Clinical and laboratory effects of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus and gout: a scoping review

doi:10.21203/rs.3.rs-7557506/v1

Background

This review aimed to map the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on clinical and laboratory outcomes in patients with type 2 diabetes mellitus (T2DM) and gout.

Methods

A scoping review was conducted following the Joanna Briggs Institute methodology and the PRISMA-ScR checklist. Searches were performed in PubMed, EMBASE, Scopus, Web of Science, LILACS/BVS, and gray literature sources. Eligible studies included patients with T2DM and gout treated with SGLT2i, assessing outcomes such as mortality, gout flares, serum uric acid (SUA) levels, emergency care visits, and hospitalizations due to gout. The full search strategy is provided in Additional file 1, and the PRISMA-ScR checklist in Additional file 2.

Results

Of 282 articles initially identified, 22 met the inclusion criteria. Most studies were retrospective cohort studies (n = 12) or post hoc analyses (n = 8). Only three studies evaluated exclusively patients with both T2DM and gout. The main findings included reductions in SUA levels (n = 8), incidence of gout (n = 12), gout flares (n = 8), initiation of urate-lowering therapy or colchicine (n = 8), and gout-related emergency care or hospital visits (n = 1). Reductions in all-cause (n = 5) and cardiovascular (CV) mortality (n = 4) were also reported. Across the included studies, SGLT2i consistently demonstrated favorable effects on the analyzed outcomes.

Conclusion

SGLT2i appear to provide multiple benefits in patients with T2DM and gout, including urate-lowering effects, reduced gout flares, and lower mortality (all-cause and CV-related). Although limited by the small number of studies focusing specifically on this population, these findings support the potential role of SGLT2i as a strategic therapeutic option in patients with coexisting T2DM and gout, to control both conditions and reduce CV-related events associated with them.

Gout

Diabetes Mellitus

Type 2

Sodium-Glucose Transporter 2 Inhibitors

Hyperuricemia

Cardiovascular Diseases

Mortality

Scoping review

Diabetes mellitus (DM) represents a serious global public health challenge, causing significant negative impacts on patients, health systems, and the global economy. According to the International Diabetes Federation [1], in 2024, approximately 589 million people between the ages of 20 and 79 lived with the disease, with projections indicating an increase to 853 million by 2050, especially in low- and middle-income countries. Approximately 90% of DM cases are type 2 diabetes mellitus (T2DM), a complex condition resulting from the interaction between genetic, environmental, socioeconomic, and lifestyle-related factors [2].

Gout is the most common inflammatory arthropathy in adults and is caused by chronic deposition of monosodium urate crystals in tissues and joints. Its clinical manifestations result from the host's inflammatory response to this deposition [3]. Hyperuricemia is the main risk factor for gout [4], defined by the presence of serum uric acid (SUA) levels above 6.8 mg/dL (> 0.41 mmol/L), which is the approximate limit of urate solubility [5]. This is a necessary but not sufficient condition for developing gout, as most individuals with hyperuricemia do not develop clinically evident disease [6, 7]. These individuals are classified as having asymptomatic hyperuricemia.

Several conditions that cause hyperuricemia are also considered risk factors for gout. These include metabolic syndrome, the use of hyperuricemic medications (such as diuretics and cyclosporine), and chronic kidney disease. Dietary habits also play a role, especially the consumption of purine-rich animal-derived foods and fructose-sweetened beverages. Alcohol intake and genetic predispositions are additional contributing factors [4].

The prevalence of gout varies widely, being approximately 4% in the United States and Canada, 1- 4.75% in Europe, and as high as 10.4% in specific subpopulations such as Taiwanese aborigines [8]. In Brazil, data on gout prevalence are lacking, although hyperuricemia affects approximately 31.9% of men and 4.8% of women [9]. In recent decades, an increase in gout prevalence has been reported, possibly related to unhealthy dietary habits, increased longevity, the use of hyperuricemic medications, chronic kidney disease, and metabolic syndrome [8].

Studies based on population databases indicate a higher prevalence of comorbidities such as hypertension, T2DM, obesity, chronic kidney disease (CKD) [10], and metabolic syndrome [11] in patients with gout. Additionally, the incidence of cardiovascular (CV) outcomes, including heart attack (HA), stroke, heart failure (HF) [12, 10), and venous thromboembolism [13], is greater. Importantly, gout, like T2DM, is an independent CV risk factor, associated with increased mortality from both CV [14–17] and non-CV causes [16, 17].

There is evidence suggesting that acute gout flares are associated with a transiently increased risk of adverse CV events, including fatal HA or stroke, particularly within the first 60 days following an episode [18, 19]

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are oral hypoglycemic agents that inhibit SGLT2 in the S1 segment of the proximal convoluted tubule of the nephron, leading to glycosuria and consequently lowering blood glucose levels [20]. In addition to glycemic control, SGLT2i exert pleiotropic effects, including blood pressure reduction, weight loss, improvements in cardiometabolic markers, favorable CV outcomes, renoprotection [20, 21] and reductions in SUA levels [21, 22]

Owing to their potential to lower SUA, data suggest a reduced risk of developing gout in T2DM patients treated with SGLT2i [23–25]. However, most studies did not report whether hyperuricemia was present before SGLT2i use, nor did they differentiate between asymptomatic hyperuricemia and gout.

Given the frequent coexistence of gout and T2DM, as well as their shared association with metabolic syndrome and their role as independent CV risk factors, it is important to consider strategic interventions for individuals affected by both conditions. The objective is not only to manage the diseases but also to reduce CV-related events.

Therefore, this scoping review aimed to map knowledge gaps regarding the use of SGLT2i in patients with T2DM and gout, particularly concerning overall and CV mortality, incidence of gout, frequency of gout flares, reduction in SUA levels, and rates of emergency room visits and gout-related hospitalizations.

