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

SGTL2

SGLT2 expression increased Increased glucose reabsorption

Increased glucose filtration

Increased urinary glucose excretion

SGLT2 inhibitor Glomeruli Proximal tubule Distal tubule SGTL1

SGLT2-Inhibition

After Marx et al. Eur Heart J 2016; 37(42):3192-3200

Increased urinary sodium excretion (temp.)

• 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

SGLT2 inhibitors – CVOTs

3P- MACE

EMPA-REG OUTCOME1 CANVAS program2 DECLARE3

• 1. Zinman B et al. N Engl J Med.

2015; 373:2117-2128

• 2. Neal B et al. N Engl J Med.

2017; 377(7):644-657.

• 3. Wiviott SD et al. N Engl J Med

2018;380:347

EMPA-REG Outcome Canvas Program DECLARE

Reduction of heart failure hospitalization or CV death by SGLT2 inhibitors

SGLT2 inhibitors reduce cardiovascular endpoints most likely through a reduction of heart failure-related events

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

Verma et al. JAMA Cardiology 2017

Potential mechanisms explaining the CV effects of SGLT2 inhibitors

Striepe et al. Circulation. 2017;136:1167–1169

Effect of empaglifozin on hemodynamic parameters

• RCT, cross-over design
• N= 76
• 6 week therapy

Central systolic blood pressure:

• surrogate for afterload
• determined by arterial stiffness
• linked to future CV events

Empagliflozin treatment exerts beneficial effects on vascular function and central hemodynamics

Zinman B et al. N Engl J Med. 2015; 373:2117-2128

Hospitalisation for heart failure

EMPA-REG Outcome

Acute hemodynamic effect?

Placebo Empagliflozin10 mg

Primary endpoint: Cardiac index, systemic vascular resistance index after day 1, day 3 and 12 weeks Secondary endpoints Echocardiographic parameters of cardiac function

• Randomized, placebo-controlled, double blind pilot-study
• 44 patients with type 2 diabetes and CVD or multiple risk factors

EMPA Hemodynamics

Non-invasive hemodynamic monitoring using the ClearSight System Baseline Day 1 Day 3 Week 12

EudraCT- Number 2016-000172-19

Non-invasive hemodynamic monitoring using the ClearSight System

• cardio output (CO)
• systemic vascular resistance

EMPA Hemodynamics

Echocardiography E/e‘

EMPA Hemodynamics

Rau, Thiele, Lehrke, Marx 2019; unpublished data

Empaglifozin leads to an acute improvement in measures

• f LV filling pressure

Reduction Blood volume Reduction

• Interstit. fluid

Relative reduction IF volume versus blood volume

SGLT2 inhibition leads to a reduction of interstitial volume with limited effects on blood volume

SGLT2 inhibitors versus diuretics: Differential regulation of interstitial versus intravascular compartment

Hallow et al. Diabetes Obes Metab. 2018; 20:479-487

Verma and McMurray Diabetologia 2018

SGLT2 inhibitors Loop diuretics

SGLT2 inhibitors may selectively reduce interstitial fluid and this may limit the reflex neurohumoral stimulation that

• ccurs

in response to intravascular volume contraction with traditional diuretics

SGLT2 inhibitors and reduction

• f interstitial fluid

Verma et al. JAMA Cardiology 2017

Potential mechanisms explaining the CV effects of SGLT2 inhibitors

The ketone hypothesis

Beneficial effects Potential harmful effects

Verma et al. JACC Basic Transl Sci. 2018; 3:575-587

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

baseline

empagliflozin 10mg/day

1 month

blood draw blood draw

Study design Untargeted serum metabolomics Statistical analysis

Detection of 1269 metabolites: ▪ 863 identified metabolites ▪ 406 unknown metabolites

Patient-matched paired analysis by Wilcoxon signed-rank test. Metabolites with p<0.05 and q<0.1 (=FDR 10%) were considered „statistically significant“ 162 metabolites were altered by empagliflozin (thereof 112 identified and and 50 unkown metabolites)

▪ prospective study including: ▪ 25 patients with type 2 diabetes and cardiovascular disease ▪ on standard antidiabetic treatment ▪ fulfilling the inclusion and exclusion criteria of the EMPA-REG OUTCOME trial

Study design and analysis

NCT03131232 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

Kappel et al. Circulation 2017; 136(10):969-972

Empagliflozin treatment leads to an expanded ketone body utilization and an increased BCAA catabolism in treated patients

Metabolomic analysis in empagliflozin-treated pat

Kappel et al. Circulation 2017; 136:969-972 after Sun et al. Biochim Biophys Acta 2016; 1862:2270-2275

Empaglifozin induces BCCA catabolism in treated patients Role of BCAA catabolism in 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

Effect on CV death and HHF

Early effects

• Sodium ↓
• Interstit. volume ↓
• Diastolic function
• ……

SGLT2 inhibition and heart failure

Mid- and longterm effects

• Cardiac remodeling
• Cardiac metabolism
• Cardiac 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

• f heart failure.

– Various mechanisms seem to contribute to the beneficial effects of SGLT2 inhibitors on heart failure