primary care in diabetes Richard Hobbs, MD Oxford University - PowerPoint PPT Presentation

The cardiovascular challenge for primary care in diabetes Richard Hobbs, MD Oxford University United Kingdom EBAC accredited satellite symposium held during EuroPrevent April 11, 2019 - Lisbon, Portugal

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

I have received honoraria, research support and consulting fees of the following companies Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Lilly, Medcon, Merck, MSD, Novo Nordisk, Novartis, Roche, Sanofi-Aventis, Servier,

Simplified view Diabetes= Assessed Hyper- HbA1c as glycemia

Typ 2 Diabetes ESRD Retino- Death pathy Poly- CHF HbA1c Neuro- pathy Stroke CHD PVD

Epidemiologie HbA1c- Diabetes- Management Management Reference category (hazard ratio 1.0) is HbA 1c <6% with log linear scales. CV, cardiovascular; MI, myocardial infarction; PVD, peripheral vascular disease Stratton IM et al. BMJ 2000;321:405 – 412.

• 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 And no reduction in microvascular!! 02.05.2019 HbA 1c , glycosylated haemoglobin

CAVE! ……legacy

Recent long term f/up studies in DM2 HbA1c Diff Yrs RX F/up HR P LEGACY Is Legacy ACCORDION 0,9% 3,7 9,7 only a Composite CVD 0.95 0,3 NO CV death legend? 1,2 0,02 NO ADVANCE-ON 0,7% 5,0 Composite CVD 12,5 1,0 0,93 NO CV death 0,97 0,6 NO VADT-F 1,5% 5,6 15+ Composite CVD 0,91 0,2 NO CV death 0,94 0,6 NO

Facts • Type 2 diabetes is associated with a high morbidity and mortality • Tackling glucose only was not successful in reducing MACE and mortality • Treatment induced adverse events (weight gain and hypoglycemia) were thought to wipe off benefits of glycemic control

Aim of Diabetes management Multi REDUCTION of Glucose control factorial COMPLICATIONS approach

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

Cardiovascular outcome trials

After years of frustrations... DECLARE HARMONY

Macrovascular risk reduction (=MACE) SGLT-2 inhibitors EMPA-REG DECLARE- CANVAS 2 OUTCOME 1 TIMI 3 Empagliflozin Canagliflozin Dapagliflozin MACE CV death Non-fatal stroke Non-fatal MI HHF All-cause death 0,5 1,0 2,0 0,3 0,5 1,0 2,0 0,5 1,0 2,0 Hazard ratio Hazard ratio Hazard ratio CV, cardiovascular; HHF, hospitalisation from heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction; SGLT-2, sodium – glucose co-transporter-2 1. Zinman B et al. N Engl J Med 2015;373:2117 – 2128; 2. Neal B et al. N Engl J Med 2017;377:644 – 657; 3. Wiviott SD et al . N Engl J Med 2018;doi: 10.1056/NEJMoa1812389 [Epub ahead of print]

MACE in GLP1-RA CV death, non-fatal myocardial infarction, or non-fatal stroke 20 2 0 2 0 Patients with an event (%) P la c e b o 15 1 5 1 5 L ira g lu tid e 10 1 0 1 0 HR=0.87 5 95% CI (0.78 ; 0.97) 5 5 p<0.001 for non-inferiority p=0.01 for superiority 0 0 0 0 0 0 6 6 6 1 2 1 2 12 1 8 1 8 18 2 4 2 4 24 3 0 3 0 30 3 6 3 6 36 4 2 4 2 42 4 8 4 8 48 5 4 5 4 54 Time from randomisation (months) Patients at risk Liraglutide 4668 4593 4496 4400 4280 4172 4072 3982 1562 424 Placebo 4672 4588 4473 4352 4237 4123 4010 3914 1543 407 The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non- fatal stroke. The cumulative incidences were estimated with the use of the Kaplan – Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

CV death 8 P la c e b o Patients with an event (%) 6 4 L ira g lu tid e HR=0.78 95% CI (0.66 ; 0.93) 2 p=0.007 0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 Time from randomisation (months) Patients at risk Liraglutide 4668 4641 4599 4558 4505 4445 4382 4322 1723 484 Placebo 4672 4648 4601 4546 4479 4407 4338 4267 1709 465 The cumulative incidences were estimated with the use of the Kaplan – Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio. Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

All-cause death SAFETY! 20 2 0 2 0 HR=0.85 Patients with an event (%) 95% CI (0.74 ; 0.97) p=0.02 15 1 5 1 5 Kidney ! P la c e b o 10 1 0 1 0 L ira g lu tid e 5 5 5 0 0 0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 0 0 6 6 12 1 2 1 8 18 2 4 24 3 0 30 3 6 36 42 4 2 4 8 48 5 4 54 Time from randomisation (months) Patients at risk Liraglutide 4668 4641 4599 4558 4505 4445 4382 4322 1723 484 Placebo 4672 4648 4601 4546 4479 4407 4338 4268 1709 465 The cumulative incidences were estimated with the use of the Kaplan – Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; HR, hazard ratio. Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

