SLIDE 1 SGLT2 inhibition in CVD & Diabetes: How can we explain the benefits?
Diabetes & Cardiovascular Disease: What are the challenges?
Asian Cardio Diabetes Forum
March 30-31, 2019 - Hanoi, Vietnam
Aachen, Germany
SLIDE 2 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
SLIDE 3 SGTL1 SGTL2
SGLT2 expression increased Increased glucose reabsorption
Increased glucose filtration
Urinary glucose excretion
Hyper- glycaemia
Glomeruli Proximal tubule Distal tubule
SLIDE 4 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.)
SLIDE 5
- 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
SGLT2 inhibitors – CVOTs
3P- MACE
EMPA-REG OUTCOME1 CANVAS program2 DECLARE3
SLIDE 6
- 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 and CV death by SGLT2 inhibitors
SGLT2 inhibitors reduce cardiovascular endpoints most likely through a reduction of heart failure-related events
SLIDE 7 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
SLIDE 8
Potential mechanisms explaining the CV effects of SGLT2 inhibitors
2016
SLIDE 9 Wanner and Marx (2018) Diabetologia DOI 10.1007/s00125-018-4678-z
Potential mechanisms explaining the CV effects of SGLT2 inhibitors
Thomas and Cherney (2018) Diabetologia DOI 10.1007/s00125-018-4669-0
2018
Still, many hypotheses – limited data
SLIDE 10
Verma et al. JAMA Cardiology 2017
Potential mechanisms explaining the CV effects of SGLT2 inhibitors
SLIDE 11 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
SLIDE 12
EMPA-REG OUTCOME
Mediation analysis
Inzucchi et al. Diabetes Care 2018;41:356–363
Volume contraction is a key determinant of the benefit seen with empagliflozin
SLIDE 13 Reduction Blood volume Reduction
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
SLIDE 14 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
in response to intravascular volume contraction with traditional diuretics
SGLT2 inhibitors and reduction
SLIDE 15 Placebo Empagliflozin 10mg OD
Primary endpoint Change in LV mass (indexed to baseline BSA)
- 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
Verma S et al., AHA 2018
EMPA-HEART
Follow-up: 6 months
SLIDE 16 Baseline (SBP) (mmHg) 138.4 139.3
Empagliflozin treatment lowers ambulatory blood pressure (ABPM)
Adjusted difference (95% CI) between groups
P=0.003 Placebo Empagliflozin
Adjusted difference (95% CI) between groups
P=0.22 Placebo Empagliflozin
Verma S et al., AHA 2018
EMPA-HEART
SLIDE 17 Results: significant reduction of LV mass index by empaglifozin
Adjusted difference (95% CI) between groups
P=0.01
LVM regression (g)
- 0.39 (10.83)
- 4.71 (15.43)
Data are presented as mean (95% CI) for the intention-to- treat population. *LV mass with papillary muscle mass index to body surface area.
Verma S et al., AHA 2018
EMPA-HEART
SLIDE 18 Secondary cMRI-endpoints
0.04 Adjusted difference (95% CI) between groups
P=0.36 Baseline LVESVI* (mL/m2)
LVESVI*
2.2
Adjusted difference (95% CI) between groups 2.21 (-0.23; 4.66) P=0.07 Baseline LVEDVI* (mL/m2) Baseline LVEF (%)
LVEDVI* LVEF
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
Adjusted difference (95% CI) between groups
P=0.55
Verma S et al., AHA 2018
EMPA-HEART
SLIDE 19
Verma S et al., AHA 2018
EMPA-HEART
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
Secondary biomarker endpoints
SLIDE 20 Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7
Diabetes-associated ventricular remodelling Healthy heart
Cardiovascular protection by SGLT2 inhibitors
SLIDE 21
Verma et al. JAMA Cardiology 2017
Potential mechanisms explaining the CV effects of SGLT2 inhibitors
SLIDE 22
Cardiomyocytes WT mice Cardiomyocytes HF mice (TAC) Cardiomyocytes HF human
Empagliflozin exposure increases GLUT1 expression in isolated cardiomyocytes
Mustroph et al. Diabetologia 2019 online
SLIDE 23
Cardiomyocytes WT mice Cardiomyocytes HF mice (TAC) Cardiomyocytes HF human
Empagliflozin exposure increases intracellular glucose concentrations in isolated cardiomyocytes
Mustroph et al. Diabetologia 2019 online
SLIDE 24
The ketone hypothesis
Beneficial effects Potential harmful effects
SLIDE 25
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.
SLIDE 26
- 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
BDH-1 SCOT
db / db + empa db / db
Möllmann et al. 2019 unpublished data
Effect of empaglifozin on cardiac expression
- f enzymes involved in ketone oxidation
d p /d tm i n [m m H g /s ]
b a s e lin e d o b u ta m in e
- 1 0 0 0 0
- 8 0 0 0
- 6 0 0 0
- 4 0 0 0
- 2 0 0 0
d b /d b
+ /-
d b /d b
d b /d b
**
Empa improves diastolic function
SLIDE 27 Verma et al. JACC Basic Transl Sci. 2018; 3:575-587
Empagliflozin Increases Cardiac Energy Production in Diabetes
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
SLIDE 28 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%.
SLIDE 29 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
SLIDE 30 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
SLIDE 31 Farkouh ME et al. J Am Coll Cardiol. 2018;71:2507-2510
SGLT2i and prevention of CHF Reduction in interstitial edema Reduced pre- /afterload + reduction in LV wall stress Improved renal function + cardiorenal physiology Improved cardiac bioenergetics Inhibition of cardiac sodium- hydrogen exchange Natriuresis
Cardiovascular protection by SGLT2 inhibitors
SLIDE 32
Byrne et al. J Am Coll Cardiol Basic Trans Science 2017
Empagliflozin preserves cardiac function in a non-diabetic murine HF model in vivo and ex vivo
SLIDE 33 Reduction of NT-proBNP and hsTNI in canagliflozin-treated patients
- retrospective analysis
- 666 T2DM patients with moderate increased CV risk
- randomized to canagliflozin 100 or 300 mg or placebo
Januzzi et al. J Am Coll Cardiol 2017; 70: 704-712
SGLT2 inhibition may prevent or delay the development of CV disease, particularly the development of heart failure.
SLIDE 34
Marx N, Libby P; JACC Basic Transl Sci. 2018; 3:858-860
Potential mechanisms through which SGLT2-inhibition and GLP-1 agonists exhibit CV beneficial effects
SLIDE 35 Effect on CV death and HHF
Early effects
- Sodium
- Interstit. volume ↓
- Hemodynamics
- ……
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
SLIDE 36 SGLT2 Inhibition in CVD & Diabetes: How can we explain the benefits?
– 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
– Various mechanisms seem to contribute to the beneficial effects of SGLT2 inhibitors on heart failure
