BACKGROUND:SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to ...determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease.
METHODS:Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide).
RESULTS:Among the 97 participants (90 men 93%, mean standard deviation age 62.8 9.0 years, type 2 diabetes mellitus duration 11.0 8.2 years, estimated glomerular filtration rate 88.4 16.9 mL/min/1.73m, LV mass indexed to body surface area 60.7 11.9 g/m), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m and 0.01 g/m for those assigned empagliflozin and placebo, respectively (adjusted difference −3.35 g/m; 95% CI, −5.9 to −0.81g/m, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference −6.8mmHg, 95% CI −11.2 to −2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference −3.2mmHg; 95% CI, −5.8 to −0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003).
CONCLUSIONS:Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT02998970.
This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).
Empagliflozin has been ...shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.
This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2.
Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: –1.40%; 95% confidence interval CI: –2.60 to –0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: –1.5 ml/m2; 95% CI: –2.6 to –0.5 ml/m2; p = 0.006), with a trend toward reduction in iICV (adjusted difference: –1.7 ml/m2; 95% CI: –3.8 to 0.3 ml/m2; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2.
In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes EMPA-HEART; NCT02998970)
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Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ...ALDH
hi
-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDH
hi
-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.
Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDH
hi
) versus mature effector (ALDH
low
) cell attributes. Samples from individuals assigned to empagliflozin ( n = 25) and placebo ( n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDH
hi
SSC
low
), monocyte (ALDH
hi
SSC
mid
), and granulocyte (ALDH
hi
SSC
hi
) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDH
hi
SSC
low
CD133
+
CD34
+
proangiogenic cells ( P = 0.048), elevated ALDH
hi
SSC
mid
CD163
+
regenerative monocyte precursors ( P = 0.012), and decreased ALDH
hi
SSC
mid
CD86
+
CD163
−
proinflammatory monocyte ( P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.
NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDH
hi
-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDH
hi
-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.
Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose ...cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure.
Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction.
Among the 169 participants (141 men 83%; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m
and 63.8±14.0 g/m
for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m
(-2.1 to 1.5 g/m
;
=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg;
=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg;
=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL;
=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups.
Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months.
URL: https://www.
gov; Unique identifier: NCT04461041.
Background: The sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular (CV) outcomes in patients with type 2 diabetes (T2DM) and established CV disease (CVD) but the mechanism ...driving their cardio-benefit remains poorly understood. Specifically, whether SGLT2 inhibitors have direct cardiac effects remains unknown.Objective: To evaluate the effects of the SGLT2 inhibitor empagliflozin on left ventricular (LV) mass index (LVMi) and myocardial extracellular volume (ECV) in individuals with T2DM and CVD.Method: We randomized 97 participants with T2DM and CVD to receive empagliflozin 10 mg daily or placebo for 6 months in addition to standard of care therapy. The primary outcome was change in LVMi from baseline to 6 months determined by cardiac magnetic resonance. Other outcomes included change in indexed LV end diastolic volume (LVEDVi), end systolic volume (LVESVi) or ejection fraction (LVEF) and in circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin I. For our sub-study with 74 participants we assessed ECV, indexed intracellular and extracellular compartment volume (iICV, iECV), the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase-2 (MMP-2).Results: In the primary study, change in LVMi from baseline to 6-months was -2·6 (7·8) g/m2 for the empagliflozin group and -0·01 (5·7) g/m2 for placebo (adjusted difference between groups -3·4 g/m2; 95% Confidence Interval (CI), -5·9 to -0·8; P=0·01). There were no significant differences between groups for LVEDVi, LVESVi, LVEF nor in NT-proBNP and troponin I. In our sub-study, empagliflozin reduced ECV compared to placebo (adjusted difference: -1.4%; 95% CI, -2.6 to -0.14; P=0.03). This reduction in ECV in the empagliflozin group was observed after 6 months, alongside the reduction in LVMi. Empagliflozin therapy compared with placebo, also reduced iECV (adjusted difference: -1.5 mL/m2; 95% CI, -2.6 to -0.5; P=0.006) with a trend towards reduction in iICV (adjusted difference: -1.7 mL/m2; 95% CI, -3.8 to 0.3; P=0.09). Empagliflozin had no difference in impact upon circulating levels of MMP-2 or sST2 when compared to placebo.Conclusions: In patients with T2DM and CVD, empagliflozin therapy was associated with a reduction in ECV in parallel to a reduction in LVMi which may contribute to its CV benefits.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors lower cardiovascular events in type 2 diabetes (T2DM) but whether they promote direct cardiac effects remains unknown. We sought to determine if ...empagliflozin causes a decrease in left ventricular (LV) mass in people with T2DM and coronary artery disease (CAD).
Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5 to 10.0%, known CAD and estimated glomerular filtration rate (eGFR) ≥60mL/min/1.73m
. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed (LVMi) to body surface area (BSA) from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to BSA (LVEDVi and LVESVi), ejection fraction (LVEF), 24-h ambulatory blood pressure, hematocrit and N-terminal pro b-type natriuretic peptide (NT-proBNP).
Among the 97 participants (90 men 93%, mean SD age 62.8 9.0 years, T2DM duration 11.0 8.2 years, eGFR 88.4 16.9 mL/min/1.73m
, LVMi 60.7 11.9 g/m
) 90 had evaluable imaging at follow-up. Mean LVMi regression over 6 months was 2.6 g/m
and 0.01 g/m
for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m
, 95% CI -5.9 to -0.81g/m
, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference -3.2mmHg, 95% CI -5.8 to -0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003).
Among people with T2DM and CAD, SGLT2 inhibition with empagliflozin was associated with significant reduction in LVMi after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME trial.
URL: https://clinicaltrials.gov Unique Identifier: NCT02998970.
IntroductionSodium glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) mortality, heart failure hospitalization, and promote left ventricular (LV) remodeling in patients with type 2 ...diabetes (T2DM) and coronary artery disease (CAD). Given that reducing extracellular volume (ECV) fraction, a measure of myocardial extracellular matrix (ECM) expansion, with renin angiotensin system (RAS) blockers improves CV outcomes, we hypothesized that SGLT2 inhibition may protect the heart via a reduction in ECV.MethodsThis is a sub-analysis of the EMPA-HEART CardioLink-6 trial in which 97 individuals with T2DM (A1C ≥6.5% and ≤10.0%) and established CAD (90 men 93%, mean SD age 62.8 9.0 years, T2DM duration 11.0 8.2 years, and eGFR 88.4 16.9 mL/min/1.73m), were randomized to empagliflozin 10 mg or placebo QD for 6 months, on top of standard of care therapies (including use of RAS blockers by >80% of participants). LV parameters and global myocardial ECV (corrected for hematocrit) were quantified on CV magnetic resonance at baseline and 6 months. T1 maps were generated with the modified Look-Locker Inversion (MOLLI) sequence. Levels of the circulating fibrotic biomarkers matrix metalloproteinase 2 (MMP-2) and soluble ST2 (sST2) were assayed.ResultsBaseline LV mass index (LVMi) and ECV in the 2 groups were comparable and similar after 6 months on placebo. Concomitant reductions in LVMi (adjusted difference between groups -3.4 g/m; 95% CI, -5.9 to -0.8 g/m; P = 0.01) and ECV (adjusted difference between groups -1.4%; 95% CI, -2.6 to -0.14 %; P=0.03) were noted after 6 months of empagliflozin use. There was no difference in LVEDVi, LVESVi, LVEF, MMP-2, or sST2 between the groups (Table 1).ConclusionsA reduction in global ECV was observed after empagliflozin was added to standard of care therapy (including RAS blockers) for 6 months. Further mechanistic studies are warranted to gain further insights on the cardioprotective role of SGLT2 inhibitors.
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