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Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease?

ABSTRACT: This year the medical community was pleasantly surprised by the results of the first large outcome trial that primarily examined the renal effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANA) in subjects with diabetes and impaired kidney function. The Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial showed that CANA, relative to placebo, reduces the risk for end-stage renal disease, doubling of creatinine or renal death by 34% [hazard ratio 0.66 (95% confidence interval 0.53-0.81]. These effects were consistent across baseline estimated glomerular filtration rate (eGFR) and haemoglobin A1c subgroups. In this review we combine the results of the CREDENCE trial with those of several cardiovascular outcome trials with SGLT2 inhibitors and show that, unexpectedly, patients with lower eGFR levels may have greater benefit with respect to cardiovascular outcome than patients with normal kidney function. The cardio- and renoprotective effects of SGLT2 inhibitors seem to be independent of their glucose-lowering effects, as shown in several post hoc analyses. In this review we discuss the alleged mechanisms of action that explain the beneficial effects of this novel class of drugs. Moreover, we discuss whether these findings indicate that this class of drugs may also be beneficial in non-diabetic chronic kidney diseases.

SUBMITTER: Dekkers CCJ

PROVIDER: S-EPMC6993196 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease?

Dekkers Claire C J CCJ Gansevoort Ron T RT

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20200101 Suppl 1

This year the medical community was pleasantly surprised by the results of the first large outcome trial that primarily examined the renal effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANA) in subjects with diabetes and impaired kidney function. The Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial showed that CANA, relative to placebo, reduces the risk for end-stage renal d ...[more]

PMID: 32003836

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Project description:Background and objectivesSodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a higher risk of skeletal fractures in some randomized, placebo-controlled trials. Secondary hyperparathyroidism and increased bone turnover (also common in CKD) may contribute to the observed fracture risk. We aimed to determine if SGLT2 inhibitor use associates with a higher risk of fractures compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which have no known association with fracture risk. We hypothesized that this risk, if present, would be greatest in patients with lower eGFR.Design, setting, participants, & measurementsWe conducted a population-based cohort study in Ontario, Canada between 2015 and 2019 using linked provincial administrative data to compare the incidence of fracture between new users of SGLT2 inhibitors and DPP-4 inhibitors. We used inverse probability of treatment weighting on the basis of propensity scores to balance the two groups of older adults (≥66 years of age) on indicators of baseline health. We compared the 180- and 365-day cumulative incidence rates of fracture between groups. Prespecified subgroup analyses were conducted by eGFR category (≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min per 1.73 m2). Weighted hazard ratios were obtained using Cox proportional hazard regression.ResultsAfter weighting, we identified a total of 38,994 new users of a SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor and observed a total of 342 fractures at 180 days and 689 fractures at 365 days. The weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of a SGLT2 inhibitor versus a DPP-4 inhibitor: weighted hazard ratio, 0.95 (95% confidence interval, 0.79 to 1.13) and weighted hazard ratio, 0.88 (95% confidence interval, 0.88 to 1.00), respectively. There was no observed interaction between fracture risk and eGFR category (P=0.53).ConclusionsIn this cohort study of older adults, starting a SGLT2 inhibitor versus DPP-4 inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR.

Project description:Diabetic kidney disease (DKD) occurs in approximately 20-40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (- 21.0%, confidence interval [CI] - 34.1 to - 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52-0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48-0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

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Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease?

Publications

Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease?

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