Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease

Kappel, B.; Lehrke, Michael; Schütt, Katharina; Artati, Anna; Adamski, Jerzy; Lebherz, Corinna; Marx, Nikolaus

doi:10.1161/circulationaha.117.029166

Cited by 126 publications

(98 citation statements)

References 5 publications

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“…The reduced hyperglycaemia favours utilization of fatty acids which, if coupled with reduced insulin, can increase ketone production, and it has been proposed that increased availability of ketones to the myocardium may contribute to improved cardiac energy metabolism . Additionally, there is emerging evidence that the detrimental effect on the myocardiium of decreased catabolism of branched‐chain amino acids in heart failure may be partially reversed by empagliflozin, providing a further mechanism through which SGLT2 inhibitors might improve myocardial energy metabolism . Another effect of SGLT2 inhibitors on the myocardium involves an inhibition of the sarcolemmal Na + /H + exchanger, which would lower intracellular sodium .…”

Section: Outcome Trials With Recently Available Glucose‐lowering Dmentioning

confidence: 99%

“…87 Additionally, there is emerging evidence that the detrimental effect on the myocardiium of decreased catabolism of branched-chain amino acids in heart failure may be partially reversed by empagliflozin, providing a further mechanism through which SGLT2 inhibitors might improve myocardial energy metabolism. 88,89 Another effect of SGLT2 inhibitors on the myocardium involves an inhibition of the sarcolemmal Na + /H + exchanger, which would lower intracellular sodium. 90 SGLT2 inhibition can produce a small increase in glucagon, which might exert an inotropic effect and assist appetite control.…”

Section: Sodium-glucose Co-transporter-2 Inhibitorsmentioning

confidence: 99%

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Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Bailey

2018

Diabetes Obesity Metabolism

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This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.

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Section: Outcome Trials With Recently Available Glucose‐lowering Dmentioning

confidence: 99%

Section: Sodium-glucose Co-transporter-2 Inhibitorsmentioning

confidence: 99%

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Bailey

2018

Diabetes Obesity Metabolism

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“…6 In the DECLARE trial, dapagliflozin reduced hospitalization for heart failure by 27% and reduced a renal composite of decreased glomerular filtration rate, end stage renal disease or death from renal or CV causes by 24%. 17,18 Decreased catabolism of branched-chain amino acids (BCAAs) in heart failure disrupts myocardial pyruvate utilization and increases susceptibility to ischaemiareperfusion injury. 9 While reduced glucotoxicity may contribute to the cardio-renal benefits of SGLT2 inhibitors, the correlation with glucose-lowering is modest.…”

Section: Introductionmentioning

confidence: 99%

“…Lowering blood glucose, together with reduced insulin concentrations, will promote lipolysis and increase diversion of fatty acids into ketones; availability of ketones will provide a rapidly usable energy source to facilitate contraction by cardiac muscle. 17,18 Decreased catabolism of branched-chain amino acids (BCAAs) in heart failure disrupts myocardial pyruvate utilization and increases susceptibility to ischaemiareperfusion injury. Improved myocardial metabolism with use of an SGLT2 inhibitor can partially overcome this effect.…”

Section: Introductionmentioning

confidence: 99%

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Bailey

2019

Diabetes Obesity Metabolism

145

118

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Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardiorenal risk.Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the "metabolic syndrome" of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes. K E Y W O R D Scardiac, gout, obesity, renal, sodium/glucose co-transporter-2 (SGLT2) inhibitor, type 2 diabetes, uric acid | CARDIO-RENAL EFFECTS OF SGLTINHIBITORSSeveral recent large prospective randomized studies in type 2 diabetes have observed reduced CV risk and improved renal function during treatment with an SGLT2 inhibitor. 3 In the EMPA-REG OUTCOME trial, treatment with empagliflozin was associated with a reduced composite 3-point MACE of CV death, nonfatal myocardial infarction (MI) and stroke by 14%; CV mortality was reduced by 38%, overall mortality by 32% and hospitalization for heart failure by 35%. 4 Empagliflozin also reduced by 39% the deterioration in nephropathy, measured as a composite of progression to macroalbuminuria, doubling of

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“…The gut microbiota may be important for the supply of the BCAA to mammalian hosts, either by de novo biosynthesis or by modifying nutrient absorption . A final fascinating preliminary set of observations is that of the effects of empagliflozin on metabolomics; evidence of increased Krebs cycle activation and of higher levels of BCAA metabolites, such as acylcarnitines, suggests that sodium–glucose cotransporter 2 (SGLT2) inhibition may, to some extent, involve BCAA metabolism.…”

mentioning

confidence: 99%

Diabetes and branched‐chain amino acids: What is the link?

Bloomgarden

2018

Journal of Diabetes

188

119

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Diabetes and branched-chain amino acids: What is the link?Branched-chain amino acids (BCAA) have increasingly been studied as playing a role in diabetes, with the PubMed search string "diabetes" AND "branched chain amino acids" showing particular growth in studies of the topic over the past decade (Fig. 1). In the Young Finn's Study, BCAA and, to a lesser extent, the aromatic amino acids phenylalanine and tyrosine were associated with insulin resistance (IR) in men but not in women, whereas the gluconeogenic amino acids alanine, glutamine, or glycine, and several other amino acids (i.e. histidine, arginine, and tryptophan) did not show an association with IR.

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Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease

Cited by 126 publications

References 5 publications

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Diabetes and branched‐chain amino acids: What is the link?

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