This scoping review was conducted following the standards of the Joanna Briggs Institute to map the literature on a specific topic [26]. To ensure methodological rigor, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), which includes a checklist of 20 essential and 2 optional items [27]. The completed PRISMA-ScR checklist is provided as Additional file 1.

This review was developed through the following sequential steps: definition and alignment of the objectives and formulation of the guiding question; development and alignment of the inclusion criteria with the objectives and the guiding question; description of the planned approach to evidence searching, selection, data extraction, and presentation; systematic search for evidence; selection of evidence in two stages (first by screening titles and abstracts, then by full-text reading); data extraction; data analysis; presentation of results; and summary of the evidence about the review objectives, drawing conclusions and noting the implications of the findings.

The guiding question was developed via the population, concept, and context (PCC) strategy, where the population was defined as patients with T2DM and gout, the concept referred to mortality rates and other clinical and laboratory outcomes, and the context was the use of SGLT2i. Therefore, the research question was as follows: "What are the clinical and laboratory outcomes in patients with T2DM and gout treated with SGLT2i?"

The search strategy was developed in collaboration with a librarian and applied to the following databases: MEDLINE/PubMed, EMBASE, Scopus, Web of Science, and LILACS/BVS. Additionally, gray literature was explored by consulting thesis databases such as the Biblioteca Digital Brasileira de Teses e Dissertações (BDTD) and ProQuest. The search strategy combined controlled descriptors and/or keywords related to the topic, with no restrictions regarding publication date, and was limited to articles written in English, Portuguese, or Spanish. Health descriptors (DeCS/MeSH), keywords, and their entry terms were used, and Boolean operators (AND, OR, NOT) were applied to optimize the search.

An initial search using the three PCC components yielded 42 studies. Owing to the limited number of results, we opted for a broader search using only the population (T2DM and gout) and the context (SGLT2i), which identified 282 articles. Each article was assessed to determine whether it met the inclusion criteria. The final search was completed on February 7, 2025. The search strategies and the number of articles retrieved from each database are detailed in Additional file 2.

All the articles were exported to the Rayyan platform in RIS format, except those from PubMed, which were exported in text format. The duplicate removal tool in Rayyan was used, resulting in 129 unique articles for screening. A manual search of the reference lists of initially selected studies was also performed, yielding 3 additional articles, for a total of 132 articles to be screened.

Eligible studies included original research articles and post hoc analyses that addressed the three PCC elements, answered the research question, and were published in English, Portuguese, or Spanish, without time restrictions. We excluded articles in other languages, those not addressing the research question, reviews, editorials, letters, pamphlets, oral presentations, abstracts, conference posters, and studies without full-text availability.

Two independent reviewers (HPS, BCHS), blinded to each other’s assessments, screened the titles and abstracts of the 129 articles (phase 1) and then conducted full-text screening (phase 2) to determine eligibility. Discrepancies were resolved through discussion and consensus, and when necessary, a third reviewer (CAN) was consulted. Data extraction followed the same independent and blinded approach.

In total, 22 articles met the predefined inclusion criteria and were included in this review. The selection process is summarized in the flowchart presented in Fig. 1. The included studies were numbered from 1 to 22.

Data were extracted via a standardized form developed by the authors in Microsoft Excel (2019 MSO - Version 2507 Build 16.0.19029.20136–32-bit), capturing the following information: author, year of publication, country of origin, journal, study design, population and sample size, percentage of individuals with gout at baseline, type of SGLT2i used, comparator (placebo or other antidiabetic drugs), outcomes analyzed, population characteristics (age, sex, ethnicity), CV comorbidities, mean follow-up time, and main findings of each study.

The results were analyzed descriptively and presented in narrative form and through summary tables, ensuring clarity and objectivity in data presentation. No formal critical appraisal of the individual studies was conducted, as the primary objective was to map existing evidence on the effects of SGLT2i in patients with T2DM and gout. Therefore, the focus was on descriptive analysis rather than methodological quality assessment. Studies were included on the basis of their relevance to the research question, adherence to eligibility criteria, and data availability.

This scoping review protocol was registered on the Open Science Framework (OSF) and is available at DOI: 10.17605/OSF.IO/A8W9Q.

Selection of sources of evidence

Most of the included studies were retrospective cohort studies (n = 12), post hoc analyses (n = 8), one cross-sectional study (n = 1), and one self-controlled sequence symmetry analysis (n = 1). These studies reported their results using descriptive statistics and involved different sample sizes. The publications ranged from 2018 to 2024 and were conducted in the United Kingdom (n = 5), Canada (n = 4), the United States (n = 3), Japan (n = 3), China (n = 2), Germany (n = 2), Taiwan (n = 1), Denmark (n = 1), and France (n = 1). The mean follow-up time ranged from 0.8 to 6 years. Table 1 lists the studies by authorship, year of publication, country, journal, study design, population, sample size, and follow-up duration.

Characteristics of the studied sample

The mean age of the participants ranged from 52 to 72 years, with a higher prevalence of male individuals (n = 21). Most samples included predominantly White (n = 11) or Asian (n = 5) participants. There was considerable variation in the percentage of individuals with gout at baseline among the studies. In three studies, 100% of the patients had gout. In seven studies, this information was not reported. In the remaining studies, the proportion of individuals with gout at baseline ranged from 0–22%. For CV comorbidities and CKD, these conditions were highly prevalent across the studies, with only three studies not reporting such data. Table 2 summarizes the studies according to mean age, sex, ethnicity, percentage of individuals with gout at baseline, and presence of CV comorbidities and CKD.

Results of individual sources of evidence and synthesis of the results

Among the studies included in this review, the most frequently used comparators were placebo (n = 7), dipeptidyl peptidase-4 inhibitors (DPP4i) (n = 4), glucagon-like peptide-1 receptor agonists (GLP1-RA) (n = 2), GLP1-RA or DPP4i (n = 2), sulfonylureas (n = 2), and other comparator groups (n = 5).

