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Faiez Zannad - One of the best experts on this subject based on the ideXlab platform.
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Alogliptin after acute coronary syndrome in patients with type 2 diabetes a renal function stratified analysis of the examine trial
BMC Medicine, 2020Co-Authors: Cyrus R Mehta, Steven E Nissen, Faiez Zannad, Joao Pedro Ferreira, Abhinav Sharma, Patrick RossignolAbstract:The EXAMINE trial tested the efficacy and safety of Alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because Alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2 and (2) eGFR < 60 ml/min/1.73m2. We aim to assess the efficacy and safety of Alogliptin vs. placebo according to the renal function strata. Cox-proportional hazard models with an interaction term by renal function strata were used. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Patient characteristics were balanced within each renal function strata. In total, 3946 patients were randomized within the eGFR ≥ 60 stratum, and 1434 patients within the eGFR < 60 stratum. The effect of Alogliptin was modified by the renal function strata. Primary outcome: eGFR ≥ 60 HR = 0.81, 95%CI, 0.65–0.99, and eGFR < 60 HR = 1.20, 95%CI, 0.95–1.53; interactionp = 0.014. Cardiovascular death: eGFR ≥ 60 HR = 0.61, 95%CI, 0.42–0.88, and eGFR < 60 HR = 1.16, 95%CI, 0.82–1.65; interactionp = 0.013. Non-fatal MI: eGFR ≥ 60 HR = 0.86, 95%CI, 0.66–1.13, and eGFR < 60 HR = 1.48, 95%CI, 1.07–2.06; interactionp = 0.013. Alogliptin may benefit patients with eGFR ≥ 60, but may be detrimental to patients with eGFR < 60 ml/min/1.73m2. These hypothesis-generating findings require further validation to assess the potential benefit and risk of Alogliptin across the renal function spectrum among patients with type 2 diabetes and a recent acute coronary syndrome. ClinicalTrials.gov, NCT00968708
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angiotensin converting enzyme inhibitor use and major cardiovascular outcomes in type 2 diabetes mellitus treated with the dipeptidyl peptidase 4 inhibitor Alogliptin
Hypertension, 2016Co-Authors: William B White, George L Bakris, Richard M Bergenstal, Christopher P Cannon, William C Cushman, Cyrus R Mehta, Steven E Nissen, C Wilson, Simon K Heller, Faiez ZannadAbstract:Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor Alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on Alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for Alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79–1.19; P =0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73–1.21; P =0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on Alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72–1.2; P =0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for Alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.
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Heart failure and mortality outcomes in patients with type 2 diabetes taking Alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial
The Lancet, 2015Co-Authors: Faiez Zannad, George L Bakris, Venu Menon, Alfonso Perez, Christopher Cannon, William Cushman, Penny Fleck, Cyrus Mehta, Stuart Kupfer, Craig WilsonAbstract:BACKGROUND: The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor Alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial. METHODS: Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned Alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708. FINDINGS: 5380 patients were assigned to Alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to Alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking Alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. INTERPRETATION: In patients with type 2 diabetes and recent acute coronary syndromes, Alogliptin did not increase the risk of heart failure outcomes.
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abstract 15319 n terminal pro brain natriuretic peptide decreases following treatment with Alogliptin in patients with type 2 diabetes and recent acute coronary syndromes results from examine
Circulation, 2014Co-Authors: Faiez Zannad, George L Bakris, Richard M Bergenstal, Christopher P Cannon, William C Cushman, Steven E Nissen, Simon K Heller, David A Morrow, Alfonso Perez, Penny R FleckAbstract:Introduction: In patients with type 2 diabetes (T2D) and recent acute coronary syndrome (ACS), EXAMINE showed that cardiovascular (CV) event rates, mortality and hospitalized heart failure (HHF) with the DPP-4 inhibitor Alogliptin were not increased compared with placebo, including in patients with history of HF and elevated levels of brain natriuretic peptide (BNP). Hypothesis: In an on-treatment biomarker study, we investigated the effects of Alogliptin on NT-pro-BNP. Methods: Patients with T2D who had an ACS within the previous 15-90 days were randomly assigned to Alogliptin or placebo added to existing anti-hyperglycemic and cardiovascular therapies. Patients with compensated HF were included (28% at baseline). Among 5380 randomized patients, NT-pro-BNP was measured in a random sample of 1010 patients stratified for HF at baseline and 6 months post-randomization. Changes from baseline were assessed with an ANCOVA model controlling for treatment, geographic region, kidney function, and baseline NT-pro-BNP. Results: Patients’ characteristics of the random subgroup of 1010 patients were similar to the entire population. Levels of NT-pro-BNP were highest in patients with a history of HF at baseline. Alogliptin significantly reduced NT-pro-BNP at 6 months compared with placebo (Figure). Furthermore, Alogliptin significantly reduced NT-pro-BNP compared with placebo in the highest baseline NT-pro-BNP quartile (LSMean change from baseline -1229 vs. -626 pg/ml, p=0.022). Subgroup analyses according to baseline NT-pro-BNP levels did not yield any significant interaction with the primary and secondary CV outcomes as well with the post hoc composite outcomes of CV death and HF hospitalization. Conclusions: Alogliptin reduces NT-pro-BNP in a post-ACS T2D population, consistent with the observation that Alogliptin does not induce new onset HF or exacerbate HF outcomes even in patients with a prior history of HF and/or with high baseline NT-pro-BNP.
