Renal haemodynamic response to sodium-glucose cotransporter-2 inhibition does not depend on protein intake: An analysis of three randomized controlled trials.
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SUBMITTER: van der Aart-van der Beek AB
PROVIDER: S-EPMC8360160 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsLittle 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).MethodsIndividual-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.ResultsSixty-six percent of participants were men; mean age, HbA1c, body mass index, eGFRMDRD and median DSI were 58.5 years, 8.0%, 25.6 kg/m2 , 83.9 mL/min/1.73 m2 and 9.3 g/d, respectively. In all participants, eGFRMDRD 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 eGFRMDRD changes at Weeks 4 and 52. Additionally, lower baseline HbA1c and DSI levels were significantly correlated with a greater increase in eGFRMDRD at Week 52.ConclusionsDietary salt intake, in addition to glycaemic control, correlates with changed eGFRMDRD via TOFO. Thus, an appropriate dietary approach to therapy should be considered before treatment of T2D patients with an SGLT2i.
| S-EPMC6619387 | biostudies-literature
Project description:Sodium-glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively.Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ? min(-1) ? 1.73 m(-2)) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes.At week 90, weight loss averaged -3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of -11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = -0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01).Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.
| S-EPMC4542276 | biostudies-literature
Project description:Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor. The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular events and HF hospitalization risk. Although SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, and decreases in blood pressure, arterial stiffness, and afterload as well, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients who have HF with and without T2D. Accordingly, in this review, we summarize the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of SGLT2 inhibitors in patients with HF who have T2D. Because these favorable effects presumably occur independent of blood glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.
| S-EPMC5846470 | biostudies-literature
Project description:UnlabelledBlood glucose-lowering treatment options generally target insulin action or beta-cell function. In diabetes, expression of the sodium-glucose cotransporter-2 (SGLT2) genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening the hyperglycemic condition. The SGLT2 inhibitors (SGLT2i) are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. The efficacy of SGLT2i is reduced in renal impairment because the ability of glucose-lowering is directly proportional to glomerular filtration rate. On the other hand, ongoing research suggests that SGLT2i may offer potential nephroprotection in diabetes. The SGLT2i have been shown to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and the biochemical progression of chronic kidney disease. Additional mechanisms through which SGLT2i exert nephroprotection may include normalizing blood pressure and uricemia. This review explores this bidirectional relationship of the SGLT2i and the glomerulus. While SGLT2i exhibit reduced efficacy in later stages, they exhibit nephroprotective effects in early stages of renal impairment.FundingJanssen India (Pharmaceutical division of Johnson & Johnson).
| S-EPMC5020120 | biostudies-literature
Project description:ObjectiveIpragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function.Research design and methodsGlycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min(-1) · 1.73 m(-2)), mild (eGFR2 ≥60 to <90), moderate (eGFR3 ≥30 to <60), or severe reduction in eGFR (eGFR4 ≤15 to <30).ResultsIpragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r(2) = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia.ConclusionsIn T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.
| S-EPMC3631866 | biostudies-literature
Project description:Sodium-glucose co-transporter 2 inhibitors (SGLT2is) reduce albuminuria and hard renal outcomes (decline of renal function, renal replacement therapy and renal death) in patients with/without type 2 diabetes at high cardiovascular or renal risk. The question arises whether baseline albuminuria also influences renal outcomes with SGLT2is as reported with renin-angiotensin-aldosterone system inhibitors. Post hoc analyses focusing on albuminuria and renal outcomes of four cardiovascular outcome trials [EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), CANVAS (Canagliflozin Cardiovascular Assessment Study), DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) and VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial)] and some renal data from two heart failure trials [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)] showed renal protection with SGLT2is without significant interaction (P > 0.10) when comparing renal outcomes according to baseline levels (A1, A2 and A3) of urinary albumin:creatinine ratio (UACR), a finding confirmed in a dedicated meta-analysis. Two trials [CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) and DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease)] specifically recruited patients with CKD and UACRs of 200-5000 mg/g. A post hoc analysis of CREDENCE that distinguished three subgroups according to UACR (300-1000, 1000-3000 and >3000 mg/g) showed a greater relative reduction in UACR in patients with lower baseline albuminuria levels (P for interaction = 0.03). Patients with a UACR >1000 mg/g showed a significantly greater reduction in absolute (P for interaction < 0.001) and a trend in relative (P for interaction = 0.25) risk of renal events versus those with lower UACR levels. In conclusion, baseline UACR levels do not significantly influence the nephroprotection by SGLT2is, yet the greater protection in patients with very high UACRs in CREDENCE deserves confirmation. The underlying mechanisms of renal protection with SGLT2is might be different in patients with or without (high) UACR.
| S-EPMC8690058 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease. Recent evidence suggests that the pathogenesis of ADPKD is a complex web of abnormal cellular processes including altered cell signaling, disordered cell metabolism, impaired autophagy, increased apoptosis, mitochondrial dysfunction and chronic inflammation. Sodium-glucose cotransporter (SGLT) inhibitors (SGLTi) reduce body weight, blood pressure and blood glucose levels, have kidney and cardiovascular protective activity, and have been reported to decrease inflammation, increase autophagy and improve mitochondrial dysfunction. We now review results from preclinical studies on SGLTi for ADPKD identified through a systematic search of the MEDLINE, Cochrane Library, Embase and PubMed databases. Potential underlying mechanisms for the conflicting results reported as well as implications for clinical translation are discussed, as ADPKD patients were excluded from clinical trials exploring kidney protection by SGLT2 inhibitors (SGLT2i). However, they were not excluded from cardiovascular safety trials or trials for cardiovascular conditions. A post-hoc analysis of the kidney function trajectories and safety of SGLT2i in ADPKD patients enrolled in such trials may provide additional information. In conclusion, SGLT2i are cardio- and nephroprotective in diverse clinical situations. Currently, it is unclear whether ADPKD patients may benefit from SGLT2i in terms of kidney function preservation, and their safety in this population remains unexplored. We propose a roadmap to address this unmet clinical need.
| S-EPMC9217633 | biostudies-literature
Project description:Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.
| S-EPMC5328165 | biostudies-literature
Project description:Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes.We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). ? Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged.In patients with type 2 diabetes, empagliflozin-induced glycosuria improved ? cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.
| S-EPMC3904627 | biostudies-literature
Project description:Treatment with empagliflozin, an inhibitor of the sodium/glucose cotransporter 2 (SGLT2), is associated with slower progression of diabetic kidney disease. In this analysis, we explored the hypothesis that empagliflozin may have an impact on urinary peptides associated with chronic kidney disease (CKD). In this post-hoc, exploratory analysis, we investigated urine samples obtained from 40 patients with uncomplicated type 1 diabetes (T1D) before and after treatment with empagliflozin for 8 weeks to for significant post-therapy changes in urinary peptides. We further assessed the association of these changes with CKD in an independent cohort, and with a previously established urinary proteomic panel, termed CKD273. 107 individual peptides significantly changed after treatment. The majority of the empagliflozin-induced changes were in the direction of "CKD absent" when compare to patients with CKD and controls. A classifier consisting of these 107 peptides scored significantly different in controls, in comparison to CKD patients. However, empagliflozin did not impact the CKD273 classifier. Our data indicate that empagliflozin induces multiple significant changes in the urinary proteomic markers such as mucin and clusterin. The relationship between empagliflozin-induced proteomic changes and clinical outcomes merits further investigation.
| S-EPMC5662219 | biostudies-literature