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Keith D Kaufman - One of the best experts on this subject based on the ideXlab platform.
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longitudinal medical resources and costs among type 2 diabetes patients participating in the trial evaluating cardiovascular outcomes with Sitagliptin tecos
Diabetes Obesity and Metabolism, 2018Co-Authors: Shelby D Reed, Jennifer B Green, John B Buse, Keith D Kaufman, Jose Leal, Larry Radican, Amanda I Adler, Joakim Alfredsson, Axel Riefflin, Frans Van De WerfAbstract:Aims TECOS, a cardiovascular safety trial (ClinicalTrials.gov identifier: NCT00790205) involving 14 671 patients with type 2 diabetes and cardiovascular disease, demonstrated that Sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome when added to best usual care. This study tested hypotheses that medical resource use and costs differed between these 2 treatment strategies. Materials and methods Information concerning medical resource use was collected on case report forms throughout the trial and was valued using US costs for: Medicare payments for hospitalizations, medical procedures and outpatient visits, and wholesale acquisition costs (WAC) for diabetes-related medications. Hierarchical generalized linear models were used to compare resource use and US costs, accounting for variable intercountry practice patterns. Sensitivity analyses included resource valuation using English costs for a UK perspective. Results There were no significant differences in hospitalizations, inpatient days, medical procedures, or outpatient visits during follow-up (mean and median 3.0 years in both groups). Hospitalization rates appeared to diverge after 2 years, with lower rates among Sitagliptin-treated vs placebo patients after 2.5 years (relative rate, 0.90 [95% CI, 0.83-0.97]; P = .01). Mean medical costs, exclusive of study medication, were 11 937 USD in the Sitagliptin arm and 12 409 USD in the placebo arm (P = .06). Mean Sitagliptin costs based on undiscounted WAC were 9978 USD per patient. Differential UK total costs including study drug costs were smaller (911 GBP), primarily because of lower mean costs for Sitagliptin (1072 GBP). Conclusions Lower hospitalization rates across time with Sitagliptin slightly offset Sitagliptin treatment costs over 3 years in type 2 diabetes patients at high risk for cardiovascular events.
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effect of Sitagliptin on cardiovascular outcomes in type 2 diabetes
The New England Journal of Medicine, 2015Co-Authors: Jennifer B Green, Angelyn M Bethel, Paul W Armstrong, John B Buse, Samuel S Engel, Jyotsna Garg, Robert G Josse, Keith D Kaufman, Joerg Koglin, Scott KornAbstract:BackgroundData are lacking on the long-term effect on cardiovascular events of adding Sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. MethodsIn this randomized, double-blind study, we assigned 14,671 patients to add either Sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether Sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. ResultsDuring a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for Sitagliptin vs. placebo, −0.29 percentage points; 95% confidence interval [CI], −0.32 to −0....
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effect of Sitagliptin on cardiovascular outcomes in type 2 diabetes
The New England Journal of Medicine, 2015Co-Authors: Jennifer B Green, Angelyn M Bethel, Paul W Armstrong, John B Buse, Samuel S Engel, Jyotsna Garg, Robert G Josse, Keith D Kaufman, Joerg Koglin, Scott KornAbstract:Background Data are lacking on the long-term effect on cardiovascular events of adding Sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. Methods In this randomized, double-blind study, we assigned 14,671 patients to add either Sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether Sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Results During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for Sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the Sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P Conclusions Among patients with type 2 diabetes and established cardiovascular disease, adding Sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).
