Empagliflozin Changes Urine Supersaturation by Decreasing pH and Increasing Citrate

Harmacek, Dusan; Pruijm, Menno; Burnier, Michel; Muller, Marie-Eve; Ghajarzadeh‐Wurzner, Arlène; Bonny, Olivier; Zanchi, Anne

doi:10.1681/asn.2021111515

Cited by 15 publications

(18 citation statements)

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“…Second, SGLT2i use can increase urinary bicarbonate excretion and thus raise urine pH, as reported in an animal study . However, a study of healthy volunteers treated with empagliflozin, 10 mg, reported lower urinary pH after 4 weeks of treatment . Third, SGLT2i use could reduce stone formation through its anti-inflammatory effects by suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation .…”

Section: Discussionmentioning

confidence: 94%

“…First, an important mechanism is increased urinary citrate excretion with SGLT2i use. One post hoc study of 40 healthy volunteers (27 who received empagliflozin and 13 who received placebo) reported increased urinary citrate excretion by almost 50% in the group receiving empagliflozin after 4 weeks of treatment . Two studies examining dapagliflozin in patients with T2D (n = 44 and n = 50) also reported increased urinary citrate excretion .…”

Section: Discussionmentioning

confidence: 99%

“…Type 2 diabetes (T2D) is associated with an increased risk of kidney stones . Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a newer class of glucose-lowering agents with demonstrated cardiovascular and renoprotective benefits in clinical trials, might lower the risk of nephrolithiasis by altering urine composition and increasing urine volume …”

Section: Introductionmentioning

confidence: 99%

“…8,9 Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a newer class of glucose-lowering agents with demonstrated cardiovascular and renoprotective benefits in clinical trials, [10][11][12] might lower the risk of nephrolithiasis by altering urine composition 13,14 and increasing urine volume. 12,15 However, while a prior meta-analysis of randomized controlled trials comparing SGLT2is with placebo or active comparators reported no association between SGLT2i use and risk of nephrolithiasis, 16 a more recent analysis of pooled clinical trial data reported a 36% decreased risk of nephrolithiasis with empagliflozin compared with placebo. 14 One recent observational active comparator cohort study on the association between SGLT2is and nephrolithiasis in a Danish registry reported a 49% lower risk of kidney stones.…”

mentioning

confidence: 99%

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Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes

Paik,

Tesfaye,

Curhan

et al. 2024

JAMA Intern Med

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ImportanceType 2 diabetes (T2D) is associated with an increased risk of kidney stones. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) might lower the risk of nephrolithiasis by altering urine composition. However, no studies have investigated the association between SGLT2i use and nephrolithiasis risk in patients receiving routine care in the US.ObjectiveTo investigate the association between SGLT2i use and nephrolithiasis risk in clinical practice.Design, Setting, and ParticipantsThis new-user, active comparator cohort study used data from commercially insured adults (aged ≥18 years) with T2D who initiated treatment with SGLT2is, glucagon-like peptide 1 receptor agonists (GLP-1RAs), or dipeptidyl peptidase 4 inhibitors (DPP4is) between April 1, 2013, and December 31, 2020. The data were analyzed from July 2021 through June 2023.ExposureNew initiation of an SGLT2i, GLP-1RA, or DPP4i.Main Outcomes and MeasuresThe primary outcome was nephrolithiasis diagnosed by International Classification of Diseases codes in the inpatient or outpatient setting. New SGLT2i users were 1:1 propensity score matched to new users of a GLP-1RA or DPP4i in pairwise comparisons. Incidence rates, rate differences (RDs), and estimated hazard ratios (HRs) with 95% CIs were calculated.ResultsAfter 1:1 propensity score matching, a total of 716 406 adults with T2D (358 203 pairs) initiating an SGLT2i or a GLP-1RA (mean [SD] age, 61.4 [9.7] years for both groups; 51.4% vs 51.2% female; 48.6% vs 48.5% male) and 662 056 adults (331 028 pairs) initiating an SGLT2i or a DPP4i (mean [SD] age, 61.8 [9.3] vs 61.7 [10.1] years; 47.4% vs 47.3% female; 52.6% vs 52.7% male) were included. Over a median follow-up of 192 (IQR, 88-409) days, the risk of nephrolithiasis was lower in patients initiating an SGLT2i than among those initiating a GLP-1RA (14.9 vs 21.3 events per 1000 person-years; HR, 0.69 [95% CI, 0.67-0.72]; RD, −6.4 [95% CI, −7.1 to −5.7]) or a DPP4i (14.6 vs 19.9 events per 1000 person-years; HR, 0.74 [95% CI, 0.71-0.77]; RD, −5.3 [95% CI, −6.0 to −4.6]). The association between SGLT2i use and nephrolithiasis risk was similar by sex, race and ethnicity, history of chronic kidney disease, and obesity. The magnitude of the risk reduction with SGLT2i use was larger among adults aged younger than 70 years vs aged 70 years or older (HR, 0.85 [95% CI, 0.79-0.91]; RD, −3.46 [95% CI, −4.87 to −2.05] per 1000 person-years; P for interaction &lt;.001).Conclusions and RelevanceThese findings suggest that in adults with T2D, SGLT2i use may lower the risk of nephrolithiasis compared with GLP-1RAs or DPP4is and could help to inform decision-making when prescribing glucose-lowering agents for patients who may be at risk for developing nephrolithiasis.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes

Paik,

Tesfaye,

Curhan

et al. 2024

JAMA Intern Med

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“…Among the pH-regulating genes of α-intercalated cells (V-ATPases, H + /K + -ATPases, carbonic anhydrases, chloride-bicarbonate exchanger; Supplementary Table S4 ) only carbonic anhydrases 2 and 15 were transcriptionally upregulated in EMPA-treated kidneys ( Figure 6B ) which possibly promote urine acidification in EMPA animals by generating protons in intercalated cells. A cidic urinary pH has been described in healthy volunteers after a 4 weeks empagliflozin treatment ( Harmacek et al, 2022 ) and for canagliflozin in patients with type 2 diabetes ( Li et al, 2020 ). The authors suspected an inhibitory effect of canagliflozin on proximal tubule NHE3 activity, for which a possible interaction with SGLT2 inhibitor empagliflozin has been described in NHE3-KO mice ( Onishi et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin increases kidney weight due to increased cell size in the proximal tubule S3 segment and the collecting duct

et al. 2023

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The inhibition of renal SGLT2 glucose reabsorption has proven its therapeutic efficacy in chronic kidney disease. SGLT2 inhibitors (SGLTi) have been intensively studied in rodent models to identify the mechanisms of SGLT2i-mediated nephroprotection. So far, the overwhelming effects from clinical trials, could only partially be reproduced in rodent models of renal injury. However, a commonly disregarded observation from these studies, is the increase in kidney weight after SGLT2i administration. Increased kidney mass often relies on tubular growth in response to reabsorption overload during glomerular hyperfiltration. Since SGLT2i suppress hyperfiltration but concomitantly increase renal weight, it seems likely that SGLT2i have a growth promoting effect on the kidney itself, independent of GFR control. This study aimed to investigate the effect of SGLT2i on kidney growth in wildtype animals, to identify enlarged nephron segments and classify the size increase as hypertrophic/hyperplastic growth or cell swelling. SGLT2i empagliflozin increased kidney weight in wildtype mice by 13% compared to controls, while bodyweight and other organs were not affected. The enlarged nephron segments were identified as SGLT2-negative distal segments of proximal tubules and as collecting ducts by histological quantification of tubular cell area. In both segments protein/DNA ratio, a marker for hypertrophic growth, was increased by 6% and 12% respectively, while tubular nuclei number (hyperplasia) was unchanged by empagliflozin. SGLT2-inhibition in early proximal tubules induces a shift of NaCl resorption along the nephron causing compensatory NaCl and H2O reabsorption and presumably cell growth in downstream segments. Consistently, in collecting ducts of empagliflozin-treated mice, mRNA expression of the Na+-channel ENaC and the H2O-channels Aqp-2/Aqp-3 were increased. In addition, the hypoxia marker Hif1α was found increased in intercalated cells of the collecting duct together with evidence for increased proton secretion, as indicated by upregulation of carbonic anhydrases and acidified urine pH in empagliflozin-treated animals. In summary, these data show that SGLT2i induce cell enlargement by hypertrophic growth and possibly cell swelling in healthy kidneys, probably as a result of compensatory glucose, NaCl and H2O hyperreabsorption of SGLT2-negative segments. Particularly affected are the SGLT2-negative proximal tubules (S3) and the collecting duct, areas of low O2 availability.

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Is There a Role for SGLT2 Inhibitors in Patients with End-Stage Kidney Disease?

Siddiqui,

Obi,

Dossabhoy

et al. 2024

Curr Hypertens Rep

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Purpose of Review Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium–glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects. Recent Findings Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. Summary This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.

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Empagliflozin Changes Urine Supersaturation by Decreasing pH and Increasing Citrate

Abstract: Clinical Trial registry name and registration number: Empagliflozin and Renal Oxygenation in Healthy Volunteers (EMPA-REIN), NCT03093103

Cited by 15 publications

References 6 publications

Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes

Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes

Empagliflozin increases kidney weight due to increased cell size in the proximal tubule S3 segment and the collecting duct

Is There a Role for SGLT2 Inhibitors in Patients with End-Stage Kidney Disease?

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