Type 2 diabetes & Cardiovascular disease update Barcelona, - PowerPoint PPT Presentation

Type 2 diabetes & Cardiovascular disease update Barcelona, March 15th 2018 Francesc Xavier Cos Claramunt Sant Martí de Provençals. Head of Innovation and Health in Barcelona city Assoc.Prof Universitat Autonoma de Barcelona Grup d’Estudi de la Diabetis a l’Atenció Primària de Salut (RedGedapS) Chairman Primary Care Diabetes Europe

Disclosures Consultant: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk and Sanofi. Research Support: AstraZeneca, Novartis. Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk and Sanofi. Type 2 diabetes & Cardiovascular disease xcos2018

Agenda § Diabetes and CV disease § Intervention trials and CV benefits § Cardiovascular outcome trials (CVOTs) § Beneficial/Neutral/Harmful § Recommendations update § Take home messages Type 2 diabetes & Cardiovascular disease xcos2018

Agenda § Diabetes and CV disease § Intervention trials and CV benefits § Cardiovascular outcome trials (CVOTs) § Beneficial/Neutral/Harmful § Recommendations update § Take home messages Type 2 diabetes & Cardiovascular disease xcos2018

IDF Atlas 2017 Type 2 diabetes & Cardiovascular disease xcos2018

Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000. Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000. Type 2 diabetes & Cardiovascular disease xcos2018

CVD difference between T2DM and non T2DM Cohort follow up (5.5 years) 34.198 T2DM 1.887.062 general population Shah, AD. Lancet Diabetes Endocrinol. 2015; 3: 105–13 Type 2 diabetes & Cardiovascular disease xcos2018

CVD difference between T2DM and non T2DM Shah, AD. Lancet Diabetes Endocrinol. 2015; 3: 105–13 Type 2 diabetes & Cardiovascular disease xcos2018

Diabetes as a CV mortality risk factor n = 3 274 472 Events per 1000-person-yr Events per 1000-person-yr Men Women DM + MI DM + MI MI DM MI DM No DM/MI No DM/MI Schramm et al, Circulation, 2008 Type 2 diabetes & Cardiovascular disease xcos2018

Kronmal i wsp ., PLoS Med ., 2006; 3 (10): e 400 Type 2 diabetes & Cardiovascular disease xcos2018

Agenda § Diabetes and CV disease § Intervention trials and CV benefits § Cardiovascular outcome trials (CVOTs) § Beneficial/Neutral/Harmful § Recommendations update § Take home messages Type 2 diabetes & Cardiovascular disease xcos2018

? ↓HbA1c Type 2 diabetes & Cardiovascular disease xcos2018

T1DM DCCT ↓HbA1c T2DM UKPDS Type 2 diabetes & Cardiovascular disease xcos2018

Mixed results on tight and rapid HbA1c control Impact of intensive therapy vs standard HbA1c (%) therapy on outcome Study Standard Intensive Microvascular CVD Mortality therapy therapy ? ←→ ↑ ACCORD 7.5 6.4 ↓ ←→ ←→ ADVANCE 7.3 6.5 ←→ ←→ ←→ VADT 8.4 6.9 ↓ ←→ ←→ UKPDS 7.9 7.0 UKPDS – ↓ ↓* ↓ ~7.9 ~7.9 follow-up * Reduction in myocardial infarction ACCORD Study Group. N Engl J Med 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572; Duckworth W, et al. N Engl J Med 2009;360:129-139; UKPDS. Lancet 1998;352:837-853; Holman RR, et al. N Engl J Med 2008;359:1577-1589. Type 2 diabetes & Cardiovascular disease xcos2018

Type 2 diabetes & Cardiovascular disease xcos2018

Type 2 diabetes & Cardiovascular disease xcos2018

History of diabetes therapy 14 SGLT-2 inhibitors New basal Insulin Dopamine agonists 12 I. Glar bs Bile-acid sequestrants Number of treatment DPP-4 inhibitors 10 classes available Amylin mimetics 8 GLP-1 analogues Modern insulin analogues 6 Meglinitides Thiazolidinediones 4 Biguanides (Met) a -Glucosidase inhibitors Animal 2 insulin Sulphonylurea 0 1950 1960 1970 1980 1990 2000 2010 Yea r DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose co-transporter-2 White JR, Diabetes Spectrum 2014; doi: 10.2337/diaspect.27.2.82. Cardiovascular safety in old and new drugs type 2 diabetes management xcos2018

Characteristics of the ‘ideal’ drug for type 2 diabetes Safe Efficacious Durable control Well-tolerated Low risk of hypoglycaemia Weight neutral or weight loss Reduction of long term complications Garber AJ et al. Endocr Pract 2013; 19: 327–36. Inzucchi SE et al. Diabetes Care 2012; 35: 1364–79. Type 2 diabetes & Cardiovascular disease xcos2018

