Nephrolithiasis and sodium-glucose co-transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials

Claudia, Cosentino; Dicembrini, Ilaria; Nreu, Besmir; Mannucci, Edoardo; Monami, Matteo

doi:10.1016/j.diabres.2019.107808

Cited by 14 publications

(21 citation statements)

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“…This is the first study to examine the risk of nephrolithiasis associated with SGLT2Is in a routine clinical setting. A metaanalysis based on secondary analyses of 16 randomised clinical trials reported a pooled OR of 0.85 (95% CI 0.57, 1.26) for risk of nephrolithiasis with SGLT2Is compared with placebo or other glucose-lowering drugs [8]. The meta-analysis was, however, limited by few events in the included trials and by the fact that nephrolithiasis was not a prespecified outcome in the trials and hence not systematically recorded.…”

Section: Discussionmentioning

confidence: 99%

“…Since type 2 diabetes is an established risk factor for nephrolithiasis [6,7], a preventive effect of SGLT2Is towards nephrolithiasis would be clinically important. The currently available clinical evidence is based on secondary analyses of randomised trial data [8]. However, the low number of recorded nephrolithiasis events in these trials and resulting insufficient power precluded firm conclusions being reached.…”

Section: Introductionmentioning

confidence: 99%

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Sodium–glucose cotransporter 2 inhibitors and risk of nephrolithiasis

et al. 2021

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Aims/hypothesis Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) may reduce nephrolithiasis risk by increasing urine flow. We aimed to investigate whether initiation of SGLT2I was associated with reduced nephrolithiasis risk. Methods We conducted an active-comparator new-user cohort study using the Danish health registries in the period 11 November 2012 to 31 December 2018. Individuals aged ≥40 years initiating SGLT2Is or glucagon-like peptide-1 receptor agonists (GLP1 RAs) were followed from treatment initiation until an inpatient or outpatient diagnosis of nephrolithiasis, death, emigration or end of study. New users of SGLT2Is were matched 1:1 on propensity scores to new users of GLP1 RAs. In supplementary analyses, risk of recurrent nephrolithiasis was assessed in individuals with a history of nephrolithiasis before treatment initiation. Results We identified 24,290 and 19,576 eligible users of SGLT2Is and GLP1 RAs, respectively. After matching, 12,325 patient pairs remained. The median age was 61 years and median follow-up was 2.0 years. The nephrolithiasis rate was 2.0 per 1000 person-years in SGLT2I initiators compared with 4.0 per 1000 person-years in GLP1 RA initiators, with a rate difference of −1.9 per 1000 person-years (95% CI −2.8, −1.0) and an HR of 0.51 (95% CI 0.37, 0.71). For recurrent nephrolithiasis (n = 731 patient pairs), the rate difference was −17 per 1000 person-years (95% CI −33, −1.5) and the HR was 0.68 (95% CI 0.48, 0.97). Conclusions/interpretation Initiation of treatment with SGLT2Is was associated with a clinically significant reduced risk of incident and recurrent nephrolithiasis.Keywords Cohort studies . Databases . Dipeptidyl peptidase 4 inhibitors . Glucagon-like peptide 1 receptor agonists . Nephrolithiasis . Observational studies . Sodium-glucose cotransporter 2 inhibitors . Type 2 diabetes Abbreviations DPP4IDipeptidyl peptidase 4 inhibitor GLP1 RA Glucagon-like peptide-1 receptor agonist SGLT2I Sodium-glucose cotransporter 2 inhibitor * Kasper B. Kristensen

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sodium–glucose cotransporter 2 inhibitors and risk of nephrolithiasis

et al. 2021

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“…Regardless of the precise mechanism, the lowering effect on serum uric acid by SGLT2 inhibitors is well established, 3–9 and the long‐term uricosuric action may lead to a reduction in the uric acid pool in the body and contribute to the reduced risk of gout reported in other studies 10,11 . In addition, a meta‐analysis of placebo‐ or active comparator–controlled studies with a duration of ≥52 weeks reported that SGLT2 inhibitors were not associated with an increased risk of nephrolithiasis 24 . While it is indicated that reduced serum uric acid may contribute to reduced renal and cardiovascular risks, 25–27 further studies are needed to determine whether the lowering effect on serum uric acid by SGLT2 inhibitors contributes to the risk reduction.…”

Section: Discussionmentioning

confidence: 99%

“… 10 , 11 In addition, a meta‐analysis of placebo‐ or active comparator–controlled studies with a duration of ≥52 weeks reported that SGLT2 inhibitors were not associated with an increased risk of nephrolithiasis. 24 While it is indicated that reduced serum uric acid may contribute to reduced renal and cardiovascular risks, 25 , 26 , 27 further studies are needed to determine whether the lowering effect on serum uric acid by SGLT2 inhibitors contributes to the risk reduction.…”

Section: Discussionmentioning

confidence: 99%

“…HbA HbA 1c 1c risk of nephrolithiasis. 24 While it is indicated that reduced serum uric acid may contribute to reduced renal and cardiovascular risks, [25][26][27] further studies are needed to determine whether the lowering effect on serum uric acid by SGLT2 inhibitors contributes to the risk reduction. Nonetheless, the present analysis had a few limitations.…”

Section: Hba Hba 1c 1cmentioning

confidence: 99%

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Factors Influencing Change in Serum Uric Acid After Administration of the Sodium‐Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus

Chino

Kuwabara

Hisatome

2021

The Journal of Clinical Pharma

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Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA 1c ) or serum uric acid, lower HbA 1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (C UA /C Cr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the C UA /C Cr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA 1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA 1c and high serum uric acid.

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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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Nephrolithiasis and sodium-glucose co-transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials

Cited by 14 publications

References 17 publications

Sodium–glucose cotransporter 2 inhibitors and risk of nephrolithiasis

Sodium–glucose cotransporter 2 inhibitors and risk of nephrolithiasis

Factors Influencing Change in Serum Uric Acid After Administration of the Sodium‐Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus

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

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