Regarding the outcomes of interest, most studies reported data on the reduction in gout incidence (n = 12), SUA levels (n = 8), gout flares (n = 8), and the prescription of new urate-lowering therapy or colchicine (n = 8). Only one study analyzed the reduction in emergency room visits and/or hospitalizations related to gout among SGLT2i users.

Table 3 presents the types of SGLT2i used, comparators, analyzed outcomes, and main findings of each study. Table 4 lists the outcomes of interest addressed in the studies and the number of studies related to each outcome.

Summary of evidence

Overall, SGLT2i have demonstrated several clinical and laboratory relevant effects in patients with T2DM and gout. In this review, among the 22 analyzed studies, SGLT2i showed beneficial effects about the following outcomes: a reduction in SUA, a decreased incidence of gout, a reduction in gout flares, a reduced prescription of new uric acid-lowering therapies or colchicine, decreased emergency room visits and/or hospitalization rates due to gout, and reductions in both all-cause and CV-related mortality. These findings were consistent across different SGLT2i types, supporting the idea of a class rather than a drug-specific effect.

Mechanistically, SGLT2i promotes uricosuria by increasing glycosuria, which competes with urate for reabsorption in the proximal tubule, thereby increasing urinary urate excretion and lowering SUA levels. Several meta-analyses [28, 29] have reported a mean reduction in SUA of approximately 0.6 mg/dL, notably in patients using dapagliflozin and empagliflozin [28–30]. This urate-lowering effect appears to be independent of baseline SUA, diuretic use, or other metabolic variables [28].

In this review, all eight studies that assessed SUA reduction reported benefits associated with SGLT2i use (Tables 3 and 4). SUA reductions ranged from 0.19 mg/dL with ertugliflozin [31] to 1.8 mg/dL in a study involving canagliflozin, dapagliflozin, or empagliflozin as interventions [32]. However, these results varied across studies evaluating the same drugs. For example, empagliflozin led to a 0.37 mg/dL reduction in the study by Ferreira et al. [33], and canagliflozin reduced SUA by 0.39 mg/dL in the study by Li et al. [34], which contrasts with the 1.8 mg/dL reduction reported by Yokose et al. [32]. Moreover, all studies revealed a statistically significant reduction in SUA among SGLT2i users compared with their respective comparators (placebo or sulfonylureas).

In addition to lowering urate levels, SGLT2i may exert anti-inflammatory effects relevant to gout pathophysiology, including the downregulation of IL-1β, IL-6, TNF-α, and MCP-1, as well as a reduction in C-reactive protein levels. These pleiotropic effects may contribute to decreased gout flares and disease severity, independent of SUA changes [35, 36]. In this review, SGLT2i use showed benefits in all studies that assessed gout flares (n = 8) and in those evaluating the prescription of anti-gout medications (n = 8), as presented in Tables 3 and 4. The comparators included placebo, GLP1-RA, DPP4i, sulfonylureas, and other oral antidiabetic drugs, such as biguanides, thiazolidinediones, α-glucosidase inhibitors, and glinides.

Three studies included in this review evaluated exclusively patients with both T2DM and gout [37, 38, 32]. All were retrospective cohort studies.

McCormick et al.[37] analyzed 8,150 patients over a mean follow-up of 1.6 years and compared different SGLT2i with DPP4i. They reported a reduction in gout flares (rate ratio [RR] 0.66 [95% confidence interval [CI], 0.57 to 0.75] and rate difference [RD] -27.4 [CI, -36.0 to -18.7] per 1000 person-years [PY]), a decrease in emergency visits or hospitalizations due to gout (RR 0.52 [CI, 0.32 to 0.84] and RD -3.4 [CI, -5.8 to − 0.9] per 1000 PY), and a reduction in HA (hazard ratio [HR] 0.69 (CI, 0.54 to 0.88)]. Stroke risk was also reduced (HR 0.81; 95% CI: 0.62–1.05), although this difference was not statistically significant.

Wei et al. [38] analyzed 5,931 patients over a mean follow-up of 2.7 years and compared SGLT2i users with those using GLP1-RA or DPP4i. The authors reported statistically significant reductions in gout flares (RR 0.79; 95% CI: 0.65–0.97) and all-cause mortality (HR 0.71; 95% CI: 0.52–0.97).

Yokose et al. [32] analyzed 56 patients treated with SGLT2i or sulfonylureas for a mean of 6 months. They reported SUA reductions in patients with and without T2DM (mean change: -1.8 mg/dL; 95% CI: -2.4 to -1.1), with more pronounced effects in those without T2DM (-2.5 mg/dL; 95% CI: -3.6 to -1.3). The sulfonylurea group showed no change in SUA.

Regarding the incidence of gout, 11 out of the 12 studies evaluating this outcome demonstrated beneficial effects of SGLT2i. The exception was the study by Subramanian et al. [39], which included 43,043 patients with T2DM and new users of SGLT2i or DPP4i (follow-up of 1.7 years), without finding a significant difference. The remaining studies demonstrated positive results compared with placebo [40, 33, 31], DPP4i [41, 23], GLP1-RA [42, 43], DPP4i or GLP1-RA or glitazones [44], sulfonylureas [45], GLP1-RA or metformin or insulin [46], and self-controlled sequence symmetry analysis (SSA) [47], reinforcing the role of SGLT2i in preventing gout onset.

Only one study [37] specifically evaluated reductions in emergency visits and/or hospitalizations due to gout, highlighting a gap and an opportunity for future research. This study reported RR and RD values of 0.52 (95% CI: 0.32–0.84) and − 3.4 (95% CI: -5.8 to -0.9) per 1000 PY, respectively.

