SGLT2-Inhibition in Cardiology: What is the profile of benefit? Nikolaus Marx, MD, FESC, FAHA Professor of Medicine / Cardiology Head of Department of Internal Medicine I, Cardiology, Pneumology, Angiology, and Intensive Care Medicine University Hospital Aachen, Germany
Faculty Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: • Speaker: Amgen, GSK, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk; Bayer • Research grant: Boehringer Ingelheim • Advisory board: Amgen, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk NM declines all personal compensation from pharma or device companies
Faculty Disclosure Declaration of non-financial interests: • University Hospital Aachen • Professor of Medicine / Cardiology; Head of the Department of Internal Medicine I • Deutsche Gesellschaft für Kardiologie – Herz- und Kreislaufforschung (DGK) • Deutsche Stiftung für Herzforschung • Deutsche Gesellschaft für Arterioskleroseforschung • European Society of Cardiology (ESC) • American Heart Association (AHA) • Deutsche Diabetes Gesellschaft (DDG) • European Association for the Study of Diabetes (EASD)
SGLT2-Inhibition in Cardiology: What is the profile of benefit? • SGLT2 inhibition – mode of action • SGLT2 inhibition and cardiovascular benefit – Clinical outcome data – Potential mechanisms
Normo- SGTL2 Distal 90% glucose reabsorption tubule glycaemia Proximal Glomeruli tubule Glucose filtration SGTL1 10% glucose reabsorption No urinary glucose excretion Marx et al. Eur Heart J 2016; 37:3192-3200
SGTL2 Hyper- Distal SGLT2 expression increased Increased glucose reabsorption tubule glycaemia Proximal Glomeruli tubule Increased glucose filtration SGTL1 Urinary glucose excretion
SGTL2 SGLT2 inhibitor Hyper- SGLT2 expression increased Increased glucose reabsorption Distal glycaemia tubule Proximal Glomeruli tubule Increased glucose filtration SGTL1 Increased urinary glucose excretion
SGLT2-Inhibition in Cardiology: What is the profile of benefit? • SGLT2 inhibition – mode of action • SGLT2 inhibition and cardiovascular benefit – Clinical outcome data – Potential mechanisms
SGLT2 inhibitors – CV benefit 3P- MACE EMPA-REG OUTCOME 1 CANVAS program 2 1. Zinman B et al. N Engl J Med. 2015; 373:2117-2128 2. Neal B et al. N Engl J Med 2017; 377:644-65
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
EMPA-REG OUTCOME Results: significant reduction of total mortality by empagliflozin HR 0.68 (95% CI 0.57, 0.82) p <0.0001 NNT: 39 Kaplan-Meier estimate. HR, hazard ratio Zinman B et al. N Engl J Med. 2015; 373:2117-2128
EMPA-REG OUTCOME Results: significant reduction of heart failure hospitalisation by empagliflozin HR 0.65 (95% CI 0.50, 0.85) p =0.0017 Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med. 2015; 373:2117-2128
Integrated CANVAS Program Results: significant reduction of heart failure hospitalisation by canagliflozin HR 0.67 (95% CI 0.52 – 0.87) Placebo Patienten mit Event (%) Canagliflozin - SGLT2 inhibitors reduce cardiovascular endpoints in patients with diabetes and high CV risk most likely through a reduction of heart failure-related events Neal B et al. New England Journal of Medicine 2017
Outcome of patients with or without heart failure at baseline Patients with event/analysed (%) Empagliflozin Placebo HR (95% CI) HR (95% CI) HHF or CV death All treatment All patients 265/4687 (5.7) 198/2333 (8.5) 0.66 (0.55, 0.79) by subgroup HF at baseline interaction No 190/4225 (4.5) 149/2089 (7.1) 0.63 (0.51, 0.78) p >0.4 1 Yes 75/462 (16.2) 49/244 (20.1) 0.72 (0.50, 1.04) HHF All patients 126/4687 (2.7) 95/2333 (4.1) 0.65 (0.50, 0.85) HF at baseline No 78/4225 (1.8) 65/2089 (3.1) 0.59 (0.43, 0.82) Yes 48/462 (10.4) 30/244 (12.3) 0.75 (0.48, 1.19) CV death All patients 172/4687 (3.7) 137/2333 (5.9) 0.62 (0.49, 0.77) HF at baseline No 134/4225 (3.2) 110/2089 (5.3) 0.60 (0.47, 0.77) Yes 38/462 (8.2) 27/244 (11.1) 0.71 (0.43, 1.16) All-cause mortality All patients 269/4687 (5.7) 194/2333 (8.3) 0.68 (0.57, 0.82) HF at baseline No 213/4225 (5.0) 159/2089 (7.6) 0.66 (0.51, 0.81) Yes 56/462 (12.1) 35/244 (14.3) 0.79 (0.52, 1.20) Favours empagliflozin Favours placebo Fitchett et al. Eur Hear J 2016; 37:1526-1534