GLP-1 receptor agonists Hazard ratio (95% CI) Hazard ratio (95% CI) MACE 0.88 (0.81; 0.96) MACE 1.02 (0.89; 1.17) LEADER 1 CV death 0.78 (0.66; 0.94) CV death 0.98 (0.78; 1.22) ELIXA 2 Non-fatal MI 0.88 (0.75; 1.03) Fatal MI 1.03 (0.87; 1.22) Non-fatal stroke 0.89 (0.72; 1.11) Fatal stroke 1.12 (0.79; 1.58) 1.0 2.0 1.0 2.0 0,3 0,3 Hazard ratio (95% CI) Hazard ratio (95% CI) Hazard ratio (95% CI) Hazard ratio (95% CI) MACE 0.74 (0.58; 0.95) MACE 0.91 (0.83; 1.00) SUSTAIN 6 3 EXSCEL 4 CV death 0.98 (0.65; 1.48) CV death 0.88 (0.76; 1.02) Non-fatal MI 0.74 (0.51; 1.08) Non-fatal and fatal MI 0.97 (0.85; 1.10) Non-fatal stroke 0.61 (0.38; 0.99) Non-fatal and fatal stroke 0.85 (0.70; 1.03) 1.0 2.0 1.0 2.0 0,3 0,3 Hazard ratio (95% CI) Hazard ratio (95% CI) Hazard ratio (95% CI) REWIND 6: Dulaglutide demonstrated superiority for 3-point MACE 0.78 (0.68; 0.90) HARMONY Outcomes 5 MACE over placebo (further details not yet available) CV death 0.93 (0.73; 1.19) Non-fatal or fatal MI 0.75 (0.61; 0.90) Non-fatal or fatal stroke 0.86 (0.66; 1.14) PIONEER-6 7 : Neutral effect on MACE versus placebo (HR=0.79 in favour of oral semaglutide; p =NS) 1.0 2.0 0,3 Hazard ratio (95% CI) CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; NS, non significant 1. Marso SP et al. N Engl J Med 2016;375:311 – 322; 2. Pfeffer MA et al. N Engl J Med 2015;373:2247 – 2257; 3. Marso SP et al . N Engl J Med 2016;375:1834 – 1844; 4. Holman RR et al . N Engl J Med 2017;377:1228-39; 5. Hernandez AF et al. Lancet 2018;392:1519 – 1529; 6. Lilly press release (5 th November 2018), available at: https://investor.lilly.com/node/39796/pdf; 7. Novo Nordisk press release (23 rd November 2018), available from: https://www.novonordisk.com/media/news-details.2226789.html)

THESE ARE THE NEW FACTS „Yes we can “ ….IMPROVE! ✓ ------ MACE ✓ ------ CV and total mortality ✓ ------ Renal Outcome ➢ In a short period of time ➢ In very sick people ➢ With best CV risk management ➢ And still elevated HbA1c……. Jacob 2016

But HOW DO GLP1 RA improve outcome? Better HbA1c, Glucose Less hypos, Improved outcome Less visceral fat, Weight loss inflammation , … BP OTHERS Jacob 2019

GLP-1 Receptor Agonists Glycaemic control HbA1c Liraglutide Semaglutide Exenatide Albiglutide Treatment diff Treatment diff Treatment diff Treatment diff – 0.4% – 0.7% – 0.5% – 0.5% (95% CI – 0.80 ; – 0.52) ( 95% CI – 0.45; – 0.34) ( 95% CI – 0.57; – 0.50) ( 95% CI – 0.58; – 0.45) p <0.001 p <0.001 p <0.001 UKPDS, TECOS-0,29% ACCORD, VADT, EXAMINE-0,36% ADVANCE Marso S P et al N Engl J Med 2016; 375:311 Holman R et al N Engl J Med 2017; 1228 Marso S P et al N Engl J Med 2016; 375:1834 Hernandez A F et al N Engl J Med 2018; 392:1519

GLP-1 Receptor Agonists Impact on blood pressure Systolic blood pressure Liraglutide Semaglutide Exenatide Albiglutide Treatment diff Treatment diff Treatment diff Treatment diff – 1.2 mmHg – 2.6 mmHg – 1.6 mmHg – 0.7 mmHg (95% CI – 4.09 ; – 1.08) (95% CI – 1.9; – 0.5) (95% CI – 1.9; – 1.2) (95% CI – 1.40; – 0.06) p <0.001 p <0.001 p <0.001 Marso S P et al N Engl J Med 2016; 375:311 Holman R et al N Engl J Med 2017; 1228 Marso S P et al N Engl J Med 2016; 375:1834 Hernandez A F et al N Engl J Med 2018; 392:1519