Penny R Fleck - One of the best experts on this subject based on the ideXlab platform.
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ON BEHALF OF THE Alogliptin STUDY 010
2016Co-Authors: Ralph A. Defronzo, Penny R Fleck, Craig A WilsonAbstract:OBJECTIVE — To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor Alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes. RESEARCHDESIGNANDMETHODS — This double-blind, placebo-controlled, mul-ticenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg Alogliptin (n 133), 25 mg Alogliptin (n 131), or placebo (n 65) for 26 weeks. Primary efficacy end point was mean change from baseline in A1C at the final visit. RESULTS — At week 26, mean change in A1C was significantly greater (P 0.001) for 12.5 mg (0.56%) and 25 mg (0.59%) Alogliptin than placebo (0.02%). Reductions in fasting plasma glucose were also greater (P 0.001) in Alogliptin-treated patients than in those receiv-ing placebo. Overall, incidences of adverse events (67.4–70.3%) and hypoglycemia (1.5–3.0%) were similar across treatment groups. CONCLUSIONS — Alogliptin monotherapy was well tolerated and significantly improved glycemic control in patients with type 2 diabetes, without raising the incidence of hypoglycemia. Diabetes Care 31:2315–2317, 2008 I nhibition of dipeptidyl peptidase-4(DPP-4) increases the concentration ofglucagon-like peptide-1, an increti
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Comparison of Alogliptin and glipizide for composite endpoint of glycated haemoglobin reduction, no hypoglycaemia and no weight gain in type 2 diabetes mellitus.
Diabetes obesity & metabolism, 2016Co-Authors: S Del Prato, C Wilson, Penny R Fleck, P. ChaudhariAbstract:This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with Alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with Alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with Alogliptin 12.5 mg, Alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured Alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with Alogliptin than with glipizide.
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durability of the efficacy and safety of Alogliptin compared with glipizide in type 2 diabetes mellitus a 2 year study
Diabetes Obesity and Metabolism, 2014Co-Authors: S Del Prato, C Wilson, R Camisasca, Penny R FleckAbstract:Aims To evaluate the long-term durability of the efficacy of Alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin. Methods This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18–80 years to 104 weeks of treatment with metformin in addition to Alogliptin 12.5 mg once daily (n = 880), Alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks. Results The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were −0.68%, −0.72% and −0.59% for Alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); Alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for Alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were −0.68, −0.89 and 0.95 kg for Alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the Alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the Alogliptin 25 mg group and three in the glipizide group. Conclusions Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone.
