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Clin Ther. 2013 Mar;35(3):273-285.e7. doi: 10.1016/j.clinthera.2013.01.010. Epub 2013 Feb 21.

Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes.

Author information

1
Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA. Brian@lexpharma.com

Abstract

BACKGROUND:

Combination therapy is required to provide adequate glycemic control in many patients with type 2 diabetes mellitus (T2DM). Because sodium-dependent glucose transporter (SGLT)-1 inhibition results in an increased release of glucagon-like peptide (GLP)-1, and because dipeptidyl peptidase (DPP)-4 inhibitors prevent its inactivation, the 2 mechanisms together provide an intriguing potential combination therapy.

OBJECTIVES:

This combination was explored in preclinical models and then tested in patients with T2DM to compare the effects of single-dose LX4211 400 mg and sitagliptin 100 mg, administered as monotherapy or in combination, on GLP-1, peptide tyrosine tyrosine (PYY), gastric inhibitory peptide (GIP), glucose, and insulin.

METHODS:

Preclinical: Obese male C57BL6J mice were assigned to 1 of 4 treatment groups: LX4211 60 mg/kg, sitagliptin 30 mg/kg, LX4211 + sitagliptin, or inactive vehicle. Clinical: This 3-treatment, 3-crossover, randomized, open-label study was conducted at a single center. Patients on metformin monotherapy were washed out from metformin and were randomly assigned to receive sequences of single-dose LX4211, sitagliptin, or the combination. In both studies, blood was collected for the analysis of pharmacodynamic variables (GLP-1, PYY, GIP, glucose, and insulin). In the clinical study, urine was collected to assess urinary glucose excretion.

RESULTS:

Preclinical: 120 mice were treated and assessed (5/time point/treatment group). With repeat daily dosing, the combination was associated with apparently synergistic increases in active GLP-1 relative to monotherapy with either agent; this finding was supported by findings from an additional 14-day repeated-dose experiment. Clinical: 18 patients were enrolled and treated (mean age, 49 years; 56% male; 89% white). The LX4211 + sitagliptin combination was associated with significantly increased active GLP-1, total GLP-1, and total PYY; with a significant reduction in total GIP; and with a significantly improved blood glucose level, with less insulin, compared with sitagliptin monotherapy. LX4211 was associated with a significant increase in total GLP-1 and PYY and a reduced total GIP, likely due to a reduction in SGLT1-mediated intestinal glucose absorption, whereas sitagliptin was associated with suppression of all 3 peptides relative to baseline. All treatments were well tolerated, with no evidence of diarrhea with LX4211 treatment.

CONCLUSIONS:

The findings from the preclinical studies suggest that the LX4211 + sitagliptin combination produced synergistic increases in active GLP-1 after a meal challenge containing glucose. These initial clinical results also suggest that a LX4211 + DPP-4 inhibitor combination may provide an option in patients with T2DM. The potential long-term clinical benefits of such combination treatment need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01441232.

PMID:
23433601
DOI:
10.1016/j.clinthera.2013.01.010
[Indexed for MEDLINE]

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