliptin 2.5 mg and metformin IR 500 mg tablets co-administered in the fed state and fasted states on separate occasions. The treatments in study 2 were a Saxagliptin/metformin IR 2.5 mg/1,000 mg FDC tablet in the fed and fasted states on separate occasions, and Saxagliptin 2.5 mg and metformin IR 1,000 mg co-administered in the fed state and fasted states on separate occasions. The pharmacokinetics, safety, and tolerability of each treatment were evaluated. For both studies, Saxagliptin and metformin in the FDCs were bioequivalent to the individual components in both the fed and the fasted states as the limits of the 90 % confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within the predefined 0.800 to 1.250 bioequivalence criteria. Co-administration of Saxagliptin and metformin IR was generally safe and well tolerated as the FDCs or as individual tablets. Saxagliptin/metformin IR 2.5 mg/500 mg and Saxagliptin/metformin IR 2.5 mg/1,000 mg FDCs were bioequivalent to individual tablets of Saxagliptin and metformin of the same strengths in both the fed and the fasted states. No unexpected safety findings were observed with Saxagliptin/metformin IR administration. The tolerability of the FDC of Saxagliptin/metformin IR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of Saxagliptin and metformin can be extended to the Saxagliptin/metformin IR FDC tablets.
Nayyar Iqbal - One of the best experts on this subject based on the ideXlab platform.
-
safety and tolerability of dapagliflozin Saxagliptin and metformin in combination post hoc analysis of concomitant add on versus sequential add on to metformin and of triple versus dual therapy with metformin
Diabetes Obesity and Metabolism, 2018Co-Authors: Stefano Del Prato, Nayyar Iqbal, Julio Rosenstock, Ricardo Garciasanchez, Lars Hansen, E Johnsson, Hungta Chen, Chantal MathieuAbstract:The safety of triple oral therapy with dapagliflozin plus Saxagliptin plus metformin versus dual therapy with dapagliflozin or Saxagliptin plus metformin was compared in a post-hoc analysis of 3 randomized trials of sequential or concomitant add-on of dapagliflozin and Saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus Saxagliptin 5 mg/d. In sequential add-on trials, patients on metformin plus either Saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or Saxagliptin 5 mg/d, respectively, as add-on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of dapagliflozin to Saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, Saxagliptin and metformin, as either concomitant or sequential add-on, were similar to dual therapy with either agent added to metformin.
-
Nonclinical and clinical pharmacology evidence for cardiovascular safety of Saxagliptin
Cardiovascular diabetology, 2017Co-Authors: Pia S. Pollack, Boaz Hirshberg, Nayyar Iqbal, Kristina D. Chadwick, David M. Smith, Martin Billger, David W. BoultonAbstract:In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, Saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with Saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of Saxagliptin with the aim of identifying any potential signals of myocardial injury. In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of Saxagliptin and its major active metabolite, 5-hydroxy Saxagliptin, on the CV system are reviewed. In addition, results from Saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). Neither Saxagliptin nor 5-hydroxy Saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with Saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. The Saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.
-
one year efficacy and safety of Saxagliptin add on in patients receiving dapagliflozin and metformin
Diabetes Obesity and Metabolism, 2016Co-Authors: Stephan Matthaei, Nayyar Iqbal, E Johnsson, Hungta Chen, Naresh Aggarwal, Pedro Garciahernandez, Alex Chin, Lars HansenAbstract:Aims Greater reductions in glycated haemoglobin (HbA1c) with Saxagliptin, a dipeptidyl peptidase-4 inhibitor, versus placebo add-on in patients with type 2 diabetes who had inadequate glycaemic control with dapagliflozin 10 mg/d plus metformin were demonstrated after 24 weeks of treatment. Results over 52 weeks of treatment were assessed in this analysis. Materials and methods Patients (mean baseline HbA1c 7.9%) receiving open-label dapagliflozin 10 mg/d plus metformin were randomized to double-blind Saxagliptin 5 mg/d or placebo add-on. Results The adjusted mean change from baseline to week 52 in HbA1c was greater with Saxagliptin than with placebo add-on −0.38% vs 0.05%; difference −0.42% (95% confidence interval −0.64, −0.20)]. More patients achieved the HbA1c target of <7% with Saxagliptin than with placebo add-on (29% vs 13%), and fewer patients were rescued or discontinued the study for lack of glycaemic control with Saxagliptin than with placebo add-on (19% vs 28%). Reductions from baseline in body weight (≤1.5 kg) occurred in both groups. Similar proportions of patients reported ≥1 adverse event with Saxagliptin (58.2%) and placebo add-on (58.0%); no new safety signals were detected. Hypoglycaemia was infrequent in both treatment groups (≤2.5%), with no major episodes. The rate of urinary tract infections was similar in the Saxagliptin and placebo add-on groups (7.8% vs 7.4%). The incidence of genital infections was 3.3% with Saxagliptin versus 6.2% with placebo add-on. Conclusions Triple therapy with Saxagliptin add-on to dapagliflozin plus metformin for 52 weeks resulted in sustained improvements in glycaemic control without an increase in body weight or increased risk of hypoglycaemia.