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abstract 15319 n terminal pro brain natriuretic peptide decreases following treatment with Alogliptin in patients with type 2 diabetes and recent acute coronary syndromes results from examine
Circulation, 2014Co-Authors: Faiez Zannad, George L Bakris, Richard M Bergenstal, Christopher P Cannon, William C Cushman, Steven E Nissen, Simon K Heller, David A Morrow, Alfonso Perez, Penny R FleckAbstract:Introduction: In patients with type 2 diabetes (T2D) and recent acute coronary syndrome (ACS), EXAMINE showed that cardiovascular (CV) event rates, mortality and hospitalized heart failure (HHF) with the DPP-4 inhibitor Alogliptin were not increased compared with placebo, including in patients with history of HF and elevated levels of brain natriuretic peptide (BNP). Hypothesis: In an on-treatment biomarker study, we investigated the effects of Alogliptin on NT-pro-BNP. Methods: Patients with T2D who had an ACS within the previous 15-90 days were randomly assigned to Alogliptin or placebo added to existing anti-hyperglycemic and cardiovascular therapies. Patients with compensated HF were included (28% at baseline). Among 5380 randomized patients, NT-pro-BNP was measured in a random sample of 1010 patients stratified for HF at baseline and 6 months post-randomization. Changes from baseline were assessed with an ANCOVA model controlling for treatment, geographic region, kidney function, and baseline NT-pro-BNP. Results: Patients’ characteristics of the random subgroup of 1010 patients were similar to the entire population. Levels of NT-pro-BNP were highest in patients with a history of HF at baseline. Alogliptin significantly reduced NT-pro-BNP at 6 months compared with placebo (Figure). Furthermore, Alogliptin significantly reduced NT-pro-BNP compared with placebo in the highest baseline NT-pro-BNP quartile (LSMean change from baseline -1229 vs. -626 pg/ml, p=0.022). Subgroup analyses according to baseline NT-pro-BNP levels did not yield any significant interaction with the primary and secondary CV outcomes as well with the post hoc composite outcomes of CV death and HF hospitalization. Conclusions: Alogliptin reduces NT-pro-BNP in a post-ACS T2D population, consistent with the observation that Alogliptin does not induce new onset HF or exacerbate HF outcomes even in patients with a prior history of HF and/or with high baseline NT-pro-BNP.
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Durability of the efficacy and safety of Alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study.
Diabetes obesity & metabolism, 2014Co-Authors: S Del Prato, C Wilson, R Camisasca, Penny R FleckAbstract:Aims To evaluate the long-term durability of the efficacy of Alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin. Methods This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18–80 years to 104 weeks of treatment with metformin in addition to Alogliptin 12.5 mg once daily (n = 880), Alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks. Results The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were −0.68%, −0.72% and −0.59% for Alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p
Tomoko Asakawa - One of the best experts on this subject based on the ideXlab platform.
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A novel dipeptidyl peptidase-4 inhibitor, Alogliptin (SYR-322), is effective in diabetic rats with sulfonylurea-induced secondary failure.
Life Sciences, 2009Co-Authors: Tomoko Asakawa, Yusuke Moritoh, Koji Takeuchi, Osamu Kataoka, Nobuhiro Suzuki, Hiroyuki OdakaAbstract:Abstract Aims Loss of efficacy over time or secondary failure occurs somewhat often and remains a major concern of sulfonylurea (SU) therapy. In this study, we investigated the benefits of Alogliptin, an oral, potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in a rat model exhibiting SU secondary failure. Main methods Neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), a non-obese model of type 2 diabetes, were used in these studies. The effects of Alogliptin on DPP-4 activity and glucagon-like peptide 1 (GLP-1) concentration were determined by measuring their levels in plasma. In addition, the effects of Alogliptin on an oral glucose tolerance test were investigated by using an SU secondary failure model. Key findings Alogliptin dose dependently suppressed plasma DPP-4 activity leading to an increase in the plasma active form of GLP-1 and improved glucose excursion in N-STZ-1.5 rats. Repeated administration of glibenclamide resulted in unresponsiveness or loss of glucose tolerance typical of secondary failure. In these rats, Alogliptin exhibited significant improvement of glucose excursion with significant increase in insulin secretion. By contrast, glibenclamide and nateglinide had no effect on the glucose tolerance of these rats. Significance The above findings suggest that Alogliptin was effective at improving glucose tolerance and therefore overcoming SU induced secondary failure in N-STZ-1.5 rats.
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The dipeptidyl peptidase-4 inhibitor Alogliptin in combination with pioglitazone improves glycemic control, lipid profiles, and increases pancreatic insulin content in ob/ob mice.
European journal of pharmacology, 2008Co-Authors: Yusuke Moritoh, Koji Takeuchi, Tomoko Asakawa, Osamu Kataoka, Hiroyuki OdakaAbstract:The combination of two agents with different but complementary mechanisms of action is a logical approach for treating patients with type 2 diabetes. Thus, we evaluated chronic combination therapy with Alogliptin, a highly selective dipeptidyl peptidase-4 inhibitor that enhances the action of incretins, and pioglitazone, a thiazolidinedione that improves peripheral and hepatic insulin sensitivity. Studies were designed to investigate the chronic metabolic and pancreatic effects of Alogliptin (0.03%) plus pioglitazone (0.003%) combination treatment in obese ob/ob mice. After 4-5 weeks of treatment, Alogliptin significantly increased plasma active glucagon-like peptide-1 levels up to 4.1-fold and decreased plasma glucagon up to 25%, whereas pioglitazone significantly increased plasma adiponectin up to 1.3-fold. Combination treatment exhibited a complementary effect, increasing plasma insulin levels by 3.2-fold (Alogliptin alone, 1.6-fold; pioglitazone alone, 1.5-fold) and decreasing glycosylated hemoglobin by 2.3% (Alogliptin alone, 1.0%; pioglitazone alone, 1.5%), and non-fasting and fasting plasma glucose by 37% and 62% (Alogliptin alone, 17% and 24%; pioglitazone alone, 30% and 45%), respectively. Combination treatment also decreased plasma triglycerides by 67% and non-esterified fatty acids by 25% (Alogliptin alone, 24% and 11%; pioglitazone alone, 54% and 8%). Moreover, combination treatment increased pancreatic insulin content by 2.2-fold (Alogliptin alone, 1.3-fold; pioglitazone alone, 1.6-fold), with no significant changes in body weight. These results indicate that combination treatment with Alogliptin and pioglitazone improved glycemic control, lipid profiles and increased pancreatic insulin content in ob/ob mice by preventing incretin inactivation and improving insulin resistance. These results provide a strong argument for using Alogliptin in combination with pioglitazone.
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chronic administration of Alogliptin a novel potent and highly selective dipeptidyl peptidase 4 inhibitor improves glycemic control and beta cell function in obese diabetic ob ob mice
European Journal of Pharmacology, 2008Co-Authors: Yusuke Moritoh, Koji Takeuchi, Tomoko Asakawa, Osamu Kataoka, Hiroyuki OdakaAbstract:Abstract Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by increasing plasma active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels. However, the effects of chronic DPP-4 inhibition on in vivo beta-cell function are poorly characterized. We thus evaluated the chronic effects of the DPP-4 inhibitor Alogliptin benzoate (formerly SYR-322) on metabolic control and beta-cell function in obese diabetic ob/ob mice. Alogliptin (0.002%, 0.01%, or 0.03%) was administered in the diet to ob/ob mice for 2 days to determine effects on plasma DPP-4 activity and active GLP-1 levels and for 4 weeks to determine chronic effects on metabolic control and beta-cell function. After 2 days, Alogliptin dose-dependently inhibited DPP-4 activity by 28–82% and increased active GLP-1 by 3.2–6.4-fold. After 4 weeks, Alogliptin dose-dependently decreased glycosylated hemoglobin by 0.4–0.9%, plasma glucose by 7–28% and plasma triglycerides by 24–51%, increased plasma insulin by 1.5–2.0-fold, and decreased plasma glucagon by 23–26%, with neutral effects on body weight and food consumption. In addition, after drug washout, Alogliptin (0.03% dose) increased early-phase insulin secretion by 2.4-fold and improved oral meal tolerance (25% decrease in glucose area under the concentration–time curve), despite the lack of measurable plasma DPP-4 inhibition. Importantly, Alogliptin also increased pancreatic insulin content up to 2.5-fold, and induced intense insulin staining of islets, suggestive of improved beta-cell function. In conclusion, chronic treatment with Alogliptin improved glycemic control, decreased triglycerides, and improved beta-cell function in ob/ob mice, and may exhibit similar effects in patients with type 2 diabetes.
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Pharmacokinetic, pharmacodynamic, and efficacy profiles of Alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys
European Journal of Pharmacology, 2008Co-Authors: Bumsup Lee, Koji Takeuchi, Tomoko Asakawa, Lihong Shi, Daniel B. Kassel, Christopher Ronald JAbstract:The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of Alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of Alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of Alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean Alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of Alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that Alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.
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discovery of Alogliptin a potent selective bioavailable and efficacious inhibitor of dipeptidyl peptidase iv
Journal of Medicinal Chemistry, 2007Co-Authors: Jun Feng, Lihong Shi, Daniel B. Kassel, Zhiyuan Zhang, Michael B Wallace, Jeffrey A Stafford, Stephen W Kaldor, Marc Navre, Robert J Skene, Tomoko AsakawaAbstract:Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of Alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.
Akira Nishiyama - One of the best experts on this subject based on the ideXlab platform.
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Clinical Study Urinary Angiotensinogen Could Be a Prognostic Marker of Renoprotective Effects of Alogliptin in Patients with Type 2 Diabetes
2016Co-Authors: Tomoko Mizushige, Hiroyuki Kobori, Yoko Nishijima, Yuichiro Yano, Koji Sakata, Manabu Hayakawa, Akira NishiyamaAbstract:Copyright © 2015 Tomoko Mizushige et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. The aims of this study were (1) to examine the renoprotective effects of Alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of Alogliptin in patients with type 2 diabetes (T2D). Methods. In 43 patients with T2D (18 women, 66.1 ± 1.71 years), 25mg/day of Alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week Alogliptin treatment. Results. Alogliptin treatment tended to decrease UAlbCR (99.6 ± 26.8 versus 114.6 ± 36.0mg/g Cr
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Urinary Angiotensinogen Could Be a Prognostic Marker of Renoprotective Effects of Alogliptin in Patients with Type 2 Diabetes.
Journal of diabetes research, 2015Co-Authors: Tomoko Mizushige, Hiroyuki Kobori, Yoko Nishijima, Yuichiro Yano, Koji Sakata, Manabu Hayakawa, Akira NishiyamaAbstract:Background. The aims of this study were (1) to examine the renoprotective effects of Alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of Alogliptin in patients with type 2 diabetes (T2D). Methods. In 43 patients with T2D (18 women, years), 25 mg/day of Alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week Alogliptin treatment. Results. Alogliptin treatment tended to decrease UAlbCR ( versus mg/g Cr, ). Based on % change in UAlbCR, patients were divided into two groups, responders () and nonresponders (), and a logistic analysis of UAGTCR before treatment showed cutoff value of 20.8 µg/g Cr. When all patients were redivided into two groups, those with higher values of UAGTCR before the treatment (Group H, ) and those with lower values (Group L), Group H showed significantly decreased UAlbCR in response to Alogliptin ( versus , ). Conclusion. Urinary AGT could be a prognostic marker of renoprotective effects of Alogliptin in patients with T2D.
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Abstract 193: Urinary Angiotensinogen Could be a Prognostic Marker of Renoprotective Effects of Alogliptin in Patients with Type 2 Diabetes
Hypertension, 2013Co-Authors: Tomoko Mizushige, Hiroyuki Kobori, Yoko Nishijima, Yuichiro Yano, Koji Sakata, Manabu Hayakawa, Akira NishiyamaAbstract:The development of dipeptidyl peptidase-IV (DPP-4) inhibitors, such as Alogliptin, has led to the improvement in glycemic control in type 2 diabetes (T2D) by preventing the degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. However, the renoprotective effects of Alogliptin have not been addressed yet. This 12-week study in Japanese patients with T2D was performed to address the renoprotective effects of Alogliptin. In addition, urinary angiotensinogen (AGT), a marker of intrarenal renin-angiotensin system (RAS) activity, was examined to demonstrate the clinical usage as a prognostic marker. Forty-three patients with T2D (18 women, age: 66.1+/-11.2) were recruited in Miyazaki University and its affiliated hospitals, and Alogliptin (25 mg/day) was added on the top of the traditional hypoglycemic agents. The urinary concentrations of albumin (Alb) and AGT were measured using commercially available ELISA kits before and after the Alogliptin treatment, and normalized by the urinary concentration of creatinine (Cr) (UAlbCR and UAGTCR, respectively). The Alogliptin treatment tended to decrease UAlbCR (99.6 +/- 26.8 vs. 114.6 +/- 36.0, mg/g Cr). However, this change was not statistically significant (p = 0.1976). Then, we defined good responders to the Alogliptin treatment in terms of %change in UAlbCR less than -25% after the 12-week treatment, and a logistic analysis of UAGTCR before the treatment showed the area under the curve (AUC) as 0.644. When we set the cutoff value of UAGTCR as 20.8 μg/g Cr, the maximum specificity (17/27 = 63.0%) and sensitivity (10/16 = 62.5%) were obtained (Youden index = 0.255). Based on this cutoff value of UAGTCR before the treatment, we divided all patients into 2 groups as higher (group H, N = 20) and lower (group L) values of UAGTCR at the baseline. %Change in UAlbCR was significantly lower in the group H compared with the group L (-14.6% +/- 8.6% vs. +22.8% +/- 16.8%, p = 0.0327). These data indicate that the T2D patients with the higher UAGTCR before the treatment would show more decrease in UAlbCR by the Alogliptin treatment. In conclusion, urinary AGT could be a prognostic marker of renoprotective effects of Alogliptin in T2D patients.
