Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Added to Ongoing Metformin Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Alone

Abstract

OBJECTIVE -The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had inadequate glycemic control (HbA 1c [A1C] Ն7 and Յ10%) with metformin alone. RESEARCH DESIGN AND METHODS-After a screening diet/exercise run-in period, a metformin dose titration/stabilization period, and a 2-week, single-blind, placebo run-in period, 701 patients, aged 19 -78 years, with mild to moderate hyperglycemia (mean A1C 8.0%) receiving ongoing metformin (Ն1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The efficacy analyses were based on an all-patients-treated population using an ANCOVA and excluded data obtained after glycemic rescue.RESULTS -At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (Ϫ0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC-to-glucose AUC ratio, homeostasis model assessment of ␤-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C Ͻ7% with sitagliptin (47.0%) than with placebo (18.3%). There was no increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared with placebo. Body weight decreased similarly with sitagliptin and placebo.CONCLUSIONS -Sitagliptin 100 mg once-daily added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

Diabesity: therapeutic options

“…Sitagliptin is approved in both USA and the European Union and many other countries; indications include its use as monotherapy and in combination therapy with metformin, a sulphonylurea or TZD in people with type 2 diabetes. In a 24-week study, sitagliptin cotherapy led to significant reductions in both HbA1c (−0.65%) and fasting glucose levels (−1.4 mmol/L) in subjects inadequately controlled on metformin alone [117]. Weight reduction was not different in the active or placebo groups (a mean decrease of 0.6 kg compared with 0.7 for placebo) [117].…”

“…In a 24-week study, sitagliptin cotherapy led to significant reductions in both HbA1c (−0.65%) and fasting glucose levels (−1.4 mmol/L) in subjects inadequately controlled on metformin alone [117]. Weight reduction was not different in the active or placebo groups (a mean decrease of 0.6 kg compared with 0.7 for placebo) [117].…”

“…In a 24-week study, sitagliptin cotherapy led to significant reductions in both HbA1c (−0.65%) and fasting glucose levels (−1.4 mmol/L) in subjects inadequately controlled on metformin alone [117]. Weight reduction was not different in the active or placebo groups (a mean decrease of 0.6 kg compared with 0.7 for placebo) [117].Similarly, sitagliptin monotherapy (100 mg; 200 mg) produced significant reductions in HbA1c (−0.79 and −0.94% respectively), but did not result in clinically meaningful weight loss (change from baseline −0.2 ± 0.2 and −0.1 ± 0.2 kg respectively) [118].A head-to-head comparison of sitagliptin, metformin and combined sitagliptin and metformin therapy revealed that combination therapy led to significantly greater improvements in HbA1c than either agent alone. All treatment groups experienced small but significant reductions in body weight (−0.6 to 1.3 kg), except those receiving sitagliptin monotherapy, in whom no change in weight (0.0 kg) was observed [119].…”

Impaired glucose tolerance and incretins in chronic liver disease

“…4 Like exenatide, sitagliptin is effective as a combination therapy with either metformin or pioglitazone. 5,6 Sitagliptin therapy for 24 weeks is associated with lowered fasting blood glucose and increased insulin sensitivity compared to placebo and less nausea and fewer hypoglycemic events than other therapies. Rodent studies indicate that improved glucose homeostasis from sitagliptin is associated with improved pancreatic beta cell function, and the human trials show increased insulin sensitivity.…”

“…Newer therapies, however, such as gemtuzumab ozogamicin, when used in the months leading up to HCT, are now recognized to lead to SOS in up to 40% of patients. 4,5 When SOS does occur, the diagnosis can usually be made on clinical grounds, without recourse to liver biopsy. Painful hepatomegaly, jaundice and fluid retention are the hallmark features.…”