Sodium-glucose linked transporter-2 inhibitors in chronic kidney disease.
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ABSTRACT:
SUBMITTER: Zanoli L
PROVIDER: S-EPMC4345065 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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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.
| S-EPMC9269654 | biostudies-literature
Project description:Sodium glucose transporter (SGLT)-2 inhibition has renoprotective effects in diabetic kidney disease. Whether similar effects can be achieved also in non-diabetic kidney disease is speculative. Chronic kidney disease was induced in C57BL/6N mice by feeding an oxalate-rich diet for 14 days, known to induce nephrocalcinosis-related tubular atrophy and interstitial fibrosis without directly affecting the glomerular compartment. Empagliflozin treatment started from day 0 of oxalate feeding had no effect on the decline of glomerular filtration rate, crystal deposition, blood urea nitrogen or serum creatinine levels on day 7 and 14. Tissue morphometry of tubular injury and kidney mRNA levels of kidney injury molecule-1 or tissue inhibitor of metalloproteinase-2 were comparable between empagliflozin- and vehicle-treated mice with oxalate nephropathy on day 7 and 14. Similarly, empagliflozin did not affect markers of interstitial fibrosis, including silver, alpha smooth muscle actin (αSMA) and collagen 1 staining, and mRNA levels of fibronectin-1, collagen 1α1, fibroblast-specific protein-1, and transforming growth factor (TGF)-β2 on day 7 and 14. Thus, the specific renoprotective mechanisms-of-action of SGLT2 inhibition in diabetic kidney disease do not apply to chronic oxalosis, a non-diabetic form of chronic kidney disease.
| S-EPMC5392518 | biostudies-literature
Project description:AimTo determine the association with cardiovascular (CV) outcomes of sodium-glucose co-transporter-2 (SGLT-2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).Materials and methodsWe conducted a population-based cohort study of new users of SGLT-2 inhibitors and DPP-4 inhibitors with T2D and CKD using data from Optum Clinformatics DataMart. We assembled three cohorts: T2D/no CKD, T2D/CKD 1-2, and T2D/CKD 3a. The study outcomes were (a) time to first heart failure (HF) hospitalization and (b) time to a composite CV endpoint comprised of non-fatal myocardial infarction (MI) or stroke. After inverse probability of treatment weighting, we used proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI).ResultsNew users of SGLT-2 inhibitors versus DPP-4 inhibitors had lower risks of HF hospitalization in the T2D/no CKD (HR, 0.76; 95% CI, 0.70, 0.82) and T2D/CKD 1-2 (HR, 0.63; 95% CI, 0.48, 0.84) cohorts, but no significant association was present in the T2D/CKD 3a cohort. Compared with prescription of DPP-4 inhibitors, SGLT-2 inhibitors were associated with lower risks of non-fatal MI or stroke of 23% (HR, 0.77; 95% CI, 0.70, 0.85) in the T2D/no CKD cohort, but no significant associations were present in the T2D/CKD 1-2 and T2D/CKD 3a cohorts.ConclusionsIncident prescription of SGLT-2 inhibitors was associated with lower risks of HF hospitalization but not with non-fatal MI or stroke despite suggesting benefit, relative to prescription of DPP-4 inhibitor across different stages of CKD.
| S-EPMC8986594 | biostudies-literature
Project description:Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.
| S-EPMC4711803 | biostudies-literature
Project description:AimTo compare the cardiovascular risks between users and non-users of sodium-glucose co-transporter-2 (SGLT2) inhibitors based on electronic medical record data from a large integrated healthcare system in South Louisiana.Materials and methodsDemographic, anthropometric, laboratory and medication prescription information for patients with type 2 diabetes who were new users of SGLT2 inhibitors, either as initial treatments or as add-on treatments, were obtained from electronic health records. Mediation analysis was performed to evaluate the association of use of SGLT2 inhibitors and changes of metabolic risk factors with the risk of incident ischaemic heart disease.ResultsA total of 5338 new users of SGLT2 inhibitors were matched with 13 821 non-users. During a mean follow-up of 3.26 years, 2302 incident cases of ischaemic heart disease were defined. After adjusting for multiple confounding factors, patients using SGLT2 inhibitors had a lower risk of incident ischaemic heart disease compared to patients not using SGLT2 inhibitors (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.73). Patients using SGLT2 inhibitors also had a lower risk of incident ischaemic heart disease within 6 months (HR 0.36, 95% CI 0.25-0.44), 12 months (HR 0.40, 95% CI 0.32-0.49), 24 months (HR 0.53, 95% CI 0.43-0.60) and 36 months (HR 0.65, 95% CI 0.54-0.73), respectively. Reductions in systolic blood pressure partly mediated lowering risk of ischaemic heart disease among patients using SGLT2 inhibitors.ConclusionsThe real-world data in the present study show the contribution of SGLT2 inhibitors to reducing risk of ischaemic heart disease, and their benefits beyond glucose-lowering.
