Effects of LX4211, a Dual SGLT1/SGLT2 Inhibitor, Plus Sitagliptin on Postprandial Active GLP-1 and Glycemic Control in Type 2 Diabetes

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• 作者：Brian Zambrowicz ; PhD¹ ; ^{Brian@lexpharma.com} ; Zhi-Ming Ding ; MD ; PhD¹ ; Ike Ogbaa ; MD¹ ; Kenny Frazier ; BS¹ ; Phillip Banks ; MS¹ ; Anne Turnage ; BA¹ ; Joel Freiman ; MD¹ ; Melinda Smith ; BS¹ ; Dennis Ruff ; MD² ; Arthur Sands ; MD ; PhD¹ ; David Powell ; MD¹
• 关键词：adult ; diabetes ; dipeptidyl peptidase-4 ; GIP ; GLP-1 ; glucose ; glycemic control ; human ; insulin ; PYY ; SGLT1 ; SGLT2 ; sitagliptin ; urinary glucose excretion
• 刊名：Clinical Therapeutics
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：35
• 期：3
• 页码：273-285.e7
• 全文大小：1408 K

文摘

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. identifier: .