In addition, SGLT2i provide established CV and renal benefits, which are especially relevant in gout patients because of their high cardiometabolic burden [21, 36]. The most robust data regarding all-cause and CV-related mortality come from post hoc analyses of major clinical trials. Doehner et al. [40] conducted a post hoc analysis of the EMPEROR-Reduced trial, which evaluated empagliflozin in 3,676 patients with HF with reduced ejection fraction (HFrEF), with or without T2DM, over a mean follow-up of 1.3 years. The percentage of patients with gout was not reported, but 53% of the samples had hyperuricemia. The main findings were that higher SUA levels were associated with worse outcomes. Specifically, patients in the highest SUA tertile (mean 9.38 ± 1.49 mg/dL) had significantly greater risks of CV death or hospitalization for HF (HR 1.64; CI: 1.28–2.10), CV mortality (HR 1.98; CI: 1.35–2.91), and all-cause mortality (HR 1.80; CI: 1.29–2.49).

Importantly, empagliflozin improved the primary endpoint regardless of baseline SUA (HR 0.76; 95% CI: 0.65–0.88; p = 0.001) or SUA reduction at four weeks (HR 0.81; 95% CI: 0.69–0.95; p = 0.012).

Several post hoc analyses — DAPA-HF [48], DAPA-HF and DELIVER [49], and EMPEROR-Preserved [50] — demonstrated similar results in all-cause and CV-related mortality, even after multivariate-adjusted analyses. All the studies used a placebo as a comparator, and the benefits of SGLT2i were independent of SUA levels and gout status.

Two retrospective cohort studies also evaluated mortality. As previously discussed, Wei et al. [38] reported lower all-cause mortality in 5,931 patients (HR 0.71; CI: 0.52–0.97). Zhou et al. [23], in a cohort of 43,201 patients with T2DM (mean follow-up: 5.6 years), reported a 51% reduction in all-cause mortality among SGLT2i users compared with DPP4i users (HR 0.49; CI: 0.42–0.58; p < 0.0001), even after adjusting for demographics, comorbidities, medications, and laboratory values.

The focus of this scoping review was to analyze the clinical and laboratory outcomes of SGLT2i specifically in patients with both T2DM and gout. However, only three studies included samples composed entirely of patients with both conditions [32, 37, 38]. In the remaining studies, the proportion of patients with gout ranged from 5% [34] to 22% [45], and in some, these data were not clearly stated.

We consider this a window of opportunity for future studies focused specifically on this subpopulation. Conversely, when evaluating gout incidence, it is necessary to exclude patients with gout at baseline to assess the occurrence of new cases during follow-up. Twelve studies in this review analyzed this outcome (Table 4).

Among the 22 studies included, SGLT2i consistently demonstrated beneficial effects across all the evaluated outcomes.

Limitations

As this was a scoping review, we did not perform a risk of bias assessment of the included studies. Furthermore, several studies failed to report clearly the proportion of patients with gout in their samples — a detail of great relevance for the scope of this review.

Another limitation is the predominance of retrospective cohort studies. This design is associated with a higher risk of bias, limited ability to establish causality, less precise temporality, and dependence on historical medical records.

This scoping review demonstrated the beneficial effects of SGLT2i in patients with gout and T2DM, including improvements in gout-related clinical, laboratory, and CV outcomes. Considering the high prevalence of T2DM and the multiple components of metabolic syndrome in patients with gout—as well as the recognition of gout as an independent CV risk factor—SGLT2i have emerged as a promising therapeutic option for this subpopulation, with the potential to control both conditions and reduce the associated CV-related events.

CAD: Coronary artery disease

CI: Confidence interval

CKD: Chronic kidney disease

CV: Cardiovascular

CVD: Cardiovascular disease

DLP: Dyslipidemia

DM: Diabetes mellitus

DPP4i: Dipeptidyl peptidase-4 inhibitors

ER: Emergency room

GLP1-RA: Glucagon-like peptide-1 receptor agonists

HA: Heart attack

HF: Heart failure

HFpEF: Heart failure with preserved ejection fraction

HFrEF: Heart failure with reduced ejection fraction

HR: Hazard ratio

HTN: Hypertension

MACE: Major adverse cardiovascular events

OAD: Oral antidiabetic drugs (sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, glinides, and DPP4i)

p: p-value

PY: Person-years

RD: Rate difference

RR: Rate ratio

SGLT2i: Sodium-glucose cotransporter 2 inhibitors

SR: Symmetry ratio

SSA: Sequence symmetry analysis

SUA: Serum uric acid

T2DM: Type 2 diabetes mellitus

ULT: Urate-lowering therapy

Ethics approval and consent to participate

Not applicable. This study did not involve human participants, human data, or human tissue.

Consent for publication

Not applicable. This manuscript does not contain data from any individual person.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files (Additional file 1: Search strategy; Additional file 2: PRISMA-ScR checklist).

Competing interests

The authors declare that they have no competing interests.

Funding

The Graduate Program in Rehabilitation Sciences at the Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo (HRAC/USP), provided financial support for the article processing charge (APC). The funder had no role in the study design, data collection, analysis, interpretation, or manuscript writing.

Authors’ contributions

HPS conceived and designed the study, conducted the search, participated in article selection, performed data extraction and analysis, and drafted the manuscript.
BCHS contributed to methodology, article selection (two stages), data extraction and analyses, and critical revision of the manuscript.
CAN, as the advisor, supervised all stages of the study, contributed with guidance, critical review, and decision-making in cases of disagreement during article selection and data extraction.
All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Authors’ information

HPS is the current coordinator of the Microcrystalline Arthropathies Committee of the Brazilian Society of Rheumatology, with a special interest in gout and microcrystalline arthropathies.

BCHS is a preceptor at the Bauru Diabetes Outpatient Clinic, Bauru School of Medicine, University of São Paulo (FMBRU-USP).

CAN is a member of the Department of Diabetes in Pregnancy of the Brazilian Diabetes Society.