| S-EPMC7547648 | biostudies-literature
Project description:AimsSodium-glucose co-transporter-2 inhibitors (SGLT2i) have been shown to have a relevant role in the prevention of hospitalizations for heart failure and improvement in the life expectancy of patients with diabetes and outpatients with chronic heart failure (CHF) with reduced left ventricular ejection fraction, independently from the presence of type 2 diabetes mellitus (T2DM). The aim of our study was to evaluate in a real-world population the number of outpatients with CHF who meet the enrolment criteria of the main randomized controlled trials (RCT) published in the last 5 years and consequently identify the percentage of patients who could potential benefit from SGLT2i therapy.Methods and resultsWe retrospectively evaluated all consecutive outpatients referred for CHF. The diagnosis of T2DM was according to the latest European Society of Cardiology Guidelines. Clinical characteristics considered for the enrolment in the RCTs were recorded. We enrolled 515 patients, 384 (75%) of whom had a left ventricular ejection fraction (LVEF) ≤ 40%, 82 (16%) had pre-diabetes, and 187 (36%) had diabetes. Most of the patients with LVEF ≤ 40% met the criteria for the DAPA-HF trial (65%), and this percentage was even higher if the serum level of N-terminal pro-brain natriuretic peptide was not considered. A high percentage of patients with diabetes and LVEF > 40% met the criteria for the DECLARE (39%), CANVAS (47%), and EMPA-REG (30%) trials. Patients meeting the enrolment criteria of RCTs evaluating SGLT2i were also characterized by a high risk of heart failure events during follow-up.ConclusionsIn spite of a low number of patients actually treated with SGLT2i, we observed that a high prevalence of patients with CHF met the clinical characteristics of RCTs that have demonstrated a beneficial effect of SGLT2i.
| S-EPMC8318395 | biostudies-literature
Project description:Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.
| S-EPMC7258222 | biostudies-literature
Project description:Patients with type 2 diabetes mellitus (T2DM) appear to have increased risk for fractures. In this context, the finding that canagliflozin, a sodium-glucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in the Canagliflozin Cardiovascular Assessment Study (CANVAS), a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors, created concern. In the present review, we summarize the data regarding the association between SGLT2 inhibitors and fracture risk in patients with T2DM. In contrast to the findings reported in CANVAS, canagliflozin did not affect the risk of fracture in a more recent, large RCT in patients with diabetic nephropathy. In addition, empagliflozin and dapagliflozin, other members of this class, also do not appear to affect the incidence of fracture. Moreover, there is no clear pathogenetic mechanism through which SGLT2 inhibitors increase the risk for fractures. Therefore, available data are inconclusive to attribute to these drugs a direct responsibility for bone fractures.
| S-EPMC6965547 | biostudies-literature
Project description:Chronic kidney disease (CKD) is a critical global public health problem associated with high morbidity and mortality, poorer quality of life and increased health care expenditures. CKD and its associated comorbidities are one of the most complex clinical constellations to manage. Treatments for CKD and its comorbidities lead to polypharmacy, which exponentiates the morbidity and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown remarkable benefits in cardiovascular and renal protection in patients with type 2 diabetes mellitus (T2DM). The pleiotropic effects of SGLT2is beyond glycosuria suggest a promising role in reducing polypharmacy in diabetic CKD, but the potential adverse effects of SGLT2is should also be considered. In this review, we present a typical case of a patient with multiple comorbidities seen in a CKD clinic, highlighting the polypharmacy and complexity in the management of proteinuria, hyperkalemia, volume overload, hyperuricemia, hypoglycemia and obesity. We review the cardiovascular and renal protection effects of SGLT2is in the context of clinical trials and current guidelines. We then discuss the roles of SGLT2is in the management of associated comorbidities and review the adverse effects and controversies of SGLT2is. We conclude with a proposal for deprescribing principles when initiating SGLT2is in patients with diabetic CKD.
| S-EPMC6768299 | biostudies-literature
Project description: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.
| S-EPMC6993196 | biostudies-literature