Diabetes & Cardiovascular Disease: What are the challenges? SGLT2 inhibition in CVD & Diabetes: How can we explain the benefits? Prof. Nikolaus Marx, MD Aachen, Germany Asian Cardio Diabetes Forum March 30-31, 2019 - Hanoi, Vietnam
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
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
Reduction of heart failure hospitalization and 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 2016
Potential mechanisms explaining the CV effects of SGLT2 inhibitors 2018 Wanner and Marx (2018) Diabetologia Thomas and Cherney (2018) Diabetologia DOI 10.1007/s00125-018-4678-z DOI 10.1007/s00125-018-4669-0 Still, 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
EMPA-REG OUTCOME Mediation analysis Volume contraction is a key determinant of the benefit seen with empagliflozin Inzucchi et al. Diabetes Care 2018;41:356 – 363
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
EMPA-HEART • Randomized study to evaluate the impact of SGLT2 inhibition with empagliflozin on LV remodeling assessed by cMRI (primary objective) • Identify the pathophysiological mechanisms of empagliflozin-associated LV remodeling (secondary objective) • 97 patients with T2DM and stable CAD • LVEF normal; 6% history of HF Empagliflozin 10mg OD Follow-up: 6 months Placebo Primary endpoint Change in LV mass (indexed to baseline BSA) Verma S et al., AHA 2018
EMPA-HEART Empagliflozin treatment lowers ambulatory blood pressure (ABPM) Baseline (SBP) 138.4 139.3 (mmHg) Placebo Empagliflozin Placebo Empagliflozin -0.8 -0.7 -2.0 -7.9 Adjusted difference (95% CI) Adjusted difference (95% CI) between groups between groups -6.7 (-11.2; -2.3) -2.1 (-5.4; 1.3) P=0.003 P=0.22 Verma S et al., AHA 2018
EMPA-HEART Results: significant reduction of LV mass index by empaglifozin Adjusted difference (95% CI) between groups -3.35 (-5.9; -0.81) P=0.01 -0.01 -2.6 Data are presented as mean (95% CI) for the intention-to- treat population. *LV mass with papillary muscle mass index to body surface area. LVM regression (g) -0.39 (10.83) -4.71 (15.43) Verma S et al., AHA 2018
EMPA-HEART Secondary cMRI-endpoints LVEDVI* LVESVI* LVEF Adjusted difference (95% CI) Adjusted difference (95% CI) Adjusted difference (95% CI) between groups between groups between groups Baseline LVEF Baseline LVESVI* Baseline LVEDVI* -1.16 (-4.99; 2.66) 2.21 (-0.23; 4.66) -1.20 (-3.77; 1.37) (mL/m 2 ) (mL/m 2 ) (%) P=0.55 P=0.07 P=0.36 2.2 0.04 -1.6 -2.1 -0.01 -1.0 Data are presented as mean (95% CI) for the per-protocol population *Left ventricular end systolic/diastolic volume, indexed to body surface area cMRI: cardiac magnetic resonance imaging Verma S et al., AHA 2018
EMPA-HEART Secondary biomarker endpoints Empagliflozin results in salutary effects on LV remodeling at 6 months among patients with T2DM and stable CAD but normal EF and without a clear history of HF Verma S et al., AHA 2018
Cardiovascular protection by SGLT2 inhibitors Diabetes-associated Healthy heart ventricular remodelling Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7
Potential mechanisms explaining the CV effects of SGLT2 inhibitors Verma et al. JAMA Cardiology 2017
Empagliflozin exposure increases GLUT1 expression in isolated cardiomyocytes Cardiomyocytes WT mice Cardiomyocytes HF mice (TAC) Cardiomyocytes HF human Mustroph et al. Diabetologia 2019 online
Empagliflozin exposure increases intracellular glucose concentrations in isolated cardiomyocytes Cardiomyocytes Cardiomyocytes Cardiomyocytes WT mice HF mice (TAC) HF human Mustroph et al. Diabetologia 2019 online
The ketone hypothesis Potential harmful effects Beneficial effects
Increased ketone utilisation in HF MCT: monocarboxylate transporter BDH: β -hydroxybutyrate dehydrogenase SCOT succinyl-CoA:3-oxoacid CoA transferase Bedi et al. Circulation. 2016;133:706-716.
Effect of empaglifozin on cardiac expression of enzymes involved in ketone oxidation • db/db mice were fed a high fat western-type diet with or without empagliflozin at a concentration of 150 mg/kg for 5 weeks Empa improves diastolic function 0 d p /d t m i n [m m H g /s ] -2 0 0 0 db / db db / db -4 0 0 0 + empa -6 0 0 0 + /- d b /d b BDH-1 -/- -8 0 0 0 d b /d b ** -/- + e m p a d b /d b SCOT -1 0 0 0 0 b a s e lin e d o b u ta m in e Möllmann et al. 2019 unpublished data
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
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