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Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function
Diabetes Obesity and Metabolism, 2013Co-Authors: Maria Alba, D Williamsherman, Edward A Oneill, Keith D Kaufman, Bo Ahren, Silvio E Inzucchi, Y Guan, M Mallick, Barry J GoldsteinAbstract:AimsThe effects of Sitagliptin and pioglitazone, alone and in combination, on - and -cell function were assessed in patients with type 2 diabetes. MethodsFollowing a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4mmol/l were randomized (1:1:1:1) to Sitagliptin, pioglitazone, Sitagliptin+pioglitazone or placebo. At baseline and after 12weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. ResultsAfter 12weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with Sitagliptin+pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with Sitagliptin versus all other treatments and increased with Sitagliptin+pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with Sitagliptin versus placebo and decreased with Sitagliptin+pioglitazone versus pioglitazone or placebo. (s), a measure of dynamic -cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with Sitagliptin+pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and Sitagliptin+pioglitazone versus placebo. The disposition index, a measure of the relationship between -cell function and insulin sensitivity, improved with all active treatments versus placebo. Conclusions Sitagliptin and pioglitazone enhanced -cell function (increasing postmeal phi(s)), and Sitagliptin improved -cell function (decreasing postmeal glucagon) after 12weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of Sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone. (Less)
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safety and tolerability of Sitagliptin in type 2 diabetes pooled analysis of 25 clinical studies
Diabetes Therapy, 2013Co-Authors: Samuel S Engel, Keith D Kaufman, Gregory T. Golm, Elizabeth Round, Barry J GoldsteinAbstract:Introduction In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with Sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the Sitagliptin clinical development program continues, additional studies with Sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of Sitagliptin by examining pooled data from 25 double-blind clinical studies.
Peter P Stein - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of treatment with Sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin a 2 year study
International Journal of Clinical Practice, 2010Co-Authors: Thomas Seck, Keith D Kaufman, M A Nauck, D Sheng, Peter P Stein, S Sunga, Melanie J Davies, John M AmatrudaAbstract:Summary Objectives: To evaluate the 2-year safety and efficacy of adding Sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes. Methods: Patients who were on a stable dose of metformin (≥ 1500 mg/day) for at least 8 weeks were randomised in a double-blind manner to receive either Sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (up-titrated up to 20 mg/day based upon prespecified glycaemic criteria) (N = 584). The efficacy analysis assessed the change in HbA1c from baseline using the per-protocol (PP) population. Results: For the PP cohort, mean baseline HbA1c was 7.3% in both groups. After 2 years, the least squares (LS) mean change in HbA1c from baseline [95% confidence interval (CI)] was −0.54% (−0.64, −0.45) with Sitagliptin (n = 248) and −0.51% (−0.60, −0.42) with glipizide (n = 256). The rise in HbA1c from week 24 to week 104 [i.e. coefficient of durability (COD)] was smaller with Sitagliptin [COD (95% CI) 0.16%/year (0.10, 0.21)] compared with glipizide [0.26%/year (0.21, 0.31)]. The proportion of patients with an HbA1c< 7% was 63% and 59% with Sitagliptin and glipizide, respectively. The beta-cell responsiveness to a meal challenge was maintained with Sitagliptin and decreased with glipizide. The proportion of patients who reported hypoglycaemia was 5% with Sitagliptin and 34% with glipizide [difference in proportions (95% CI) = −29% (−33, −25)]. Relative to baseline, Sitagliptin was associated with weight loss (−1.6 kg) compared with weight gain (+0.7 kg) with glipizide. Conclusion: In patients with type 2 diabetes, adding Sitagliptin to metformin monotherapy improved glycaemic control over 2 years, similar to the glucose-lowering efficacy observed with adding glipizide, but with greater durability and generally better maintenance of beta-cell function. Sitagliptin was generally well tolerated with a lower risk of hypoglycaemia and weight loss compared with weight gain observed with glipizide.