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Table 1. Study characteristics: authors, country, journal, design, population, sample, and follow-up

Study	Author and year	Country	Journal	Study design	Population and study sample	Follow-up (years)
S1	Ouchi et al., 2018 [51]	Japan	Diabetes, Obesity, and Metabolism	Integrated analysis	1,046 with T2DM	2
S2	Li et al., 2019 [34]	China	The Lancet. Rheumatology	Post hoc analysis (CANVAS program)	10,142 with T2DM	3,6
S3	Fralick et al., 2020 [42]	USA	Annals of Internal Medicine	Retrospective cohort study	205,907 with T2DM	0,8
S4	Chung et al., 2021 [41]	Taiwan	JAMA Network Open.	Retrospective cohort study	231,208 with T2DM	2,5
S5	Lund et al., 2021 [43]	Denmark	Pharmacoepidemiology and Drug Safety	Retrospective cohort study with PSM and SA	22,094 with T2DM	3
S6	Doehner et al., 2022 [40]	Germany	European Heart Journal	Post hoc analysis (EMPEROR-Reduced trial)	3,676 with HFrEF with or without T2DM	1,3
S7	Ferreira et al., 2022 [33]	France	Diabetes, Obesity, and Metabolism	Post hoc analysis (EMPA-REG OUTCOME trial)	7,020 with T2DM	2,6
S8	Gouda et al., 2022 [52]	Japan	Journal of Diabetes Investigation.	Cross-sectional study with PSM	856,796 with T2DM without prior use of antihypertensive, anti-gout or anti-dyslipidemic drugs for ≥1 year	2
S9	McDowell et al., 2022 [48]	United Kingdom	European Journal of Heart Failure.	Post hoc analysis (DAPA-HF)	3,119 with HFrEF with or without T2DM	1,1
S10	Butt et al., 2023 [49]	United Kingdom	JAMA Cardiology	Post hoc analysis (DAPA-HF and DELIVER)	11,005 with HF with or without T2DM	1,8
S11	McCormick et al., 2023 [37]	Canada	Annals of Internal Medicine	Retrospective cohort study	8,150 with gout and T2DM	1,6
S12	Subramanian et al., 2023 [39]	United Kingdom	Diabetes, Obesity, and Metabolism	Retrospective cohort study	43,043 with T2DM	1,7
S13	Wei et al., 2023 [38]	United Kingdom	JAMA Network Open	Retrospective cohort study	5,931 with gout and T2DM	2,7
S14	Wood et al., 2023 [44]	USA	Clinical Rheumatology	Retrospective cohort study with SSA	27,158 with T2DM	2
S15	Zhou et al., 2023 [23]	China	Rheumatology	Retrospective cohort study	43,201 with T2DM	5,6
S16	Doehner et al., 2024 [50]	Germany	JACC Heart Fail	Post hoc analysis (EMPEROR-Preserved trial)	5,924 with HFpEF	2
S17	McCormick et al., 2024 [45]	Canada	BMJ: British Medical Journal / British Medical Association.	Retrospective cohort study	20,144 with T2DM and nephrolithiasis	1,2
S18	McCormick et al., 2024 [35]	Canada	JAMA Internal Medicine.	Retrospective cohort study	34,604 with T2DM using metformin	1,4
S19	Preston et al., 2024 [46]	United Kingdom	Clinical Therapeutics	Retrospective cohort study with PSM	2,890,000 with T2DM	5
S20	Sridhar et al., 2024 [31]	Canada	Diabetes, Obesity, and Metabolism	Post hoc analysis (VERTIS CV Trial)	8,246 with T2DM	3,6
S21	Yokose et al., 2024 [32]	USA	Seminars in Arthritis and Rheumatism	Retrospective cohort study	56 with gout and with or without T2DM	6
S22	Yokoyama et al., 2024 [47]	Japan	Biological & Pharmaceutical Bulletin	Self-controlled SSA	12,396 SGLT2i initiators and uric acid-lowering agents	2

Abbreviations: PSM - Propensity score matching; SA - Symmetry analysis; SSA - Sequence symmetry analysis; T2DM - Type 2 diabetes mellitus; SGLT2i - Sodium-glucose cotransporter 2 inhibitor; GLP1-RA - Glucagon like peptide-1 receptor agonists; DPP4i - Dipeptidyl peptidase-4 inhibitors; HF - Heart failure; HfrEF - HF with reduced ejection fraction; HFpEF - Heart failure with preserved ejection fraction
USA - United States of America; CANVAS - Canagliflozin Assessment in Nephropathy and Vascular Adiseases Study; EMPEROR - Empagliflozin outcome trial in patients with chronic heart failure; DAPA-HF - Dapagliflozin and the prevention of adverse outcomes in heart failure; DELIVER - Dapagliflozin evaluation to improve the lives of individuals with ventricular dysfunction; VERTIS CV - Cardiovascular outcomes following ertugliflozin treatment in type 2 diabetes mellitus participants with vascular disease

Table 2. Baseline characteristics: age, sex, ethnicity, gout, CV comorbidities, and CKD.

