Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SGLT2). We studied mechanistic effects of dual SGLT1/2 inhibition of SGLT1 in the gut and SGLT1/2 in the kidneys.

Methods: Effects of LIK066 on weight, glucose and a variety of incretin hormones (GLP-1, PYY, GIP, glucagon, insulin) were investigated in: 1) a single dose cross-over study in T2DM, 2) a 14 day randomized, double-masked study in T2DM, 3) a 12-week randomized, double-masked, placebo-controlled study in obese subjects with normoglycemia (NG) or dysglycemia (DG; HbA1c: ≥5.7% and <10%).

Results: LIK066 (2.5, 30, 300 mg single dose) significantly reduced glucose excursion and insulin secretion (p<0.01 at 30 and 300 mg) following oral glucose tolerance test (OGTT) in patients with T2DM (n=12), with the 300 mg dose completely suppressing glucose and insulin excursions. In patients with T2DM (n=30), LIK066 15 mg qd for 14 days reduced blood glucose (41 mg/dL by continuous glucose monitoring) and increased 24-hour urinary glucose excretion (100 g/d on day 14). Furthermore total GLP-1 and PYY increased (AUC0-3hrs >1.5-fold; p<0.05) post-OGTT, while GIP levels were reduced (>50%; p<0.05). In obese subjects (n=88), LIK066 150 mg qd for 12 weeks reduced weight by 5.70% (p<0.001) compared to placebo, with higher effects in DG (6.85%) vs. NG (4.55%). Additionally multiple metabolic parameters improved (reduced waist circumference, postprandial glucose and insulin, and increased postprandial glucagon). LIK066 was generally safe and well tolerated. The most common AEs were headache, flatulence and diarrhea.

Conclusions: LIK066 treatment leads to favorable changes in a variety of metabolic hormones (increased GLP-1, PYY and glucagon, reduced GIP, glucose and insulin), all contributing to WL effects of LIK066. The dual inhibition of SGLT1/2 in both the gut and kidneys is an attractive strategy for obesity or diabetes treatment.


Y. He: None. W.G. Haynes: Employee; Self; AstraZeneca. C.D. Meyers: Employee; Self; Janssen Research & Development. A. Amer: Employee; Self; Novartis Pharmaceuticals Corporation. Stock/Shareholder; Self; Novartis AG. Y. Zhang: Employee; Self; Novartis Pharmaceuticals Corporation. P.C. Mahling: None. A.E. Mendonza: None. S. Ma: None. W. Chutkow: Employee; Self; Novartis Pharmaceuticals Corporation. E.S. Bachman: None.

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