Diabetes & Cardiovascular Disease: What are the challenges? Targeting HbA1c in diabetes management: What are the key lessons from glucose lowering trials Prof. Nikolaus Marx, MD Aachen, Germany Asian Cardio Diabetes Forum March 30-31, 2019 - Hanoi, Vietnam
Heart Failure: The next frontier for SGLT2 inhibitors? Nikolaus Marx, MD, FESC, FAHA Professor of Medicine / Cardiology Head of Department of Internal Medicine I, Cardiology, Angiology, and Intensive Care Medicine University Hospital Aachen, Germany
Conflict of interest Nikolaus Marx • Speaker: Amgen, Bayer, Boehringer Ingelheim, Sanofi- Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk • Research grant: Boehringer Ingelheim, MSD • Advisory board: Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk NM declines all personal compensation from pharma or device companies
Heart Failure: The next frontier for SGLT2 inhibitors? • Heart failure in diabetes • SGLT2 inhibition and heart failure • Effects of SGLT2 inhibitors in subjects without diabetes
Systolic heart failure = HFREF (Heart failure with reduced ejection fraction) Systolic heart failure: - reduced contractile function Normal Dilatative cardiomyopathy
Diastolic heart failure = HFPEF (Heart failure with preserved ejection fraction) Diastolic heart failure: - reduced relaxation - impaired ventricular filling Normal Hypertrophic cardiomyopathy
Heart failure in diabetes HF incidence HF mortality by age group in diabetes Diabetes No diabetes ~ 55% Gustafsson et al. JACC 2004; 43:771-777 Nichols GA et al. Diabetes Care 2004;27:1879
Impact of diabetes on outcomes in patients with HFrEF and HFpEF (CHARM program) CV death or HHF in patients with or without diabetes based on ejection fraction category 60 Diabetes No diabetes HF r EF: unadjusted HR 1.60 HF r EF (95% CI 1.4, 1.77); p <0.0001 Cumulative incidence (%) HF p EF: unadjusted HR 2.0 (95% CI 1.70, 2.36); p <0.0001 40 HF p EF HF r EF 20 HF p EF - Increased risk for mortality and hospitalisation for HF in 0 0 0.5 1 1.5 2 2.5 3 3.5 HF patients with diabetes Follow-up (years) - HFpEF prognosis better than HFrEF MacDonald et al. Eur Heart J 2008; 29:1377 – 1385 8
PARADIGM-HF – CV mortality in DM CV mortality: 17% Overall mortality: 21% - Heart failure with recurrent hospitalisation and a high risk for CV death and total mortality is the leading problem in type 2 diabetes in 2019! Median FU: 27 months Kristensen SL et al. Circ Heart Fail. 2016; 9:e002560
Pathophysiology Bugger et al, Diabetologia 2014; 57:660-671
Pathophysiology Free fatty acids Insulin resistance Hyperinsulinemia Altered myocardial metabolism Hyperglykämie Myocardial hypertrophy Fatty acid oxidation Hexosamine pathway Myocardial Oxidative AGE energy production Altered myocardial stress deposition Ca levels Decreased Ca handling Inflammation Myocardial apoptosis Microangiopathy Fibrosis Myocardial stiffness Impaired systolic Impaired diastolic function function Diabetic cardiomyopathy after Savvaidis, Marx, Schütt Der Diabetologe 2015; 11:379-387
Heart Failure: The next frontier for SGLT2 inhibitors? • Heart failure in diabetes • SGLT2 inhibition and heart failure – Data from CVOTs – Patients with or without HF at baseline – Time course of risk reduction – Patients with or without HFrEF • Effects of SGLT2 inhibitors in subjects without diabetes
SGLT2-Inhibition SGTL2 SGLT2 inhibitor SGLT2 expression increased Increased glucose reabsorption Distal tubule Proximal Glomeruli tubule Increased glucose filtration SGTL1 Increased urinary sodium excretion (temp.) Increased urinary glucose excretion After Marx et al. Eur Heart J 2016; 37(42):3192-3200
CVOTs with SGLT2 inhibitors Baseline characteristics EMPA REG Integrated Baseline DECLARE Outcome CANVAS Program Variables (Dapagliflozin) (Empaglifozin) (Canaglifozin) Participants (n) 7,034 10,142 17,160 Age (y) 63 63 64 Diabetes 57% > 10 y 13.5 y 10 y Duration (y) BMI (kg/m 2 ) 31 32.0 32 A1C (%) 8.1 8.2 8.3 Prior CVD (%) 99 64.8 40 Prior HF 10 14 10 Comparator Placebo Placebo Placebo
Reduction of heart failure hospitalization and CV death by SGLT2 inhibitors EMPA-REG Outcome 1 Canvas Program 2 DECLARE 3 Empagliflozin, canagliflozin and dapagliflozin reduce the 1. Zinman B et al. N Engl J Med. 2015; 373:2117-2128 2. Neal B et al. N Engl J Med. combined endpoint of heart failure hospitalisation and CV 2017; 377(7):644-657. 3. Wiviott SD et al. N Engl J Med death 2018;380:347
Reduction of heart failure hospitalisation by SGLT2 inhibitors EMPA-REG Outcome Canvas Program HR 0.67 (95%CI 0.52-0.87) HR 0.65 (95%CI 0.50-0.85) p=0.0017 Zinman B et al. N Engl J Med. Neal B et al. N Engl J Med. 2015; 373:2117-2128 2017 Aug 17;377(7):644-657.
