Empagliflozin does not affect left ventricular diastolic function in patients with type 2 diabetes mellitus and coronary artery disease: insight from the EMPA-HEART CardioLink-6 randomized clinical trial

Rai, Archana; Connelly, Kim A.; Verma, Subodh; Mazer, C. David; Teoh, Hwee; Ng, Ming-Yen; Roifman, Idan; Quan, Adrian; Pourafkari, Marina; Jiménez-Juan, Laura; Ramanan, Venkat; Ge, Yin; Deva, Djeven P.; Yan, Andrew T.

doi:10.1007/s00592-021-01823-6

Cited by 6 publications

(3 citation statements)

References 8 publications

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“…In people with type 2 diabetes and coronary artery disease, empagliflozin was reported to reduce LVMi over a 6-month period in a randomized placebo-controlled study (adjusted difference, –3.35 g/m 2 [95% CI, –5.9 to –0.81 g/m 2 ]; P =0.01). 17,70,75,79–85 A similar reduction in LV mass was observed with dapagliflozin in the DAPA-LVH trial (Does Dapagliflozin Regress Left Ventricular Hypertrophy in Patients With Type 2 Diabetes? ), which studied people with type 2 diabetes and LV hypertrophy (–3.95±4.85 g in the dapagliflozin group versus –1.13±4.55 g in the placebo group; P =0.018).…”

Section: Discussionmentioning

confidence: 68%

“…These clinical observations have driven a lot of interest to elucidate the mechanisms underlying how SGLT2 inhibitors retard the development and progression of heart failure. 17,57–81 Both direct and indirect cardiac pathways have been postulated to be modulated by SGLT2 inhibitors. For example, SGLT2 inhibitors have been suggested to directly affect cardiac ion channels and regulate pathways involved in cardiomyocyte autophagy, mitophagy, and inflammasome activation.…”

Section: Discussionmentioning

confidence: 99%

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Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial

et al. 2023

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Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. While it has been theorized that SGLT2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine if SGLT2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40-80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomized to empagliflozin (10 mg/day; 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 (BSA) as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to baseline BSA and LV ejection fraction. Results: Among the 169 participants (141 men [83%], mean age 59.3 ± 10.5 years), baseline LVMi was 63.2 ± 17.9 g/m 2 and 63.8 ± 14.0 g/m 2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group vs. placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1,1.5 g/m 2 ) (P=0.74). Median baseline (IQR) NT-proBNP 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 vs. placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mmHg (-5.2, 2.6 mmHg) (P=0.52), 0.69 mmHg (-1.9, 3.3 mmHg) (P=0.60) and -6.1 pg/mL (-37.0, 24.8 pg/mL) (P=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 BSA) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, SGLT2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04461041clinicaltrials.gov Identifier: NCT04461041

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial

et al. 2023

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“…Recent data from a subgroup analysis of the Empire HF trial showed that empagliflozin reduced left ventricular and left atrial volumes in patients with heart failure and reduced ejection fraction, which is consistent with findings from another randomized trial in non-diabetic subjects with heart failure and reduced ejection fraction [ 19 , 20 ]. In contrast, the EMPA-HEART CardioLink-6 trial did not show a positive impact of empagliflozin on left ventricular diastolic function in individuals with diabetes mellitus and coronary artery disease [ 21 ]. The improvement in diastolic function found in the EmDia trial is also supported by recent data establishing a reduction in pulmonary pressures measured with an implanted pulmonary artery pressure sensor by empagliflozin compared to placebo [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of empagliflozin on left ventricular diastolic function in addition to usual care in individuals with type 2 diabetes mellitus—results from the randomized, double-blind, placebo-controlled EmDia trial

et al. 2023

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Background The sodium-glucose co-transporter 2 inhibitor empagliflozin improves cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM) and heart failure. Experimental studies suggest a direct cardiac effect of empagliflozin associated with an improvement in left ventricular diastolic function. Methods In the randomized, double-blind, two-armed, placebo-controlled, parallel group trial EmDia, patients with T2DM and elevated left ventricular E/E´ ratio were enrolled and randomized 1:1 to receive empagliflozin 10 mg/day versus placebo. The primary endpoint was the change of left ventricular E/E´ ratio after 12 weeks of intervention. Results A total of 144 patients with T2DM and an elevated left ventricular E/e´ ratio (age 68.9 ± 7.7 years; 14.1% women; E/e´ ratio 9.61[8.24/11.14], left ventricular ejection fraction 58.9% ± 5.6%). After 12 weeks of intervention, empagliflozin resulted in a significant higher decrease in the primary endpoint E/e´ ratio by − 1.18 ([95% confidence interval (CI) − 1.72/− 0.65]; P < 0.0001) compared with placebo. The beneficial effect of empagliflozin was consistent across all subgroups and also occurred in subjects with heart failure and preserved ejection fraction (n = 30). Additional effects of empagliflozin on body weight, HbA1c, uric acid, red blood cell count, hemoglobin, mean corpuscular hemoglobin, and hematocrit were detected (all P < 0.001). Approximately one-third of the reduction in E/e´ by empagliflozin could be explained by the variables examined. Conclusions Empagliflozin improves diastolic function in patients with T2DM and elevated end-diastolic pressure. Since the positive effects were consistent in patients with and without heart failure with preserved ejection fraction, the data add a mechanistic insight for the beneficial cardiovascular effect of empagliflozin. Trial registration Clinicaltrials.gov, unique identifier: NCT02932436. Graphical abstract

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Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling

Bakbak,

Verma,

Krishnaraj

et al. 2023

American Journal of Physiology-Heart and Circulatory Physiology

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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-month 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 (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 months, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ pro-angiogenic cells ( P=0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors ( P=0.012) and decreased ALDHhiSSCmidCD86+CD163- pro-inflammatory monocyte ( P=0.011) polarization compared to placebo. Empagliflozin promoted the recovery of multiple circulating pro-vascular 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.

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Empagliflozin does not affect left ventricular diastolic function in patients with type 2 diabetes mellitus and coronary artery disease: insight from the EMPA-HEART CardioLink-6 randomized clinical trial

Cited by 6 publications

References 8 publications

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial

Effects of empagliflozin on left ventricular diastolic function in addition to usual care in individuals with type 2 diabetes mellitus—results from the randomized, double-blind, placebo-controlled EmDia trial

Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling

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