SGLT2 inhibition and kidney protection.
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SUBMITTER: Nespoux J
PROVIDER: S-EPMC6648703 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
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SGLT2 inhibition and kidney protection.
Nespoux Josselin J Vallon Volker V
Clinical science (London, England : 1979) 20180628 12
Type 2 diabetes mellitus (T2DM) is a growing public health concern worldwide. Numerous drug classes are available for treatment, however, their efficacy with regard to diabetes-induced renal and cardiovascular (CV) complications remains limited. Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) are a new class of blood glucose lowering medications that block renal glucose reabsorption and have protective effects on the kidney and the heart. This review focusses on the effects of SGLT2 inh ...[more]
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Project description:Purpose of reviewThis review offers a critical narrative evaluation of emerging evidence that sodium-glucose co-transporter-2 (SGLT2) inhibitors exert nephroprotective effects in people with type 2 diabetes.Recent findingsThe SGLT2 inhibitor class of glucose-lowering agents has recently shown beneficial effects to reduce the onset and progression of renal complications in people with and without diabetes. Randomised clinical trials and 'real world' observational studies, mostly involving type 2 diabetes patients, have noted that use of an SGLT2 inhibitor can slow the decline in glomerular filtration rate (GFR), reduce the onset of microalbuminuria and slow or reverse the progression of proteinuria. The nephroprotective effects of SGLT2 inhibitors are class effects observed with each of the approved agents in people with a normal or impaired GFR. These effects are also observed in non-diabetic, lean and normotensive individuals suggesting that the mechanisms extend beyond the glucose-lowering, weight-lowering and blood pressure-lowering effects that accompany their glucosuric action in diabetes patients. A key mechanism is tubuloglomerular feedback in which SGLT2 inhibitors cause more sodium to pass along the nephron: the sodium is sensed by macula cells which act via adenosine to constrict afferent glomerular arterioles, thereby protecting glomeruli by reducing intraglomerular pressure. Other effects of SGLT2 inhibitors improve tubular oxygenation and metabolism and reduce renal inflammation and fibrosis. SGLT2 inhibitors have not increased the risk of urinary tract infections or the risk of acute kidney injury. However, introduction of an SGLT2 inhibitor in patients with a very low GFR is not encouraged due to an initial dip in GFR, and it is prudent to discontinue therapy if there is an acute renal event, hypovolaemia or hypotension.
| S-EPMC8888485 | biostudies-literature
Project description:Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.
| S-EPMC5383382 | biostudies-literature
Project description:Background and objectivesSodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1.Design, setting, participants, & measurementsWe conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured.ResultsIn the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both P<0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both P<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (P<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (P<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (P=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r=0.35; P=0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy.ConclusionsIn conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1.Clinical trial registry name and registration numberRenoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517.
| S-EPMC9269569 | biostudies-literature
Project description:Sodium-glucose cotransporter 2 (SGLT2) inhibitors enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes by targeting Na+ and glucose reabsorption along the proximal convoluted tubule. A goal of this study was to predict the effects of SGLT2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease. To that end, we employed computational rat kidney models to explore how SGLT2 inhibition affects renal solute transport and metabolism when nephron populations are normal or reduced. Model simulations suggested that in a nondiabetic rat, acute and chronic SGLT2 inhibition induces glucosuria, diuresis, natriuresis, and kaliuresis. Those effects were stronger with chronic SGLT2 inhibition (due to SGLT1 downregulation) and tempered by nephron loss. In a diabetic rat with normal nephron number, acute SGLT2 inhibition similarly elevated urine fluid, Na+, and K+ excretion, whereas the urinary excretory effects of chronic SGLT2 inhibition were attenuated in proportion to its plasma glucose level lowering effect. Nephron loss in a diabetic kidney was predicted to lower the glucosuric and blood glucose-reducing effect of chronic SGLT2 inhibition, but due to the high luminal glucose delivery in the remaining hyperfiltering nephrons, nephron loss enhanced proximal tubular paracellular Na+ secretion, thereby augmenting the natriuretic, diuretic, and kaliuretic effects. A proposed shift in oxygen-consuming active transport to the outer medulla, which may simulate systemic hypoxia and enhance erythropoiesis, was also preserved with nephron loss. These effects may contribute to the protective effects of SGLT2 inhibitors on blood pressure and heart failure observed in diabetic patients with chronic kidney diseases.
| S-EPMC6031905 | biostudies-literature
Project description:Globally, diabetes mellitus is a leading cause of kidney disease, with a critical percent of patients approaching end-stage kidney disease. In the current era, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as phenomenal agents in halting the progression of kidney disease. Positive effects of SGLT2i are centered on multiple mechanisms, including glycosuric effects, tubule-glomerular feedback, antioxidant, anti-fibrotic, natriuretic, and reduction in cortical hypoxia, alteration in energy metabolism. Concurrently, multiple kidney and cardiovascular outcome studies have reported remarkable advantages of SGLT2i including mortality benefits. Additionally, the superiority of combination therapies (SGLT2I along with metformin/DDP-4 Inhibitors) in treatment-naïve diabetic patients is further looked into with potential signal towards glycemic and blood pressure control. Reported promising results initiate a gateway for future research targeting kidney outcomes with combination therapies as an initial approach. In the current paper, we summarize leading cardiovascular and kidney outcome trials in patients with type 2 diabetes, the role of SGLT2i in non-diabetic proteinuric kidney disease, and the potential mechanisms of action of SGLT2i with special focus on combination therapy as an initial therapeutic approach in treatment-naïve diabetic patients.
| S-EPMC7564486 | biostudies-literature
Project description:Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition.