Study	Author and year	Mean age (with SD)	Female (%)	Ethnicity	% gout at baseline	CV comorbidities and CKD (%)
S1	Ouchi et al., 2018 [51]	58.3 ± 10.3	30	Asians	NR	NR
S2	Li et al., 2019 [34]	63 ± 8	36	White (78%)	5	HTN 9; CAD 56; HF 15; CVD 19
S3	Fralick et al., 2020 [42]	54.62 ± 9.73	52	NR	Zero	HTN 70; DLP 68; CAD 9,3; CVD 1,2; HF 2,2; Overweight or obesity 30
S4	Chung et al., 2021 [41]	61.53 ± 12,86	49	Asians	Zero	HTN 10; DLP 66.97; CVD 1.8; CAD 16,69; Obesity 1,46; CKD 11,53
S5	Lund et al., 2021 [43]	61 ± 8	43	White	NR	HTN 37; Obesity 25; CKD 2; HA 8; HF 5
S6	Doehner et al., 2022 [40]	66.7 ± 11.6	24	White (70%)	NR; 53% with hyperuricemia	HTN 70; T2DM 50
S7	Ferreira et al., 2022 [33]	63,0 ± 8,7	30	White (72%)	5.9	HTN 71; HF 10
S8	Gouda et al., 2022 [52]	51.4 ± 7.4	18	Asians	NR	HA 1; HF 5; CVD 8; Obesity 20; CKD 1
S9	McDowell et al., 2022 [48]	67.3 ± 10.4	20	White (80%)	10.3	CKD 40; T2DM 40
S10	Butt et al., 2023 [49]	69.3 ± 10.6	37% (without gout); 20% (with gout)	White (70%)	10.1	HTN 85; T2DM 45; HA 30; CVD 10; Obesity 45; CKD 50
S11	McCormick et al., 2023 [37]	64.11 ± 11.26	30	NR	100	HTN 90; Obesity 13; HA 17; CVD 19; HF 23; CKD 25
S12	Subramanian et al., 2023 [39]	57.71 ± 10.64	43	White (50%) NR (45%)	Zero	Obesity 70; HTN 55; CAD13; HA 6; CVD 3; CKD 5 (stage ≥ 4)
S13	Wei et al., 2023 [38]	66.0 ± 11.6	18	White	100	HTN 70; HA 9; CVD 4; HF 8; CAD 20; CKD 11
S14	Wood et al., 2023 [44]	65.4 ± 10	4	White (74%)	NR	NR
S15	Zhou et al., 2023 [23]	63,23 ± 8.02	45	Asians	Zero	HTN 26; HF 2,5; DLP 4; CAD 14; HA 3,5; CVD 3; Obesity 2; CKD 5
S16	Doehner et al., 2024 [50]	72 ± 9.8	45	White (75%)	5% with gout; 15% using anti-gout medications; 49% with hyperuricemia	HTN 90; T2DM 50; Obesity 45;
S17	McCormick et al., 2024 [45]	62.53 ± 11.45	45	NR	22	HTN 65, Obesity 15; CAD 43; HA 15; CVD 13; HF 15; CKD 17
S18	McCormick et al., 2024 [35]	60 ± 12.4	40	NR	15.6	HTN 66; Obesity 10; HA 10; CVD 9; HF 10; CAD 40; CKD 8
S19	Preston et al., 2024 [46]	62.7 ± 12.1	40	NR	NR	HTN 80; Obesity 30; DLP 60; HF 20; CAD 40; CKD 20
S20	Sridhar et al., 2024 [31]	64.6 ± 8.2	30	White (90%)	7.5	HTN 95; DLP 90
S21	Yokose et al., 2024 [32]	66.8 ± 9.8	10	NR	100	CKD 18; HF 18
S22	Yokoyama et al., 2024 [47]	53 ± 6	25	Asians	NR	NR

Abbreviations: CV - Cardiovascular; CKD - Chronic kidney disease; NR - Not reported; HTN - Hypertension; CAD - Coronary artery disease; CVD - Cerebrovascular disease; HF - Heart failure; DLP - Dyslipidemia; HA - Heart attack; SD - Standard deviation

Table 3. SGLT2i types, comparators, outcomes, and main findings.

