New Mechanisms of Action



LX4211 is an orally-delivered, small molecule drug candidate that inhibits both sodium-dependent glucose transporter 1 (SGLT1) and sodium-dependent glucose transporter 2 (SGLT2).  SGLT1 is the primary transporter responsible for glucose and galactose absorption in the gastrointestinal tract, while SGLT2 is the transporter responsible for most of the glucose reabsorption performed by the kidney.  LX411 is unique as the first dual inhibitor of SGLT1 and SGLT2 in clinical development for diabetes. 

This figure depicts a nephron, the basic functional unit of the kidney. The glucose reabsorption transporter, SGLT2, is expressed in the first segment of the proximal convoluted tubule (PCT S1) and is responsible for most of the glucose reabsorption that happens in the kidney where SGLT1 has a lesser role. Abbreviations: PCT S1 and S2, proximal convoluted tubule segments 1 and 2; PST S3, proximal straight tubule segment 3.


SGLT1 is the primary transporter for absorption of glucose and galactose in the gastrointestinal tract.


Clinical Data
In a Phase 2b study, LX4211 demonstrated a statistically-significant, dose-dependent, reduction in hemoglobin A1c (HbA1c) in patients diagnosed with poorly-controlled type 2 diabetes, who were concurrently treated with metformin. Top-line results showed that patients in the LX4211 treatment arms had mean HbA1C reductions from baseline of 0.43, 0.52, 0.79 and 0.95 percent, respectively (p<0.001 for all treatment arms). In patients randomized to placebo, HbA1C decreased by 0.09 percent. LX4211 treatment also produced significant reductions in body weight and blood pressure. Importantly, LX4211 treatment had a favorable safety profile and was well tolerated in the study.  For more detailed information, please see our press release here.

In a Phase 2a study, patients with type 2 diabetes mellitus receiving LX4211 demonstrated a statistically significant decrease in fasting plasma glucose, post-prandial glucose and, most importantly, a reduction in HbA1c, by as much as 1.25%, as compared to 0.49% in the placebo group after only four weeks of therapy. HbA1c levels, a reflection of blood glucose levels over time, were reduced to less than or equal to 7% for half the patients in both dose groups (150 mg and 400 mg once per day). Patients taking LX4211 also showed improvements in metabolic and cardiovascular safety parameters, including weight reduction, decreased blood pressure and decreased triglycerides.  LX4211 displayed a favorable safety profile in the study with no dose-limiting toxicities or hypoglycemia.

In a separate mechanistic study in patients with type 2 diabetes, a single dose of LX4211 was able to significantly increase circulating levels of GLP-1 (active and total) and PYY, important regulators of glycemic and appetite control. In another such mechanistic study, LX4211’s unique mechanism of action demonstrated synergy with a widely prescribed medication for type 2 diabetes, sitagliptin, a DPP-4 inhibitor. For more information on the results of these studies, please see our press releases.

LX4211 has completed a Phase 2b trial in patients with type 2 diabetes (see press release here), as well as a proof-of-concept trial in type 2 diabetes patients with renal impairment (see press release here). Enrollment is also ongoing for a proof-of-concept trial in type 1 diabetes (see more trial information here).

About Diabetes
Diabetes mellitus is a common metabolic disorder associated with abnormally high blood sugar levels. Diabetes is classified as either type 1, which is characterized by severely diminished insulin production, or type 2, which is characterized by moderately diminished insulin production in conjunction with insulin resistance (insensitivity of the tissues of the body to insulin). Insulin, a hormone that regulates blood glucose levels, is required to convert sugar, starches, and other food into energy needed for daily life. Diabetes can seriously impair overall quality of life and may lead to multiple complications including heart disease, stroke, and kidney failure. 

Diabetes Prevalence
According to the International Diabetes Foundation, more than 246 million people worldwide are afflicted with diabetes, with type 2 diabetes being the most common.  The National Institutes of Health (NIH) estimates that more than 20 million Americans have diabetes.  Diabetes is increasing as the population ages.  Obesity, a leading cause of the disease, is also on the increase. While weight loss can be an effective way to help prevent and treat type 2 diabetes, many diabetics also need to manage the disease with drugs.  Most diabetics control blood glucose levels by injecting insulin, or by taking newer drugs that either signal the pancreas to produce the right amount of insulin or reduce resistance to insulin.

Related Publications
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* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.