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GLP1-RA: Where Do They Fit In CV Risk Management? Professor John - PowerPoint PPT Presentation

GLP1-RA: Where Do They Fit In CV Risk Management? Professor John Deanfield, UCL ESC Paris: Monday 2 September 2019 Deanfield UCL Professor John Deanfield: Disclosures Received CME honoraria and/or consulting fees from Amgen, Boehringer


  1. GLP1-RA: Where Do They Fit In CV Risk Management? Professor John Deanfield, UCL ESC Paris: Monday 2 September 2019 Deanfield  UCL

  2. Professor John Deanfield: Disclosures ▪ Received CME honoraria and/or consulting fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer ▪ Research grants from BHF, MRC(UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate, Roche ▪ No conflicts of interest for this presentation ▪ Member of SOUL and SELECT Study Steering Committees for Novo Nordisk ▪ Board Director of Cydar Ltd Deanfield  UCL

  3. GLP1-RA In CV Risk Management • T2DM and CV disease Deanfield  UCL

  4. GLP-1RA CV Outcome Trials Time to first occurrence of CV death, non-fatal MI or non-fatal stroke LEADER SUSTAIN 6 2 0 HR: 0.74 HR: 0.87 (95% CI: 0.58 ; 0.95) (95% CI: 0.78 ; 0.97) Patients with event (%) Patients with event (%) p <0.001 for non-inferiority p <0.001 for non-inferiority Placebo p =0.02 for superiority p =0.01 for superiority 1 5 Placebo 1 0 Liraglutide 5 Semaglutide 0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 Time from randomisation (months) Time from randomisation (weeks) Source: Marso SP et al. N Engl J Med 2016;375:311 – 322 Source: Marso SP et al. N Engl J Med 2016;375:1834 – 1844 Deanfield  UCL

  5. Impact of Diabetes Duration On Outcome In LEADER and SUSTAIN-6 Deanfield  UCL Source: Vermer et al, Diabetes Obes Motab; 2019:21: 1745-1751

  6. Diabetes Treatment for CVD Reduction SGLT-2 Inhibitors GLP-1R Agonists Deanfield  UCL Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

  7. New Diabetes Drugs: Give together? SGLT-2i GLP-1RA • Complementary actions • Good for HbA 1c but no CVOT trials • Specific patient populations? • Guidelines adopting • Price will be an issue Source: Das, S, Everett B et al, J Am Coll Cardiol 2018;72(24):3200-23, 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease Deanfield  UCL

  8. CVOT Impact on Clinical Guidelines ADA 2018 recommendation In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycaemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently, empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1). Deanfield  UCL Source: Diabetes Care 2018;41(Suppl 1):S73 – S85

  9. GLP1-RA In CV Risk Management • T2DM and CV disease • T2DM without clinical CV disease Deanfield  UCL

  10. REWIND: Primary Outcome CV Death, Non-Fatal Myocardial Infarction or Non-fatal Stroke Deanfield  UCL Source: Lancet. 2019;394:121-130

  11. Source: Lingvay I and Leiter LA. Circulation 2018; 137: 2200-2202 Deanfield  UCL

  12. Liraglutide in Children and Adolescents with T2DM Mean Change from Baseline (mmol/l) Glycated Hemoglobin (mmol/mol) Mean Change from Baseline (%) Fasting Plasma Glucose (mg/dl) Deanfield  UCL Source: Tamborlane et al, NEJM DOI/l 10,1056/NEJMoa1903822

  13. Deanfield  UCL Source: N Engl J Med 2019; 380:2295-2306

  14. ACC/AHA: Updated Guidelines for Primary Prevention of CVD March 17 2019 “For adults with T2DM and additional ASCVD risk factors who require glucose lowering therapy despite initial lifestyle modifications and metformin, it may be reasonable to initiate a SGLT2i or a GLP-1RA to improve glycaemic control and reduce CVD risk ” Deanfield  UCL Source: Arnett DK, et al. Circulation 2019; doi: 10.1161/CIR.0000000000000678

  15. GLP1-RA In CV Risk Management • T2DM and CV disease • T2DM without clinical CV disease • Clinical CV disease without T2DM Deanfield  UCL