Study	Author and year	SGLT2i	Comparator	Outcomes analyzed	Main findings
S1	Ouchi et al., 2018 [51]	Tofogliflozin	Placebo	Decrease in SUA concerning quartiles of glycated Hb	Significant ↓ SUA, especially in patients with HbA1c ≤ 7.4% (quartile 1); greatest ↓ in the first 4 weeks (approximately 0.8 mg/dL)
S2	Li et al., 2019 [34]	Canagliflozin	Placebo	Gout flares or starting a gout medication	6.7% ↓ SUA (–23.3 μmol/L, 95% CI –25.4 to –21.3) and ↓ gout flares or need for gout treatment in the canagliflozin vs. placebo group (HR 0.53, 95% CI 0.40–0.71; p<0.0001).
S3	Fralick et al., 2020 [42]	Any	GLP1-RA	Incidence of gout	↓ incidence of gout in SGLT2i users (HR 0.64 [95% CI, 0.57 to 0.72]) and rate difference of -2.9 (95% CI, -3.6 to -2.1) per 1000 PY.
S4	Chung et al., 2021 [41]	CanagliflozinDapagliflozin Empagliflozin	DPP4i	Incidence of gout	↓ risk of gout (HR, 0.89; 95% CI, 0.82-0.96) in the SGLT2i group (already adjusted for risk factors)
S5	Lund et al., 2021 [43]	Any	GLP1-RA	Incidence of gout	↓ incidence of gout in the SGLT2i group (difference rate of -3.0 [95% CI: -4.4 to -1.5] per 1,000 PY and HR of 0.58 [0.44 to 0.75])
S6	Doehner et al., 2022 [40]	Empagliflozin	Placebo	Association between SUA and the primary composite outcome of CV death or hospitalization for worsening HF, its components, and all-cause mortality	Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) were associated with advanced HF severity and worse outcomes (composite outcome, HR 1.64 [95% CI, 1.28-2.10]; CV mortality, HR 1.98 [95% CI 1.35-2.91]; all-cause mortality, HR 1.8 [95% CI 1.29-2.49], all P < 0.001), compared with the lowest SUA tertile; SUA was reduced after empagliflozin treatment at 4 weeks (vs. placebo: -1.12 ± 0.04 mg/dL, P = 0.0001) and remained lower throughout follow-up. Empagliflozin ↓ events of acute gout, gouty arthritis, or initiation of anti-gout therapy by 32% (HR 0.68 [95% CI 0.52-0.89], P = 0.004); The beneficial effect of empagliflozin on the 1ª outcome was independent of baseline SUA (HR 0.76 [95% CI 0.65-0.88], P = 0.001) and change in SUA at 4 weeks (HR 0.81 [95% CI 0.69-0.95], P = 0.012).
S7	Ferreira et al., 2022 [33]	Empagliflozin	Placebo	Composite outcome of new prescription of anti-gout medications or gout episodes	Adjusted mean difference reduction in SUA at week 52 = - 0.37 mg/dL (95% CI, -0.42, -0.31) and composite endpoint (HR 0.67 [95% CI 0.53, 0.85; P = 0.001]) in the empagliflozin group (10 or 25 mg).
S8	Gouda et al., 2022 [52]	Any	Other OAD	Need to start anti-gout/anti-hyperuricemic medications	SGLT2i group: less need to initiate anti-gout/ anti-hyperuricemic treatment (RR 0.37; 95% CI 0.20–0.68; p <0.001)
S9	McDowell et al., 2022 [48]	Dapagliflozin (tertile 3)	Dapagliflozin (tertile 1) or placebo	Association between SUA and 1ª composite outcome of CV death or worsening HF, its components, and all-cause mortality, comparing patients by SUA tertiles [tertile 3 (SUA ≥6.8 mg/dL) versus tertile 1 (<5.4 mg/dL)], after adjustment for other prognostic variables; Change in SUA from baseline over 12 months.	Higher SUA were associated with a higher risk of the 1ª outcome (adjusted HR tertile 3 vs. tertile 1: 1.32, 95% CI 1.06–1.66; p = 0.01). The risk of HF hospitalization and CV death increased by 7% and 6%, respectively, per 1 mg/dl increase in SUA (p = 0.04 and p = 0.07). SUA reduced by 0.84 mg/dl (95% CI -0.93 to -0.74) over 12 months (p < 0.001) in the dapagliflozin group. Dapagliflozin improved outcomes regardless of baseline SUA concentration.
S10	Butt et al., 2023 [49]	Dapagliflozin	Placebo	1ª outcome: composite of worsening HF or CV death. Other clinical outcomes were: Hospitalization for HF or CV death; Worsening HF; Hospitalization for HF; CV death; All-cause death; Total hospitalizations for HF and CV death. Analyzed the association between gout and clinical outcomes and the effect of dapagliflozin in patients with and without gout, and the introduction of a new uric acid-lowering therapy and colchicine (as a surrogate for gout flares).	Patients with gout vs without gout showed a greater association with the following outcomes: Worsening of HF or CV death (HR 1.15 [1.01-1.31] 95% CI); Hospitalization for HF or CV death (HR 1.16 [1.01-1.32] 95% CI); Worsening of HF (HR 1.19 [1.02-1.38] 95% CI); Hospitalization for HF (HR 1.19 [1.01-1.39] 95% CI) already corrected for the various risk and demographic factors. Compared with placebo, dapagliflozin reduced the risk of worsening HF or CV death (primary outcome) by the same amount in patients with gout (HR, 0.84; 95% CI, 0.66-1.06) and without gout (HR, 0.79; 95% CI, 0.71-0.87). Dapagliflozin was also associated with a reduced risk of starting a uric acid–lowering therapy (HR, 0.43; 95% CI, 0.34-0.53) or colchicine (HR, 0.54; 95% CI, 0.37-0.80) vs. placebo.
S11	McCormick et al., 2023 [37]	Any	DPP4i	Gout flares (determined by emergency room, hospitalizations, outpatient, and medication dispensing records); 2ª outcomes: HA and stroke.	Gout flares rate was lower among SGLT2i initiators RR 0.66 (95% CI, 0.57 to 0.75) and RD, -27.4 (CI, -36.0 to -18.7) per 1000 PY; RR and RD for emergency room visits and hospitalizations for gout were 0.52 (CI, 0.32 to 0.84) and -3.4 (CI, -5.8 to -0.9) per 1000 PY, respectively. The corresponding HR and RD for HA were 0.69 (CI, 0.54 to 0.88) and -7.6 (CI, -12.4 to -2.8) per 1000 PY; the HR for stroke was 0.81 (CI, 0.62 to 1.05).
S12	Subramanian et al., 2023 [39]	Any	DPP4i	Incidence of gout	In the adjusted model, the adjusted HR was 1.3 (95% CI 0.90-2.29). Sensitivity analyses did not alter the findings.
S13	Wei et al., 2023 [38]	Any	GLP1-RA or DPP4i	1ª outcome: number of recurrent gout flares; 2ª outcomes: first recurrent gout flare and all-cause mortality.	The relative rate of recurrent flares with SGLT2i vs. active comparators was 0.79 (95% CI, 0.65-0.97). For the first recurrent flare with SGLT2i vs. active comparators, the RD was -8.8 (95% CI, -17.2 to -0.4) per 1000 PY and HR 0.81 (95% CI, 0.65-0.98). All-cause mortality per 1000 PY was 18.8 for SGLT2i and 24.9 for active comparators, with an RD of -6.1 (95% CI, -10.6 to -1.6) per 1000 PY and HR 0.71 (95% CI, 0.52-0.97).
S14	Wood et al., 2023 [44]	Any	GLP1-RA, DPP4i or glitazones	Comparison of gout incidence before and after initiation of SGLT2i	↓ gout incidence (SR = 0.62; 95% CI: 0.53–0.72) after SGLT2i use. A ↓ in gout incidence was also observed in exposure counterfactual cohorts initiating DPP4i (SR = 0.67; 95% CI: 0.63–0.72) and thiazolidinediones (SR = 0.72; 95% CI: 0.65–0.79), but not with GLP1-RA (SR = 0.93; 95% CI: 0.77–1.12).
S15	Zhou et al., 2023 [23]	Any	DPP4i	Incidence of gout; all-cause mortality	SGLT2I were associated with 51% ↓ risks of gout (HR: 0.49; 95% CI: 0.42, 0.58; P < 0.0001) and 51% ↓ risks of all-cause mortality (HR: 0.49; 95% CI: 0.42, 0.58; P < 0.0001) after adjustment for significant demographics, prior comorbidities, medications, and laboratory results.
S16	Doehner et al., 2024 [50]	Empagliflozin	Placebo	Clinical effect of SUA reduction on the primary composite outcome of CV mortality or HF hospitalization, their individual components, and all-cause mortality in patients with HFpEF.	Elevated SUA (highest tertile of SUA 8.8 ± 1.4 g/dL) were associated with advanced HF severity and higher risk of adverse outcomes (1ª outcome HR: 1.23 [95% CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; P = 0.01); SUA was reduced early (after 4 weeks vs. placebo - 0.99 +/- 0.03 mg/dL; P < 0.0001) and throughout follow-up, with ↓ in all prespecified subgroups. Empagliflozin ↓ clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; P < 0.0001). Treatment benefit on the primary outcome was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; P = 0.0004).
S17	McCormick et al., 2024 [45]	Any	GLP1-RA or DPP4i	Nephrolithiasis resulting in hospitalization or emergency room visits and gout flare-ups.	SGLT2i were associated with a lower rate of gout flares (rate ratio of 0.72, 0.54 to 0.95, rate difference of –16, –31 to –1 per 1000 PY) versus GLP1-RA (0.65, 0.52 to 0.82 and –21, –33 to –9 per 1000 PY) versus DPP4i.
S18	McCormick et al., 2024 [35]	Any	Sulfonylureas	Primary outcome: incident gout; Secondary outcome: primary gout-related hospitalizations and ER visits, and MACE, as well as flare recurrence rates among patients with prior gout.	The SGLT2i group had a lower incidence of gout (RR, 0.62 [95% CI, 0.48-0.80]) and RD, -2.64 (95% CI, -3.99 to -1.29) per 1000 PY. (regardless of sex, age, or baseline diuretic use) and fewer recurrent flares among patients with gout (RR, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 PY). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 PY.
S19	Preston et al., 2024 [46]	Any	GLP1-RA; Metformin or insulin alone	Incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control)	↓ incidence of gout at 5 years in the SGLT2i plus metformin vs. metformin (HR 0.75 [95% CI 0.69-0.82], P < 0.0001) and the comparison SGLT2i plus insulin vs. insulin (HR 0.83 [95% CI 0.74-0.92], P < 0.0001). No significant disparity in the incidence of gout was observed between GLP-1RA and matched controls. Subgroup analysis demonstrated an ↓ incidence of gout with SGLT2i vs. GLP-1RA, in groups that used metformin (HR 0.77 [95% CI 0.70-0.86], P < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91], P < 0.0001).
S20	Sridhar et al., 2024 [31]	Ertugliflozin	Placebo	Composite outcome of incidence of new cases of gout or initiation of anti-gout medication; ↓ SUA	The incidence of the composite endpoint was 3.3% for placebo and 2.6% for ertugliflozin (HR 0.76 [95% CI 0.580, 1.002]). Ertugliflozin were associated with ↓ SUA across all SUA quintiles from baseline compared with placebo.
S21	Yokose et al., 2024 [32]	Canagliflozin Dapagliflozin Empagliflozin	Sulfonylureas	↓ SUA with SGLT2i in patients with and without T2DM; comparison of SUA changes between SGLT2i and sulfonylurea.	Among SGLT2i initiators, the within-group mean change in SUA was -1.8 (95% CI, -2.4 to -1.1) mg/dL, including -1.2 (-1.8 to -0.6) mg/dL and -2.5 (-3.6 to -1.3) mg/dL among patients with and without T2DM, respectively, with an adjusted difference between those with and without T2DM of -1.4 (-2.4 to -0.5) mg/dL; SUA did not change after sulfonylurea initiation (+0.3 [-0.3 to 1.0] mg/dL). The adjusted difference in SUA between SGLT2i initiation and sulfonylurea initiation was -1.8 (-2.7 to -0.9) mg/dL in all patients.
S22	Yokoyama et al., 2024 [47]	Any	Self-controlled SSA	Initiation of a hypouricemic agent or incidence of gout	Trend-adjusted sequence ratios were calculated at 6, 12, 18, and 24-month intervals. Significant inverse signals were observed at all intervals between SGLT2i and hypouricemic agents, with the strongest effect observed at the 24-month interval (adjusted sequence ratio 0.52 [95% CI 0.49–0.55]). Significant inverse signals were observed for each of the six types of SGLT2i at all intervals.

