Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes.
OBJECTIVE
Enhancing the physiologic actions of the endogenous incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, by inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for their degradation, is an emerging treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the safety and efficacy of dose ranges of the DPP-4 inhibitor saxagliptin (BMS-477118) in patients with T2DM.


METHODS
In a 12-week, multicentre, randomized, parallel-group, double-blind, placebo-controlled trial conducted at 152 out-patient US study centres, 338 (low-dose cohort) and 85 (high-dose cohort) drug-naive patients with T2DM and inadequate glycaemic control (baseline HbA1c > or =6.8 and < or =9.7%) were randomized. Following a 2-week washout, patients received saxagliptin 2.5, 5, 10, 20 or 40 mg once daily, or placebo, for 12 weeks (low-dose cohort). In a second cohort, patients received saxagliptin 100 mg once daily, or placebo, for 6 weeks (high-dose cohort). The main outcome measure was saxagliptin dose response assessed as change from baseline in HbA1c following double-blind treatment.


RESULTS
In all treatment arms, saxagliptin significantly reduced HbA1c by 0.7-0.9% from an average baseline of 7.9% vs. placebo (0.3% reduction) in the low-dose cohort. Placebo-subtracted HbA1c reductions were 0.45-0.63% (low-dose cohort). Saxagliptin had significant placebo-subtracted reductions in fasting serum glucose (14-25 mg/dl). Postprandial glucose levels at 60 min following a standard liquid meal test were reduced by 24-41 mg/dl vs. placebo. Saxagliptin was weight neutral. Adverse events were similar across treatment groups, including placebo, with a very low incidence of confirmed hypoglycaemia in saxagliptin treatment arms.


CONCLUSIONS
Saxagliptin effectively improved glycaemic control in drug-naive patients with T2DM and was generally safe, with a tolerability profile similar to placebo.
Rosenstock
J
J
Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX 75230, USA. juliorosenstock@dallasdiabetes.com
Sankoh
S
S
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D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004151:Dipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000218:Adamantane; D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; C502994:saxagliptin