Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

Investigators, Declare–Timi

doi:10.1056/nejmoa1812389

Cited by 4,836 publications

(5,353 citation statements)

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“…Nevertheless, an unexpected increased risk of lower extremity amputations and fractures was also reported . In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 Study (DECLARE–TIMI 58), though no effect on MACE was noted, the administration of dapagliflozin resulted in a slower rate of cardiovascular death or hospitalization for heart failure . A positive impact of dapagliflozin on renal function was also documented in a post hoc analysis of 166 patients with stage 3 CKD and increased albuminuria .…”

Section: Sglt2i Use: Clinical Scenariomentioning

confidence: 92%

Mineral and Electrolyte Disorders With SGLT2i Therapy

et al. 2019

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The newly developed sodium‐glucose cotransporter 2 inhibitors (SGLT2is) effectively modulate glucose metabolism in diabetes. Although clinical data suggest that SGLT2is (empagliflozin, dapagliflozin, ertugliflozin, canagliflozin, ipragliflozin) are safe and protect against renal and cardiovascular events, very little attention has been dedicated to the effects of these compounds on different electrolytes. As with other antidiabetic compounds, some effects on water and electrolytes balance have been documented. Although the natriuretic effect and osmotic diuresis are expected with SGLT2is, these compounds may also modulate urinary potassium, magnesium, phosphate, and calcium excretion. Notably, they have had no effect on plasma sodium levels and promoted only small increases in serum potassium and magnesium concentrations in clinical trials. Moreover, SGLT2is may induce an increase in serum phosphate, FGF‐23, and PTH; reduce 1,25‐dihydroxyvitamin D; and generate normal serum calcium. Some published and preliminary reports, as well as unconfirmed reports have suggested an association with bone fractures. Some homeostasis perturbations are transient, whereas others may persist, suggesting that the administration of SGLT2is may affect electrolyte balances in exposed subjects. Although current evidence supports their safety, additional efforts are needed to elucidate the long‐term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited follow‐up studies and the heterogeneity of the case‐mix of different randomized controlled trials preclude a definitive answer on the impact of these compounds on long‐term outcomes such as the risk of bone fracture. Here we review the current understanding of the mechanisms involved in electrolyte handling and the available data on the clinical implications of electrolytes and mineral metabolism perturbations induced by SGLT2i administration. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Sglt2i Use: Clinical Scenariomentioning

confidence: 92%

Mineral and Electrolyte Disorders With SGLT2i Therapy

et al. 2019

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“…One possible contributing factor may be a reduction in the circulating concentration of uric acid. 7 Several large database studies have noted reductions in CV deaths and hospitalization for heart failure among type 2 diabetes patients treated with an SGLT2 inhibitor, 8 and there is emerging evidence that the occurrence of acute kidney injury is reduced. serum creatinine, initiation of renal-replacement therapy or death from renal disease.…”

Section: Introductionmentioning

confidence: 99%

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Bailey

2019

Diabetes Obesity Metabolism

143

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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 existence of a causal relationship between the use of SGLT2i and FG seems, at present, to be unproven. In the report of the Dapagliflozin Effect on Cardiovascular Events (DECLARE) study, the authors state, “Six cases of Fournier's gangrene were reported, one [of 8574] in the dapagliflozin group and five [of 8569] in the placebo group” …”

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confidence: 99%