SGLT2-Inhibition in Cardiology: What is the profile of benefit? - - PowerPoint PPT Presentation

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SGLT2-Inhibition in Cardiology: What is the profile of benefit? - - PowerPoint PPT Presentation

Dec 17, 2022 336 likes •617 views

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

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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

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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

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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)
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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

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SGTL2

90% glucose reabsorption

SGTL1

10% glucose reabsorption

Glucose filtration

No urinary glucose excretion

Proximal tubule Distal tubule Glomeruli

Normo- glycaemia

Marx et al. Eur Heart J 2016; 37:3192-3200

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SGTL1 SGTL2

SGLT2 expression increased Increased glucose reabsorption

Increased glucose filtration

Urinary glucose excretion

Hyper- glycaemia

Glomeruli Proximal tubule Distal tubule

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SGTL2

SGLT2 expression increased Increased glucose reabsorption

Increased glucose filtration

Increased urinary glucose excretion

SGLT2 inhibitor Glomeruli Proximal tubule Distal tubule SGTL1

Hyper- glycaemia

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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

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  • 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

SGLT2 inhibitors – CV benefit

3P- MACE

EMPA-REG OUTCOME1 CANVAS program2

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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

3P-MACE and single endpoints

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Kaplan-Meier estimate. HR, hazard ratio

EMPA-REG OUTCOME

HR 0.68 (95% CI 0.57, 0.82) p<0.0001

NNT: 39

Results: significant reduction of total mortality by empagliflozin

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

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Cumulative incidence function. HR, hazard ratio

HR 0.65 (95% CI 0.50, 0.85) p=0.0017

EMPA-REG OUTCOME

Results: significant reduction of heart failure hospitalisation by empagliflozin

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

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Placebo Canagliflozin HR 0.67 (95% CI 0.52 – 0.87) Patienten mit Event (%)

Results: significant reduction of heart failure hospitalisation by canagliflozin

Integrated CANVAS Program

Neal B et al. New England Journal of Medicine 2017

  • SGLT2 inhibitors reduce cardiovascular endpoints in

patients with diabetes and high CV risk most likely through a reduction of heart failure-related events

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Outcome of patients with or without heart failure at baseline

Fitchett et al. Eur Hear J 2016; 37:1526-1534

Patients with event/analysed (%) Empagliflozin Placebo HR (95% CI) HR (95% CI) HHF or CV death All patients 265/4687 (5.7) 198/2333 (8.5) 0.66 (0.55, 0.79) HF at baseline No 190/4225 (4.5) 149/2089 (7.1) 0.63 (0.51, 0.78) 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)

All treatment by subgroup interaction p>0.41

Favours placebo Favours empagliflozin

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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

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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

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Many hypotheses – limited data

Potential mechanisms explaining the CV effects of SGLT2 inhibitors

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Verma et al. JAMA Cardiology 2017

Potential mechanisms explaining the CV effects of SGLT2 inhibitors

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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

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Verma et al. JAMA Cardiology 2017

Potential mechanisms explaining the CV effects of SGLT2 inhibitors

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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%.

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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

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Disturbed BCAA catabolism in heart failure

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Cardiac Hypertrophy and Dysfunction

Electron transfer chain Branch-chain keto-acids Branch-chain amino-acids

Mitochondria

mTOR

ROS

BCAA Catabolic Activity

Disturbed BCAA catabolism in heart failure

after Sun et al. Biochim Biophys Acta 2016; 1862:2270-2275

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

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Effect on CV death and HHF

Early effects

  • Sodium
  • Volume
  • Hemodynamics
  • ……

SGLT2 inhibition and heart failure

Mid- and longterm effects

  • Cardiac metabolism
  • Cardiac function
  • Cardiac oxygen demand
  • Reduced oxidative stress
  • Glucagon effects
  • ……

Fitchett et al. Eur Hear J 2016; 37:1526-1534

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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