Next Article in Journal
Quality of Life and Kidney Function in Older Adults: Prospective Data of the SCOPE Study
Next Article in Special Issue
Real-World Retrospective Study into the Effects of Oral Semaglutide (As a Switchover or Add-On Therapy) in Type 2 Diabetes
Previous Article in Journal
Electroretinographic and Optical Coherence Tomographic Evaluations of Eyes with Vitreoretinal Lymphoma
Previous Article in Special Issue
High Prevalence of Severe Hepatic Fibrosis in Type 2 Diabetic Outpatients Screened for Non-Alcoholic Fatty Liver Disease
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 12
Issue 12
10.3390/jcm12123958
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

by
Alessandro Nani
1,
Federica Carrara
1,2,
Chiara Maria Eleonora Paulesu
1,
Chiara Dalle Fratte
1,
Matteo Padroni
1,
Silvia Enisci
1,
Maria Concetta Bilancio
1,
Maria Silvia Romio
1,
Federico Bertuzzi
3 and
Basilio Pintaudi
3,*
1
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
2
Hospital Pharmacy, Humanitas Gavazzeni, 24125 Bergamo, Italy
3
Department of Diabetology, Niguarda Hospital, 20162 Milan, Italy
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2023, 12(12), 3958; https://doi.org/10.3390/jcm12123958
Submission received: 29 April 2023 / Revised: 4 June 2023 / Accepted: 5 June 2023 / Published: 9 June 2023
(This article belongs to the Special Issue Diabetes Therapy: From Bench to Bedside)
Browse Figures
Versions Notes

Abstract

:
Our aim was to evaluate osteomyelitis and other major lower limb safety outcomes (i.e., peripheral artery disease or PAD, ulcers, atraumatic fractures, amputations, symmetric polyneuropathy, and infections) in patients affected by type 2 diabetes mellitus (T2DM) and treated with sodium-glucose cotransporter 2 inhibitors (SGLT2-is). We thus performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing SGLT2-is at approved doses for T2DM with a placebo or standard of care. MEDLINE, Embase, and Cochrane CENTRAL were searched through August 2022. Separate intention-to-treat analyses were implemented for each molecule to calculate Mantel-Haenszel risk ratios (RRMH) with 95% confidence intervals (CIs) through a random-effects model. We processed data from 42 RCTs for a total of 29,491 and 23,052 patients, respectively assigned to SGLT2-i and comparator groups. SGLT2-is showed a pooled neutral effect on osteomyelitis, PAD, fractures, and symmetric polyneuropathy, whereas slightly deleterious sway on ulcers (RRMH 1.39 [1.01–1.91]), amputations (RRMH 1.27 [1.04–1.55]), and infections (RRMH 1.20 [1.02–1.40]). In conclusion, SGLT2-is appear to not significantly interfere with the onset of osteomyelitis, PAD, lower limb fractures, or symmetric polyneuropathy, even though the number of these events proved consistently higher in the investigational groups; otherwise, local ulcers, amputations, and overall infections may be favoured by their employment. This study is registered with the Open Science Framework (OSF).

Graphical Abstract

1. Introduction

Diabetes is a chronic multisystemic disease primarily compromising micro- and macrocirculation, bone mineral density, and host immune defence, especially when associated with other risk factors such as obesity, arterial hypertension, and dyslipidaemias. Despite recent significant progress in the comprehension of its pathophysiology and the consequent constant amelioration of prevention and treatment regimens, incidence and prevalence are still globally on the rise. In 2021, according to the World Development Indicators of the World Bank, 9.8% of the world population had diagnosed diabetes, of whom over 90% were type 2 cases.
Introduced over a decade ago, sodium-glucose cotransporter 2 inhibitors (SGLT2-is) have by now grown into a cornerstone of advanced anti-diabetic therapy. Their good safety profile [1,2,3], together with the varied therapeutic combinations with insulin and all the main oral anti-diabetic agents, has proved them useful for contrasting type 2 diabetes mellitus by promoting glycosuria. In clinical practice, SGLT2-is can indeed diminish both glycated haemoglobin by 0.6–1.2% (regardless of patient age and disease span) and cardiovascular risk (yet unconfirmed for ertugliflozin), fostering a concomitant reduction in blood pressure, body weight, and uricaemia [4,5,6,7,8]. Apparently, their cardiorenal protection is highly dependent on the glomerular filtration rate, for they exert their chief therapeutic activity on the SGLT2s located in the S1/S2 segments of preserved proximal convoluted tubules, where they can effectively hinder both sodium and glucose resorption [9,10,11]. Hypoglycaemias are rare and almost exclusively ascribable to the attendant employment of sulphonylureas or insulin [12,13,14], whereas urinary tract infections and genital mycoses are generally mild, easy to treat with standard antimicrobial agents, and rather prevalent over the first weeks of treatment (distinctly in women and the elderly, in the case of poor personal hygiene and dehydration) [15]. Further plausible adverse events may include euglycaemic diabetic ketoacidosis, accelerated osteoporosis, and an increased risk of peripheral artery disease (PAD), lower limb amputations, and fractures (singularly significant with canagliflozin), but appurtenant results from hitherto issued secondary studies are still inconclusive [7,16,17,18].
Osteomyelitis is typically a bacterial infection of the bone mediated by S. aureus (the commonest pathogen in both acute and chronic forms), coagulase-negative staphylococci, streptococci, and other less-represented bacteria. While acute onset is peculiar to either haematogenous seeding or direct inoculation (due to wound contamination through surgery or trauma), subacute and chronic infections suppose the contiguous spread from adjacent soft tissues and joints and are characteristic of patients with type 2 diabetes mellitus [19]. Although still widely underdiagnosed, the overall annual incidence of osteomyelitis has progressively risen over the past 50 years, with a doubling of diabetes-related cases to almost one-third of the total [19].
Given the complete lack, or rather, the limited availability of systematic analyses (however often contradictory or inconclusive) surveying the lower limb safety outcomes of SGLT2-is, in this review our aims are to establish whether this drug class plays a protective, neutral, or noxious role towards a so far unexplored event, i.e., osteomyelitis, and re-assess its effects on some of the other major diabetic complications affecting this body district.

2. Methods

This systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

2.1. Search Strategy and Selection Criteria

From June to 15 August 2022, we implemented a thorough MEDLINE (PubMed), Embase, and Cochrane Library (CENTRAL) search harnessing the strings reported in the Supplementary Materials (Supplementary Table S1), which included all the following keywords: “Type 2 Diabetes Mellitus”, “Canagliflozin”, “Dapagliflozin”, “Empagliflozin”, “Ertugliflozin”, “Ipragliflozin”, “Luseogliflozin”, and “Tofogliflozin”; different filters were applied according to the database involved. Hence, we comprehended all randomised controlled trials (RCTs) executed on human patients affected by type 2 diabetes and exposed to SGLT2-is, provided that the following criteria were met: availability of the full-text article; exclusive investigation of adult (over 18 years old) non-pregnant patients; evidence of comparison between SGLT2-is at approved therapeutic dosage(s) for type 2 diabetes (intervention), with or without other anti-diabetic therapy, and placebo or standard of care (comparator); the presence of at least one of our selected outcomes, whether primary or secondary.
We excluded all the RCTs conducted on diabetes other than type 2 or published in languages diverse from English, and all the redundant entries from both PubMed and Embase searched through the Cochrane Central Register of Controlled Trials (CENTRAL), due to a less refined proprietary filter algorithm. Case reports, case series, commentaries, conference abstracts, cost-effectiveness analyses, editorials, letters, and studies with no comparator were rejected as well. Neither secondary studies nor study protocols (unless the latter provided relevant data for unedited papers) were included. No date restriction was applied. Some study authors were contacted to retrieve missing full-text articles and information.
The selection process summarised in the PRISMA flow diagram (Figure 1) was carried out by three independent groups, and eventual conflicts were resolved by an external investigator (B.P.). Given the initial rather high number of screenable trials, the whole screening process was fulfilled through Rayyan—a web and mobile app for systematic reviews [20]—which streamlined our manual deduplication process by suggesting all possible duplicates.