C Wilson - One of the best experts on this subject based on the ideXlab platform.
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angiotensin converting enzyme inhibitor use and major cardiovascular outcomes in type 2 diabetes mellitus treated with the dipeptidyl peptidase 4 inhibitor Alogliptin
Hypertension, 2016Co-Authors: William B White, George L Bakris, Richard M Bergenstal, Christopher P Cannon, William C Cushman, Cyrus R Mehta, Steven E Nissen, C Wilson, Simon K Heller, Faiez ZannadAbstract:Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor Alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on Alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for Alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79–1.19; P =0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73–1.21; P =0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on Alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72–1.2; P =0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for Alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.
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Comparison of Alogliptin and glipizide for composite endpoint of glycated haemoglobin reduction, no hypoglycaemia and no weight gain in type 2 diabetes mellitus.
Diabetes obesity & metabolism, 2016Co-Authors: S Del Prato, C Wilson, Penny R Fleck, P. ChaudhariAbstract:This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with Alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with Alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with Alogliptin 12.5 mg, Alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured Alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with Alogliptin than with glipizide.
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durability of the efficacy and safety of Alogliptin compared with glipizide in type 2 diabetes mellitus a 2 year study
Diabetes Obesity and Metabolism, 2014Co-Authors: S Del Prato, C Wilson, R Camisasca, Penny R FleckAbstract:Aims To evaluate the long-term durability of the efficacy of Alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin. Methods This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18–80 years to 104 weeks of treatment with metformin in addition to Alogliptin 12.5 mg once daily (n = 880), Alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks. Results The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were −0.68%, −0.72% and −0.59% for Alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); Alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for Alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were −0.68, −0.89 and 0.95 kg for Alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the Alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the Alogliptin 25 mg group and three in the glipizide group. Conclusions Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone.
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Durability of the efficacy and safety of Alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study.
Diabetes obesity & metabolism, 2014Co-Authors: S Del Prato, C Wilson, R Camisasca, Penny R FleckAbstract:Aims To evaluate the long-term durability of the efficacy of Alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin. Methods This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18–80 years to 104 weeks of treatment with metformin in addition to Alogliptin 12.5 mg once daily (n = 880), Alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks. Results The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were −0.68%, −0.72% and −0.59% for Alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p
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Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia a prospective double blind randomized 1 year study
Diabetes Obesity and Metabolism, 2013Co-Authors: Julio Rosenstock, C Wilson, Penny R FleckAbstract:Aim To prospectively evaluate the efficacy and safety of Alogliptin versus glipizide in elderly patients with type 2 diabetes mellitus (T2DM) over 1 year of treatment. Methods This was a randomized, double-blind, active-controlled study of elderly T2DM patients (aged 65–90 years) with mild hyperglycaemia on diet/exercise therapy alone [glycosylated haemoglobin (HbA1c) 6.5–9.0%] or plus oral antidiabetic monotherapy (HbA1c 6.5–8.0%). Patients were randomized to once-daily Alogliptin 25 mg or glipizide 5 mg titrated to 10 mg, if needed. Hypoglycaemic episodes were systematically captured under predefined criteria. Results In the primary analysis, HbA1c mean changes from a baseline of 7.5% were −0.14% with Alogliptin (n = 222) and −0.09% with glipizide (n = 219) at the end of the study, demonstrating non-inferiority of Alogliptin to glipizide [least squares (LS) mean difference = −0.05%; one-sided 97.5% confidence interval (CI): −∞, 0.13%]. More clinically relevant HbA1c reductions occurred among patients who completed the study: −0.42 and −0.33% with Alogliptin and glipizide, with non-inferiority again confirmed (LS mean difference = −0.09%; one-sided 97.5% CI: −∞, 0.07%). Overall, Alogliptin was safe and well tolerated, with notably fewer hypoglycaemic episodes than glipizide [5.4% (31 episodes) vs. 26.0% (232 episodes), respectively]; three patients experienced severe hypoglycaemia, all with glipizide. Alogliptin also resulted in favourable weight changes versus glipizide (−0.62 vs. 0.60 kg at week 52; p < 0.001). Conclusions Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1 year of treatment, with substantially lower risk of hypoglycaemia and without weight gain.