SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart

Patients with type 2 diabetes (T2D) are often overweight/obese and affected by arterial hypertension, dyslipidaemia, and have high serum levels of uric acid. Moreover, T2D patient have a higher risk of developing cardiovascular or renal complications, which are leading causes of morbidity and mortality in this population. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering medications that block the reabsorption of glucose in the kidney, thereby increasing urinary glucose excretion, and lowering blood glucose levels. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, and include improvement in blood pressure, body weight, uric acid concentrations, liver steatosis, oxidative stress, and inflammation. In dedicated cardiovascular outcome trials, SGLT2i treatment was associated with a significant reduction in the rate of cardiovascular events and renal endpoints. In this review, we summarize the evidence for extra-glycemic effects of SGLT2i and the potential mechanisms driving cardiorenal protection exerted by this class of medications.

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“…Furthermore, empagliflozin significantly reduced the expression of Nox4, lipid hydroperoxide concentration, and malondialdehyde level. 106…”

Section: Cardiac Fibrosismentioning

confidence: 99%

<p>Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence</p>

Bonora

Avogaro

Fadini

2020

DMSO

115

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“…We used KK/Ta mice because they exhibit characteristics of hyperglycaemia that are very similar to those in humans. KK/Ta mice fed on HFD chow develop fatty livers and IR and are a good model for NAFLD (Akagiri et al., ); in addition, they have been used as a T2DM model (Akutagawa et al., ; Iizuka et al., ; C. Li et al., ). Exercise is an effective treatment for diabetes and/or hepatic lipid accumulation, but exercise at a higher intensity increases the risk of hypoglycaemia in T2DM patients during sulfonylurea or insulin therapy.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combined treatment of dipeptidyl peptidase‐4 inhibitor and exercise training improves lipid profile in KK/Ta mice

Tanimura

Aoi

Mizushima

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice. What is the main finding and its importance?The combination of a DPP‐4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36. Abstract The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP‐4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP‐4 inhibitor, enhances the preventive effect of exercise‐induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high‐fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K‐A, KK/Ta mice with alogliptin (0.01%); K‐Ex, KK/Ta mice with exercise training (3 days week−1, 15–20 m min−1 for 30 min); and K‐Ex+A, KK/Ta mice with alogliptin and exercise training (n = 8 or 9 mice per group). After 8 weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K‐Ex+A group than in the K group. The liver expression level of PPAR‐γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K‐Ex+A and B groups than in the K group. Thus, combined therapy of a DPP‐4 inhibitor with exercise training was effective against high‐fat diet‐induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP‐4 inhibitor.

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“…Therefore, the use of SGLT-2iespecially those less selective for SGLT-2 with partial inhibition of SGLT-1 -may be responsible for the lower oxidative stress in the myocardium [21,67]. Regarding cardiac fibrosis, it is curious that these drugs may exert antifibrotic effects, with decreased myocardial oxidative stress [52,68]. There may also be a reduction in left ventricular (LV) mass index [69].…”

Section: Other Possible Mechanismsmentioning

confidence: 99%

SGLT-2 Inhibitors in Heart Failure and Type-2 Diabetes: Hitting Two Birds with One Stone?

2019

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Type 2 diabetes mellitus (T2DM) and heart failure (HF) have a tremendous impact worldwide, markedly reducing life-expectancy and quality of life. It is now known that each disease represents a risk factor for the other. Moreover, when they are combined, the prognosis is significantly worse. Until recently, these pathologies have been managed independently. However, their treatment paradigm is rapidly changing, with recent cardiovascular outcome trials showing that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are effective in the management of both diseases. This article explores the interactions between T2DM and HF and the concept of diabetic cardiomyopathy and summarizes recent data regarding the effects of SGLT-2i on HF hospitalization and the proposed pathophysiological mechanisms involved. sively "glucocentric approach," T2DM management should rather contemplate the use of strategies that can reduce the risk of cardiovascular (and renal) events, including these new drugs and integrated control of all cardiovascular risk factors.This article aims to review the interaction between T2DM and HF and the concept of diabetic cardiomyopathy and to summarize recent data regarding the effects of SGLT-2i on HF hospitalization (HHF) and the proposed pathophysiological mechanisms involved.

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SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart

Cited by 379 publications

References 55 publications

<p>Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence</p>

<p>Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence</p>

Combined treatment of dipeptidyl peptidase‐4 inhibitor and exercise training improves lipid profile in KK/Ta mice

SGLT-2 Inhibitors in Heart Failure and Type-2 Diabetes: Hitting Two Birds with One Stone?

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