Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes

Hammoudi, Nadjib; Jeong, Dongtak; Singh, Rajvir; Farhat, Ahmed; Komajda, Michel; Mayoux, Eric; Hajjar, Roger J.; Lebeche, Djamel

doi:10.1007/s10557-017-6734-1

Cited by 122 publications

(115 citation statements)

References 48 publications

(42 reference statements)

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“…While there were no alterations in the systolic function at steady state, dobutamine induced response was significantly improved with empagliflozin treatment. These observations confirm that the employed preclinical model in the present study accurately recapitulates the clinical findings with human trials [7]. However, a particular strength of the study is the elucidation of the underlying molecular mechanisms, specifically, identification of several intrinsic pathways potentially mediating the favorable cardiac outcome (Figure).…”

supporting

confidence: 78%

“…The study by Hammoudi et al [7] in this issue of Cardiovascular Drugs and Therapy examined the underlying signaling mechanism of empagliflozin mediated cardiac benefits in a mouse model of T2DM. Hammoudi et al [7] employed a comparatively simple study design with three experimental groups, the first group included lean mice ob/ + which served as controls, the second group included ob/ob mice that were fed diet containing vehicle and the third group included ob/ob mice fed on diet mixed with Empagliflozin (10mg/kg/day) for six weeks.…”

mentioning

confidence: 99%

“…Hammoudi et al [7] employed a comparatively simple study design with three experimental groups, the first group included lean mice ob/ + which served as controls, the second group included ob/ob mice that were fed diet containing vehicle and the third group included ob/ob mice fed on diet mixed with Empagliflozin (10mg/kg/day) for six weeks. Authors demonstrated that empagliflozin significantly lowered HbA1c, improved diastolic function (reduced E velocity and deceleration time) and increased left ventricle compliance (increased end diastolic pressure volume relationship).…”

mentioning

confidence: 99%

“…Therefore, Hammoudi et al [7] tested the hypothesis that molecular machinery regulating diastolic Ca 2 + levels, such as phospholamban (PLB) phosphorylation or SERCA2a expression, may act as downstream targets of Empagliflozin. While SERCA2a expression was comparable between the groups, empagliflozin treatment led to significantly increased phosphorylation of PLB at both PLB-Ser 16 and PLB-Thr 17, supporting the notion that increased phospholamban activity augment the SERCA2a function leading to an improved diastolic function.…”

mentioning

confidence: 99%

“…Importantly, all these signaling cascades are strongly implicated in the pathological cardiac hypertrophy and heart failure. However, Hammoudi et al [7] are the first to identify that empagliflozin may exert its cardiac benefits by blunting the activation of MAPKs. As pointed out earlier, direct studies with isolated cardiomyocytes are needed to further confirm the effect of empagliflozin on the regulation of MAPKs signaling in the heart.…”

mentioning

confidence: 99%

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

Gupte

Umbarkar

Lal

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Cardiovasc Drugs Ther

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supporting

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Gupte

Umbarkar

Lal

2017

Cardiovasc Drugs Ther

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The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions

et al. 2019

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti-hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo-controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.

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Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

Packer

2018

European J of Heart Fail

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Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.

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Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes

Cited by 122 publications

References 48 publications

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

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

The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions

Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

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