Renal Handling of Ketones in Response to Sodium–Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes

Ferrannini, Ele; Baldi, Simona; Frascerra, Silvia; Astiarraga, Brenno; Barsotti, Elisabetta; Clerico, A.; Muscelli, Elza

doi:10.2337/dc16-2724

Cited by 148 publications

(138 citation statements)

References 35 publications

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“…Increased erythropoietin and a median 7% increase in red blood cell mass, measured with 51 Cr-labeled erythrocytes, were observed in a small study (n = 30) of the SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes (26). In a larger study, a mean increase in erythropoietin of 30-40% was observed 4 weeks after initiating empagliflozin, which may be related to changes in blood flow between the renal cortex and the medulla (27). The extent to which this mechanism contributes to the CV benefits observed with empagliflozin is unclear, however.…”

Section: Discussionmentioning

confidence: 99%

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

et al. 2017

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OBJECTIVEIn the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin. RESEARCH DESIGN AND METHODSEffects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed. RESULTSChanges in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA 1c . In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death. CONCLUSIONSIn this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, was the first glucose-lowering agent to demonstrate a reduction in cardiovascular (CV) death in patients with type 2 diabetes and high CV risk (1). In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, over a median observation time of 3.1 years, treatment

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Section: Discussionmentioning

confidence: 99%

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

et al. 2017

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“…Regarding CV disease markers, an important observation was that regardless of RAS inhibition at baseline, haematocrit levels were increased, which could indicate either volume contraction or increase in erythropoiesis . Volume contraction corresponds to one of the main hypotheses for the CV benefits observed in the SGLT‐2 inhibitor CVOTs: an increase in haematocrit, resulting in beneficial cardiac haemodynamics .…”

Section: Discussionmentioning

confidence: 99%

The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

Scholtes

Raalte

Correa‐Rotter

et al. 2019

Diabetes Obesity Metabolism

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Aims Renin‐angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium‐glucose co‐transporter‐2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. Materials and methods We evaluated the effects of dapagliflozin 10 mg/day over 12–24 weeks across 13 placebo‐controlled studies in patients with T2D with a urinary albumin‐to‐creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. Results Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo‐adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. Conclusions Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline.

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“…In diabetes, increased expression and activity of SGLT2, and fully activated SGLT1, account for almost 50 g of sodium, which may represent over 10% of the filtered sodium load, may be reabsorbed via SGLT‐dependent pathways . Although post meal urinary sodium excretion, in addition to urinary glucose excretion, was increased from baseline, both acutely and chronically, by administration of an SGLT2 inhibitor (SGLT2i), little is known about the association of sodium intake with the clinical effects of SGLT2is. Fundamental experiments indicated that genetic and pharmacological inhibition of SGLT2 attenuated primary proximal tubule hyper‐reabsorption of sodium and glucose in diabetic models and, thereby, lowered glomerular hyperfiltration via TGF .…”

Section: Introductionmentioning

confidence: 99%

Renal effects of a sodium‐glucose cotransporter 2 inhibitor, tofogliflozin, in relation to sodium intake and glycaemic status

Nunoi

Sato

Kaku

et al. 2019

Diabetes Obesity Metabolism

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Aims Little is known about whether sodium intake is associated with the clinical effects of SGLT2 inhibitors (SGLT2is); however, SGLT2is may increase urinary sodium excretion. Thus, we investigated the impact of daily sodium intake on the estimated glomerular filtration rate (eGFR) via an SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D). Methods Individual‐level data on 775 T2D patients in TOFO Phase 3 trials were analysed. Adjusted changes in variables during 52 weeks of TOFO therapy were compared according to basal daily salt intake (DSI), which was measured based on estimated daily urinary sodium excretion using the Tanaka formula. Multivariable analysis was used to investigate the impact of basal DSI on changes in eGFR at Weeks 4 and 52. Results Sixty‐six percent of participants were men; mean age, HbA1c, body mass index, eGFR MDRD and median DSI were 58.5 years, 8.0%, 25.6 kg/m 2 , 83.9 mL/min/1.73 m 2 and 9.3 g/d, respectively. In all participants, eGFR MDRD sharply dipped during Week 4, and gradually increased by Week 52, showing a significant increase overall from baseline to Week 52. Multivariable analysis showed that basal DSI and HbA1c levels were independently correlated with eGFR MDRD changes at Weeks 4 and 52. Additionally, lower baseline HbA1c and DSI levels were significantly correlated with a greater increase in eGFR MDRD at Week 52. Conclusions Dietary salt intake, in addition to glycaemic control, correlates with changed eGFR MDRD via TOFO. Thus, an appropriate dietary approach to therapy should be considered before treatment of T2D patients with an SGLT2i.

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Renal Handling of Ketones in Response to Sodium–Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes

Cited by 148 publications

References 35 publications

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

Renal effects of a sodium‐glucose cotransporter 2 inhibitor, tofogliflozin, in relation to sodium intake and glycaemic status

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