Lexicon’s Unique Experimental Medication LX4211 Impresses in Early Trials

When your blood sugar gets too high, don’t you wish you could just filter the sugar out of your blood stream? In fact, along with waste products, the kidneys filter about 180 grams of glucose out of the blood each day, although almost none of that sugar makes it to the toilet. Since our bodies are designed to never waste calories, a special pump works hard in the kidneys to push this filtered sugar back into the blood stream. This pump, which is called the sodium glucose transporter-2 (SGLT-2), is now the target of a new class of investigational diabetes medication called SGLT-2 inhibitors. By turning off the kidneys' glucose pump, this class of investigational medication improves glycemic control by allowing people to urinate excess glucose (see our Learning Curve in diaTribe #8).

There are a number of SGLT-2 inhibitors in development, of which the furthest along is called dapagliflozin. It has been developed through a joint venture between the pharmaceutical companies Bristol-Myers Squibb and AstraZeneca, and it could become available for people with type 2 diabetes by the end of 2011. Another experimental medication that blocks SGLT-2 called LX4211 lags years behind dapagliflozin, but has some particularly interesting attributes. LX4211, which is being developed by Texas-based Lexicon Pharmaceuticals, is unique because it blocks not only SGLT-2, but also a second glucose pump called SGLT-1 that is found in the gut (and also in the kidneys to a lesser extent). Therefore, LX4211 not only causes the kidney to excrete glucose, but it also has the added benefit of blocking the absorption of glucose in the gut. One longstanding objection of SGLT-1 inhibition is that blocking sugar absorption in the gut could theoretically lead to lots of diarrhea and flatulence because the left-behind sugar could become a feast for gut bacteria. In a similar fashion, there are concerns of yeast infections and other urinary tract infections with SGLT-2 inhibitors. However, in the first small studies of LX4211, neither of these has been an issue. In fact, the left-over sugar in the gut has instead proved to be yet another bonus, because it seems to stimulate the gut to secrete “incretin” hormones like GLP-1 and PYY, which make us feel full, cause weight loss, and stimulate the secretion of insulin. (Several approved diabetes medications like the GLP-1 agonists Byetta and Victoza, and the DPP-4 inhibitors Januvia, Tradjenta, and Onglyza, work by leveraging one or both of these hormones.) In a recent four-week trial in individuals with type 2 diabetes, individuals treated with LX4211 had a 0.76% reduction in A1c and just over four pounds of weight loss beyond placebo (inactive pill). Lexicon expects to initiate a larger 12-week study of LX4211 in June; if recruitment goes smoothly, initial results could be released in the first half of 2012.  --MY