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efficacy and safety of Sitagliptin in the treatment of patients with type 2 diabetes in china india and korea
Diabetes Research and Clinical Practice, 2009Co-Authors: Viswanathan Mohan, John M Amatruda, Peter P Stein, Wenying Yang, Hoyoung Son, Liliane Noble, Ronald B Langdon, Keith D KaufmanAbstract:The efficacy and safety of Sitagliptin as monotherapy were evaluated in Chinese, Indian, and Korean patients with type 2 diabetes inadequately controlled by diet and exercise. In a randomized, placebo-controlled, double-blind, 18-week trial, 530 patients with HbA(1c) >or=7.5% and
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effect of Sitagliptin a dipeptidyl peptidase 4 inhibitor on beta cell function in patients with type 2 diabetes a model based approach
Diabetes Obesity and Metabolism, 2008Co-Authors: Dalla C Man, D Williamsherman, Melanie J Davies, B Charbonnel, G Meninger, Claudio Cobelli, Peter P SteinAbstract:PURPOSE The purpose of this exploratory analysis was to assess the effect of Sitagliptin, a dipeptidyl peptidase-4 inhibitor, on pancreatic beta-cell function using a model-based analysis. METHODS Data for this analysis were from three large, placebo-controlled clinical studies that examined Sitagliptin 100 mg q.d. as add-on to metformin therapy or as monotherapy over 18 or 24 weeks. In these studies, subsets of patients consented to undergo extensive blood sampling as part of a nine-point meal tolerance test performed at baseline and study end-point. Blood samples were collected at -10, 0, 10, 20, 30, 60, 90, 120 and 180 min relative to the start of a meal and subsequently were assayed for plasma glucose and serum C-peptide concentrations. Parameters for beta-cell function were calculated using the C-peptide minimal model, which estimates insulin secretion rate (ISR) and partitions the ISR into basal (Phi(b); ISR at basal glucose concentrations), static (Phi(s); ISR at above basal glucose concentrations following a meal) and dynamic (Phi(d); ISR in response to the rate of increase in above basal glucose concentrations following a meal) components. The total responsivity index (Phi(total); average ISR over the average glucose concentration) is calculated as a function of Phi(s), Phi(d )and Phi(b. )Insulin sensitivity was assessed with a validated composite index (ISI). Disposition indices (DI), which assess insulin secretion in the context of changes in insulin sensitivity, were calculated as the product of Phiand ISI. RESULTS When administered in combination with ongoing metformin therapy or as monotherapy, Sitagliptin was associated with substantial reductions in postprandial glycaemic excursion following a meal challenge relative to placebo. Sitagliptin produced significant (p < 0.05 vs. placebo) improvements in Phi(s )and Phi(total), regardless of treatment regimen (add-on to metformin or as monotherapy). For Phi(d), there was a numerical, but not statistically significant, improvement with Sitagliptin relative to placebo. Treatment with Sitagliptin increased Phi(b), but the difference relative to placebo was only significant with monotherapy. ISI was not significantly different between Sitagliptin and placebo. The DIs for the static, dynamic and total measures were significantly (p < 0.05) increased with Sitagliptin treatment relative to placebo. CONCLUSIONS In this model-based analysis, Sitagliptin improved beta-cell function relative to placebo in both fasting and postprandial states in patients with type 2 diabetes.
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safety and efficacy of Sitagliptin in patients with type 2 diabetes and chronic renal insufficiency
Diabetes Obesity and Metabolism, 2008Co-Authors: Juliana C N Chan, Russell S Scott, Keith D Kaufman, John M Amatruda, D Sheng, Peter P Stein, Melanie J Davies, J Arjona C Ferreira, Edward J Gonzalez, D WilliamshermanAbstract:Objective: To assess the safety of Sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of Sitagliptin in this patient population was also assessed. Methods: In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A1c (HbA1c) values of 6.5–10% were allocated (2:1) to Sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg Sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive Sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. Results: Patients (N = 91) with a mean baseline HbA1c value of 7.7% (range: 6.2–10.3%) were randomized to Sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA1c was −0.6% (−0.8, −0.4) in the Sitagliptin group compared with −0.2% (−0.4, 0.1) in the placebo group [between-group difference (95% CI) = −0.4% (−0.7, −0.1)]. At 54 weeks, patients continuously treated with Sitagliptin had a mean change (95% CI) from baseline in HbA1c of −0.7% (−0.9, −0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the Sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the Sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. Conclusions: In this study, Sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.
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safety and efficacy of Sitagliptin in patients with type 2 diabetes and chronic renal insufficiency
Diabetes Obesity and Metabolism, 2008Co-Authors: Juliana C N Chan, Keith D Kaufman, John M Amatruda, D Sheng, Peter P Stein, Melanie J Davies, J Arjona C Ferreira, R S Scott, Edward Gonzalez, D WilliamshermanAbstract:Objective: To assess the safety of Sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of Sitagliptin in this patient population was also assessed. Methods: In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A1c (HbA1c) values of 6.5–10% were allocated (2:1) to Sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg Sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive Sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. Results: Patients (N = 91) with a mean baseline HbA1c value of 7.7% (range: 6.2–10.3%) were randomized to Sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA1c was −0.6% (−0.8, −0.4) in the Sitagliptin group compared with −0.2% (−0.4, 0.1) in the placebo group [between-group difference (95% CI) = −0.4% (−0.7, −0.1)]. At 54 weeks, patients continuously treated with Sitagliptin had a mean change (95% CI) from baseline in HbA1c of −0.7% (−0.9, −0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the Sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the Sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. Conclusions: In this study, Sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.
Barry J Goldstein - One of the best experts on this subject based on the ideXlab platform.
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Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function
Diabetes Obesity and Metabolism, 2013Co-Authors: Maria Alba, D Williamsherman, Edward A Oneill, Keith D Kaufman, Bo Ahren, Silvio E Inzucchi, Y Guan, M Mallick, Barry J GoldsteinAbstract:AimsThe effects of Sitagliptin and pioglitazone, alone and in combination, on - and -cell function were assessed in patients with type 2 diabetes. MethodsFollowing a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4mmol/l were randomized (1:1:1:1) to Sitagliptin, pioglitazone, Sitagliptin+pioglitazone or placebo. At baseline and after 12weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. ResultsAfter 12weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with Sitagliptin+pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with Sitagliptin versus all other treatments and increased with Sitagliptin+pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with Sitagliptin versus placebo and decreased with Sitagliptin+pioglitazone versus pioglitazone or placebo. (s), a measure of dynamic -cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with Sitagliptin+pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and Sitagliptin+pioglitazone versus placebo. The disposition index, a measure of the relationship between -cell function and insulin sensitivity, improved with all active treatments versus placebo. Conclusions Sitagliptin and pioglitazone enhanced -cell function (increasing postmeal phi(s)), and Sitagliptin improved -cell function (decreasing postmeal glucagon) after 12weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of Sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone. (Less)
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safety and tolerability of Sitagliptin in type 2 diabetes pooled analysis of 25 clinical studies
Diabetes Therapy, 2013Co-Authors: Samuel S Engel, Keith D Kaufman, Gregory T. Golm, Elizabeth Round, Barry J GoldsteinAbstract:Introduction In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with Sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the Sitagliptin clinical development program continues, additional studies with Sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of Sitagliptin by examining pooled data from 25 double-blind clinical studies.
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efficacy and safety of Sitagliptin versus glipizide in patients with type 2 diabetes and moderate to severe chronic renal insufficiency
Diabetes Care, 2013Co-Authors: Juan Camilo Arjona Ferreira, Keith D Kaufman, Michel Marre, Nir Barzilai, Gregory T. Golm, Christine Mccrary Sisk, Barry J GoldsteinAbstract:OBJECTIVE Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease have an increased risk of micro- and macrovascular disease, but limited options for antihyperglycemic therapy. We compared the efficacy and safety of Sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control. RESEARCH DESIGN AND METHODS Patients ( n = 426) were randomized 1:1 to Sitagliptin (50 mg every day [q.d.] for moderate renal insufficiency and 25 mg q.d. for severe renal insufficiency) or glipizide (2.5 mg q.d., adjusted based on glycemic control to a 10-mg twice a day maximum dose). Randomization was stratified by: 1 ) renal status (moderate or severe renal insufficiency); 2 ) history of cardiovascular disease; and 3 ) history of heart failure. RESULTS At week 54, treatment with Sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (−0.8 vs. −0.6%; between-group difference −0.11%; 95% CI −0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with Sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with Sitagliptin (−0.6 kg) versus an increase (1.2 kg) with glipizide (difference, −1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments. CONCLUSIONS In patients with T2DM and chronic renal insufficiency, Sitagliptin and glipizide provided similar A1C-lowering efficacy. Sitagliptin was generally well-tolerated, with a lower risk of hypoglycemia and weight loss versus weight gain, relative to glipizide.