Type 2 diabetes & Cardiovascular disease xcos2018

The rosiglitazone issue “Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance.” Nissen SE et al. N Engl J Med 2007;156:2457–2471. Cardiovascular safety in old and new drugs type 2 diabetes management xcos2018

FDA guidance for industry • In December 2008, the US FDA issued guidance to industry for evaluating CV safety in diabetes drugs • Industry should demonstrate that new therapy will not result in an unacceptable increase in CV risk – The upper bound of the two-sided 95% CI of the risk ratio should be <1.8 CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration. FDA. Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

FDA criteria for requirement of a postmarketing CV outcomes trial Non-inferiority Non-inferiority boundary boundary HR 1.3 HR 1.8 Superiority Approvable: no need for postmarketing study Non-inferiority Upper limit of 95% CI Approvable: need for Non-inferiority postmarketing study Inferior Not approvable Underpowered 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 2.2 Hazard ratio Hirshberg B, Raz I. Diabetes Obes Metab 2011;34(Suppl. 2):S101–S106.

Agenda § Diabetes and CV disease § Intervention trials and CV benefits § Cardiovascular outcome trials (CVOTs) § Beneficial/Neutral/Harmful § Recommendations update § Take home messages Type 2 diabetes & Cardiovascular disease xcos2018

Cardiovascular outcomes trials within diabetes SUSTAIN 6 CANVAS-R REWIND (Semaglutide, GLP-1) (Canagliflozin, SGLT2i) (Dulaglutide, QW GLP-1) n=3,260; duration ~2.8 yrs n=5,700; duration ~3 yrs n=9,622; duration ~6.5yrs completion Q1 2016 completion Q2 2017 completion Q2 2019 ALECARDIO EMPA-REG OUTCOME CANVAS CREDENCE (cardio-renal) NCT01986881 (Aleglitazar, PPAR- αγ ) (Empagliflozin, SGLT2i) (Canagliflozin, SGLT2i) (Canagliflozin, SGLT2i) (Ertugliflozin, SGLT2i) n=7,226; follow-up 2.0 yrs n=7,000; duration up to 5yrs n=4,330; duration 4+yrs n= 3,627; duration ~5.5 yrs n=3,900; duration~6.3 yrs Termin. Q3 2013 RESULTS completion Q2 2015 completion Q1 2017 completion Q1 2019 completion Q2 2020 EXAMINE ELIXA NCT01703208 FREEDOM (Nesina, DPP4i) n=5,380; (Lyxumia, GLP-1) (Omarigliptin, QW DPP4i) (ITCA 650, GLP-1 in DUROS) follow-up ~1.5 yrs n=6,000; duration ~4 yrs n=4,000; duration ~3 yrs n=2-3,000; duration ~2 yrs Q3 2013 - RESULTS completion Q1 2015 completion Q4 2017 completion Q3 2018 SAVOR TIMI-53 LEADER EXSCEL DECLARE-TIMI-58 (Onglyza, DPP4i) (Victoza, GLP-1) (Bydureon, QW GLP-1) (Forxiga, SGLT2i) n=16,492; follow-up ~2 yrs n=9,340; duration 3.5-5 yrs n=14,000; duration ~7.5 yrs n=22,220; duration~6 yrs Q2 2013 - RESULTS completion Q4 2015 completion Q4 2017 completion Q2 2019 TECOS CARMELINA CAROLINA (Januvia, DPP4i) (Tradjenta, DPP4i) (Tradjenta, DPP4i vs SU) n=14,000; duration ~4-5 yrs n= 8,300; duration ~4 yrs n= 6,000; duration ~8 yrs completion Q4 2014 completion Q1 2018 completion Q3 2018 2013 2014 2015 2016 2017 2018 2019 2020 Pre-approval Pre+post-approval Post-approval Other Terminated Source: ClinicalTrials.gov (April 2014). ‘Completion date’ is the estimated completion date for the primary outcomes measure CVOT, cardiovascular outcomes trial; DPP4i; dipeptidyl peptidase 4 inhibitor; GLP-1, glucagon-like peptide 1; SU, sulphonylurea McMurray JJ et al, Lancet Diabetes Endocrinol 2014;2:843–51

3-P MACE : 3 - point major adverse cardiac events (composite of cardiovascular death, nonfatal stroke and nonfatal myocardial infarction) 4-P MACE : Composite of 3-P MACE plus unstable angina, ACS, hospitalization for HF. Type 2 diabetes & Cardiovascular disease xcos2018