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Project description:The introduction of sodium/glucose cotransporter 2 inhibitors (SGLT2i) has opened new perspectives for the management of diabetic population at risk of or with chronic kidney disease (CKD). More important, recent, large real-world studies have repositioned the nephroprotective efficacy of SGLT2i emerged from randomized trials within the frame of effectiveness. Furthermore, the salutary effects of these agents may extend to the nondiabetic population according to the positive results of current studies. Nevertheless, the clear benefits of these agents on the prevention of organ damage contrast with their unexpected, limited use in clinical practice. One potential barrier is the acute decline in glomerular filtration rate (GFR) commonly observed at the beginning of treatment. This phenomenon is reminiscent of the early response to the traditional nephroprotective interventions, namely blood pressure lowering, dietary protein and salt restriction and the inhibition of the renin-angiotensin system. Under this perspective, the "check-mark" sign observed in the GFR trajectory over the first weeks of SGT2i therapy should renew interest on the very basic goal of CKD treatment, i.e., alleviate hyperfiltration in viable nephrons in order to prolong their function.
| S-EPMC7408701 | biostudies-literature
Project description:BackgroundMatrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion.MethodsHuman kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD).ResultsMarkers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers.ConclusionsBased on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.
| S-EPMC4915675 | biostudies-literature
Project description:AIMS/HYPOTHESIS:The glucosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA1c. We hypothesised that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys. METHODS:This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30-65 years old, with a BMI of 25-35 kg/m2 and stable body weight (±2 kg) over the preceding 3 months, and HbA1c <42 mmol/mol (6.0%). Participants had undergone renal transplant with and without removal of native kidneys and were on a stable dose of immunosuppressive medications. Participants received a single dose of dapagliflozin 10 mg or placebo on two separate days, at a 5- to 14-day interval, according to randomisation performed by our hospital pharmacy, which provided dapagliflozin and matching placebo, packaged in bulk bottles that were sequentially numbered. Both participants and investigators were blinded to group assignment. RESULTS:Twenty non-diabetic renal transplant patients (ten with residual native kidneys, ten with bilateral nephrectomy) participated in the study. Dapagliflozin induced greater glucosuria in individuals with residual native kidneys vs nephrectomised individuals (8.6?±?1.1 vs 5.5?±?0.5 g/6 h; p?=?0.02; data not shown). During the 6 h study period, plasma glucose decreased only slightly and similarly in both groups, with no difference compared with placebo (data not shown). Following administration of placebo, there was a progressive time-related decline in EGP that was similar in both nephrectomised individuals and individuals with residual native kidneys. Following dapagliflozin administration, EGP declined in both groups, but the differences between the decrement in EGP with dapagliflozin and placebo in the group with bilateral nephrectomy (??=?1.11?±?0.72 ?mol min-1 kg-1) was significantly lower (p?=?0.03) than in the residual native kidney group (??=?2.56?±?0.33 ?mol min-1 kg-1). In the population treated with dapagliflozin, urinary glucose excretion was correlated with EGP (r?=?0.34, p?<?0.05). Plasma insulin, C-peptide, glucagon, prehepatic insulin:glucagon ratio, lactate, alanine and pyruvate concentrations were similar following placebo and dapagliflozin treatment. ?-Hydroxybutyrate increased with dapagliflozin treatment in the residual native kidney group, while a small increase was observed only at 360 min in the nephrectomy group. Plasma adrenaline (epinephrine) did not change after dapagliflozin and placebo treatment in either group. Following dapagliflozin administration, plasma noradrenaline (norepinephrine) increased slightly in the residual native kidney group and decreased in the nephrectomy group. CONCLUSIONS/INTERPRETATION:In nephrectomised individuals, the hepatic compensatory response to acute SGLT2 inhibitor-induced glucosuria was attenuated, as compared with individuals with residual native kidneys, suggesting that SGLT2 inhibitor-mediated stimulation of hepatic glucose production via efferent renal nerves occurs in an attempt to compensate for the urinary glucose loss (i.e. a renal-hepatic axis). TRIAL REGISTRATION:ClinicalTrials.gov NCT03168295 FUNDING: This protocol was supported by Qatar National Research Fund (QNRF) Award No. NPRP 8-311-3-062 and NIH grant DK024092-38. Graphical abstract.
| S-EPMC7527374 | biostudies-literature
Project description:Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin-angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection.
| S-EPMC9953060 | biostudies-literature