Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Gupte, Manisha; Umbarkar, Prachi; Lal, Hind

doi:10.1007/s10557-017-6741-2

“…8A-8C). Notably, EMP is gaining importance in T2DM patients as its bene ts extend beyond its glucose-lowering action [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

“…A meta-analysis of RCTs has also con rmed the bene ts of EMP [43]. Gupte et al [40] summarized clinical, preclinical and metaanalysis of SGLT2 inhibitors mediated cardiac bene ts. Ongoing RCTs are planned to study the effects of EMP in HFpEF [44,45].…”

Section: Discussionmentioning

confidence: 99%

“…As roughly 130 million diabetics live in the Western Paci c region, with a signi cant proportion in East Asia including China, Philippines, Japan and Korea [33], a sub analysis of EMP treatment in the Asian population within EMPA-REG OUTCOME was performed; it revealed that EMP was bene cial to Asians as well [47] which underscores our interest to focus on the ALDH2*2 mutation which increases the propensity to develop diabetic cardiac dysfunction [37] as well as HFpEF in East Asians [17]. There are few diabetic animal studies where the bene cial cardiovascular effects of EMP were shown [40,48,49] including our previous study in which EMP was shown to improve cardiac function and exercise tolerance in same animal model by diminishing hyperglycemia-mediated 4HNE adducts [18].…”

Section: Discussionmentioning

confidence: 99%

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Aldehyde dehydrogenase 2 activator augments the beneficial effects of empagliflozin in diabetes associated HFpEF

Palaniyandi

¹

,

Pan

²

,

Roy

³

et al. 2022

Preprint

0

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Objectives: To ameliorate diabetes mellitus associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.Background: 4HNE, a cellular reactive carbonyl species (RCS), was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH)2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes associated HFpEF. Methods: We fed high-fat diet to ALDH2*2 mice which have intrinsically low ALDH2 activity to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF and along with increased 4HNE adducts and we treated them with vehicle, empagliflozin (EMP) (3mg/kg/d) to reduce 4HNE and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. Results: EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway in ALDH2*2 mice with diabetes associated HFpEF. This combination was even more effective than EMP alone. Conclusions: Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes associated HFpEF.

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“…8A-8C). Notably, EMP is gaining importance in T2DM patients as its bene ts extend beyond its glucose-lowering action [40][41][42]. Speci cally, its effect which led to improvements in heart failure patients and cardiovascular death is striking in the landmark randomized clinical trial (RCT) EMPA-REG OUTCOME (Empagli ozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) [20].…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase 2 Activator Augments the Beneficial Effects of Empagliflozin in Diabetes Aassociated HFpEF

Pan

¹

,

Roy

²

,

Giri

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Objectives: To ameliorate diabetes mellitus associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.Background: 4HNE, a cellular reactive carbonyl species (RCS), was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH)2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes associated HFpEF. Methods: We fed high-fat diet to ALDH2*2 mice which have intrinsically low ALDH2 activity to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF and along with increased 4HNE adducts and we treated them with vehicle, empagliflozin (EMP) (3mg/kg/d) to reduce 4HNE and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. Results: EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway in ALDH2*2 mice with diabetes associated HFpEF. This combination was even more effective than EMP alone. Conclusions: Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes associated HFpEF.

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“…SGLT2i have potent diuretic properties, which may partially explain their beneficial effects on HF hospitalisations [13,14]. Nevertheless, the diuretic effects of SGLT2i could also limit the use of SGLT2i in HF patients without T2D.…”

mentioning

confidence: 99%

Effects of Sodium–Glucose Co-transporter 2 Inhibition with Empaglifozin on Renal Structure and Function in Non-diabetic Rats with Left Ventricular Dysfunction After Myocardial Infarction

Yurista

¹

,

Silljé

²

,

Goor

³

et al. 2020

Cardiovasc Drugs Ther

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Background The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) is currently expanding to cardiovascular risk reduction in non-diabetic subjects, but renal (side-)effects are less well studied in this setting. Methods Male non-diabetic Sprague Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing empagliflozin (EMPA) (30 mg/kg/day) or control chow. Renal function and electrolyte balance were measured in metabolic cages. Histological and molecular markers of kidney injury, parameters of phosphate homeostasis and bone resorption were also assessed. Results EMPA resulted in a twofold increase in diuresis, without evidence for plasma volume contraction or impediments in renal function in both sham and MI animals. EMPA increased plasma magnesium levels, while the levels of glucose and other major electrolytes were comparable among the groups. Urinary protein excretion was similar in all treatment groups and no histomorphological alterations were identified in the kidney. Accordingly, molecular markers for cellular injury, fibrosis, inflammation and oxidative stress in renal tissue were comparable between groups. EMPA resulted in a slight increase in circulating phosphate and PTH levels without activating FGF23-Klotho axis in the kidney and bone mineral resorption, measured with CTX-1, was not increased. Conclusions EMPA exerts profound diuretic effects without compromising renal structure and function or causing significant electrolyte imbalance in a non-diabetic setting. The slight increase in circulating phosphate and PTH after EMPA treatment was not associated with evidence for increased bone mineral resorption suggesting that EMPA does not affect bone health.

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Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Cited by 8 publications

References 17 publications

Aldehyde dehydrogenase 2 activator augments the beneficial effects of empagliflozin in diabetes associated HFpEF

Aldehyde dehydrogenase 2 activator augments the beneficial effects of empagliflozin in diabetes associated HFpEF

Aldehyde Dehydrogenase 2 Activator Augments the Beneficial Effects of Empagliflozin in Diabetes Aassociated HFpEF

Effects of Sodium–Glucose Co-transporter 2 Inhibition with Empaglifozin on Renal Structure and Function in Non-diabetic Rats with Left Ventricular Dysfunction After Myocardial Infarction

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