  16. Change In Body Weight (% ) Baseline to week 52: J2R-MI data (phase 2) Placebo pool Semaglutide 0.05 mg Semaglutide 0.3 mg Liraglutide 3.0 mg Semaglutide 0.1 mg Semaglutide 0.4 mg Semaglutide 0.2 mg 0 Change in body weight (%) -2.3% -5 -6.0% -7.8% -8.6% -10 -11.2% -11.6% -13.8% -15 0 2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 44 48 52 Weeks Deanfield  UCL Source: O’Neil et al. Presented at: ENDO 2018: Chicago, IL; 17 -20 March 2018. Abstract OR12-5

  17. SELECT: GLP1-RA in High CVD Risk Non Diabetics N=17,500 patients Semaglutide s.c. 2.4 mg once-weekly Male or female ≥45 years of age BMI ≥ 27 Placebo s.c. once-weekly Event driven 1225 first MACEs Randomisation (1:1) Primary endpoint: Time from randomisation to first occurrence of a Prior Prior composite endpoint consisting of either: PAD • CV death MI stroke • Non-fatal myocardial infarction • Non-fatal stroke Deanfield  UCL

  18. GLP1-RA In CV Risk Management • T2DM and CV disease • T2DM without clinical CV disease • Clinical CV disease without T2DM • Barriers To Use Deanfield  UCL

  19. GLP1-RA Prescriptions: Partners Health Care System 7,609 patients aged 61yrs (54% women, 34% CVD) Deanfield  UCL Source: Vaduganathan,M et al., JACC, 73(12) April 2019:1596-600

  20. New Oral Formulation of SNAC and Semaglutide Semaglutide SNAC Microvilli Stomach Intracellular space Columnar epithelial cell Deanfield  UCL

  21. Oral Semaglutide and CV Outcomes in T2DM: PIONEER-6 Composite Primary Outcome: MACE Percentage of Patients (%) Weeks Since Randomisation Deanfield  UCL Source: Husain et al, NEJM DOI: 10.1056/NEJMoa1901118

  22. SOUL – Trial Design 9,462 patients T2D Oral semaglutide 14 mg OD + SoC Established CVD or Placebo + SoC CKD HbA1c 6.5% - 10% Up to 5 years (1,225 events) End of treatment Randomisation (1:1) Trial objective: Demonstrate oral semaglutide lowers risk of MACE compared to placebo Key endpoints • Primary: CV death, non-fatal MI or non-fatal stroke (MACE) • Secondary confirmatory: 5-component composite CKD endpoint: CV death, renal death, onset of macroalbuminuria, 50% reduction in eGFR, onset of eGFR < 15 ml/min/1.73m 2 or initiation of chronic renal replacement therapy • CV Death • Composite PAD endpoint: Acute and chronic limb ischemia (MALE) Deanfield  UCL

  23. Treatment algorithm in patients with T2DM and ASCVD or high/very high CV risk - drug naïve (1) ESC/EASD guideline 2019 a) Type 2 DM - Drug naïve patients + - ASCVD, or high / very high CV risk (target organ damage or multiple risk factors) a SGLT2 inhibitoror Metformin GLP-1 RAMonotherapy b Monotherapy If HbA 1c abovetarget If HbA 1c above target SGLT2i DPP-4i GLP-1 RA TZD if eGFR AddMetformin adequate If HbA 1c above target Source: Eur Heart J 2019. https://doi.org/10.1093/eurheartj/ehz486

  24. Treatment algorithm in patients with T2DM and ASCVD or high/very high CV risk - drug naïve (1) ESC/EASD guideline 2019 a) Type 2 DM - Drug naïve patients + - ASCVD, or high / very high CV risk (target organ damage or multiple risk factors) a SGLT2 inhibitoror Metformin GLP-1 RAMonotherapy b Monotherapy If HbA 1c abovetarget If HbA 1c above target SGLT2i DPP-4i GLP-1 RA TZD if eGFR AddMetformin adequate If HbA 1c above target Source: Vaduganathan,M et al., JACC, 73(12) April 2019:1596-600 Source: Eur Heart J 2019. https://doi.org/10.1093/eurheartj/ehz486

  25. Exciting New Era for CVD Management (in DM) • GLP1- RA’s can reduce the major cause of morbidity and mortality in patients with Cardiologists Diabetologists Diabetes • May also have a role in patients with CVD or CV risk factors without Diabetes • Clinical use vs SGLT2i or in combination needs further study Nephrology Primary Care Could benefit millions of subjects with cardiometabolic risk! Deanfield  UCL

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