SGLT2-Inhibition in Cardiology: What is the profile of benefit? • SGLT2 inhibition – mode of action • SGLT2 inhibition and cardiovascular benefit – Clinical outcome data – Potential mechanisms
Potential mechanisms explaining the CV effects in SGLT2 inhibitor outcome trials • Glucose lowering - unlikely • Blood pressure lowering - may contribute • Weight loss - may contribute • Reduced arterial stiffness - may contribute Even the combination of these effects is unlikely to solely explain the results in EMPA-REG OUTCOME and CANVAS
Potential mechanisms explaining the CV effects of SGLT2 inhibitors Many hypotheses – limited data
Potential mechanisms explaining the CV effects of SGLT2 inhibitors Verma et al. JAMA Cardiology 2017
Effect of empaglifozin on hemodynamic parameters Central systolic blood pressure: • surrogate for afterload • determined by arterial stiffness • linked to future CV events - RCT, cross-over design - N= 76 - 6 week therapy Empagliflozin treatment exerts beneficial effects on vascular function and central hemodynamics Striepe et al. Circulation. 2017;136:1167 – 1169
Potential mechanisms explaining the CV effects of SGLT2 inhibitors Verma et al. JAMA Cardiology 2017
Study design and analysis Study design Untargeted serum metabolomics ▪ prospective study including: ▪ 25 patients with type 2 diabetes Detection of 1269 metabolites : and cardiovascular disease ▪ 863 identified metabolites ▪ on standard antidiabetic treatment ▪ 406 unknown metabolites ▪ fulfilling the inclusion and exclusion criteria of the EMPA-REG OUTCOME trial Statistical analysis blood draw blood draw Patient-matched paired analysis by Wilcoxon signed-rank test . Metabolites with p<0.05 and q<0.1 (=FDR 10%) were considered „statistically significant“ baseline 1 month empagliflozin 10mg/day 162 metabolites were altered by empagliflozin (thereof 112 identified and and 50 unkown NCT03131232 metabolites) Patients characteristics: age 64.1 ± 9.9 y; BMI 31.6 ± 5.0 kg/m²; duration of diabetes 11.5 ± 5.8 y; HbA1c: 8.5 ± 1.3%; LV-function: EF 48.7 ± 13.0%; therapy: antihypertensive 96%; lipid-lowering 92%; antiplatelet / anticoagulation 96%.
Metabolomic analysis in empagliflozin-treated pat Empagliflozin treatment leads to an expanded ketone body utilization and an increased BCAA catabolism in Kappel et al. Circulation 2017; treated patients 136(10):969-972
Disturbed BCAA catabolism in heart failure
Disturbed BCAA catabolism in heart failure Electron transfer Mitochondria BCAA chain Catabolic Activity Branch-chain Branch-chain amino-acids keto-acids Since BCAA catabolism is diminished in HF, empagliflozin could potentially restore these defects ROS mTOR and provide - an optimal energy source for the heart and / or - exhibit direct effects on cardiac function by influencing Cardiac Hypertrophy and Dysfunction various signaling pathways after Sun et al. Biochim Biophys Acta 2016; 1862:2270-2275
SGLT2 inhibition and heart failure Mid- and longterm effects - Cardiac metabolism Effect on CV death and HHF - Cardiac function - Cardiac oxygen demand - Reduced oxidative stress Early effects - Glucagon effects - Sodium …… - - Volume - Hemodynamics …… - Fitchett et al. Eur Hear J 2016; 37:1526-1534
SGLT2-Inhibition in Cardiology: What is the profile of benefit? – SGLT2 inhibitors reduce cardiovascular endpoints in patients with diabetes and high CV risk most likely through a reduction of heart failure-related events – Empagliflozin treatment leads to an expanded ketone body utilization and BCAA catabolism in treated patients – Various mechanisms seem to contribute to the beneficial effects of SGLT2 inhibitors on heart failure
Recommend
More recommend
