Greater dose-ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy

Julio Rosenstock, William T Cefalu, Pablo Lapuerta, Brian Zambrowicz, Ike Ogbaa, Phillip Banks, Arthur Sands, Julio Rosenstock, William T Cefalu, Pablo Lapuerta, Brian Zambrowicz, Ike Ogbaa, Phillip Banks, Arthur Sands

Abstract

Objective: To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in type 2 diabetes.

Research design and methods: Type 2 diabetic patients inadequately controlled on metformin were randomly assigned to 75 mg once daily, 200 mg once daily, 200 mg twice daily, or 400 mg once daily of LX4211 or placebo. Primary end point was A1C change from baseline to week 12. Secondary end points included changes in blood pressure (BP) and body weight.

Results: Baseline characteristics in 299 patients randomly assigned to LX4211 or placebo in this 12-week dose-ranging study were similar: mean age 55.9 years, A1C 8.1% (65 mmol/mol), BMI 33.1 kg/m(2), and BP 124/79 mmHg. LX4211 significantly reduced A1C to week 12 in a dose-dependent manner by 0.42% (4.6 mmol/mol), 0.52% (5.7 mmol/mol), 0.80% (8.7 mmol/mol), and 0.92% (10.0 mmol/mol), respectively (P < 0.001 each), compared with 0.09% (1.0 mmol/mol) for placebo. Greater A1C reductions were produced by 400 mg once a day than 200 mg once a day LX4211 without higher urinary glucose excretion, suggesting a contribution of SGLT1 inhibition. Significant reductions were seen in body weight (-1.85 kg; P < 0.001) and systolic BP (-5.7 mmHg; P < 0.001), but diastolic BP was unchanged (-1.6; P = 0.164). Adverse events with LX4211 were mild to moderate and similar to placebo, including urinary tract infections and gastrointestinal-related events; genital infections were limited to LX4211 groups (0-5.0%). No hypoglycemia occurred.

Conclusions: Dual inhibition of SGLT1/SGLT2 with LX4211 produced significant dose-ranging improvements in glucose control without dose-increasing glucosuria and was associated with reductions in weight and systolic BP in metformin-treated patients with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01376557.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1
Figure 1
A1C, weight, and UGE changes. PBO, placebo.

References

    1. Starke A, Grundy S, McGarry JD, Unger RH. Correction of hyperglycemia with phloridzin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes. Proc Natl Acad Sci U S A 1985;82:1544–1546
    1. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 1987;79:1510–1515
    1. Malathi P, Crane RK. Phlorizin hydrolase: a beta-glucosidase of hamster intestinal brush border membrane. Biochim Biophys Acta 1969;173:245–256
    1. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012;8:495–502
    1. Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int 2009;75:1272–1277
    1. Zambrowicz B, Freiman J, Brown PM, et al. . LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther 2012;92:158–169
    1. Washburn WN, Poucher SM. Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs 2013;22:463–486
    1. Gorboulev V, Schürmann A, Vallon V, et al. . Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 2012;61:187–196
    1. Powell DR, DaCosta CM, Gay J, et al. . Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab 2013;304:E117–E130
    1. Wright EM. I. Glucose galactose malabsorption. Am J Physiol 1998;275:879–882
    1. Ikumi Y, Kida T, Sakuma S, Yamashita S, Akashi M. Polymer-phloridzin conjugates as an anti-diabetic drug that inhibits glucose absorption through the Na+/glucose cotransporter (SGLT1) in the small intestine. J Control Release 2008;125:42–49
    1. Sakuma S, Teraoka Y, Sagawa T, et al. . Carboxyl group-terminated polyamidoamine dendrimers bearing glucosides inhibit intestinal hexose transporter-mediated D-glucose uptake. Eur J Pharm Biopharm 2010;75:366–374
    1. Dobbins R, Chen L, Liu YJ, et al. Glucose transport via SGLT1 is critical for post-prandial GIP secretion in rats and humans. Presented at the 2012 American Diabetes Association annual meeting, 8–12 June 2012, Philadelphia, PA. Available at . Accessed 13 February 2014
    1. Shibazaki T, Tomae M, Ishikawa-Takemura Y, et al. . KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther 2012;342:288–296
    1. Powell DR, Smith M, Greer J, et al. . LX4211 increases serum GLD-1 PYY levels by reducing SGLT-1 mediated absorption of intestinal glucose. J Pharmacol Exp Ther 2014;350:232–242
    1. Zambrowicz B, Ding ZM, Ogbaa I, et al. . Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes. Clin Ther 2013;35:273–285, e7
    1. Zambrowicz B, Ogbaa I, Frazier K, et al. . LX4211, a dual SGLT1 and 2 inhibitor, reduced postprandial glucose in a dose timing study in healthy subjects. Clin Ther 2013;35:1162–1173
    1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132:2131–2157
    1. Batterham RL, Cowley MA, Small CJ, et al. . Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002;418:650–654
    1. Kaku H, Tajiri Y, Yamada K. Anorexigenic effects of miglitol in concert with the alterations of gut hormone secretion and gastric emptying in healthy subjects. Horm Metab Res 2012;44:312–318
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481
    1. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009;32:650–657
    1. Rosenstock J, Aggarwal N, Polidori D, et al. .; Canagliflozin DIA 2001 Study Group . Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232–1238
    1. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab 2013;15:721–728
    1. Lapuerta P, Sands A, Ogbaa I, Strumph P, Powell D, Banks P, Zambrowicz B. LX4211, a dual inhibitor of SGLT1/SGLT2, reduces postprandial glucose in patients with type 2 diabetes mellitus and moderate to severe renal impairment (Abstract). Diabetes 2014;63(Suppl. 1A):132-LB.
    1. Chao EC, Henry RR. SGLT2 inhibition—a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010;9:551–559
    1. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011;91:733–794
    1. Xin B, Wang H. Multiple sequence variations in SLC5A1 gene are associated with glucose-galactose malabsorption in a large cohort of Old Order Amish. Clin Genet 2011;79:86–91
    1. Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin 2012;28:1173–1178
    1. Stein P. Canagliflozin: an overview of presentations at the American Diabetes Association 2012. Presented at the 72nd Scientific Sessions of the American Diabetes Association, 8–12 June 2012, at the Pennsylvania Convention Center, Philadelphia, Pennsylvania
    1. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223–2233
    1. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration . Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–1535
    1. Draft ICH Consensus Principle. Principles for Clinical Evaluation of New Antihypertensive Drugs E12A [Internet], 2000. Available at . Accessed 26 September 2012

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