LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial.
Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.
Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA.
B
B
Zambrowicz
J
J
Freiman
P M
PM
Brown
K S
KS
Frazier
A
A
Turnage
J
J
Bronner
D
D
Ruff
M
M
Shadoan
P
P
Banks
F
F
Mseeh
D B
DB
Rawlins
N C
NC
Goodwin
R
R
Mabon
B A
BA
Harrison
A
A
Wilson
A
A
Sands
D R
DR
Powell
D000284:Administration, Oral; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006027:Glycosides / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D019894:Peptide YY / Q000097:blood; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D006027:Glycosides; D007004:Hypoglycemic Agents; D019894:Peptide YY; D051269:Sodium-Glucose Transporter 1; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014280:Triglycerides; C517652:hemoglobin A1c protein, human; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol