Greater Dose-Ranging Effects onA1C Levels Than on GlucosuriaWith LX4211, a Dual Inhibitor ofSGLT1 and SGLT2, in PatientsWith Type 2 Diabetes onMetformin MonotherapyDiabetes Care 2015;38:431–438 | DOI: 10.2337/dc14-0890

OBJECTIVE

To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor ofsodium–glucose cotransporter (SGLT) 1 and SGLT2, in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Type 2 diabetic patients inadequately controlled on metformin were randomlyassigned to 75 mg once daily, 200 mg once daily, 200 mg twice daily, or 400 mgonce daily of LX4211 or placebo. Primary end point was A1C change from baselineto week 12. Secondary end points included changes in blood pressure (BP) andbody weight.

RESULTS

Baseline characteristics in 299 patients randomly assigned to LX4211 or placebo inthis 12-week dose-ranging study were similar: mean age 55.9 years, A1C 8.1% (65mmol/mol), BMI 33.1 kg/m2, and BP 124/79 mmHg. LX4211 significantly reducedA1C toweek 12 in a dose-dependentmanner by 0.42% (4.6 mmol/mol), 0.52% (5.7mmol/mol), 0.80% (8.7 mmol/mol), and 0.92% (10.0 mmol/mol), respectively (P <0.001 each), compared with 0.09% (1.0 mmol/mol) for placebo. Greater A1Creductions were produced by 400 mg once a day than 200 mg once a dayLX4211 without higher urinary glucose excretion, suggesting a contribution ofSGLT1 inhibition. Significant reductions were seen in body weight (21.85 kg;P < 0.001) and systolic BP (25.7mmHg; P < 0.001), but diastolic BP was unchanged(21.6; P = 0.164). Adverse events with LX4211 were mild to moderate and similarto placebo, including urinary tract infections and gastrointestinal-related events;genital infections were limited to LX4211 groups (0–5.0%). No hypoglycemiaoccurred.

CONCLUSIONS

Dual inhibition of SGLT1/SGLT2 with LX4211 produced significant dose-rangingimprovements in glucose control without dose-increasing glucosuria and wasassociated with reductions in weight and systolic BP in metformin-treatedpatients with type 2 diabetes.

1Dallas Diabetes and Endocrine Center atMedicalCity, Dallas, TX2Pennington Biomedical Research Center,Louisiana State University System, BatonRouge, LA3Lexicon Pharmaceuticals, Inc., The Woodlands,TX

Corresponding author: Julio Rosenstock,juliorosenstock@dallasdiabetes.com.

Received 8 April 2014 and accepted 14 August2014.

Clinical trial reg. no. NCT01376557, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-0890/-/DC1.

© 2015 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

See accompanying articles, pp. 352,355, 365, 373, 376, 384, 394, 403,412, 420, and 429.

Julio Rosenstock,1 William T. Cefalu,2

Pablo Lapuerta,3 Brian Zambrowicz,3

Ike Ogbaa,3 Phillip Banks,3 and

Arthur Sands3

Diabetes Care Volume 38, March 2015 431

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