Abbreviations: SGLT2i - Sodium-glucose cotransporter 2 inhibitor; GLP1-RA - Glucagon like peptide-1 receptor agonists; DPP4i - dipeptidyl peptidase-4 inhibitors; OAD - Oral antidiabetic drugs (sulfonylureas, biguanides, thiazolidinediones, a-glucosidase inhibitors, glinides and DPP4i); SSA - Sequence symmetry analysis; SUA - serum uric acid; P - p-value; PY - Person-Years; HR - Hazard ratio; CI - Confidence interval; RR - Rate ratio; RD - Rate difference; SR - Symmetry ratio; CV - Cardiovascular; HF - Heart failure; HA - Heart attack; HFpEF - Heart failure with preserved ejection fraction; ER - Emergency room; MACE - Major adverse cardiovascular events

Table 4. Outcomes of interest evaluated in the studies and the number of related studies

Outcomes	Studies	Nº
Reduction in serum uric acid	S1, S2, S6, S7, S9, S16, S20, S21	8
Decreased incidence of gout	S3, S4, S5, S6, S7, S12*, S14, S15, S18, S19, S20, S22	12
Reduction in gout attacks	S2, S6, S7, S11, S13, S16, S17, S18	8
Reduction in the prescription of a new uric acid-lowering therapy or colchicine	S2, S6, S7, S8, S10, S16, S20, S22	8
Decreased emergency room visit rates and/or hospitalization rates for gout	S11	1
Decrease in all-cause mortality	S6, S9, S13, S15, S16	5
Decrease in cardiovascular mortality	S6, S9, S10, S16	4

*S12: No statistical difference. Neutral effects of SGLT2i.

No competing interests reported.

Additionalfile1PRISMAScRchecklist.docx
Additional file 1: PRISMA-ScR checklist. Completed checklist for scoping reviews.
Additionalfile2SearchStrategyFINAL.docx
Additional file 2: Search strategy. Complete database search strings used in the review.

Clinical and laboratory effects of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus and gout: a scoping review

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