Reduction of heart failure hospitalisation by SGLT2 inihibitors DECLARE Empagliflozin, canagliflozin and dapagliflozin reduce heart failure hospitalisation
EMPA-REG OUTCOME 3P-MACE and single endpoints Patients with event/analysed Empagliflozin Placebo HR (95% CI) p -value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI
CANVAS Program 3P-MACE and single endpoints
DECLARE 3P-MACE and single endpoints - Empagliflozin but not canagliflozin or dapagliflozin reduce CV death in the respective outcome trials
Heart Failure: The next frontier for SGLT2 inhibitors? • Heart failure in diabetes • SGLT2 inhibition and heart failure – Data from CVOTs – Patients with or without HF at baseline – Time course of risk reduction – Patients with or without HFrEF • Effects of SGLT2 inhibitors in subjects without diabetes
Outcome of patients with or without heart failure at baseline CV death and HHF HF No HF Empagliflozin, canagliflozin, and dapagliflozin reduce heart failure hospitalisation and CV death in patients with or without heart failure at baseline Zelniker et al. Lancet. 2019; 393:31-33
Heart Failure: The next frontier for SGLT2 inhibitors? • Heart failure in diabetes • SGLT2 inhibition and heart failure – Data from CVOTs – Patients with or without HF at baseline – Time course of risk reduction – Patients with or without HFrEF • Effects of SGLT2 inhibitors in subjects without diabetes
Reduction in CV mortality was immediate, with benefit sustained throughout the trial EMPA-REG Outcome Hazard ratio over time HR 0.62 Favours placebo * (95.02% CI 0.49, 0.77); p <0.0001* Favours empagliflozin Placebo Empagliflozin Hazard ratio 95% CI
Reduced risk of HHF was observed early and sustained throughout the trial EMPA-REG Outcome Hazard ratio over time HR 0.65 (95% CI 0.50, 0.85) p =0.0017* Placebo Empagliflozin Hazard ratio 95% CI
Heart Failure: The next frontier for SGLT2 inhibitors? • Heart failure in diabetes • SGLT2 inhibition and heart failure – Data from CVOTs – Patients with or without HF at baseline – Time course of risk reduction – Patients with or without HFrEF • Effects of SGLT2 inhibitors in subjects without diabetes
DECLARE Prespecified analysis planned to examine the clinical benefit of dapagliflozin in patients with and without HFrEF Kato et al; Circulation 2019 online
DECLARE Combination of CV death / HHF (by HFrEF vs not HFrEF subgroups) HFrEF Dapagliflozin Placebo (N=671) 30 27.1% HFrEF: Not HFrEF: Dapagliflozin 25 Cumulative incident rate (%) HR 0.62 Placebo (N=16,489) [0.45; 0.86] 20 17.9% P for interaction: 15 0.046 10 Not HFrEF: 4.8% HR 0.88 5 Not HFrEF defined as pts with HF [0.76; 1.02] 4.3% without known reduced EF and pts 0 without hx of HF 0 1 2 3 4 yrs Kato et al; Circulation 2019 online
DECLARE HHF and CV death (by HFrEF vs not HFrEF subgroups) - Treatment with dapagliflozin resulted in a lower rate of HHF vs placebo in a broad spectrum of patients including those with preserved EF. - Dapagliflozin reduced CV death in patients with HFrEF, but not in those without HFrEF. Kato et al; Circulation 2019 online
Heart Failure: The next frontier for SGLT2 inhibitors? • Heart failure in diabetes • SGLT2 inhibition and heart failure • Effects of SGLT2 inhibitors in subjects without diabetes
Patients with heart failure have similar pathophysiological features as patients with diabetes Heart failure Diabetes Shared pathological features Endothelial Impaired contractility Hyperglycaemia dysfunction ↓ Pancreatic Cardiomyocyte Insulin resistance apoptosis/fibrosis beta-cell function Mitochondrial Neurohormonal Advanced glycated dysfunction activation end-product toxicity RAAS activation Neuronal degeneration/ LV remodelling demyelination Inflammation LV, left ventricular; RAAS, renin-angiotensin-aldosterone system Adapted from: Sena CM et al. BBA Mol Basis Dis 2013;1832:2216; Aroor AR et al. Heart Fail Clin 2012;8:609; Anker SD et al. Heart 2004;90:464; Sivitz WI et al. Antioxid Redox Signal 2010;12:557; Bauters C et al. Cardiovasc Diabetol 2003;2:1
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