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efficacy and safety of Sitagliptin in patients with type 2 diabetes and esrd receiving dialysis a 54 week randomized trial
American Journal of Kidney Diseases, 2013Co-Authors: Juan Camilo Arjona Ferreira, Keith D Kaufman, Gregory T. Golm, Michael J Davies, Edward Gonzalez, Dalila B Corry, Carl Erik Mogensen, Lance Sloan, Barry J GoldsteinAbstract:Background Treatment with oral antihyperglycemic agents has not been well characterized in patients with type 2 diabetes and end-stage renal disease (ESRD). The efficacy and safety of Sitagliptin and glipizide monotherapy in patients with type 2 diabetes and ESRD on dialysis therapy were assessed in this study. Study Design 54-week, randomized, double-blind, parallel-arm study. Setting & Participants From 31 clinical sites in 12 countries, 129 patients 30 years or older with type 2 diabetes and ESRD who were on dialysis therapy and had a hemoglobin A 1c (HbA 1c ) level of 7%-9% were randomly assigned 1:1 to treatment. Intervention Monotherapy with Sitagliptin, 25 mg daily or glipizide (initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia). Outcomes Primary end points were 54-week change in HbA 1c level from baseline and tolerability with Sitagliptin. A secondary end point was the comparison of Sitagliptin versus glipizide on the incidence of symptomatic hypoglycemia. Results Of 129 patients randomly assigned, 64 were in the Sitagliptin group (mean baseline age, 61 years; HbA 1c , 7.9%) and 65 were in the glipizide group (mean baseline age, 59 years; HbA 1c , 7.8%). After 54 weeks, the least squares mean change from baseline in HbA 1c level was −0.72% (95% CI, −0.95% to −0.48%) with Sitagliptin and −0.87% (95% CI, −1.11% to −0.63%) with glipizide, for a difference of 0.15% (95% CI, −0.18% to 0.49%). The incidences of symptomatic hypoglycemia and severe hypoglycemia were 6.3% versus 10.8% (between-group difference, −4.8% [95% CI, −15.7% to 5.6%]) and 0% versus 7.7% (between-group difference, −7.8% [95% CI, −17.1% to −1.9%]) in the Sitagliptin and glipizide groups, respectively. Higher incidences (ie, 95% CI around between-treatment difference excluded 0) of cellulitis and headache were found with Sitagliptin compared to glipizide (6.3% vs 0%, respectively, for both). Limitations Small sample size limits between-group comparisons. Conclusions Treatment with Sitagliptin or glipizide monotherapy was effective and well tolerated over 54 weeks in patients with type 2 diabetes and ESRD who were receiving dialysis.
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cardiovascular safety of Sitagliptin in patients with type 2 diabetes mellitus a pooled analysis
Cardiovascular Diabetology, 2013Co-Authors: Samuel S Engel, Keith D Kaufman, Gregory T. Golm, Melanie J Davies, Deborah R Shapiro, Barry J GoldsteinAbstract:To compare the incidence of cardiovascular events and mortality in patients with type 2 diabetes mellitus treated with Sitagliptin or non-Sitagliptin comparators. A post hoc assessment of cardiovascular safety in 14,611 patients was performed by pooling data from 25 double-blind studies, which randomised patients at baseline to Sitagliptin 100 mg/day or a non-Sitagliptin comparator (i.e., non-exposed). Included studies were limited to those at least 12 weeks in duration (range: 12 to 104 weeks). Patient-level data were used in this analysis of major adverse cardiovascular events (MACE) including ischaemic events and cardiovascular deaths. Analyses were performed in three cohorts: the entire 25-study cohort, the cohort from placebo-controlled portions of studies (n=19), and the cohort from studies comparing Sitagliptin to a sulphonylurea (n=3). In the entire cohort analysis, 78 patients had at least 1 reported MACE-related event, with 40 in the Sitagliptin group and 38 in the non-exposed group. The exposure-adjusted incidence rate was 0.65 per 100 patient-years in the Sitagliptin group and 0.74 in the non-exposed group (incidence rate ratio = 0.83 [95% confidence interval (CI): 0.53, 1.30]). In the analysis comparing Sitagliptin to placebo, the exposure-adjusted incidence rate was 0.80 per 100-patient-years with Sitagliptin and 0.76 with placebo (incidence rate ratio = 1.01 [95% CI: 0.55, 1.86]). In the analysis comparing Sitagliptin to sulphonylurea, the exposure-adjusted incidence rate was 0.00 per 100 patient-years with Sitagliptin and 0.86 with sulphonylurea (incidence rate ratio = 0.00 [95% CI: 0.00, 0.31]). A pooled analysis of 25 randomised clinical trials does not indicate that treatment with Sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus. In a subanalysis, a higher rate of cardiovascular-related events was associated with sulphonylurea relative to Sitagliptin.
