Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes.

OBJECTIVE: To assess the efficacy and tolerability of alogliptin plus pioglitazone for initial combination therapy in drug-naïve type 2 diabetic patients. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: 25 mg alogliptin (A25) q.d. monotherapy, 30 mg pioglitazone (P30) q.d. monotherapy, or 12.5 (A12.5) or 25 mg alogliptin q.d. plus pioglitazone (P30) q.d. combination therapy. Primary efficacy was A1C change from baseline with the high-dose combination (A25+P30) versus each monotherapy. RESULTS: Combination therapy with A25+P30 resulted in greater reductions in A1C (-1.7±0.1% from an 8.8% mean baseline) vs. A25 (-1.0±0.1%, P<0.001) or P30 (-1.2±0.1%, P<0.001) and in fasting plasma glucose (-2.8±0.2 mmol/l) vs. A25 (-1.4±0.2 mmol/l, P<0.001) or P30 (-2.1±0.2 mmol/l, P=0.006). The A25+P30 safety profile was consistent with those of its component monotherapies. CONCLUSIONS: Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes.

Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies.

OBJECTIVES: To compare the efficacy and safety of alogliptin, a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, in elderly (> or =65) and younger (<65) patients with type 2 diabetes mellitus. DESIGN: Pooled analysis of six randomized, double-blind, placebo-controlled studies of alogliptin. PARTICIPANTS: Patients aged 18 to 80 with type 2 diabetes mellitus and inadequate glycemic control. INTERVENTIONS: Elderly (mean age 70.0; n=455) and younger (mean age 51.8; n=1,911) patients received alogliptin 12.5 mg (n=922), alogliptin 25 mg (n=910), or placebo (n=534) for 26 weeks (12 weeks in a Phase 2 study). The studies evaluated alogliptin as monotherapy and coadministered with pioglitazone, glyburide, metformin, or insulin. MEASUREMENTS: Efficacy endpoints included change from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, and lipid values. Safety variables included hypoglycemic events, adverse events, and blood pressure. RESULTS: Least-squares mean HbA1c decreased from baseline by 0.7% and 0.8% in elderly patients receiving alogliptin 12.5 and 25 mg, respectively, and 0.5% and 0.6%, respectively, in younger patients (P<.001 for both alogliptin doses vs placebo for both age groups P=.70 for 12.5 mg and .68 for 25 mg for differences between age groups). Results were similar for FPG. Incidence of hypoglycemia was 8.3% or less in all alogliptin groups (< or =10.5% for placebo), with no apparent difference between elderly and younger patients. Changes in weight were negligible in all treatment groups in both age categories. The safety profiles of alogliptin were similar in the age and dose groups. CONCLUSION: Alogliptin was effective and well tolerated in the elderly patients enrolled in these studies. Improvements in HbA1c were similar to those seen in younger patients, and no increase in the risk of hypoglycemia, weight gain, or other adverse events was apparent in elderly patients.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18-80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA(1c)] 7.0-10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted. MAIN OUTCOME MEASURES: The primary efficacy endpoint was change in HbA(1c) from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG > or = 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia. RESULTS: Least squares (LS) mean change in HbA(1c) was significantly (p < 0.001) greater for alogliptin 12.5 mg (-0.66%) or 25 mg (-0.80%) than for placebo (-0.19%). A significantly (p < or = 0.016) larger proportion of patients achieved HbA(1c) < or = 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p = 0.003) greater with alogliptin 12.5 mg (-19.7 mg/dL [-1.09 mmol/L]) or 25 mg (-19.9 mg/dL [-1.10 mmol/L]) than with placebo (-5.7 mg/dL [-0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (< or =25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo. CONCLUSIONS: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety. CLINICAL TRIAL REGISTRATION: NCT00286494, clinicaltrials.gov.

Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants.

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter 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 receiving 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.

Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes.

BACKGROUND: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D). OBJECTIVES: This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA(1c)), C-peptide, and fructosamine values. RESULTS: Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose. CONCLUSIONS: In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.

Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects.

BACKGROUND: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. OBJECTIVE: This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. METHODS: This was a randomized, double-blind, placebo-controlled study in which healthy, nonobese male subjects between the ages of 18 and 55 years were assigned to 1 of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide -1(GLP-1) concentrations. RESULTS: Thirty-six subjects (66 per cohort) were enrolled and completed the study (29/36 [81% ] white; mean age, 26.6 years; mean weight, 76.0 kg). Alogliptin was rapidly absorbed (median T(max), 1-2 hours) and eliminated slowly (mean t(1/2), 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%-71%). C(max) and AUC(0-infinity) increased dose proportionally over the range from 25 to 100 mg. The metabolites M-I (N-demethylated) and M-II (N-acetylated) accounted for <2% and <6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptomatic) was reported in 5 subjects (11 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, 1 receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in 1 subject each: dizziness (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo). CONCLUSION: In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients. CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.

Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study.

OBJECTIVE: To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX. METHODS: This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%). CONCLUSION: In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.