Prof. Dr. Stephan Jacob Internist, endocrinologist, diabetologist, - PowerPoint PPT Presentation

AG Herz und Diabetes Prof. Dr. Stephan Jacob Internist, endocrinologist, diabetologist, clinical hypertension specialist ESH Cardio-Metabolic-Institute Villingen-Schwenningen

Faculty Disclosure Stephan Jacob Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a research grant(s)/ in kind support A From current sponsor(s) NO B From any institution NO II I have been a speaker or participant in accredited CME/CPD A From current sponsor(s) YES B From any institution YES NO III I have been a consultant/strategic advisor etc A For current sponsor(s) YES NO B For any institution YES NO IV I am a holder of (a) patent/shares/stock ownerships A Related to presentation NO B Not related to presentation NO

Faculty Disclosure Declaration of non-financial interests: German diabetes association (DDG) Board member of working group diabetes and the heart Board member of working group diabetes prevention German Hypertension Association (DHL) board member of commission Hypertension and metabolism

Data from 528,877 participants – adjusted for age sex, cohort, SBP, smoking, and BMI Number Outcome I 2 (95% CI) of cases HR (95% CI) Coronary heart disease 26 505 2.00 (1.83 – 2.19) 64 (54 – 71) 2.31 (2.05 – 2.60) 41 (24 – 54) 11 556 Coronary death 1.82 (1.64 – 2.03) 37 (19 – 51) 14 741 Non-fatal myocardial infarction 11 176 1.82 (1.65 – 2.01) 42 (25 – 55) Cerebrovascular disease Ischaemic stroke 2.27 (1.95 – 2.65) 1 (0 – 20) 3799 Haemorrhagic stroke 1.56 (1.19 – 2.05) 0 (0 – 26) 1183 Unclassified stroke 1.84 (1.59 – 2.13) 33 (12 – 48) 4973 1.73 (1.51 – 1.98) 0 (0 – 26) 3826 Other vascular deaths AND MICROVASCULAR 1 2 4 Hazard Ratio (diabetes vs. no diabetes) COMPLICATIONS BMI, body mass index; CI, confidence interval; HR, hazard ratio; SBP, systolic blood pressure Seshasai SR et al . Lancet. 2010; 375: 2215 – 2222

A simplified view Diabetes= measured Hyper- HbA1c as as a measure of glycemia MEAN glycemia

Type 2 Diabetes… close associations Renal epidemiology problems Retino- DEATH pathy Poly- HbA1c CHF Neuropathy Stroke CHD PVD Jacob 2018

Epidemiology 160 140 Adjusted incidence per 1000 120 person years (%) 100 80 60 40 20 0 5 6 7 8 9 10 11 Updated mean haemoglobin HbA 1c concentration (%) Incidence rate and 95% confidence intervals for any end point related to diabetes by category of updated mean haemoglobin HbA 1c concentration, adjusted for age, sex, and ethnic group, expressed for white men aged 50 – 54 years at diagnosis and with mean duration of diabetes of 10 years HbA 1c , glycosylated haemoglobin. Stratton et al . Diabetologia 2006;49:1761 – 9

Higher HbA 1c predicts higher CV risk 10 10 Fatal & non-fatal stroke Fatal & non-fatal MI p =0.035 p <0.0001 Hazard ratio 1 1 14% decrease 12% decrease per 1% reduction in HbA 1c per 1% reduction in HbA 1c 5 6 7 8 9 10 5 6 7 8 9 10 Amputation/death from PVD Heart failure 10 10 p <0.0001 p =0.021 Hazard ratio 1 1 43% decrease 16% decrease per 1% reduction in HbA 1c per 1% reduction in HbA 1c 5 6 7 8 9 10 5 6 7 8 9 10 HbA 1c (%) HbA 1c (%) Reference category (hazard ratio 1.0) is HbA 1c <6% with log linear scales CV, cardiovascular; HbA 1c , glycosylated haemoglobin; MI, myocardial infarction; PVD, peripheral vascular disease Stratton IM et al. BMJ 2000;321:405 – 412

A simple consequence A simplified view Diabetes= HbA1c- Diabetes = measured Hyper- HbA1c as - Management as a measure of Management glycemia MEAN glycemia

• UKPDS 7 vs 7.9 • ADVANCE 6.3 vs 7 • VADT MAX diff. 6.9 vs 8.4 1.5% • ACCORD 6.4 vs 7.5 HbA 1c , glycosylated haemoglobin

What could we expect? -1.5% >6.5 years

Higher HbA 1c predicts higher CV risk VADT – 1.5% 10 10 Fatal & non-fatal stroke Fatal & non-fatal MI p =0.035 p <0.0001 Hazard ratio ? 1 1 14% decrease 12% decrease per 1% reduction in HbA 1c per 1% reduction in HbA 1c 5 6 7 8 9 10 5 6 7 8 9 10 Heart failure Amputation/death from PVD 10 10 p <0.0001 Hazard ratio p =0.021 1 1 43% decrease 16% decrease And no reduction per 1% reduction in HbA 1c per 1% reduction in HbA 1c 5 6 7 8 9 10 5 6 7 8 9 10 in microvascular!! HbA 1c (%) HbA 1c (%) Reference category (hazard ratio 1.0) is HbA 1c <6% with log linear scales CV, cardiovascular; HbA 1c , glycosylated haemoglobin; MI, myocardial infarction; PVD, peripheral vascular disease Stratton IM et al. BMJ 2000;321:405 – 412