D Williamsherman - One of the best experts on this subject based on the ideXlab platform.
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Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function
Diabetes Obesity and Metabolism, 2013Co-Authors: Maria Alba, D Williamsherman, Edward A Oneill, Keith D Kaufman, Bo Ahren, Silvio E Inzucchi, Y Guan, M Mallick, Barry J GoldsteinAbstract:AimsThe effects of Sitagliptin and pioglitazone, alone and in combination, on - and -cell function were assessed in patients with type 2 diabetes. MethodsFollowing a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4mmol/l were randomized (1:1:1:1) to Sitagliptin, pioglitazone, Sitagliptin+pioglitazone or placebo. At baseline and after 12weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. ResultsAfter 12weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with Sitagliptin+pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with Sitagliptin versus all other treatments and increased with Sitagliptin+pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with Sitagliptin versus placebo and decreased with Sitagliptin+pioglitazone versus pioglitazone or placebo. (s), a measure of dynamic -cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with Sitagliptin+pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and Sitagliptin+pioglitazone versus placebo. The disposition index, a measure of the relationship between -cell function and insulin sensitivity, improved with all active treatments versus placebo. Conclusions Sitagliptin and pioglitazone enhanced -cell function (increasing postmeal phi(s)), and Sitagliptin improved -cell function (decreasing postmeal glucagon) after 12weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of Sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone. (Less)
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a treatment strategy implementing combination therapy with Sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents
Diabetes Obesity and Metabolism, 2011Co-Authors: L Olansky, Charles A Reasner, D Williamsherman, Menghui Chen, L Terranella, T. Seck, A Mehta, Keith D Kaufman, Barry J GoldsteinAbstract:Aims: Combination therapy with Sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with Sitagliptin/metformin as a fixed-dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. Methods: We evaluated the Sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients with type 2 diabetes mellitus in a two-part, double-blind, randomized, controlled clinical trial. The initial 18-week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26-week Phase B portion of the study during which double-blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. Results: There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving Sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with Sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: −2.3% and −1.8% (p < 0.001 for difference) for Sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the Sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the Sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the Sitagliptin/metformin FDC group compared with the metformin monotherapy group. Conclusions: A strategy initially implementing combination therapy with Sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated.
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efficacy and safety of treatment with Sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy a randomized double blind non inferiority trial
Diabetes Obesity and Metabolism, 2011Co-Authors: R Arechavaleta, D Williamsherman, Thomas Seck, Yu Chen, Karl J Krobot, Edward A Oneill, Lorraine Duran, Keith D Kaufman, Barry J GoldsteinAbstract:Aim: To evaluate the efficacy and safety of adding Sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy. Methods: Patients with type 2 diabetes and an HbA1c of 6.5–9.0% while on a stable dose of metformin (≥1500 mg/day) combined with diet and exercise for at least 12 weeks were randomized in a double-blind manner to receive either Sitagliptin 100 mg daily (N = 516) or glimepiride (starting dose 1 mg/day and up-titrated, based upon patient's self-monitoring of blood glucose results, to a maximum dose of up to 6 mg/day) (N = 519) for 30 weeks. The primary analysis assessed whether Sitagliptin is non-inferior to glimepiride in reducing HbA1c at week 30 (based on the criterion of having an upper bound of the 95% CI less than the prespecified non-inferiority bound of 0.4%). Results: The mean baseline HbA1c was 7.5% in both the Sitagliptin group (n = 443) and the glimepiride group (n = 436). After 30 weeks, the least squares (LS) mean change in HbA1c from baseline was −0.47% with Sitagliptin and −0.54% with glimepiride, with a between-group difference (95% CI) of 0.07% (−0.03, 0.16). This result met the prespecified criterion for declaring non-inferiority. The percentages of patients with an HbA1c < 7.0% at week 30 were 52 and 60% in the Sitagliptin and glimepiride groups, respectively. The LS mean change in fasting plasma glucose from baseline (95% CI) was −0.8 mmol/l (−1.0, −0.6) with Sitagliptin and −1.0 mmol/l (−1.2, −0.8) with glimepiride, for a between-group difference (95% CI) of 0.2 mmol/l (−0.1, 0.4). The percentages of patients for whom hypoglycaemia was reported were 7% in the Sitagliptin group and 22% in the glimepiride group (percentage-point difference = −15, p < 0.001). Relative to baseline, Sitagliptin was associated with a mean weight loss (−0.8 kg), whereas glimepiride was associated with a mean weight gain (1.2 kg), yielding a between-group difference of −2.0 kg (p < 0.001). Conclusions: In patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of Sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks. Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with Sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain (ClinicalTrials.gov: NCT00701090).
