Cardiovascular effects and mechanisms of sodium-glucose cotransporter-2 inhibitors

Fan Yang; Ran Meng; Da-Long Zhu

doi:10.1016/j.cdtm.2020.07.002

Cardioprotective mechanisms of sodium-glucose cotransporter 2 inhibitors

Diabetes Mellitus ◽

10.14341/dm12541 ◽

2021 ◽

Vol 24 (3) ◽

pp. 291-299

Author(s):

A. M. Mkrtumyan ◽

T. N. Markova ◽

N. K. Mishchenko

Keyword(s):

Large Scale ◽

Troponin I ◽

Ketone Bodies ◽

Cardiovascular Effects ◽

Metabolic Effects ◽

Atp Production ◽

Cardiovascular Outcome Trials ◽

Sodium Glucose Cotransporter ◽

Myocardial Energetics ◽

Highly Sensitive Troponin

The findings of large-scale cardiovascular outcome trials have been demonstrated that sodium-glucose cotransporter 2 inhibitors (iSGLT-2) have shown beneficial cardiovascular effects. In this review proposed mechanisms underlying iSGLT-2-associated cardiovascular benefits have been discussed: haemodynamic and intracellular effects, including metabolic effects and electrolyte changes; and also, the effect on markers of cardiovascular disease (CVD). The hemodynamic effects of SGLT-2 are characterized by reduction of cardiac preload and afterload as a result of osmotic diuresis, a decrease in blood pressure and arterial stiffness. The metabolic effects of this medicine are accompanied by an increase the production of ketone bodies, followed by improving ATP production and myocardial energetics. Also, iSGLT-2 modulate ion transporters (NHE1 and NHE3). A reduction of cytoplasmic sodium and calcium levels and increasing mitochondrial calcium levels in the cardiomyocytes enhances the synthesis of ATP and increases cell viability. Effect of iSGLT-2 on CVD markers showed a decrease in the levels of the N-terminal pro-B-type natriuretic peptide and highly sensitive troponin I in elderly patients with type 2 diabetes mellitus (T2DM). Thus, this class of agents has a multifactorial effect on the functioning of cardiovascular system. Further studies will help to explain the all possible cardioprotective effects of iSGLT-2 in individuals with and without T2DM.

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Sodium-Glucose Cotransporter-2 Inhibitors Improve Cardiovascular Dysfunction in Type 2 Diabetic East Asians

Metabolites ◽

10.3390/metabo11110794 ◽

2021 ◽

Vol 11 (11) ◽

pp. 794

Author(s):

Muhammad Afzal ◽

Fahad A. Al-Abbasi ◽

Muhammad Shahid Nadeem ◽

Sultan Alshehri ◽

Mohammed M. Ghoneim ◽

...

Keyword(s):

Glycemic Control ◽

Diabetes Management ◽

Cardiovascular Effects ◽

Sglt2 Inhibitors ◽

Diabetic Patients ◽

East Asians ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Renal Glucose Reabsorption

In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption and thereby improve glycemic control. They are used alone or in combination with insulin and other antihyperglycemic medications to treat diabetes, and they are also helpful in protecting against the progression of complications. This review has evaluated the available evidence not only on the efficacy of SGLT2 inhibitors in T2DM, but also on their favourable cardiovascular events in East Asians. DM is an independent risk factor for cardiovascular diseases. As a result, in addition to glycemic control in diabetes management, the therapeutic goal in East Asian diabetic patients should be to improve adverse cardiovascular outcomes. Besides establishing antidiabetic effects, several studies have reported cardioprotective benefits of SGLT2 inhibitors via numerous pathways. SGLT2 inhibitors show promising antidiabetic drugs with potential cardiovascular advantages, given that a high number of diabetic patients in East Asia have co-existing cardiovascular disorders. Despite significant positive results in favour of SGLT2, more research is needed to determine how SGLT2 inhibitors exert these impressive cardiovascular effects.

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Diabetes Mellitus and Heart Failure

Journal of Clinical Medicine ◽

10.3390/jcm10163682 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3682

Author(s):

Filippos Triposkiadis ◽

Andrew Xanthopoulos ◽

Alexandra Bargiota ◽

Takeshi Kitai ◽

Niki Katsiki ◽

...

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Cardiovascular Effects ◽

Sodium Glucose Cotransporter ◽

Rigorous Treatment ◽

Resistance To Insulin ◽

Artery Disease ◽

Type 1 Dm ◽

New Onset

Diabetes mellitus (DM) is a major risk factor for new-onset heart failure (HF) and vice versa. The pathogenesis of new-onset HF in DM is complex and has been largely attributed to the toxic cardiovascular effects of hyperglycemia and relevant metabolic abnormalities (diabetic cardiomyopathy) as well as the frequently coexisting morbidities such as hypertension (HTN), coronary artery disease (CAD), and diabetic nephropathy. In patients with type 1 DM (T1DM), HF develops in the setting of a dysregulated immune response, whereas in most patients with type 2 DM (T2DM), against a background of overweight/obesity. HF prevention in DM is feasible with rigorous treatment of cardiovascular risk factors and selective antidiabetic agents. Conversely, development of new-onset T2DM in HF (cardiogenic DM) is common and has been attributed to an increase in the resistance to insulin, especially in the skeletal muscle, liver, and adipose tissue as well as in diminished insulin secretory response to hyperglycemia by pancreatic β-cells. Cardiogenic DM further deteriorates cardiac dysfunction and adversely affects outcome in HF. Novel lifesaving medications employed in HF management such as sacubitril/valsartan and sodium glucose cotransporter 2 inhibitors (SGLT-2i) have a favorable metabolic profile and lower the incidence of cardiogenic diabetes. Whether mitigation of cardiogenic DM should be a treatment target in HF deserves further investigation.

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Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial

BMJ Open ◽

10.1136/bmjopen-2017-018097 ◽

2017 ◽

Vol 7 (10) ◽

pp. e018097 ◽

Cited By ~ 24

Author(s):

Natalie A Mordi ◽

Ify R Mordi ◽

Jagdeep S Singh ◽

Fatima Baig ◽

Anna-Maria Choy ◽

...

Keyword(s):

Heart Failure ◽

Cardiovascular Effects ◽

Sglt2 Inhibitors ◽

Loop Diuretics ◽

Diabetic Patients ◽

Creatinine Ratio ◽

Double Blind ◽

Sodium Glucose Cotransporter ◽

Sglt2 Inhibition ◽

Secondary Outcomes

IntroductionType 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium–glucose cotransporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics are limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics and the benefits of SGLT2 inhibitors may extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters. The effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study.Methods and analysisTo assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure) trial is a single-centre, randomised, double-blind, placebo-controlled, cross-over trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 and 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 and 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio and urinary albumin/creatinine ratio when compared with placebo.Ethics and disseminationEthics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03226457; Pre-results.

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