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Active (Glipizide)-Controlled Study in Combination with Metformin: Long- term maintenance of
effect was evaluated in a 52-week, double-blind, glipizide-controlled trial in patients with
type 2 diabetes and inadequate glycemic control on metformin monotherapy at
≥1500 mg/day. In this study, patients were randomized to the addition of either sitagliptin
100 mg daily (N=588) or glipizide (N=584) for 52 weeks. Patients receiving glipizide were given an
initial dosage of 5 mg/day and then electively titrated by the investigator to a target FPG
of <110 mg/dL, without significant hypoglycemia, over the next 18 weeks. A maximum dosage of
20 mg/day was allowed to optimize glycemic control. Thereafter, the glipizide dose was to have
been kept constant. The mean dose of glipizide after the titration period was 10.3 mg.
Both treatments resulted in a statistically significant improvement in glycemic control
from baseline. After 52 weeks, the reduction from baseline in HbA1c was 0.67% for
sitagliptin 100 mg daily and 0.67% for glipizide, confirming comparable efficacy of the 2 agents.
The reduction in FPG was 10 mg/dL for sitagliptin and 7.5 mg/dL for glipizide. In a post-hoc analysis,
patients with higher baseline HbA1c (≥9%) in both groups had greater reductions
from baseline in HbA1c (sitagliptin, -1.68%; glipizide, -1.76%). In this study,
the proinsulin to insulin ratio, a marker of efficiency of insulin synthesis and release,
improved with sitagliptin and deteriorated with glipizide treatment. The incidence of hypoglycemia
in the sitagliptin group (4.9%) was significantly lower than that in the glipizide group (32%).
Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight
compared to a significant weight gain in patients administered with glipizide (-1.5 kg vs +1.1 kg).
Metformin HCI: The prospective randomized (UKPDS) study has established the long-term benefit
of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients
treated with metformin after failure of diet alone showed:
A significant reduction of the absolute risk of any diabetes-related complication
in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years),
p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034.
A significant reduction of the absolute risk of diabetes-related mortality:
Metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017.
A significant reduction of the absolute risk of overall mortality: Metformin 13.5 events/1000
patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined
sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021).
A significant reduction in the absolute risk of myocardial infarction: Metformin 11 events/1000
patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Pharmacokinetics: The results of a definitive bioequivalence study in healthy subjects
demonstrated that the Janumet (sitagliptin/metformin HCI) 50 mg/500 mg and 50 mg/1000 mg combination
tablets are bioequivalent to co-administration of corresponding doses of sitagliptin phosphate
(Januvia) and metformin HCI as individual tablets.
Because bioequivalence is demonstrated at the lowest and highest combination tablet dose
strengths available, bioequivalence is conferred to the (sitagliptin/metformin) 50 mg/850 mg fixed-dose
combination (FDC) tablet. Absorption: Sitagliptin Phosphate: The absolute bioavailability of sitagliptin
is approximately 87%. Co-administration of a high-fat meal with sitagliptin phosphate had no effect on the pharmacokinetics of sitagliptin.
Metformin HCI: The absolute bioavailability of a metformin HCI 500 mg tablet given under
fasting conditions is approximately 50-60%. Studies using single oral doses of metformin HCI tablets
500-1500 mg, and 850- 2550 mg, indicate that there is a lack of dose proportionality with increasing doses,
which is due to decreased absorption rather than an alternation in elimination.
Food decreases the extent of and slightly delays the absorption of metformin, as shown by
approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under
the plasma concentration versus time curve (AUC), and a 35-min prolongation of time to peak plasma
concentration (Tmax) following administration of a single 850-mg tablet of metformin with food,
compared to the same tablet strength administered during fasting. The clinical relevance of these decreases is unknown.
Distribution: Sitagliptin Phosphate: The mean volume of distribution at steady state following
a single 100-mg IV dose of sitagliptin to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
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