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efficacy and safety of Sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes
Diabetes Obesity and Metabolism, 2010Co-Authors: D Williamsherman, Barry J Goldstein, Keith D Kaufman, Gregory T. Golm, Jeremy Johnson, R Teng, John M AmatrudaAbstract:Aim: To assess the 104-week efficacy and safety of Sitagliptin and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes and inadequate glycaemic control (HbA1c 7.5–11%) on diet and exercise. Methods: This study was a 50-week, double-blind extension of a 54-week, randomized, double-blind, factorial study of the initial combination of Sitagliptin and metformin, metformin monotherapy and Sitagliptin monotherapy (104 weeks total duration). Patients assigned to active therapy in the 54-week base study remained on those treatments in the extension study: Sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (higher dose combination), Sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (lower dose combination), metformin 1000 mg b.i.d. (higher dose), metformin 500 mg b.i.d. (lower dose) and Sitagliptin 100 mg q.d. Patients randomized to receive the sequence of placebo/metformin were switched, in a blinded manner, from placebo to metformin monotherapy uptitrated to 1000 mg b.i.d. beginning at week 24 and remained on higher dose metformin through the extension. Results: Amongst patients who entered the extension study without having initiated glycaemic rescue therapy, least-squares mean changes in HbA1c from baseline at week 104 were −1.7% (higher dose combination), −1.4% (lower dose combination), −1.3% (higher dose), −1.1% (lower dose) and −1.2% (Sitagliptin). The proportions of patients with an HbA1c <7% at week 104 were 60% (higher dose combination), 45% (lower dose combination), 45% (higher dose), 28% (lower dose) and 32% (Sitagliptin). Fasting and postmeal measures of glycaemic control and β-cell function improved in all groups, with glycaemic responses generally maintained over the 104-week treatment period. The incidence of hypoglycaemia was low across all groups. The incidences of gastrointestinal adverse experiences were generally lower in the Sitagliptin group and similar between the metformin monotherapy and combination groups. Conclusions: Initial combination therapy with Sitagliptin and metformin and monotherapy with either drug alone provided substantial and sustained glycaemic improvements and were well tolerated over 104 weeks in patients with type 2 diabetes.
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safety and tolerability of Sitagliptin in clinical studies a pooled analysis of data from 10 246 patients with type 2 diabetes
BMC Endocrine Disorders, 2010Co-Authors: D Williamsherman, Samuel S Engel, Keith D Kaufman, Gregory T. Golm, Elizabeth Round, Jeremy Johnson, Bret J Musser, Michael J Davies, Barry J GoldsteinAbstract:In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of Sitagliptin continues, additional studies have been completed, and more patients have been exposed to Sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of Sitagliptin by pooling data from 19 double-blind clinical studies. The present analysis included data from 10,246 patients with type 2 diabetes who received either Sitagliptin 100 mg/day (N = 5,429; Sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of Sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed Sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events. Summary measures of overall adverse events were similar in the Sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the Sitagliptin group. Treatment with Sitagliptin was not associated with an increased risk of major adverse cardiovascular events. In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, Sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.
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Sitagliptin an dipeptidyl peptidase 4 inhibitor does not alter the pharmacokinetics of the sulphonylurea glyburide in healthy subjects
British Journal of Clinical Pharmacology, 2008Co-Authors: Goutam C Mistry, Miguel A Zinny, Keith M Gottesdiener, Arthur J Bergman, John A Wagner, Gary A Herman, David Hreniuk, Wei Zheng, Marcella RuddyAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • No data are available on the potential drug interaction of Sitagliptin and glyburide. • Sitagliptin belongs to a new class of drugs called DPP-4 inhibitors recently approved for the treatment of Type 2 diabetes. WHAT THIS STUDY ADDS • Glyburide is a commonly used sulphonylurea medication to treat Type 2 diabetes. • Combination therapy is often required to achieve adequate glucose control in Type 2 diabetes. • Sitagliptin does not appear to interfere with glyburide pharmacokinetics and therefore may be potentially co-administered with glyburide for the treatment of Type 2 diabetes. AIMS Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of Sitagliptin on glyburide pharmacokinetics. METHODS In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22–44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with Sitagliptin on day 5 following a multiple-dose regimen for Sitagliptin (200-mg q.d. ×6 days) in the other period. RESULTS The geometric mean ratios and 90% confidence intervals [(glyburide + Sitagliptin)/glyburide] for AUC0–∞ and Cmax were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively. CONCLUSION Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.
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once daily Sitagliptin a dipeptidyl peptidase 4 inhibitor for the treatment of patients with type 2 diabetes
Current Medical Research and Opinion, 2007Co-Authors: M Hanefeld, Gary A Herman, M Sanchez, Carolyn Mickel, Peter P Stein, Sitagliptin Study InvestigatorsAbstract:ABSTRACTObjective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP‑4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to Sitagliptin 100 mg daily was evaluated as a once-daily (100 mg once-daily) or twice-daily (50 mg twice-daily) dosing regimen.Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, Sitagliptin 25, 50 or 100 mg once-daily, or Sitagliptin 50 mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.Results: Mean baseline HbA1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤ 7%. After 12 weeks, treatment with all doses of Sitagliptin signif...
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effect of single oral doses of Sitagliptin a dipeptidyl peptidase 4 inhibitor on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Gary A Herman, Arthur J Bergman, Catherine Stevens, Paul Kotey, Peng Zhao, Bruno Dietrich, George Golor, Andreas Schrodter, Bart Keymeulen, Kenneth C LasseterAbstract:Context: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. Objective: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of Sitagliptin. Design: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. Setting: The study was conducted at six investigational sites. Patients: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. Interventions: Interventions included Sitagliptin 25 mg, sitaglipti...
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pharmacokinetics and pharmacodynamic effects of the oral dpp 4 inhibitor Sitagliptin in middle aged obese subjects
The Journal of Clinical Pharmacology, 2006Co-Authors: Gary A Herman, Arthur J Bergman, Cathy Stevens, Karen Snyder, Deborah Hilliard, Fang Liu, Amy Qiu Wang, Wei Zeng, Li Chen, Michael TanenAbstract:Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of Sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to Sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of Sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with Sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.
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pharmacokinetics and pharmacodynamics of Sitagliptin an inhibitor of dipeptidyl peptidase iv in healthy subjects results from two randomized double blind placebo controlled studies with single oral doses
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Gary A Herman, Arthur J Bergman, Cathy Stevens, Kristien Van Dyck, Bingming Yi, Marina De Smet, Karen Snyder, Deborah Hilliard, Michael Tanen, Wesley TanakaAbstract:Background Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes. Methods Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of Sitagliptin (1.5–600 mg) in healthy male volunteers. Results Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of Sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration–time curve for Sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of Sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, Sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia. Conclusions This study provides proof of pharmacologic characteristics for Sitagliptin in humans. By inhibiting plasma DPP-IV activity, Sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. Clinical Pharmacology & Therapeutics (2005) 78, 675–688; doi: 10.1016/j.clpt.2005.09.002
