title: Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes.
abstract: BACKGROUND
  Combination therapy is required to provide adequate glycemic control in many patients with type 2 diabetes mellitus (T2DM). Because sodium-dependent glucose transporter (SGLT)-1 inhibition results in an increased release of glucagon-like peptide (GLP)-1, and because dipeptidyl peptidase (DPP)-4 inhibitors prevent its inactivation, the 2 mechanisms together provide an intriguing potential combination therapy.
  
  
  OBJECTIVE
  This combination was explored in preclinical models and then tested in patients with T2DM to compare the effects of single-dose LX4211 400 mg and sitagliptin 100 mg, administered as monotherapy or in combination, on GLP-1, peptide tyrosine tyrosine (PYY), gastric inhibitory peptide (GIP), glucose, and insulin.
  
  
  METHODS
  Preclinical: Obese male C57BL6J mice were assigned to 1 of 4 treatment groups: LX4211 60 mg/kg, sitagliptin 30 mg/kg, LX4211 + sitagliptin, or inactive vehicle. Clinical: This 3-treatment, 3-crossover, randomized, open-label study was conducted at a single center. Patients on metformin monotherapy were washed out from metformin and were randomly assigned to receive sequences of single-dose LX4211, sitagliptin, or the combination. In both studies, blood was collected for the analysis of pharmacodynamic variables (GLP-1, PYY, GIP, glucose, and insulin). In the clinical study, urine was collected to assess urinary glucose excretion.
  
  
  RESULTS
  Preclinical: 120 mice were treated and assessed (5/time point/treatment group). With repeat daily dosing, the combination was associated with apparently synergistic increases in active GLP-1 relative to monotherapy with either agent; this finding was supported by findings from an additional 14-day repeated-dose experiment. Clinical: 18 patients were enrolled and treated (mean age, 49 years; 56% male; 89% white). The LX4211 + sitagliptin combination was associated with significantly increased active GLP-1, total GLP-1, and total PYY; with a significant reduction in total GIP; and with a significantly improved blood glucose level, with less insulin, compared with sitagliptin monotherapy. LX4211 was associated with a significant increase in total GLP-1 and PYY and a reduced total GIP, likely due to a reduction in SGLT1-mediated intestinal glucose absorption, whereas sitagliptin was associated with suppression of all 3 peptides relative to baseline. All treatments were well tolerated, with no evidence of diarrhea with LX4211 treatment.
  
  
  CONCLUSIONS
  The findings from the preclinical studies suggest that the LX4211 + sitagliptin combination produced synergistic increases in active GLP-1 after a meal challenge containing glucose. These initial clinical results also suggest that a LX4211 + DPP-4 inhibitor combination may provide an option in patients with T2DM. The potential long-term clinical benefits of such combination treatment need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01441232.
authors: Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA. Brian@lexpharma.com
authors: Brian
authors: B
authors: Zambrowicz
authors: Zhi-Ming
authors: ZM
authors: Ding
authors: Ike
authors: I
authors: Ogbaa
authors: Kenny
authors: K
authors: Frazier
authors: Phillip
authors: P
authors: Banks
authors: Anne
authors: A
authors: Turnage
authors: Joel
authors: J
authors: Freiman
authors: Melinda
authors: M
authors: Smith
authors: Dennis
authors: D
authors: Ruff
authors: Arthur
authors: A
authors: Sands
authors: David
authors: D
authors: Powell
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D006027:Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D019518:Postprandial Period; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors*; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D006027:Glycosides; D007004:Hypoglycemic Agents; D011719:Pyrazines; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014230:Triazoles; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate