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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 4 of 4. Incorporating SGLT2 Inhibitors into Practice:. Updates from EASD Mark W. Stolar, MD Associate Professor Clinical Medicine, General Internal Medicine and Geriatrics Feinberg School of Medicine

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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 4 of 4

  2. Incorporating SGLT2 Inhibitors into Practice: Updates from EASD Mark W. Stolar, MD Associate Professor Clinical Medicine, General Internal Medicine and Geriatrics Feinberg School of Medicine Northwestern University Chicago, IL

  3. SGLT2 Inhibitors: Use in Challenging or Special Populations • Non-insulin dependent mechanism of action allows for use in low insulin secreting or high insulin resistance type 2 diabetics • Safety/efficacy in older adults and /or renally impaired patients • Effects on weight, blood pressure and lipids

  4. Decision-MakingElementsin DeterminingA1CTargets MORE STRINGENT LESS STRINGENT Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, poor self-care capacities High Long-standing Short Severe Severe Limited RiskspotentiallyassociatedwithLow hypoglycemia, other adverse events Disease duration Newlydiagnosed Lifeexpectancy Long Importantcomorbidities Absent Established vascular complications Absent Resources,supportsystem Readilyavailable Hypotheticalpatient.Examplesare forillustrativepurposes only. AdaptedfromInzucchiSE,et al.DiabetesCare.2012;35(6):1364-1379.

  5. Decision-MakingElementsin DeterminingA1CTargets MORE STRINGENT LESS STRINGENT Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, poor self-care capacities High Long-standing Short Severe Severe Limited RiskspotentiallyassociatedwithLow hypoglycemia, other adverse events Disease duration Newlydiagnosed Lifeexpectancy Long Importantcomorbidities Absent Established vascular complications Absent Resources,supportsystem Readilyavailable Hypotheticalpatient.Examplesare forillustrativepurposes only. AdaptedfromInzucchiSE,et al.DiabetesCare.2012;35(6):1364-1379.

  6. Decision-MakingElementsin DeterminingA1CTargets MORE STRINGENT LESS STRINGENT Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, poor self-care capacities High Long-standing Short Severe Severe Limited RiskspotentiallyassociatedwithLow hypoglycemia, other adverse events Disease duration Newlydiagnosed Lifeexpectancy Long Importantcomorbidities Absent Established vascular complications Absent Resources,supportsystem Readilyavailable Hypotheticalpatient.Examplesare forillustrativepurposes only. AdaptedfromInzucchiSE,et al.DiabetesCare.2012;35(6):1364-1379.

  7. OminousOctet Reprintedwithpermissionfrom DeFronzoRA.Diabetes.2009;58:773-795.

  8. Increasedhepaticglucoseproduction Reduced peripheral glucose uptake Reduced pancreatic insulin secretion Insulin resistance Hyperglycemia Inhibition of glucose reabsorption from renal tubules Urinaryglucosedisposal Reduce fasting plasma glucose Improveglucosetolerance A1C reduction Urinary calorie loss/ Weight Loss AdaptedfromIdrisI, et al.DiabObes Metab.2009;11:79-88.

  9. EfficacyofSGLT2Inhibitorsin OlderAdults

  10. Efficacy of Canagliflozin in Older Adults: A1C and Weight Pooleddatafrom4 randomized,placebo-controlled,26-weekstudies(N=2,313) SinclairA, etal.Presentedatthe49thEASDAnnualMeeting;Barcelona,Spain;Sept,2013.Abstract955.

  11. EfficacyofCanagliflozininOlderSubjects:LipidandBPeffects Pooleddatafrom4 randomized,placebo-controlled,26-weekstudies(N=2,313) SinclairA, etal.Presentedatthe49thEASDAnnualMeeting;Barcelona,Spain;Sept2013Abstract955.