-
predisposing factors for any and major hypoglycemia with Saxagliptin versus placebo and overall analysis from the savor timi 53 trial
Diabetes Care, 2016Co-Authors: Avivit Cahn, Boaz Hirshberg, Gil Leibowitz, Nayyar Iqbal, Itamar Raz, Ofri Mosenzon, Ilan Yanuv, Aliza Rozenberg, Mikaela Sjostrand, Christina StahreAbstract:OBJECTIVE To analyze the impact of adding Saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes ( n = 16,492) were randomized to Saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement RESULTS At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to Saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with Saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with Saxagliptin in those with baseline HbA 1c ≤7.0% and not in those with baseline HbA 1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to Saxagliptin, long duration of diabetes, increased updated HbA 1c , macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to Saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.
-
Saxagliptin Responder Analysis: A Pooled Analysis of 5 Clinical Trials
Journal of Diabetes & Metabolism, 2016Co-Authors: Mikaela Sjostr, Gil Leibowitz, Nayyar Iqbal, William Cook, Cheryl Wei, Boaz HirshbergAbstract:Objective: To assess the treatment response of patients with T2DM to Saxagliptin at 24 weeks based on their initial response to Saxagliptin at 12 weeks. Methods: Data were pooled from five 24-week, randomized, placebo-controlled trials of Saxagliptin. Patients (N=1994) were categorized by change in glycated hemoglobin (HbA1c) after 12 weeks of Saxagliptin treatment as responders (HbA1c decrease ≥ 0.5%; 61% of Saxagliptin-treated patients), intermediate responders (HbA1c decrease ≥ 0.2% and
Roland Chen - One of the best experts on this subject based on the ideXlab platform.
-
the efficacy and safety of the dipeptidyl peptidase 4 inhibitor Saxagliptin in treatment naive patients with type 2 diabetes mellitus a randomized controlled trial
Diabetology & Metabolic Syndrome, 2012Co-Authors: Robert Frederich, Robert Mcneill, Niklas Berglind, Douglas Fleming, Roland ChenAbstract:The aim of this study was to assess efficacy and safety of Saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks. 365 treatment-naive patients with T2DM (HbA1c 7.0%–10.0%) were treated with Saxagliptin 2.5 mg q.A.M., Saxagliptin 2.5 mg q.A.M. with possible titration to Saxagliptin 5 mg, Saxagliptin 5 mg q.A.M., Saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to Saxagliptin 10 mg based on HbA1c ≥7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. At week 24, placebo-subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the Saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in Saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (Saxagliptin-treated, 2 [0.7]; control, 1 [1.4]). In treatment-naive patients with T2DM, Saxagliptin monotherapy demonstrated statistically significant improvement in HbA1c compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks. ClinicalTrials.gov Identifier: NCT00316082
-
the design and rationale of the Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus thrombolysis in myocardial infarction savor timi 53 study
American Heart Journal, 2011Co-Authors: Benjamin M. Scirica, Boaz Hirshberg, Eugene Braunwald, Deepak L Bhatt, Ph Gabriel Steg, Jaime A Davidson, Peter Ohman, Deborah L Price, Roland ChenAbstract:Objectives Saxagliptin, a dipeptidyl peptidase 4 inhibitor, improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by increasing endogenous active, intact glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in response to food, which augments insulin secretion and decreases glucagon release. Research Design and Methods SAVOR-TIMI 53 is a phase 4, randomized, double-blind, placebo-controlled trial conducted in 25 countries that is designed to evaluate the safety and efficacy of Saxagliptin during long-term treatment of approximately 16,500 patients with T2DM. Eligible patients who are either treatment naive or on any background antidiabetic treatment (except incretin therapy) with history of established cardiovascular (CV) disease or multiple risk factors are randomized 1:1 to Saxagliptin 5 mg QD (2.5 mg in subjects with moderate/severe renal impairment) or matching placebo, stratified by qualifying disease state. The primary end point is the composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke. The trial will continue until approximately 1,040 primary end points accrue, providing 85% power to identify a 17% relative reduction of the primary end point with Saxagliptin versus placebo and 98% power to test for noninferiority of Saxagliptin versus placebo (reject the upper limit of 95% CI for a hazard ratio Conclusion SAVOR-TIMI 53 is testing the hypothesis that treatment with Saxagliptin is safe and reduces CV events in high-risk patients with T2DM.
-
Safety and efficacy of Saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks.
Diabetes & vascular disease research, 2011Co-Authors: Antonio Roberto Chacra, Roland Chen, James F List, Gerry H Tan, Shoba Ravichandran, Cv Study InvestigatorsAbstract:To assess the long-term efficacy and safety of Saxagliptin in patients with type 2 diabetes mellitus inadequately controlled on sulphonylurea monotherapy, 768 patients were randomised to Saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg versus placebo added to up-titrated glyburide over 76 weeks (24 weeks plus 52-week extension) in this phase 3, double-blind, placebo-controlled trial; 557 patients completed the study, 142 without being rescued. At 76 weeks, adjusted mean changes from baseline HbA(1C) (repeated measures model) (95% confidence interval) for Saxagliptin 2.5 mg, Saxagliptin 5 mg, and up-titrated glyburide were 0.11% (-0.05, 0.27), 0.03% (-0.14, 0.19), and 0.69% (0.47, 0.92), respectively (post hoc and nominal p < 0.0001 for Saxagliptin 2.5 and 5 mg vs. up-titrated glyburide). Adverse event frequency was similar in all treatment groups; reported hypoglycaemia event rates were 24.2%, 22.9%, and 20.6% with Saxagliptin 2.5 mg, Saxagliptin 5 mg, and up-titrated glyburide, respectively. Saxagliptin plus glyburide provided sustained incremental efficacy compared with up-titrated glyburide over 76 weeks, and was generally well tolerated.
-
Initial combination therapy with Saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks.
Diabetes obesity & metabolism, 2011Co-Authors: Andreas Pfutzner, E. Allen, E. Paz‐pacheco, R. Frederich, Roland ChenAbstract:Aim: To assess the efficacy and safety of Saxagliptin + metformin initial combination therapy compared with Saxagliptin or metformin alone over 76 weeks (24-week short-term + 52-week long-term extension) in treatment-naIve type 2 diabetes mellitus patients with inadequate glycaemic control. Methods: In this phase 3, parallel-group, double-blind, active-controlled study, 1306 patients 18–77 years of age (HbA1c 8.0–12.0%) were randomized to Saxagliptin 5 mg + 500 mg metformin, Saxagliptin 10 mg + 500 mg metformin, Saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1–5 of the short-term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin-based treatment groups. No titration of metformin was permitted during the long-term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120-min postprandial glucose (PPG) and PPG-area under the curve (AUC) from baseline to week 76 were analysed using a repeated-measures model. Results: At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for Saxagliptin 5 mg + metformin, Saxagliptin 10 mg + metformin, Saxagliptin 10 mg and metformin were −2.31 (−2.44, −2.18), −2.33 (−2.46, −2.20), −1.55 (−1.70, −1.40) and −1.79% (−1.93, −1.65), respectively (post hoc and nominal p < 0.0001 vs. metformin and Saxagliptin monotherapies for Saxagliptin 5 mg + metformin and Saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for Saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG-AUC or 120-min PPG was observed between weeks 24 and 76 for Saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency. Conclusion: Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone.
-
safety and efficacy of Saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus
Diabetes and Vascular Disease Research, 2011Co-Authors: Priscilla L Hollander, Roland Chen, E. Allen, Robert Frederich, Cv InvestigatorsAbstract:To assess the long-term efficacy and safety of Saxagliptin in patients with type 2 diabetes mellitus inadequately controlled with thiazolidinedione monotherapy, 565 patients were randomised to Saxagliptin (2.5 mg or 5 mg) or placebo added to thiazolidinedione over 76 weeks (24-week short-term + 52-week long-term extension period) in this phase 3, double-blind, placebo-controlled trial; 360 patients completed the study. At 76 weeks, adjusted mean changes from baseline HbA(1C) (repeated measures model; 95% CI) for Saxagliptin 2.5 mg, 5 mg, and placebo were -0.59% (-0.75, -0.43), -1.09% (-1.26, -0.93), and -0.20% (-0.39, -0.01), respectively (post hoc and nominal p=0.0019 and p<0.0001 for Saxagliptin 2.5 mg and 5 mg vs. placebo, respectively). Adverse event frequency was similar between groups. Confirmed hypoglycaemic events were 1.0% and 0% vs. 0.5% for Saxagliptin 2.5 mg and 5 mg vs. placebo, respectively. Results should be interpreted with caution given the proportion of patients who discontinued or required glycaemic rescue therapy during the 76-week course of study. Saxagliptin added to thiazolidinedione provided sustained incremental efficacy vs. placebo with little hypoglycaemia for up to 76 weeks and was generally well tolerated.
Chantal Mathieu - One of the best experts on this subject based on the ideXlab platform.
-
dapagliflozin versus Saxagliptin as add on therapy in patients with type 2 diabetes inadequately controlled with metformin
Archives of Endocrinology and Metabolism, 2018Co-Authors: Julio Rosenstock, Ricardo Garciasanchez, Hungta Chen, Chantal Mathieu, Gabriela Luporini SaraivaAbstract:OBJECTIVE This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, Saxagliptin, both added on to metformin. MATERIALS AND METHODS This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and Saxagliptin 5 mg (n = 176) treatment arms. RESULTS Dapagliflozin showed significantly greater mean reductions versus Saxagliptin in HbA1c (difference versus Saxagliptin [95% CI]: -0.32% [-0.54, -0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, -0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, -1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, -1.63] mmHg; p < 0.001). More dapagliflozintreated than Saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus Saxagliptin (0.6%) experienced genital infections. CONCLUSION Dapagliflozin demonstrated greater glycemic efficacy than Saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.
-
safety and tolerability of dapagliflozin Saxagliptin and metformin in combination post hoc analysis of concomitant add on versus sequential add on to metformin and of triple versus dual therapy with metformin
Diabetes Obesity and Metabolism, 2018Co-Authors: Stefano Del Prato, Nayyar Iqbal, Julio Rosenstock, Ricardo Garciasanchez, Lars Hansen, E Johnsson, Hungta Chen, Chantal MathieuAbstract:The safety of triple oral therapy with dapagliflozin plus Saxagliptin plus metformin versus dual therapy with dapagliflozin or Saxagliptin plus metformin was compared in a post-hoc analysis of 3 randomized trials of sequential or concomitant add-on of dapagliflozin and Saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus Saxagliptin 5 mg/d. In sequential add-on trials, patients on metformin plus either Saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or Saxagliptin 5 mg/d, respectively, as add-on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of dapagliflozin to Saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, Saxagliptin and metformin, as either concomitant or sequential add-on, were similar to dual therapy with either agent added to metformin.
-
randomized double blind phase 3 trial of triple therapy with dapagliflozin add on to Saxagliptin plus metformin in type 2 diabetes
Diabetes Care, 2015Co-Authors: Chantal Mathieu, Boaz Hirshberg, William Cook, Lars Hansen, Hungta Chen, Aurelian Ranetti, Ella Ekholm, Nayyar IqbalAbstract:OBJECTIVE To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to Saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with Saxagliptin plus metformin treatment. RESEARCH DESIGN AND METHODS Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0–11.5% [64–102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5–10.5% [58–91 mmol/mol]) for ≥8 weeks received open-label Saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (Saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7–10.5% [53–91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus Saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of <7% (53 mmol/mol). RESULTS Treatment with dapagliflozin add-on to Saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (−0.82 vs. −0.10% [−9 vs. −1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (∼1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%). CONCLUSIONS Triple therapy with dapagliflozin add-on to Saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with Saxagliptin plus metformin therapy.
