A compound is being investigated as a Type II diabetes treatment by Lexicon Pharmaceuticals, although it is in an early stage of development.
LX4211 is not selective for just sodium glucose co-transporter-2, or SGLT-2 – it also inhibits SGLT-1.1 Inhibiting this second transporter, responsible for the absorption of glucose in the intestines, it also results in an increase in the release of glucagon-like peptide-1 (GLP-1), but might be combated by administering the dual inhibitor in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor to prevent it being activated.
In one clinical trial, a total of 36 patients with Type II diabetes were given 150 or 300mg doses of LX4211 or placebo for 28 days.2 Compared with placebo, both doses of the drug increased glucose excretion by inhibiting renal glucose reabsorption mediated by SGLT-2. It had a significant increase on various measures of glycaemic control, including fasting plasma glucose, oral glucose tolerance and HbA1c levels. It also produced a significant lowering of serum triglycerides.
A follow-up single dose study was carried out in 12 further patients, who were given 300mg of the drug and were found to have significantly increased GLP-1 levels, which were assumed to be a result of SGLT-1 mediated intestinal glucose absorption.
A larger and longer Phase II trial has also been carried out. A total of 299 patients with Type II diabetes that was poorly controlled by metformin were given 200 or 400mg of LX4211 once a day, 200mg twice a day, or placebo.3 The drug was found to reduce HbA1c in a dose-dependent way, with the 400mg dose reducing it further without any rise in the glucose to creatinine levels in the urine.
Significant reductions in blood pressure and bodyweight were seen compared with placebo. Adverse events were largely mild to moderate, and the overall incidence similar between the treated groups and placebo.
Following promising studies in mice on the therapeutic potential of LX4211 when administered with the DPP-4 inhibitor sitagliptin,4 clinical trials of the combination are now underway.
1. N.C. Goodwin et al. J. Med. Chem. 2009, 52, 6201
2. B. Zambrowicz et al. Clin. Pharmacol. Ther. 2012, 92, 158
3. J. Rosenstock et al. Amer. Heart Assoc. Sci. Sessions 2012 (Los Angeles, 3–7 Nov), Abst.
4. B. Zambrowicz et al. Clin. Ther. 2013, Feb 20, epub ahead of print, doi: 10.1016/j.clinthera.2013.01.010