  12. PatientswithChronicKidney Disease

  13. Diabetes Therapy in the Setting of Impaired Renal Function • Metformin not indicated based on eGFR • Sulfonylureas should be used cautiously if at all due to hypoglycemic risk • TZD drugs are safe, but risk of edema increased with low • eGFR • DPP-4 inhibitors may require dosage adjustment • GLP-1 receptor agonists may require dosage adjustment • Insulin clearance is decreased, and risk of hypoglycemia is increased • SGLT2 inhibitors safe, but efficacy may be decreased

  14. Efficacy andSafetyofCanagliflozininPatientswith T2DM andChronicKidneyDisease:A1CandWeight NietoJ, etal. Presentedatthe49thEASDAnnualMeeting;Barcelona,Spain;Sept2013.Abstract951.

  15. Efficacy and Safety of Canagliflozin in Patients with T2DM and Chronic Kidney Disease: Lipid and Blood Pressure Effects NietoJ, etal. Presentedatthe49thEASDAnnualMeeting;Barcelona,Spain;Sept2013.Abstract951.

  16. ChangeinA1CwithCanagliflozininSubjectswithT2DMandStage3ChronicKidneyDiseaseChangeinA1CwithCanagliflozininSubjectswithT2DMandStage3ChronicKidneyDisease Pooled analysis in patients with T2DM from placebo-controlled studies with eGFR >30 and <60 mL/min/1.73m2 (n=1,085) and in subgroups with eGFR >45 and <60 (n=721) or > 30 and <45 (n=364). Data presented as Least Squares Mean (SE) change from baseline using ANCOVA and placebo-subtracted Least Squares mean (95% CI) values. † Mean baseline age 67 years; A1C 8.1%; eGFR 48.2; body weight 91 kg. ‡ Mean baseline age 66 years; A1C 8.1%; eGFR 53.3; body weight 90 kg; §Mean baseline age 66 years; A1C 8.1%; eGFR 38.2; body weight 92 kg. ¥ P < 0.001 vs placebo. P values reported for prespecified comparisons only. WooV,et al.PresentedatAmericanDiabetes2013ScientificSessions;Chicago,IL; June2013.Abstract73-LB.

  17. RecommendedDosing in PatientswithRenalImpairment Canagliflozin Dapagliflozin • Increase dose to 300 mg daily if eGFR • >60 mL/min/1.73 m2 • eGFR 45 to < 60 mL/min/1.73 m2: Limit dose to 100 mg daily • Do not initiate or discontinue if eGFR • < 45 mL/min/1.73 m2 • Do not initiate or discontinue if eGFR • < 60 mL/min/1.73 m2 Canagliflozin[packageinsert].Titusville,NJ: JanssenPharmaceuticals;2013. Dapagliflozin[packageinsert].Princeton,NJ: Bristol-MyersSquibbCompany;2014.

  18. ChangesinLipid Profileswith SGLT2 Inhibitors

  19. ChangesinLipidProfilesof PatientsonDapagliflozin Plasmalipidchangesfrombaseline(%,95%CI)inpooledDAPAstudiesat24weeks 12phase2b/3double-blind, controlledtrials forupto24weekswereanalyzed.(n=3,731) HardyE, etal.Presentedatthe49thEASDAnnualMeeting.Barcelona,Spain.Sept2013.Abstract947.

  20. WeightLossandBlood PressureEffects

  21. Dapagliflozin-inducedWeightLossAffects24WeekA1CandBloodPressureLevelsDapagliflozin-inducedWeightLossAffects24WeekA1CandBloodPressureLevels ∆ BW,kg -5 -4 -3 -2 -1 0 0 Effectofother 14% 17% variables Added benefit of weight loss during dapagliflozin treatment that contributes to overall changes in A1C and to changes in blood pressure after 24 weeks of treatment -1 37% -2 Effect of ∆ In BW 49% ∆SBP,mmHg -3 46% -4 Non-BW ∆ related -5 37% treatmenteffect Dapagliflozin10mg -6 Placebo -7 SjöströmCD, etal. Presentedatthe49thEASDAnnualMeeting.Barcelona,Spain.Sept2013.Abstract181.