CAVE! ……legacy

Good glycaemic control ….matters in T2DM 10- and 20-year follow-up data from UKPDS UKPDS original results: 10-year post-trial follow-up period Intensive vs. conventional treatment (non-interventional) “…During years 6 to 10, because of funding constraints, … 1998 2008 1977 – 1991 (10-year follow-up) (20-year follow-up) Randomisation questionnaires were used to follow all patients remotely. After the censoring date of post-trial monitoring (September 30, 2007), 9%* 12%* final questionnaires were sent to all remaining patients” 15%* 16% Any diabetes-related endpoint Microvascular disease 24%* MI 25%* * p <0.05; intensive vs. conventional treatment. MI, myocardial infarction; UKPDS, UK Prospective Diabetes Study; T2DM, type 2 diabetes mellitus 1. Adapted from: Holman et al. N Engl J Med 2008;359:1577 – 1589; 2. UKPDS Group. Lancet 1998;352:837 – 853

Keep in mind: Co-medication Do we still have these UKPDS- patients? ASA, acetylsalicylic acid

VADT Legacy

No reduction of MACE Hypos and weight Some reduction of microvascular 2013

Anti-hyperglycaemic medication in the last 90 years 12 in 25 Insulin years degludec SGLT-2 inhibitors Exenatide LAR Saxagliptin/Linagliptin Sitagliptin/Vildagliptin Exenatide/Liraglutide Pramlintide 5 in 70 Insulin Detemir years Insulin Aspart Insulin Glargine Glinide Glitazone (Pioglitazone) Insulin Lispro Acarbose Human Insulin Metformin Sulfonylureas Animal Insulin LAR, long-acting release; SGLT-2, sodium-glucose cotransporter-2. Adapted from: Schernthaner G. Internist 2012;53:1399 – 1410

”OUTCOME“ Studies Safety Efficacy FDA requirement Benefit No Harm of new TX with new TX [NNT] [NNH] Jacob 2015

CVOTs in diabetes Ongoing ELIXA SUSTAIN 6 ACE TOSCA IT Published results (Lixisenatide, GLP-1RA) (Semaglutide, GLP-1RA) (Acarbose, AGI) (Pioglitazone, TZD) n=6068; follow-up ~2 yrs n=3297; duration ~2.8 yrs n=6526; duration ~8 yrs n=3371; duration ~10 yrs Q1 2015 – RESULTS Q3 2016 – RESULTS Q2 2017 – RESULTS completion Q4 2018 ALECARDIO EMPA-REG OUTCOME CANVAS REWIND DECLARE-TIMI-58 SCORED (Aleglitazar, PPAR- αγ ) (Empagliflozin, SGLT-2i) (Canagliflozin, SGLT-2i) (Dulaglutide, QW GLP-1RA) (Dapagliflozin, SGLT-2i) (sotagliflozin, SGLT-2i) n=7226; follow-up 2 yrs n=7020; duration up to 5 years n=4330; duration 4+yrs n=9622; duration ~6.5 yrs n=17276; duration ~6 yrs n=10500 * ; duration ~4.5 yrs Termin. Q3 2013 – RESULTS Q3 2015 – RESULTS Q2 2017 - RESULTS completion Q3 2018 completion Q2 2019 completion Q1 2022 EXAMINE LEADER CANVAS-R HARMONY OUTCOME VERTIS CV (Alogliptin, DPP-4i) (Liraglutide, GLP-1RA) (Canagliflozin, SGLT-2i) (Albiglutide, QW GLP-1RA) (Ertugliflozin, SGLT-2i) n=5380; follow-up 1.5 yrs n=9340; duration 3.5 – 5 yrs n=5813; duration ~3 yrs n~9400; duration ~4 yrs n=8000; duration ~6.3 yrs Q3 2013 – RESULTS Q2 2016 – RESULTS Q2 2017 - RESULTS completion Q2 2018 completion Q4 2019 SAVOR TIMI-53 FREEDOM-CVO EXSCEL CREDENCE (cardio-renal) PIONEER 6 (Saxagliptin, DPP-4i) (ITCA 650, GLP-1RA in DUROS) (Exenatide ER, QW GLP-1RA) (Canagliflozin, SGLT-2i) (Oral semaglutide, QW n=16492; follow-up ~2 yrs Q2 n=4000; duration ~2 yrs n=14752; follow-up ~3 yrs GLP-1RA) n=3176; duration ~2 yrs n=4466; duration ~5.5 yrs completion Q4 2018 2013 – RESULTS completion Q2 2016 Q3 2017 – RESULTS completion Q2 2019 TECOS DEVOTE CARMELINA CAROLINA (Sitagliptin, DPP-4i) (Insulin degludec, insulin) (Linagliptin, DPP-4i) (Linagliptin, DPP-4i vs SU) n=8300 * ; duration ~4 yrs n=14671; duration ~3 yrs n=7637; duration ~2 yrs n=6072; duration ~8 yrs Q4 2014 – RESULTS Q2 2017 – RESULTS completion Q4 2018 completion Q1 2019 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 PPAR- αγ DPP-4i GLP-1RA SGLT-2i Insulin AGI TZD • *Estimated enrolment. CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; ER, extended release; GLP-1RA, glucagon-like peptide-1 receptor agonist; ITCA 650, continuous subcutaneous delivery of exenatide; PPAR- receptors- αγ, peroxisome proliferator‐activated receptors - α and γ; QW, once weekly; SGLT -2i, sodium-glucose cotransporter 2 inhibitor; SU, sulphonylurea; T2DM, type 2 diabetes mellitus. ClinicalTrials.gov. Accessed 20 September 2017