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Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients

Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients. Part 3 of 4. L X 4 2 1 1, a D ual Inhibito r , SG L T1 and SG L T2, Reduces Blo o d Pres sure in Patients with T2DM. LX4211, a dual inhibitor, SGLT1 and SGLT2 (N=299)

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Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients

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  1. Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients Part 3 of 4

  2. LX4211,aDualInhibitor,SGLT1andSGLT2,Reduces BloodPressureinPatientswithT2DM • LX4211, a dual inhibitor, SGLT1 and SGLT2 (N=299) • SBP reductions were 0, 4, 4, 6, and 0 mm Hg with LX4211 75 mg qd, 200 mg qd, 200 mg bid, 400 mg qd, and placebo, respectively (P<0.05 vs. placebo for LX4211 200 mg bid and 400 mg qd). • DBP reductions were 1, 3, 2, 2, and 0 mm Hg (P=NS vs. placebo for all dose arms). • In those with baseline SBP ≥130 mm Hg, placebo-subtracted SBP reductions for LX4211 400 mg were 14 mm Hg (P=0.002) as compared with 1 mm Hg (P=0.6) for those with baseline SBP <130 mm Hg. • Placebo-subtracted DBP reductions for LX4211 400 mg were 3 mm Hg (P=0.2) and 0 mm Hg (P=0.9) in those with baseline DBP ≥80 mm Hg and DBP <80 mm Hg, respectively. LapuertaP, etal. Presentedatthe49thEASDAnnualMeeting;Sept2013;Barcelona,Spain.Abstract948.

  3. EmpagliflozinCardiovascular Outcome EventTrial Ongoing multicenter, randomized, double-blind, placebo-controlled trial designed to assess the impact of the empagliflozin 10 or 25 mg, compared with placebo (1:1:1), on cardiovascular events; 7,000 patients Abbreviations: CAD=coronary artery disease, revasc.=revascularization. *CAD defined as ≥50% luminal narrowing detected on invasive coronary angioplasty or multisliced computed tomography angiography. Inzucchi S, et al. Presented at the 49th EASD Annual Meeting; Sept 2013; Barcelona, Spain. Abstract 944.

  4. Summary: Investigational SGLT2 Inhibitors • Multiple new SGLT2 inhibitors are in development with apparent comparable efficacy • Safety issues with each new agent need to be • monitored • Combining SGLT2 inhibition with a tolerable degree of SGLT1 inhibition may lead to more efficacious therapy

  5. Safety of SGLT2 Inhibitors in Patients with T2DM:Updates from EASD Vivian Fonseca, MD Professor of Medicine and Pharmacology Tullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University Health Sciences Center New Orleans, LA

  6. GenitalMycoticInfections

  7. GenitalMycoticInfectionswithCanagliflozin Pooledanalysesofdatafrom4randomized,double-blind,26-week,placebo-controlledstudiesin subjectswith type2diabetesmellitus(N=2,313) † Including genital fungal infection, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection and vulvovaginitis ‡ Possibly, probably, or very likely related to study drug, as assessed by investigators § Including balanitis, balanitis candida, balanoposthitis, and genital fungal infection Ways K, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, 2013. Abstract 950.

  8. OsmoticDiuresisandReduced IntravascularVolume

  9. AdverseEventsRelatedtoOsmoticDiuresisandReducedIntravascularVolumewithCanagliflozinAdverseEventsRelatedtoOsmoticDiuresisandReducedIntravascularVolumewithCanagliflozin Pooledanalysesofdatafrom4randomized,double-blind,26-week,placebo-controlledstudiesin subjectswith type2diabetesmellitusatweek26(N=2,313) Adverse events were generally mild or moderate in severity and led to few discontinuations. WeirM, et al.Presentedat the49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract945.

  10. SafetyofSGLT2Inhibitorsin OlderPatients

  11. Safety of Canagliflozinin OlderAdults withT2DM Pooled from 4 randomized, placebo- controlled, 26-week studies (N=2,313) SinclairA, etal.Presentedatthe49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract955.

  12. Safety of Dapagliflozinin Older Patients with T2DM Safety variables were analyzed using pooled data from 12 phase 2b/3 studies of dapagliflozin (N=4,684; placebo=1,393; dapagliflozin=3,291), including studies as monotherapy or in combination with metformin, pioglitazone, sulfonylurea or insulin. FiorettoP, etal.Presentedatthe49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract954.

  13. Long-termSafety

  14. 52 Week Data: Canagliflozin in Patients with T2DM Inadequately Controlled with Metformin Plus Sulfonylurea Randomized,double-blind, placebo- controlled,52-week,phase3study Placebo (n=156) Canagliflozin 100 mg (n=157) Canagliflozin 300 mg (n=156) Subjects,n(%) Anyadverseevent 111(71.2) 106(67.5) 114(73.1) Seriousadverseevents 13(8.3) 7(4.5) 8(5.1) Adverseeventsleadingto discontinuation 7(4.5) 11(7.0) 12(7.7) VercruysseF, et al.Presentedat the49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract934.

  15. 52-week Data: Canagliflozin in Patients with T2DM Inadequately Controlled with Metformin Plus Sulfonylurea Placebo (n=156) Canagliflozin 100 mg (n=157) Canagliflozin 300 mg (n=156) Subjects,n(%) Genitalmycoticinfection Male‡,§ Femaleı,¶ 1(1.3) 4(5.0) 6(7.9) 15(18.5) 5(5.7) 13(18.8) Osmoticdiuresis-relatedadverseevents# 3(1.9) 9(5.7) 11(7.1) Urinarytractinfection 12(7.7) 13(8.3) 13(8.3) Volume-related adverse events** Documented hypoglycemia episodes†† Severe episodes 3(1.9) 28(17.9) 1(0.6) 1(0.6) 53(33.8) 1(0.6) 6(3.8) 57(36.5) 1(0.6) *All adverse events are reported regardless of rescue medication; hypoglycemia episodes are reported for prior to rescue medication. †Possibly, probably or very likely related to study drug, as assessed by investigators. ‡Placebo, n=76; canagliflozin 100 mg, n=76; canagliflozin 300 mg, n=87. §Including balanitis, balanitis candida, and balanoposthisis. ı Placebo, n=80; canagliflozin 100 mg, n=81; canagliflozin 300 mg, n=69. ¶Including vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovsginitis. #Including dry mouth, nocturia, pollakiuria, polyuria, thirst, and urine output increased. **Including dizziness postural, hypotension, orthostatic hypotension, and syncope. ††Including biochemically documented episodes (≤3.9 mmol/L) with or without symptoms and several episodes (ie, requiring the assistance of another individual or resulting in seizure or loss of consciousness). VercruysseF, et al.Presentedat the49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract934.

  16. 4-year Data: Dapagliflozin vs Glipizide as Add-on Therapies in T2DM Inadequately • Controlled on Metformin • Double-blind extension of this study, patients continued to receive dapagliflozin (n=204) and glipizide (n=188) added to metformin • Overall frequencies of adverse events and serious adverse events were similar between groups LangkildeA, etal.Presentedatthe49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract936.

  17. 4-year Data: Dapagliflozin vs Glipizide as Add-on Therapies in T2DM Inadequately ControlledonMetformin • Genital infections: • The majority of patients with genital infections and urinary tract • infections first presented during year 1. • The majority of events were of mild/moderate intensity and resolved with standard treatment. • There were no signs of deteriorating renal function as • measured by eGFR over 4 years. LangkildeA, etal.Presentedatthe49thEASDAnnualMeeting.Barcelona,Spain.September23–27,2013.Abstract936.

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