  22. Canagliflozin Lowers A1C Through Weight Loss–Independent and Weight Loss–Associated Mechanisms RelationshipbetweenchangesinA1Candbodyweightatweek26* 0.2 0 -0.2 -0.4 -0.6 -0. -1.0 -1.2 -1.4 Placebo Canagliflozin 100 mg Canagliflozin 300 mg ∆ A1C(%) Weightloss- independent Weight loss- associated Most (85%) of the A1C-lowering effect of canagliflozin is independent of weight loss -10 -5 0 5 ∆ body weight (%) Across all 3 treatment groups, subjects with greater weight loss had greater reductions in A1C, and the slope associated weight loss for A1C was similar across all 3 groups. Each 1% reduction in BW was associated with a 0.045% reduction in A1C. *Solid symbols represent mean changes within each decile of weight change, and open symbols are mean changes in the entire treatment group. Pooled analysis of 4 previously reported, randomized, double-blind, 26-week, phase 3 studies (N=2,250). Wilding L, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept 2013. Abstract 946. Reproduced with the permission of Janssen Research & Development, LLC

  23. Canagliflozin Lowers A1C Through Weight Loss–Independent and Weight Loss–Associated Mechanisms Relationshipbetweenchangesinsystolic bloodpressureandbodyweightatWeek 26* 6 4 2 0 -2 -4. -6 -8 -10 Placebo Canagliflozin 100 mg Canagliflozin 300 mg ∆SBP(mmHg) Weight loss contributes to ~40% of the SBP-lowering effect of canagliflozin -10 -5 0 5 ∆ body weight (%) In each treatment group, subjects with greater weight loss had greater reductions in systolic blood pressure, with similar slopes associated with weight loss observed across all 3 groups. Each 1% reduction in body weight was associated with a 0.62% mm Hg reduction in systolic blood pressure. *Solid symbols represent mean changes within each decile of weight change, and open symbols are mean changes in the entire treatment group. Pooled analysis of 4 previously reported, randomized, double-blind, 26-week, phase 3 studies (N=2,250). Wilding L, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept 2013. Abstract 946. Reproduced with the permission of Janssen Research & Development, LLC

  24. Effects of Dapagliflozinon Body Weight Placebo + Metformin Dapagliflozin 10 mg + Metformin 0.5 1.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 Changeintotalbodyweight (kg)* LOCF Differencefrom placebo -2.08kg (95%CI-2.84, -1.31) P<0.0001 0 4 Samplesizepertime point 8 16 Study Week 24 Baselinevalue(kg) Dapagliflozinreducestotalbody weightpredominantly by reducingfatmass,visceral adiposetissueandSCadiposetissuevolume. Reprintedwithpermissionfrom BolinderJ, et al. J ClinEndocrinolMetab.2012.97(3):1020–1031.

  25. EffectsofDapagliflozinonRegionalAdiposeTissueDistribution Meanchangefrom baselineinVATandSATvolumewithtreatmentat 24wk Placebo + Metformin n=42; n=37 Dapagliflozin 10 mg + Metformin n=37; n=30 200 Change in adipose tissue volume(cm3) 0 -39.2 -121.4 -200 -297.5‡ -400 -306.4§ -600 VisceralAT SubcutaneousAT -800 Dapagliflozinreducestotalbody weightpredominantly by reducingfatmass,visceral adiposetissueandSCadiposetissuevolume. ‡, VAT, -258.4 cm3 (95 CI = -448.1 to -68.6; nominal P = 0.0084); §, SAT, -184.9 cm3 (95% CI = -359 to -10.1; nominal P = 0.0385). Reprintedwithpermissionfrom BolinderJ, et al. J ClinEndocrinolMetab.2012.97(3):1020–1031.

  26. Summary • SGLT2 inhibitors are effective therapies in challenging patient populations • Efficacy of these therapies is reduced in older adults and renally impaired patients, but safety is maintained • Beneficial effects on weight and blood pressure are consistently seen, but clinical impact remains to be determined • Minor changes in LDL-C, but not HDL-C or triglycerides, • are observed • – Minor changes in non-HDL-C with canagliflozin • Cardiovascular outcome studies are in progress

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