Lexicon Pharmaceuticals has announced the top-line results from the first clinical study evaluating the combined effects of LX4211, a sodium glucose transporter 1 and 2 (SGLT1 and SGLT2) inhibitor, with dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin.
The mechanistic study involved 18 type 2 diabetic patients, who received single doses of either LX4211 (400mg), sitagliptin (100mg) or LX4211 plus sitagliptin on days one, eight, or 15. The study assessed pharmacodynamic parameters, including postprandial glucose, insulin, total and active glucagon-like peptide-1, PYY, and urinary glucose excretion.
The study showed that single doses of LX4211 in combination with sitagliptin produced lower blood glucose levels after meals (postprandial) as compared to treatment with sitagliptin alone.
Lexicon chief medical officer Pablo Lapuerta said LX4211 alone shows improvement in postprandial blood glucose by delaying intestinal glucose absorption and increasing urinary glucose excretion, and when combined, the two agents produce enhanced benefits on blood glucose, insulin, GLP-1 and PYY relative to sitagliptin alone.
The improved enhanced glycemic control was associated with an elevation of active GLP-1 over treatment with either LX4211 or sitagliptin alone.
Lexicon executive vice-president and chief scientific officer Brian Zambrowicz said that the new clinical results are supported by the recent pre-clinical studies in mice, which demonstrated a considerable increase in active GLP-1 after combination treatment with LX4211 and sitagliptin, an effect that is both synergistic and sustained.
“This ability of LX4211 to synergize with DPP-4 inhibition to further increase active GLP-1 is likely to evolve as a significant differentiating feature from SGLT2-selective inhibitors which have not been shown to affect GLP-1,” Zambrowicz said.
DPP-4 inhibitors have been shown to decrease total GLP-1, and are often used along with other agents, such as metformin, to treat diabetes.