2.2. Data Analysis

Data collection was independently accomplished by two authors (A.N. and B.P.), and possible conflicts were settled by internal discussion. Whenever available, summary estimates of the variables of interest were directly extracted just from the principal publications, otherwise suitably integrated with the possibly missing entries gathered from the results accompanying their protocols on online registries such as ClinicalTrials.gov, EU Clinical Trials Register, and UMIN-CTR; pertinent data from the intention-to-treat (ITT) population were always privileged. Further parameters/information collected were: first author, publication year, country, mean follow-up span, initial and in-between (only for crossover designs) washout periods, mean treatment extent, sample size, gender, ethnicity, average age, body mass index (BMI), obesity, smoke history, preliminary mean glycated haemoglobin, initial diabetic complications, background insulin therapy (with mean dosages), investigational drugs (with daily dosages) and comparators. All these data were reported in an electronic spreadsheet.
The major outcome considered was the incidence of osteomyelitis, a so far unexplored serious adverse event (SAE). For the sake of completeness and homology, we designated as secondary outcomes some of the main diabetic complications affecting the lower limbs: peripheral artery disease, lower limb ulcer(s), lower limb atraumatic fracture(s), lower limb amputation(s), symmetric polyneuropathy, and lower limb infections of each anatomical compartment. All the equivalent MedDRA terms accounting for our results were fully listed in Supplementary Tables S2–S5.
The risk of bias was gauged using the Cochrane risk of bias tool for RCTs on seven specific domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and overall bias. The results of these seven domains were consequently graded as either “low” risk of bias, “high” risk of bias, or “uncertain” risk of bias. The appraisal of bias risks was concomitantly achieved by two authors (B.P. and A.N.); possible conflicts were consequently fixed through consensus.
Mantel-Haenszel risk ratios (RRMH) with 95% confidence intervals (95% CI) were calculated for all the outcomes considered on an ITT basis, including also RCTs with zero events of interest (only when explicitly reported) and harnessing a random-effects model, independently of the heterogeneity level detected, as the validity of its values is limited in the case of a small number of component studies. Separate subgroup analyses were then performed for each outcome, pooling all the different SGLT2-i molecules at registered therapeutic doses. Likewise, given the rather long latency for most of them, every outcome was further analysed using only the related data from RCTs showing a mean follow-up span of at least 52 weeks. Study heterogeneity was evaluated thanks to the I2 statistics; whenever exceeding 50%, apposite sensitivity analyses were carried out. In order to estimate the existence of possible publication/disclosure biases, we examined the funnel plots generated for each outcome. The GRADE methodology was applied to rate the overall quality of the eligible RCTs for each outcome (Supplementary Table S7), utilising the GRADEpro GDT (GRADEpro Guideline Development Tool [Software], McMaster University and Evidence Prime, 2022, available from https://gradepro.org/, accessed on 21 November 2022).
Analyses were conducted through Review Manager (RevMan [Computer program], Version 5.4, The Cochrane Collaboration, 2020).
This work has been registered on the Open Science Framework (OSF, https://doi.org/10.17605/OSF.IO/PF8G5, accessed on 16 November 2022). Due to the secondary nature of already published data, institutional review board (IRB) approval and patient consent were superfluous.

3. Results

Figure 1 displays the PRISMA flow chart. In total, 42 trials were eventually included in our meta-analysis; their characteristics are summarised in Table 1. Gross study heterogeneity, measured by I2 tests, was mostly low with rare exceptions; results from each of the four sensitivity analyses executed for I2 values ≥ 50% were commensurable with their corresponding pooled RRMH (Supplementary Figures S14–S17). The risk of bias assessment is shown beside every trial in all the forest plots; no publication bias was detected upon visual analysis of each funnel plot (Supplementary Figures S1–S7). Retrieved trials, respectively enrolled 29,491 and 23,052 patients in SGLT2-i and comparator groups, with a mean follow-up span of 50.9 weeks. At baseline, the mean age, HbA1c, and BMI of enrolled patients were 59.3 vs. 58.9 years, 64.8 vs. 65.0 mmol/mol, and 29.7 vs. 29.6 kg/m2, respectively for the two aforementioned subsets; moreover, Asian males (49.2 and 59.8%, respectively) were the most representative sample (Supplementary Table S6). Summary information on the event rates of every pre-specified outcome was systematically collected from all the published reports. Drug doses considered for all the investigational arms were canagliflozin 100–300 mg/day, dapagliflozin 10 mg/day, empagliflozin 10–25 mg/day, ertugliflozin 5–15 mg/day, ipragliflozin 25–50 mg/day, luseogliflozin 2.5–5 mg/day, and tofogliflozin 20 mg/day.
Osteomyelitis was reported in 12 trials (3, 2, 6, and 1 with canagliflozin, dapagliflozin, ertugliflozin, and ipragliflozin, respectively) for a total of 79 events with SGLT2-is versus 71 events with comparators, thus resulting in a global RRMH of 1.04 [0.76–1.44] (Figure 2). This neutral effect was confirmed in all sub-analyses, both by molecule (Canagliflozin: RRMH 1.05 [0.61–1.80]; Dapagliflozin: RRMH 0.68 [0.40–1.18]; Ertugliflozin: RRMH 1.69 [0.93–3.08]; Ipragliflozin: RRMH 1.40 [0.06–34.01]) and by follow-up span ≥ 52 weeks (RRMH 1.04 [0.75–1.44]) (Figure 3).
PAD was delineated in seven trials (2, 2, 2, and 1 with canagliflozin, dapagliflozin, ertugliflozin, and tofogliflozin, respectively) for an amount of 216 events with SGLT2-is versus 193 events with comparators, thus resulting in a pooled RRMH of 1.04 [0.67–1.61] (Figure 4). This casual effect was only substantiated with Dapagliflozin (RRMH 0.97 [0.68–1.37]) and Tofogliflozin (RRMH 3.04 [0.12–73.99]), and in the follow-up span sub-analysis (RRMH 1.04 [0.67–1.61]) (Supplementary Figure S8). Conversely, RRMH was significantly increased for Canagliflozin (RRMH 1.83 [1.17–2.87]), but slightly decreased for Ertugliflozin (RRMH 0.67 [0.48–0.92]); the difference across molecules was statistically significant (p 0.004).
Lower limb ulcers were outlined in nine trials (4, 1, 2, and 2 with canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, respectively) for a total of 305 events with SGLT2-is versus 181 events with comparators, thus resulting in a global RRMH of 1.39 [1.01–1.91] (Figure 5). Whilst concordant with the result of the relevant follow-up span sub-analysis (RRMH 1.44 [1.03–2.01]) (Supplementary Figure S9), this marginally augmented risk was debunked by each molecule-based sub-analysis (Canagliflozin: RRMH 1.53 [0.88–2.64]; Dapagliflozin: RRMH 1.05 [0.58–1.90]; Empagliflozin: RRMH 0.34 [0.04–3.17]; Ertugliflozin: RRMH 1.36 [0.78–2.36]).
Lower limb fractures were described in 33 trials (5, 7, 5, 14, and 2 with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and tofogliflozin, respectively) for an amount of 237 events with SGLT2-is versus 177 events with comparators, thus resulting in a pooled RRMH of 1.15 [0.95–1.40] (Figure 6). As for osteomyelitis, this incidental effect was confirmed in all sub-analyses, both by molecule (Canagliflozin: RRMH 1.23 [0.96–1.58]; Dapagliflozin: RRMH 1.00 [0.62–1.64]; Empagliflozin: RRMH 0.69 [0.11–4.22]; Ertugliflozin: RRMH 1.11 [0.73–1.67]; Tofogliflozin: RRMH 0.95 [0.10–8.96]) and by follow-up span ≥ 52 weeks (RRMH 1.17 [0.96–1.43]) (Supplementary Figure S10).
Amputations were attested in 34 trials (6, 7, 8, 12, and 1 with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and tofogliflozin, respectively) for a total of 556 events with SGLT2-is versus 386 events with comparators, thus resulting in a global RRMH of 1.27 [1.04–1.55] (Figure 7). As already occurred for the ulcers, this mildly inflated risk, though also disclosed by the pertinent follow-up span sub-analysis (RRMH 1.26 [1.02–1.56]) (Supplementary Figure S11), was confuted in every molecule-driven sub-analysis (Canagliflozin: RR 1.49 [0.85–2.62]; Dapagliflozin: RRMH 1.06 [0.85–1.32]; Ertugliflozin: RRMH 1.25 [0.95–1.63]; specific RRs uncomputable for Empagliflozin and Tofogliflozin due to the complete lack of events).
Symmetric polyneuropathy was recorded in 11 trials (5, 3, 1, and 2 with canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, respectively) for an amount of 229 events with SGLT2-is versus 166 events with comparators, thus resulting in a pooled RRMH of 1.17 [0.82–1.65] (Figure 8). As for osteomyelitis and fractures, this random effect was confirmed in all sub-analyses, both by molecule (Canagliflozin: RRMH 1.21 [0.79–1.87]; Dapagliflozin: RRMH 0.64 [0.25–1.66]; Empagliflozin: RRMH 2.95 [0.12–71.01]; Ertugliflozin: RRMH 1.22 [0.15–10.15]) and by follow-up span ≥ 52 weeks (RRMH 1.22 [0.80–1.87]) (Supplementary Figure S12).
Lower limb infections, as the sum of all the infections affecting every single lower anatomical compartment (Supplementary Table S5), were detailed in 31 trials (3, 6, 3, 16, and 3 with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and ipragliflozin, respectively) for a total of 585 events with SGLT2-is versus 456 events with comparators, thus resulting in a global RRMH of 1.20 [1.02–1.40] (Figure 9). Albeit undermined both by the related follow-up span sub-analysis (RRMH 1.22 [0.97–1.52]) (Supplementary Figure S13) and by some clashing molecular sub-analysis (Canagliflozin: RRMH 1.28 [0.78–2.09]; Dapagliflozin: RRMH 0.87 [0.71–1.08]; Empagliflozin RRMH 1.00 [0.17–5.72]; Ipragliflozin: RRMH 1.27 [0.32–4.98]), this datum of accrued risk was frankly validated with Ertugliflozin (RRMH 1.49 [1.16–1.91]); the difference across molecules was statistically significant (p 0.03).

4. Discussion

Benefits from gliflozins have been by now acknowledged worldwide by all the leading international scientific societies [60,61,62]. This drug class has indeed revealed remarkable effects both in people affected by type 2 diabetes mellitus—by decreasing glycated haemoglobin and enhancing major metabolic parameters—and in cardiopathic or nephropathic patients, regardless of diabetes, where there is clear proof of cardio- and nephroprotective advantages [63]. In addition to all these assets, it was also highlighted a significant abatement of both all-cause and cardiovascular mortality, which allowed SGLT2-is to receive a privileged collocation in relevant therapeutic algorithms [64]. All this evidence, accrued from RCTs and observational studies based upon broad databases or populations, enables a larger-scale generalization of the efficacy of these drugs. Yet, it remains needful a constant parallel evaluation of their safety profile. In this regard, so far there has been plenty of real-world evidence supporting their decent safety, although the significant incidence of genitourinary tract infections demands carefulness whenever gliflozins are employed in common clinical scenarios [1,65]. Over the last few years, then, some warnings were also issued about possible adverse events affecting the lower limbs of subjects with type 2 diabetes, especially referring to an augmented risk of amputation [66,67]. This has consequently triggered a series of appraisals (mostly through secondary studies) which, despite their somewhat heterogeneous results, generally led to conclusions for the absence of an amplified risk, except for some subsets of patients and exquisitely for certain molecules from the class [18,68]. Nonetheless, it is still mandatory to gauge more thoroughly some of the other safety outcomes featured in admissible RCTs; in our case, some heretofore scantly explored events, i.e., lower limb ulcers and osteomyelitis or other infections affecting the same body district, represent all rapidly evolving situations which may be quite perilous for patients with type 2 diabetes. Hence, an added value of our systematic review is unquestionably embodied by the deeper knowledge of possible correlations between SGLT2-is and such potential risks to this population.
It is legitimate to make a direct comparison between our data and those in the literature only for a few of our outcomes, such as PAD and amputations. What has been so far published in this context is however exclusively limited to extended follow-up analyses [18,67,69]; otherwise, our work has also allowed us to highlight the hazards related to some early onset events. Particularly, after starting gliflozins, the risk ratio of lower limb infections, excluding osteomyelitides, is more pronounced (and statistically significant) in the pooled analysis, which incorporates trials with follow-up spans even inferior to six months; in fact, from a clinical perspective, infections generally constitute an acute complication, which is therefore likely to manifest itself precociously.
Among the outcomes explored by our research, it is also viable to hypothesise about some pathophysiological mechanisms for the ones which displayed an increased risk of development bound to gliflozin consumption, especially in the case of the coexistence of certain comorbidities (i.e., either local neuropathic or ischaemic alterations). Overall, individuals with type 2 diabetes mellitus exhibit a magnified ulcerative risk compared to the general population [70]: within the ulcer milieu, besides the noted higher inherent risk of infection, this process spreads far more easily to perilesional soft tissues and, in the most severe cases, to deeper bone structures. It follows an aggravated burden of amputations, both minor and major, which is independent of the primary lesion site. Several aetiopathological hypotheses have been sifted over the years to try to correlate the outset of such injuries of the lower limbs with a protracted gliflozin administration. Among the most accredited pathophysiological mechanisms now, there are already well-documented fluctuations of hematocrit and local vascular conditions [71]. As a clear example stands the exacerbated risk of mostly minor amputations, at first apparently associated with the exclusive employment of canagliflozin, where both the rise in blood viscosity (derived from haemoconcentration) and the relative hypovolemia induced by SGLT2-is may engender such a marked small blood vessel remodelling that could itself justify these data [7].
Further considerations are entailed by other outcomes, such as ulcers and infections, where a positive pathological anamnesis for either late-stage PAD or previous amputations constitutes an independent risk factor itself, alone sufficient to cause these events. In this regard, in our meta-analysis we reported data from RCTs with inclusion and exclusion criteria uneven as to these predisposing elements; hence, it ensued that the case mix of the enrolled population was also composed of secondary prevention subjects (often bearing pre-existent regional resections), who inevitably swayed, at least partially, risk ratio estimates. More limitations in our study could be attributed to both the heterogeneity of the measured outcome definitions (peculiarly the ones contemplating PAD, ulcers, diabetic neuropathy, and infections) and the frequent complete absence of their focussed external adjudication, which contributed to rife, albeit underestimated, detection and reporting biases. An effective, yet less practicable, expedient to remedy this criticality would consist in performing patient-level meta-analyses. Lastly, the clinical interpretation of discrepancies among data from some molecular sub-analyses demands a deeper enquiry, as they may expose proper peculiarities of certain gliflozins, unlike what has been hitherto reported in the literature.

5. Conclusions

In conclusion, SGLT2-is appear to not significantly interfere with the onset of osteomyelitis, PAD, lower limb fractures, or symmetric polyneuropathy, even though the number of these events proved consistently higher in almost all the investigational groups; otherwise, local ulcers, amputations, and overall infections may be favoured by their employment. These results underline how prior it is to carefully choose the optimum drug for each patient. All healthcare professionals should thus weigh the possible consequences elicited by an indiscriminate SGLT2-i prescription to subjects already affected by, or even at high risk of developing lower limb trophic lesions. These people would indeed appear more prone to rapidly worsening relapses. Despite the known advantages in terms of cardiovascular and renal protection, physicians should conveniently balance benefits and harms whenever they decide to either commence or pursue gliflozin therapy in patients more susceptible to lower limb complications. In light of such evidence, it would be appropriate if regulatory authorities and scientific societies explored more punctiliously any risk association, also through studies tailored to specific patient subgroups. Finally, a prompter pharmacovigilance network would definitely help clinicians and decision-makers to better judge the real extent of these phenomena.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12123958/s1, Figure S1: Funnel plot for osteomyelitis. Figure S2: Funnel plot for peripheral artery disease. Figure S3: Funnel plot for lower limb ulcers. Figure S4: Funnel plot for lower limb fractures. Figure S5: Funnel plot for lower limb amputations. Figure S6: Funnel plot for symmetric polyneuropathy. Figure S7: Funnel plot for lower limb infections. Figure S8: Follow-up span sub-analysis for peripheral artery disease. Figure S9: Follow-up span sub-analysis for lower limb ulcers. Figure S10: Follow-up span sub-analysis for lower limb fractures. Figure S11: Follow-up span sub-analysis for lower limb amputations. Figure S12: Follow-up span sub-analysis for symmetric polyneuropathy. Figure S13: Follow-up span sub-analysis for lower limb infections. Figure S14: Sensitivity analysis for overall peripheral artery disease. Figure S15: Sensitivity analysis for peripheral artery disease with a follow-up ≥ 52 weeks. Figure S16: Sensitivity analysis for lower limb ulcers with a follow-up ≥ 52 weeks. Figure S17: Sensitivity analysis for symmetric polyneuropathy with a follow-up ≥ 52 weeks. Table S1: Database query strings and filters. Table S2: MedDRA terms for peripheral artery disease. Table S3: MedDRA terms for lower limb ulcers. Table S4: MedDRA terms for symmetric polyneuropathy. Table S5: MedDRA terms for lower limb infections. Table S6: Baseline characteristics. Table S7: GRADE summary.

Author Contributions

B.P. conceptualised the research goals and aims with input from A.N., designed the methodology, did the statistical analysis, and participated in the initial draft writing. A.N. contributed to both data collection and extraction, and wrote the manuscript. F.C., C.M.E.P., C.D.F., M.P., S.E., M.C.B. and M.S.R. were involved in data collection and critical manuscript revision. F.B. was in charge of final oversight and external mentorship. B.P. and A.N. are the guarantors of this work. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.

Acknowledgments

We would like to thank Gloria Innocenti, medical librarian of Niguarda Hospital, for retrieving some of the otherwise inaccessible full-text articles through direct requests from study authors.

Conflicts of Interest

B.P. received both honoraria as a speaker from Novo Nordisk and Eli Lilly and funds for serving on the MSD advisory board. F.B. reports funds for serving on the BD advisory board and received honoraria as a speaker from Eli Lilly. The remaining authors declare no competing interests.

References

  1. Salah, H.M.; Al’aref, S.J.; Khan, M.S.; Al-Hawwas, M.; Vallurupalli, S.; Mehta, J.L.; Mounsey, J.P.; Greene, S.J.; McGuire, D.K.; Lopes, R.D.; et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors initiation in patients with acute heart failure, with and without type 2 diabetes: A systematic review and meta-analysis. Cardiovasc. Diabetol. 2022, 21, 20. [Google Scholar] [CrossRef] [PubMed]
  2. Scheen, A.J. Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Expert Opin. Drug Saf. 2020, 19, 243–256. [Google Scholar] [CrossRef]
  3. Donnan, J.R.; Grandy, C.A.; Chibrikov, E.; Marra, C.A.; Aubrey-Bassler, K.; Johnston, K.; Swab, M.; Hache, J.; Curnew, D.; Nguyen, H.; et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: A systematic review and meta-analysis. BMJ Open 2019, 9, e022577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Cannon, C.P.; Pratley, R.; Dagogo-Jack, S.; Mancuso, J.; Huyck, S.; Masiukiewicz, U.; Charbonnel, B.; Frederich, R.; Gallo, S.; Cosentino, F.; et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N. Engl. J. Med. 2020, 383, 1425–1435. [Google Scholar] [CrossRef]
  5. Kluger, A.Y.; Tecson, K.M.; Lee, A.Y.; Lerma, E.; Rangaswami, J.; Lepor, N.E.; Cobble, M.E.; McCullough, P.A. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc. Diabetol. 2019, 18, 99. [Google Scholar] [CrossRef] [Green Version]
  6. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357. [Google Scholar] [CrossRef]
  7. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R.; et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017, 377, 644–657. [Google Scholar] [CrossRef]
  8. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef] [Green Version]
  9. Hou, Y.-C.; Zheng, C.-M.; Yen, T.-H.; Lu, K.-C. Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection. Int. J. Mol. Sci. 2020, 21, 7833. [Google Scholar] [CrossRef] [PubMed]
  10. Ni, L.; Yuan, C.; Chen, G.; Zhang, C.; Wu, X. SGLT2i: Beyond the glucose-lowering effect. Cardiovasc. Diabetol. 2020, 19, 98. [Google Scholar] [CrossRef] [PubMed]
  11. Zelniker, T.A.; Braunwald, E. Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 75, 422–434. [Google Scholar] [CrossRef] [PubMed]
  12. Nakamura, A. Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Pancreatic β-Cell Mass and Function. Int. J. Mol. Sci. 2022, 23, 5104. [Google Scholar] [CrossRef]
  13. Li, C.-X.; Liang, S.; Gao, L.; Liu, H. Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis. PLoS ONE 2021, 16, e0244689. [Google Scholar] [CrossRef]
  14. Gebrie, D.; Getnet, D.; Manyazewal, T. Cardiovascular safety and efficacy of metformin-SGLT2i versus metformin-sulfonylureas in type 2 diabetes: Systematic review and meta-analysis of randomized controlled trials. Sci. Rep. 2021, 11, 137. [Google Scholar] [CrossRef]
  15. Tahrani, A.A.; Barnett, A.H.; Bailey, C.J. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013, 1, 140–151. [Google Scholar] [CrossRef] [PubMed]
  16. Johansen, M.E.; Argyropoulos, C. The cardiovascular outcomes, heart failure and kidney disease trials tell that the time to use Sodium Glucose Cotransporter 2 inhibitors is now. Clin. Cardiol. 2020, 43, 1376–1387. [Google Scholar] [CrossRef] [PubMed]
  17. Custódio, J.S., Jr.; Roriz-Filho, J.; Cavalcanti, C.A.J.; Martins, A.; Salles, J.E.N. Use of SGLT2 Inhibitors in Older Adults: Scientific Evidence and Practical Aspects. Drugs Aging 2020, 37, 399–409. [Google Scholar] [CrossRef] [PubMed]
  18. Dicembrini, I.; Tomberli, B.; Nreu, B.; Baldereschi, G.I.; Fanelli, F.; Mannucci, E.; Monami, M. Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials. Diabetes Res. Clin. Pract. 2019, 153, 138–144. [Google Scholar] [CrossRef] [Green Version]
  19. Kremers, H.M.; Nwojo, M.E.; Ransom, J.E.; Wood-Wentz, C.M.; Melton, L.J., 3rd; Huddleston, P.M., 3rd. Trends in the epidemiology of osteomyelitis: A population-based study, 1969 to 2009. J. Bone Joint Surg. Am. 2015, 97, 837–845. [Google Scholar] [CrossRef] [Green Version]
  20. Ouzzani, M.; Hammady, H.; Fedorowicz, Z.; Elmagarmid, A. Rayyan—A web and mobile app for systematic reviews. Syst. Rev. 2016, 5, 210. [Google Scholar] [CrossRef] [Green Version]
  21. Akasaka, H.; Sugimoto, K.; Shintani, A.; Taniuchi, S.; Yamamoto, K.; Iwakura, K.; Okamura, A.; Takiuchi, S.; Fukuda, M.; Kamide, K.; et al. Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes and heart failure with preserved ejection fraction: The EXCEED randomized controlled multicenter study. Geriatr. Gerontol. Int. 2022, 22, 298–304. [Google Scholar] [CrossRef]
  22. Amin, N.B.; Wang, X.; Jain, S.M.; Lee, D.S.; Nucci, G.; Rusnak, J.M. Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin. Diabetes Obes. Metab. 2015, 17, 591–598. [Google Scholar] [CrossRef]
  23. Ando, Y.; Shigiyama, F.; Hirose, T.; Kumashiro, N. Simplification of complex insulin regimens using canagliflozin or liraglutide in patients with well-controlled type 2 diabetes: A 24-week randomized controlled trial. J. Diabetes Investig. 2021, 12, 1816–1826. [Google Scholar] [CrossRef]
  24. Bae, J.; Huh, J.H.; Lee, M.; Lee, Y.-H.; Lee, B.-W. Glycaemic control with add-on thiazolidinedione or a sodium-glucose co-transporter-2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24-week, randomized controlled trial. Diabetes Obes.Metab. 2021, 23, 609–618. [Google Scholar] [CrossRef]
  25. Barnett, A.H.; Mithal, A.; Manassie, J.; Jones, R.; Rattunde, H.; Woerle, H.J.; Broedl, U.C. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014, 2, 369–384. [Google Scholar] [CrossRef]
  26. Carbone, S.; Billingsley, H.; Canada, J.M.; Bressi, E.; Ba, B.R.; Kadariya, D.; Dixon, D.L.; Markley, R.; Trankle, C.R.; Cooke, R.; et al. The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study. Diabetes/Metabolism Res. Rev. 2020, 36, e3335. [Google Scholar] [CrossRef]
  27. Chehrehgosha, H.; Sohrabi, M.R.; Ismail-Beigi, F.; Malek, M.; Babaei, M.R.; Zamani, F.; Ajdarkosh, H.; Khoonsari, M.; Fallah, A.E.; Khamseh, M.E. Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Diabetes Ther. 2021, 12, 843–861. [Google Scholar] [CrossRef] [PubMed]
  28. Dagogo-Jack, S.; Liu, J.; Eldor, R.; Amorin, G.; Bs, J.J.; Hille, D.; Liao, Y.; Huyck, S.; Golm, G.; Terra, S.G.; et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes. Metab. 2018, 20, 530–540. [Google Scholar] [CrossRef]
  29. Fioretto, P.; Del Prato, S.; Buse, J.B.; Goldenberg, R.; Giorgino, F.; Reyner, D.; Langkilde, A.M.; Sjöström, C.D.; Sartipy, P. On Behalf of the DERIVE Study Investigators Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study. Diabetes Obes. Metab. 2018, 20, 2532–2540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Gallo, S.; Charbonnel, B.; Bs, A.G.; Shi, H.; Huyck, S.; Darekar, A.; Lauring, B.; Terra, S.G. Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial. Diabetes Obes. Metab. 2019, 21, 1027–1036. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Hollander, P.; Liu, J.; Hill, J.; Johnson, J.; Jiang, Z.W.; Golm, G.; Huyck, S.; Terra, S.G.; Mancuso, J.P.; Engel, S.S.; et al. Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Ther. 2018, 9, 193–207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Inagaki, N.; Harashima, S.-I.; Maruyama, N.; Kawaguchi, Y.; Goda, M.; Iijima, H. Efficacy and safety of canagliflozin in combination with insulin: A double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc. Diabetol. 2016, 15, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Isshiki, M.; Sakuma, I.; Hayashino, Y.; Sumita, T.; Hara, K.; Takahashi, K.; Shiojima, I.; Satoh-Asahara, N.; Kitazato, H.; Ito, D.; et al. Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration. Endocr. J. 2020, 67, 1127–1138. [Google Scholar] [CrossRef] [PubMed]
  34. Jensen, J.; Omar, M.; Kistorp, C.; Poulsen, M.K.; Tuxen, C.; Gustafsson, I.; Køber, L.; Gustafsson, F.; Faber, J.; Fosbøl, E.L.; et al. Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial. Am. Heart J. 2020, 228, 47–56. [Google Scholar] [CrossRef]
  35. Kaku, K.; Watada, H.; Iwamoto, Y.; Utsunomiya, K.; Terauchi, Y.; Tobe, K.; Tanizawa, Y.; Araki, E.; Ueda, M.; Suganami, H.; et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: A combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc. Diabetol. 2014, 13, 1–15. [Google Scholar] [CrossRef] [Green Version]
  36. Kashiwagi, A.; Kazuta, K.; Takinami, Y.; Yoshida, S.; Utsuno, A.; Nagase, I. Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: The BRIGHTEN study. Diabetol. Int. 2015, 6, 8–18. [Google Scholar] [CrossRef]
  37. Kashiwagi, A.; Akiyama, N.; Shiga, T.; Kazuta, K.; Utsuno, A.; Yoshida, S.; Ueyama, E. Efficacy and safety of ipragliflozin as an add-on to a sulfonylurea in Japanese patients with inadequately controlled type 2 diabetes: Results of the randomized, placebo-controlled, double-blind, phase III EMIT study. Diabetol. Int. 2014, 6, 125–138. [Google Scholar] [CrossRef]
  38. Katakami, N.; Mita, T.; Yoshii, H.; Shiraiwa, T.; Yasuda, T.; Okada, Y.; Torimoto, K.; Umayahara, Y.; Kaneto, H.; Osonoi, T.; et al. Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: A prospective, randomized, open-label, parallel-group comparative study. Cardiovasc. Diabetol. 2020, 19, 1–16. [Google Scholar] [CrossRef]
  39. Kawamori, R.; Haneda, M.; Suzaki, K.; Cheng, G.; Shiki, K.; Miyamoto, Y.; Solimando, F.; Lee, C.; Lee, J.; George, J. Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial. Diabetes Obes. Metab. 2018, 20, 2200–2209. [Google Scholar] [CrossRef]
  40. Kitazawa, T.; Seino, H.; Ohashi, H.; Inazawa, T.; Inoue, M.; Ai, M.; Fujishiro, M.; Kuroda, H.; Yamada, M.; Anai, M.; et al. Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB). Diabetes Obes. Metab. 2020, 22, 1659–1663. [Google Scholar] [CrossRef]
  41. Lambers Heerspink, H.J.; de Zeeuw, D.; Wie, L.; Leslie, B.; List, J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes. Metab. 2013, 15, 853–862. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Lingvay, I.; Catarig, A.-M.; Frias, J.P.; Kumar, H.; Lausvig, N.L.; le Roux, C.W.; Thielke, D.; Viljoen, A.; McCrimmon, R.J. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): A double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019, 7, 834–844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Miller, S.; Krumins, T.; Zhou, H.; Huyck, S.; Johnson, J.; Golm, G.; Terra, S.G.; Mancuso, J.P.; Engel, S.S.; Lauring, B. Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study. Diabetes Ther. 2018, 9, 253–268. [Google Scholar] [CrossRef] [Green Version]
  44. Nassif, M.E.; Windsor, S.L.; Tang, F.; Khariton, Y.; Husain, M.; Inzucchi, S.E.; McGuire, D.K.; Pitt, B.; Scirica, B.M.; Austin, B.; et al. Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. Circulation 2019, 140, 1463–1476. [Google Scholar] [CrossRef]
  45. Palau, P.; Amiguet, M.; Domínguez, E.; Sastre, C.; Mollar, A.; Seller, J.; Pinilla, J.M.G.; Larumbe, A.; Valle, A.; Doblas, J.J.G.; et al. Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO 2): A randomized clinical trial. Eur. J. Heart Fail. 2022, 24, 1816–1826. [Google Scholar] [CrossRef]
  46. Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306. [Google Scholar] [CrossRef] [Green Version]
  47. Pollock, C.; Stefánsson, B.; Reyner, D.; Rossing, P.; Sjöström, C.D.; Wheeler, D.C.; Langkilde, A.M.; Heerspink, H.J.L. Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019, 7, 429–441. [Google Scholar]
  48. Pratley, R.E.; Eldor, R.; Raji, A.; Golm, G.; Huyck, S.B.; Qiu, Y.; Sunga, S.; Bs, J.J.; Terra, S.G.; Mancuso, J.P.; et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes. Metab. 2018, 20, 1111–1120. [Google Scholar] [CrossRef] [Green Version]
  49. Rau, M.; Thiele, K.; Hartmann, N.-U.K.; Schuh, A.; Altiok, E.; Möllmann, J.; Keszei, A.P.; Böhm, M.; Marx, N.; Lehrke, M. Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: A randomized controlled study. Cardiovasc. Diabetol. 2021, 20, 1–12. [Google Scholar] [CrossRef]
  50. Rosenstock, J.; Vico, M.; Wei, L.; Salsali, A.; List, J.F. Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy. Diabetes Care 2012, 35, 1473–1478. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Sargeant, J.A.; King, J.A.; Yates, T.; Redman, E.L.; Bodicoat, D.H.; Chatterjee, S.; Edwardson, C.L.; Gray, L.J.; Poulin, B.; Waheed, G.; et al. The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial. Diabetes Obes. Metab. 2022, 24, 1509–1521. [Google Scholar] [CrossRef]
  52. Schumm-Draeger, P.-M.; Burgess, L.; Koranyi, L.; Hruba, V.; Hamer-Maansson, J.E.; De Bruin, T.W.A. Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: A 16-week randomized, placebo-controlled clinical trial. Diabetes Obes. Metab. 2015, 17, 42–51. [Google Scholar] [CrossRef]
  53. Sone, H.; Kaneko, T.; Shiki, K.; Tachibana, Y.; Pfarr, E.; Lee, J.; Tajima, N. Efficacy and safety of empagliflozin as add-on to insulin in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Diabetes Obes. Metab. 2020, 22, 417–426. [Google Scholar] [CrossRef] [PubMed]
  54. Spertus, J.A.; Birmingham, M.C.; Nassif, M.; Damaraju, C.V.; Abbate, A.; Butler, J.; Lanfear, D.E.; Lingvay, I.; Kosiborod, M.N.; Januzzi, J.L. The SGLT2 inhibitor canagliflozin in heart failure: The CHIEF-HF remote, patient-centered randomized trial. Nat. Med. 2022, 28, 809–813. [Google Scholar] [CrossRef]
  55. Takashima, H.; Yoshida, Y.; Nagura, C.; Furukawa, T.; Tei, R.; Maruyama, T.; Maruyama, N.; Abe, M. Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial. Diabetes Vasc. Dis. Res. 2018, 15, 469–472. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Torimoto, K.; Okada, Y.; Goshima, Y.; Tokutsu, A.; Sato, Y.; Tanaka, Y. Addition of canagliflozin to insulin improves glycaemic control and reduces insulin dose in patients with type 2 diabetes mellitus: A randomized controlled trial. Diabetes Obes. Metab. 2019, 21, 2174–2179. [Google Scholar] [CrossRef] [PubMed]
  57. Wheeler, D.C.; Stefánsson, B.V.; Jongs, N.; Chertow, G.M.; Greene, T.; Hou, F.F.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Toto, R.D.; et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021, 9, 22–31. [Google Scholar] [CrossRef] [PubMed]
  58. Yang, W.; Ma, J.; Li, Y.; Li, Y.; Zhou, Z.; Kim, J.H.; Zhao, J.; Ptaszynska, A. Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: A randomized controlled trial. J. Diabetes 2018, 10, 589–599. [Google Scholar] [CrossRef] [PubMed]
  59. Yang, W.; Han, P.; Min, K.-W.; Wang, B.; Mansfield, T.; T’Joen, C.; Iqbal, N.; Johnsson, E.; Ptaszynska, A. Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial. J. Diabetes 2016, 8, 796–808. [Google Scholar] [CrossRef]
  60. De Boer, I.H.; Khunti, K.; Sadusky, T.; Tuttle, K.R.; Neumiller, J.J.; Rhee, C.M.; Rosas, S.E.; Rossing, P.; Bakris, G. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022, 45, 3075–3090. [Google Scholar] [CrossRef]
  61. Davies, M.J.; Aroda, V.R.; Collins, B.S.; Gabbay, R.A.; Green, J.; Maruthur, N.M.; Rosas, S.E.; Del Prato, S.; Mathieu, C.; Mingrone, G.; et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2022, 65, 1925–1966. [Google Scholar] [CrossRef] [PubMed]
  62. Cosentino, F.; Grant, P.; Aboyans, V.; Bailey, C.J.; Ceriello, A.; Delgado, V. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 2020, 41, 255–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Palmer, S.C.; Tendal, B.; Mustafa, R.A.; Vandvik, P.O.; Li, S.; Hao, Q.; Tunnicliffe, D.; Ruospo, M.; Natale, P.; Saglimbene, V.; et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials. BMJ 2021, 372, m4573. [Google Scholar] [CrossRef]
  64. McGuire, D.K.; Shih, W.J.; Cosentino, F.; Charbonnel, B.; Cherney, D.Z.I.; Dagogo-Jack, S.; Pratley, R.; Greenberg, M.; Wang, S.; Huyck, S.; et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis. JAMA Cardiol. 2021, 6, 148–158. [Google Scholar] [CrossRef] [PubMed]
  65. Kaze, A.D.; Zhuo, M.; Kim, S.C.; Patorno, E.; Paik, J.M. Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: A meta-analysis. Cardiovasc. Diabetol. 2022, 21, 47. [Google Scholar] [CrossRef]
  66. Heyward, J.; Mansour, O.; Olson, L.; Singh, S.; Alexander, G.C. Association between sodium-glucose cotransporter 2 (SGLT2) inhib-itors and lower extremity amputation: A systematic review and meta-analysis. PLoS ONE 2020, 15, e0234065. [Google Scholar] [CrossRef]
  67. Chang, H.-Y.; Singh, S.; Mansour, O.; Baksh, S.; Alexander, G.C. Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes. JAMA Intern. Med. 2018, 178, 1190–1198. [Google Scholar] [CrossRef] [Green Version]
  68. Paul, S.K.; Bhatt, D.L.; Montvida, O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: Real-world study. Eur. Heart J. 2021, 42, 1728–1738. [Google Scholar] [CrossRef]
  69. Huang, C.-Y.; Lee, J.-K. Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 individuals. Diabetes Obes. Metab. 2020, 22, 2348–2355. [Google Scholar] [CrossRef]
  70. Chen, L.; Sun, S.; Gao, Y.; Ran, X. Global mortality of diabetic foot ulcer: A systematic review and meta-analysis of observational studies. Diabetes Obes. Metab. 2022, 25, 36–45. [Google Scholar] [CrossRef]
  71. Shah, N.K.; Deeb, W.E.; Choksi, R.; Epstein, B.J. Dapagliflozin: A Novel Sodium-Glucose Cotransporter Type 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2012, 32, 80–94. [Google Scholar] [CrossRef] [PubMed]
Jcm 12 03958 g001 550
Figure 1. PRISMA flow diagram. * Cochrane CENTRAL redundant entries and CT.gov protocols of either already screened published articles or without outcomes of interest.
Figure 1. PRISMA flow diagram. * Cochrane CENTRAL redundant entries and CT.gov protocols of either already screened published articles or without outcomes of interest.
Jcm 12 03958 g001
Jcm 12 03958 g002 550
Figure 2. Overall analysis and molecular sub-analysis for osteomyelitis. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,28,29,30,37,42,46].
Figure 2. Overall analysis and molecular sub-analysis for osteomyelitis. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,28,29,30,37,42,46].
Jcm 12 03958 g002
Jcm 12 03958 g003 550
Figure 3. Follow-up span sub-analysis for osteomyelitis. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,28,30,42,46].
Figure 3. Follow-up span sub-analysis for osteomyelitis. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,28,30,42,46].
Jcm 12 03958 g003
Jcm 12 03958 g004 550
Figure 4. Overall analysis and molecular sub-analysis for peripheral artery disease. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,38,46,52].
Figure 4. Overall analysis and molecular sub-analysis for peripheral artery disease. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,38,46,52].
Jcm 12 03958 g004
Jcm 12 03958 g005 550
Figure 5. Overall analysis and molecular sub-analysis for lower limb ulcers. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,27,42,46,56].
Figure 5. Overall analysis and molecular sub-analysis for lower limb ulcers. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,27,42,46,56].
Jcm 12 03958 g005
Jcm 12 03958 g006 550
Figure 6. Overall analysis and molecular sub-analysis for lower limb fractures. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,25,26,28,29,30,31,32,35,39,40,42,43,46,47,48,49,50,52,53,59].
Figure 6. Overall analysis and molecular sub-analysis for lower limb fractures. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,25,26,28,29,30,31,32,35,39,40,42,43,46,47,48,49,50,52,53,59].
Jcm 12 03958 g006
Jcm 12 03958 g007 550
Figure 7. Overall analysis and molecular sub-analysis for amputations. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,26,29,30,31,34,38,39,42,43,44,45,46,47,48,51,53,54,55,57].
Figure 7. Overall analysis and molecular sub-analysis for amputations. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,26,29,30,31,34,38,39,42,43,44,45,46,47,48,51,53,54,55,57].
Jcm 12 03958 g007
Jcm 12 03958 g008 550
Figure 8. Overall analysis and molecular sub-analysis for symmetric polyneuropathy. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,23,24,33,42,46,56,58].
Figure 8. Overall analysis and molecular sub-analysis for symmetric polyneuropathy. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,23,24,33,42,46,56,58].
Jcm 12 03958 g008
Jcm 12 03958 g009 550
Figure 9. Overall analysis and molecular sub-analysis for lower limb infections. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,21,22,24,28,29,30,31,33,36,37,41,42,43,46,47,48,53].
Figure 9. Overall analysis and molecular sub-analysis for lower limb infections. SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s); M-H = Mantel-Haenszel; CI = confidence interval [4,6,7,21,22,24,28,29,30,31,33,36,37,41,42,43,46,47,48,53].
Jcm 12 03958 g009
Table
Table 1. Trials included in the meta-analysis. RR = risk ratio; CI = confidence interval; T2DM = type 2 diabetes mellitus; HF = heart failure; HFpEF = HF with preserved ejection fraction; NA = not available; CKD = chronic kidney disease; NE = not estimable; CV = cardiovascular; ACVD = atherosclerotic CV disease; HFrEF = HF with reduced ejection fraction; NAFLD = non-alcoholic fatty liver disease; BMI = body mass index; ERD = energy-restricted diet, i.e., −360 kcal/die; SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s). 1 Study branches not included in the meta-analysis because not meeting all the inclusion criteria (i.e., administered SGLT2-i are not at approved therapeutic dosages for T2DM). 2 Higher dose available only for the last 12 weeks in the case of uncontrolled diabetes. 3 Risk ratio values not estimable because of the complete lack of related events. 4 Lower dose administered for the first 12 ± 2 weeks. 5 Patients with T2DM were only a subset of the overall study population. 6 Different doses were administered according to prolonged eGFR fluctuations over or under 60 mL/min per 1.73 m2.
Table 1. Trials included in the meta-analysis. RR = risk ratio; CI = confidence interval; T2DM = type 2 diabetes mellitus; HF = heart failure; HFpEF = HF with preserved ejection fraction; NA = not available; CKD = chronic kidney disease; NE = not estimable; CV = cardiovascular; ACVD = atherosclerotic CV disease; HFrEF = HF with reduced ejection fraction; NAFLD = non-alcoholic fatty liver disease; BMI = body mass index; ERD = energy-restricted diet, i.e., −360 kcal/die; SGLT2-i = sodium-glucose cotransporter 2 inhibitor(s). 1 Study branches not included in the meta-analysis because not meeting all the inclusion criteria (i.e., administered SGLT2-i are not at approved therapeutic dosages for T2DM). 2 Higher dose available only for the last 12 weeks in the case of uncontrolled diabetes. 3 Risk ratio values not estimable because of the complete lack of related events. 4 Lower dose administered for the first 12 ± 2 weeks. 5 Patients with T2DM were only a subset of the overall study population. 6 Different doses were administered according to prolonged eGFR fluctuations over or under 60 mL/min per 1.73 m2.
PopulationStudy TypeDatesInterventionParticipantsControlsOsteomyelitis RR (95% CI)Peripheral Artery Disease RR (95% CI)Ulcers RR (95% CI)Fractures RR (95% CI)Amputations RR (95% CI)Symmetric Polineuropathy RR (95% CI)Infections RR (95% CI)
Akasaka et al., 2022 [21]Japanese adults with T2DM and HFpEF aged ≥20 yearsRandomised controlled trial2017–2019Ipragliflozin 25 mg + Ipragliflozin50 mg4033NANANANANANA0.28 (0.01–6.57)
Amin et al., 2015 (1)1(2)1(3)(4)(5)1(6)1(7)1(8)1 [22]Adults with T2DM aged 18–70 yearsRandomised controlled trial2010–2011Ertugliflozin 1 mg;
Ertugliflozin 1 mg;
Ertugliflozin 5 mg;
Ertugliflozin 5 mg;
Ertugliflozin 10 mg;
Ertugliflozin 10 mg;
Ertugliflozin 25 mg;
Ertugliflozin 25 mg		54
54
55
55
55
55
55
55		54
55
54
55
54
55
54
55		NA
NA
NA
NA
NA
NA
NA
NA		NA
NA
NA
NA
NA
NA
NA
NA		NA
NA
NA
NA
NA
NA
NA
NA		NA
NA
NA
NA
NA
NA
NA
NA		NA
NA
NA
NA
NA
NA
NA
NA		NA
NA
NA
NA
NA
NA
NA
NA		NA
NA
2.95 (0.12–70.77)
3.00 (0.12–72.08)
NA
NA
NA
NA
Ando et al., 2021 [23]Japanese adults with T2DM aged ≥20 yearsRandomised controlled trial2015–2018Canagliflozin 100 mg2020NANANANANA1.00 (0.07–14.90)NA
Bae et al., 2020 [24]Korean adults with T2DM aged 19–80 yearsRandomised controlled trial2019–2020Empagliflozin 10 mg + Empagliflozin25 mg26059NANANANANA2.95 (0.12–71.01)2.95 (0.12–71.01)
Barnett et al., 2014 [25]Adults with T2DM and CKD aged ≥18 yearsRandomised controlled trial2010–2012Empagliflozin 25 mg3737NANANANE3NANANA
Cannon et al., 2020 (1)(2) [4]Adults with T2DM and ACVD aged ≥40 yearsRandomised controlled trial2013–2019Ertugliflozin 5 mg;
Ertugliflozin 15 mg		2752
2747		2747
2747		1.87 (0.79–4.41)
1.38 (0.55–3.41)		0.58 (0.36–0.93)
0.76 (0.49–1.18)		1.09 (0.48–2.46)
1.64 (0.77–3.46)		1.28 (0.69–2.36)
1.11 (0.59–2.10)		1.20 (0.81–1.77)
1.27 (0.86–1.87)		2.99 (0.81–11.05)
0.33 (0.03–3.20)		1.34 (0.92–1.94)
1.70 (1.19–2.43)
Carbone et al., 2020 [26]Adults with T2DM and HFrEF aged ≥18 yearsRandomised controlled trial2016–2018Canagliflozin 100 mg1719NANANANE3NE3NANA
Chehrehgosha et al., 2021 (1)(2) [27]Iranian adults with T2DM and NAFLD aged 20–65 yearsRandomised controlled trial2019–2020Empagliflozin 10 mg;
Empagliflozin 10 mg		35
35		37
34		NA
NA		NA
NA		0.35 (0.01–8.36)
0.32 (0.01–7.69)		NA
NA		NA
NA		NA
NA		NA
NA
Dagogo-Jack et al., 2017 (1)(2) [28]Adults with T2DM aged ≥18 yearsRandomised controlled trial2014–2016Ertugliflozin 5 mg;
Ertugliflozin 15 mg		156
155		153
153		2.94 (0.12–71.68)
NE3		NA
NA		NA
NA		0.98 (0.06–15.54)
0.33 (0.01–8.02)		NA
NA		NA
NA		0.98 (0.06–15.54)
0.33 (0.01–8.02)
Fioretto et al., 2018 [29]Adults with T2DM and CKD 3A aged 18–74 yearsRandomised controlled trial2015–2017Dapagliflozin 10 mg1601610.34 (0.01–8.17)NANANE3NE3NA1.01 (0.06–15.95)
Gallo et al., 2019 (1)(2) [30]Adults with T2DM aged ≥18 yearsRandomised controlled trial2013–2017Ertugliflozin 5 mg;
Ertugliflozin 15 mg		207
205		209
209		3.03 (0.12–73.92)
NE3		NA
NA		NA
NA		0.34 (0.01–8.21)
0.34 (0.01-8.29)		3.03 (0.12-73.92)
5.10 (0.25–105.52)		NA
NA		3.03 (0.12–73.92)
3.06 (0.13–74.64)
Hollander et al., 2017 (1)(2) [31]Adults with T2DM aged ≥18 yearsRandomised controlled trial2013–2016Ertugliflozin 5 mg;
Ertugliflozin 15 mg		448
441		437
437		NA
NA		NA
NA		NA
NA		0.33 (0.01–7.96)
1.98 (0.18–21.78)		0.33 (0.01-7.96)
0.99 (0.06–15.79)		NA
NA		0.98 (0.06–15.55)
0.33 (0.01–8.09)
Inagaki et al., 2016 [32]Japanese adults with T2DM aged ≥20 yearsRandomised controlled trial2014–2015Canagliflozin 100 mg7670NANANA0.31 (0.01–7.42)NANANA
Isshiki et al., 2020 [33]Japanese adults with T2DM aged 20–74 yearsRandomised controlled trial2016–2019Dapagliflozin 5 mg4 + Dapagliflozin10 mg5045NANANANANA0.30 (0.01–7.20)0.30 (0.01–7.20)
Jensen et al., 2020 [34]Adults with HFrEF aged 18–84 years5Randomised controlled trial2017–2020Empagliflozin 10 mg1914NANANANANE3NANA
Kaku et al., 2014 (1)1(2)(3)1 [35]Japanese adults with T2DM aged 20–74 yearsRandomised controlled trial2010–2012Tofogliflozin 10 mg;
Tofogliflozin 20 mg;
Tofogliflozin 40 mg		59
60
59		57
57
57		NA
NA
NA		NA
NA
NA		NA
NA
NA		NA
0.32 (0.01–7.62)
NA		NA
NA
NA		NA
NA
NA		NA
NA
NA
Kashiwagi et al., 2014 (1) [36]Japanese adults with T2DM aged ≥20 yearsRandomised controlled trial2010Ipragliflozin 50 mg6268NANANANANANA1.65 (0.28–9.52)
Kashiwagi et al., 2014 (2) [37]Japanese adults with T2DM aged ≥20 yearsRandomised controlled trial2010Ipragliflozin 50 mg166771.40 (0.06–34.01)NANANANANA2.34 (0.11–48.07)
Katakami et al., 2020 [38]Japanese adults with T2DM aged 30–74 yearsRandomised controlled trial2016–2019Tofogliflozin 20 mg169171NA3.04 (0.12–73.99)NANANE3NANA
Kawamori et al., 2018 [39]Japanese adults with T2DM aged ≥20 yearsRandomised controlled trial2015–2017Empagliflozin 10 mg + Empagliflozin25 mg18293NANANA2.57 (0.12–52.95)NE3NANA
Kitazawa et al., 2020 [40]Japanese adults with T2DM aged 20–74 yearsRandomised controlled trial2017–2018Tofogliflozin 20 mg3331NANANA2.82 (0.12–66.82)NANANA
Lambers Heerspink et al., 2013 [41]Adults with T2DM aged 18–70 yearsRandomised controlled trial2009–2010Dapagliflozin 10 mg2451NANANANANANA6.24 (0.26–147.80)
Lingvay et al., 2019 [42]Adults with T2DM aged ≥18 yearsRandomised controlled trial2017–2018Canagliflozin 300 mg6 + Canagliflozin 100 mg63943940.33 (0.01–8.16)NA0.20 (0.01–4.15)2.00 (0.18–21.97)NE32.00 (0.91–4.40)5.00 (0.59–42.60)
Miller et al., 2018 (1)(2) [43]Adults with T2DM aged ≥18 yearsRandomised controlled trial2014–2016Ertugliflozin 5 mg + Sitagliptin 100 mg;
Ertugliflozin 15 mg + Sitagliptin 100 mg		98
96		97
97		NA
NA		NA
NA		NA
NA		NE3
NE3		NE3
NE3		NA
NA		0.33 (0.01–8.00)
0.34 (0.01–8.17)
Nassif et al., 2019 [44]Adults with HFrEF aged >185Randomised controlled trial2016–2019Dapagliflozin 10 mg8185NANANANANE3NANA
Neal et al., 2017 [7]Adults with T2DM and ACVD aged ≥30 years OR
Adults with T2DM and ≥2 CV risk factors aged ≥50 years		Randomised controlled trial2009–2017Canagliflozin 100 mg + Canagliflozin 300 mg579543470.94 (0.44–2.00)2.12 (1.38–3.25)2.27 (1.63–3.16)1.20 (0.92–1.57)1.97 (1.53–2.54)1.48 (1.11–1.97)1.51 (1.19–1.91)
Palau et al., 2022 [45]Adults with HFrEF aged >18 years5Randomised controlled trial2019–2021Dapagliflozin 10 mg1613NANANANANE3NANA
Perkovic et al., 2019 [46]Adults with T2DM and CKD aged ≥30 yearsRandomised controlled trial2014–2018Canagliflozin 100 mg220221991.27 (0.58–2.79)1.27 (0.58–2.79)1.31 (1.00–1.72)1.50 (0.72–3.10)1.11 (0.79–1.55)0.83 (0.59–1.17)0.91 (0.65–1.27)
Pollock et al., 2019 (1)(2) [47]Adults with T2DM and CKD aged ≥18 yearsRandomised controlled trial2015–2018Dapagliflozin 10 mg + Saxagliptin 2.5 mg;
Dapagliflozin 10 mg		155
145		148
148		NA
NA		NA
NA		NA
NA		0.19 (0.01–3.95)
0.20 (0.01–4.22)		2.87 (0.12–69.79)
3.06 (0.13–74.55)		NA
NA		2.87 (0.12–69.79)
NE3
Pratley et al., 2017 (1)(2)(3)(4) [48]Adults with T2DM aged ≥18 yearsRandomised controlled trial2014–2016Ertugliflozin 5 mg;
Ertugliflozin 15 mg;
Ertugliflozin 5 mg + Sitagliptin 100 mg;
Ertugliflozin 15 mg + Sitagliptin 100 mg		250
248
243
245		247
247
247
247		NA
NA
NA
NA		NA
NA
NA
NA		NA
NA
NA
NA		NE3
NE3
NE3
NE3		NE3
2.99 (0.12–72.99)
NE3
NE3		NA
NA
NA
NA		NE3
2.99 (0.12–72.99)
NE3
3.02 (0.12–73.88)
Rau et al., 2021 [49]Adults with T2DM aged 18–84 yearsRandomised controlled trial2017–2019Empagliflozin 10 mg2222NANANANE3NANANA
Rosenstock et al., 2012 (1)1(2) [50]Adults with T2DM aged ≥18 yearsRandomised controlled trial2008–2010Dapagliflozin 5 mg;
Dapagliflozin 10 mg		141
140		139
139		NA
NA		NA
NA		NA
NA		NA
NE3		NA
NA		NA
NA		NA
NA
Sargeant et al., 2022 (1)(2)(3)(4) [51]Adults with T2DM and BMI ≥25 kg/m2 aged 30–75 yearsRandomised controlled trial2017–2019Empagliflozin 25 mg;
Empagliflozin 25 mg;
Empagliflozin 25 mg + ERD;
Empagliflozin 25 mg + ERD		17
17
17
17		17
17
17
17		NA
NA
NA
NA		NA
NA
NA
NA		NA
NA
NA
NA		NA
NA
NA
NA		NE3
NE3
NE3
NE3		NA
NA
NA
NA		NA
NA
NA
NA
Schumm-Draeger et al., 2014 (1)1(2) [52]Adults with T2DM aged 18–77 yearsRandomised controlled trial2010–2011Dapagliflozin 5 mg;
Dapagliflozin 10 mg		100
199		101
101		NA
NA		NA
NE3		NA
NA		NA
NE3		NA
NA		NA
NA		NA
NA
Sone et al., 2019 (1)(2) [53]Japanese adults with T2DM aged 20–74 yearsRandomised controlled trial2015–2018Empagliflozin 10 mg;
Empagliflozin 25 mg		89
90		90
90		NA
NA		NA
NA		NA
NA		0.34 (0.01–8.16)
0.33 (0.01–8.08)		NE3
NE3		NA
NA		0.34 (0.01–8.16)
1.00 (0.06–15.74)
Spertus et al., 2022 [54]Adults with HF aged ≥18 years5Randomised controlled trial2020–2021Canagliflozin 100 mg6659NANANANANE3NANA
Takashima et al., 2018 [55]Japanese adults with T2DM and CKD aged 20–80 yearsRandomised controlled trial2016–2017Canagliflozin 100 mg2121NANANANANE3NANA
Torimoto et al., 2019 [56]Japanese adults with T2DM aged 18–79 yearsRandomised controlled trial2015–2018Canagliflozin 100 mg1717NANA0.33 (0.01–7.65)NANA0.33 (0.01–7.65)NA
Wheeler et al., 2021 [57]Adults with proteinuric CKD aged ≥18 years5Randomised controlled trial2017–2020Dapagliflozin 10 mg14551451NANANANA0.92 (0.58–1.45)NANA
Wiviott et al., 2019 [6]Adults with T2DM and ACVD or multiple CV risk factors aged ≥40 years OR
Men with T2DM and ≥1 CV risk factor aged ≥55 years OR
Women with T2DM and ≥1 CV risk factor aged ≥60 years		Randomised controlled trial2013–2018Dapagliflozin 10 mg858285780.70 (0.40–1.22)0.97 (0.68–1.37)1.05 (0.58–1.90)1.07 (0.64–1.79)1.09 (0.84–1.40)0.75 (0.26–2.16)0.86 (0.70–1.07)
Yang et al., 2018 [58]Asian adults with T2DM aged ≥18 yearsRandomised controlled trial2014–2016Dapagliflozin 10 mg139133NANANANANA0.32 (0.01–7.76)NA
Yang et al., 2015 (1)1(2) [59]Asian adults with T2DM aged ≥18 yearsRandomised controlled trial2010–2013Dapagliflozin 5 mg;
Dapagliflozin 10 mg		147
152		145
145		NA
NA		NA
NA		NA
NA		NA
1.91 (0.17–20.81)		NA
NA		NA
NA		NA
NA
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Nani, A.; Carrara, F.; Paulesu, C.M.E.; Dalle Fratte, C.; Padroni, M.; Enisci, S.; Bilancio, M.C.; Romio, M.S.; Bertuzzi, F.; Pintaudi, B. Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. J. Clin. Med. 2023, 12, 3958. https://doi.org/10.3390/jcm12123958

AMA Style

Nani A, Carrara F, Paulesu CME, Dalle Fratte C, Padroni M, Enisci S, Bilancio MC, Romio MS, Bertuzzi F, Pintaudi B. Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Journal of Clinical Medicine. 2023; 12(12):3958. https://doi.org/10.3390/jcm12123958

Chicago/Turabian Style

Nani, Alessandro, Federica Carrara, Chiara Maria Eleonora Paulesu, Chiara Dalle Fratte, Matteo Padroni, Silvia Enisci, Maria Concetta Bilancio, Maria Silvia Romio, Federico Bertuzzi, and Basilio Pintaudi. 2023. "Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials" Journal of Clinical Medicine 12, no. 12: 3958. https://doi.org/10.3390/jcm12123958

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop