The cardioprotective mechanisms of SGLT2 inhibitors: What do - PowerPoint PPT Presentation

The cardioprotective mechanisms of SGLT2 inhibitors: What do cardiologists need to know? 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

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

SGLT2 inhibitors – CVOTs 3P- MACE CANVAS program 2 DECLARE 3 EMPA-REG OUTCOME 1 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 3. Wiviott SD et al. N Engl J Med 2018;380:347

Reduction of heart failure hospitalization or CV death by SGLT2 inhibitors EMPA-REG Outcome Canvas Program DECLARE 1. Zinman B et al. N Engl J Med. 2015; 373:2117-2128 SGLT2 inhibitors reduce cardiovascular endpoints most 2. Neal B et al. N Engl J Med. 2017; 377(7):644-657. 3. Wiviott SD et al. N Engl J Med likely through a reduction of heart failure-related events 2018;380:347

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, CANVAS, and DECLARE

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

EMPA-REG Outcome Hospitalisation for heart failure Acute hemodynamic effect? Zinman B et al. N Engl J Med. 2015; 373:2117-2128

EMPA Hemodynamics • Randomized, placebo-controlled, double blind pilot-study • 44 patients with type 2 diabetes and CVD or multiple risk factors Empagliflozin10 mg Placebo Baseline Day 1 Day 3 Week 12 Non-invasive hemodynamic monitoring using the ClearSight System Primary endpoint: Cardiac index, systemic vascular resistance index after day 1, day 3 and 12 weeks Secondary endpoints Echocardiographic parameters of cardiac function EudraCT- Number 2016-000172-19

EMPA Hemodynamics Non-invasive hemodynamic monitoring using the ClearSight System - cardio output (CO) - systemic vascular resistance

EMPA Hemodynamics Echocardiography E/e‘ Empaglifozin leads to an acute improvement in measures of LV filling pressure Rau, Thiele, Lehrke, Marx 2019; unpublished data

SGLT2 inhibitors versus diuretics: Differential regulation of interstitial versus intravascular compartment Reduction Reduction Relative reduction IF volume versus Blood volume Interstit. fluid blood volume SGLT2 inhibition leads to a reduction of interstitial volume with limited effects on blood volume Hallow et al. Diabetes Obes Metab. 2018; 20:479-487

SGLT2 inhibitors and reduction of interstitial fluid SGLT2 inhibitors Loop diuretics SGLT2 inhibitors may selectively reduce interstitial fluid and this may limit the reflex neurohumoral stimulation that occurs in response to intravascular volume contraction with traditional diuretics Verma and McMurray Diabetologia 2018

Potential mechanisms explaining the CV effects of SGLT2 inhibitors Verma et al. JAMA Cardiology 2017

The ketone hypothesis Potential harmful effects Beneficial effects

Empagliflozin Increases Cardiac Energy Production in Diabetes • diabetic (db/db) mice treated with or without empagliflozin SGLT2 inhibition enhances the cardiac energy pool by increasing cardiac energy production from glucose and fatty acid oxidation, but not ketone oxidation Verma et al. JACC Basic Transl Sci. 2018; 3:575-587

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

Metabolomic analysis in empagliflozin-treated pat Role of BCAA catabolism in Empaglifozin induces BCCA catabolism in treated patients Heart failure Empagliflozin Since BCAA catabolism is diminished in HF, empagliflozin could potentially restore these defects and provide - an optimal energy source for the heart and / or - exhibit direct effects on cardiac function by influencing various signaling pathways Kappel et al. Circulation 2017; 136:969-972 after Sun et al. Biochim Biophys Acta 2016; 1862:2270-2275

SGLT2 inhibition and heart failure Mid- and longterm effects Effect on CV death and HHF - Cardiac remodeling - Cardiac metabolism - Cardiac function Early effects …… - Sodium ↓ - Interstit. volume ↓ - - Diastolic function …… - Fitchett et al. Eur Hear J 2016; 37:1526-1534

The cardioprotecitve mechanisms of SGLT2 inhibitors: What do cardiologists need to know? – SGLT2 inhibitors reduce cardiovascular endpoints in patients with diabetes and high CV risk most likely through a reduction of heart failure-related events – SGLT2 inhibition may prevent or delay the development of heart failure. – Various mechanisms seem to contribute to the beneficial effects of SGLT2 inhibitors on heart failure