1
SUPPLEMENTARY APPENDIX to
Piperidou et al. The effect of SGLT2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials
Supplementary Table 1. Quality assessment of the present meta-analysis according to
PRISMA checklist 2009 ………2
Supplementary Table 2. Search strategy for MEDLINE database ………...4
Supplementary Table 3. Level of albuminuria at baseline as identified in each study .……...6
Supplementary Figure 1. Risk of bias summary: review author’s judgement about each risk
of bias item for each included study ….………..7
Supplementary Figure 2. Funnel plot assessing publication bias for the primary outcome .…8
Supplementary Figure 3. Mean difference in change in UPCR (mg/g). SGLT-2 inhibitors
versus other antidiabetic agents .……….9
Supplementary Figure 4. Weighted mean difference in change in SBP. SGLT-2 inhibitors
versus placebo or other antidiabetic agents .……….10
Supplementary Figure 5. Weighted mean difference in change in DBP. SGLT-2 inhibitors
versus placebo or other antidiabetic agents .……….11
Supplementary Figure 6. Weighted mean difference in change in uric acid. SGLT-2 inhibitors
versus placebo or other antidiabetic agents ..………12
Supplementary Figure 7. The effect of SGLT-2 inhibitors on eGFR compared to placebo or
active control .………..13
Supplementary Figure 8. The effect of the SGLT-2 inhibitors on AKI ....………..14
Supplementary Figure 9. Subgroup analysis based on type of comparator (placebo versus
active control) .……….15
Supplementary Figure 10. Subgroup analysis based on type of SGLT-2 inhibitor utilized ...16
Supplementary Figure 11. Subgroup analysis based on study design (parallel versus
crossover design) ……….17
2
Supplementary Table 1. Quality assessment of the present meta-analysis according to PRISMA checklist 2009
Section/topic # Checklist item Reported
on page #
TITLETitle 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
1
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 1-2
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
2 METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
2 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale.
2 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify
additional studies) in the search and date last searched.
2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis).
2 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for
obtaining and confirming data from investigators.
2 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and
simplifications made.
2-3 Risk of bias in individual
studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
2
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 2-3
3
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.
3-4 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting
within studies)
3-4 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating
which were pre-specified
3-4 RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
3-4 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and
provide the citations.
4-5 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention
group (b) effect estimates and confidence intervals, ideally with a forest plot
5-6 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency 5-6 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15) 5 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 6 DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
6-8 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of
identified research, reporting bias).
8 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 8 FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
8-9
4
Supplementary Table 2. Search strategy for MEDLINE database
*We restricted our results by language applying the appropriate filter for English- language articles from the Filter section in Pubmed.
#1 sglt2
#2 “sglt2 inhibitor*”
#3 sglt-2
#4 “sglt-2 inhibitor*”
#5 “Sodium-Glucose Transporter 2” [Mesh]
#6 “Sodium-Glucose Transporter 2”
#7 “Sodium-Glucose Cotransporter 2”
#8 “Sodium-Glucose Co-transporter 2”
#9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8
#10 invokana
#11 canagliflozin
#12 “canagliflozin” [Mesh]
#13 #10 OR #11 OR #12
#14 jardiance
#15 empagliflozin
#16 "empagliflozin" [Supplementary Concept]
#17 #14 OR #15 OR #16
#18 farxiga
#19 forxiga
#20 dapagliflozin
#21 "2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5- triol" [Supplementary Concept]
#22#18OR#19OR#20OR21
#23 tofogliflozin
#24 "6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-
(hydroxymethyl)spiro(isobenzofuran- 1(3H),2'-(2H)pyran)-3',4',5'-triol" [Supplementary Concept]
#25 #23 OR #24
5
#26 ipragliflozin
#27 "ipragliflozin" [Supplementary Concept]
#28 ASP1941
#29 #26 OR #27 OR #28
#30 luseogliflozin
#31 "1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol"
[Supplementary Concept]
#32 #30 OR #31
#33 ertugliflozin
#34 “5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-hydroxymethyl-6,8- dioxabicyclo(3.2.1)octane-2,3,4-triol”
#35 #33 OR #34
#36 #9OR#13OR#17OR#22OR#25OR#29OR#32OR#35
#37 "Albuminuria"[Mesh]
#38 Albuminuria
#39 "Proteinuria"[Mesh]
#40 Proteinuria
#41 Microalbuminuria
#42 Macroalbuminuria
#43 “urine albumin”
#44 “urinary albumin excretion”
#45 "urine protein"
#46 "urinary protein excretion"
#47#37OR#38OR#39OR#40OR#41OR#42OR#43OR#44OR#45OR#46
#36 AND #47
6
Supplementary Table 3. Level of albuminuria at baseline as identified in each study.
Study Level of albuminuria at baseline
Normal to mildly increased
Moderately increased
Severely increased
Normal to
mildly/Moderately increased *
Moderately/Severely increased †
Not defined
Cherney et al 2016 + +
Cherney et al 2017 + + +
Haneda et al 2016 +
Heerspink et al 2016 + +
Heerspink et al 2016
(CANTATA-SU) + ‡ +
Kashiwagi et al 2014
(SPOTLIGHT) +
Kashiwagi et al 2015
(LANTERN) +
Kashiwagi et al 2014
(EMIT) +
Kohan et al 2016 +
Kohan et al 2014 +
Nauck et al 2011 +
Nomoto et al 2017 +
Petrykiv et al 2017 +
Ridderstraele et al 2014 + + +
Yale et al 2014 +
* The authors excluded patients with UACR >300mg/g † The authors included patients with UACR >/=30mg/g ‡ Subgroup analysis as part of
the main study including patients with baseline UACR >/= 30 mg/g
7
Supplementary Figure 1. Risk of bias summary: review author’s judgement about each risk
of bias item for each included study.
8
Supplementary Figure 2. Funnel plot assessing publication bias for the primary outcome.
9
Supplementary Figure 3. Mean difference in change in UPCR (mg/g). SGLT-2 inhibitors
versus other antidiabetic agents.
10
Supplementary Figure 4. Weighted mean difference in change in SBP. SGLT-2 inhibitors
versus placebo or other antidiabetic agents.
11
Supplementary Figure 5. Weighted mean difference in change in DBP. SGLT-2 inhibitors
versus placebo or other antidiabetic agents.
12
Supplementary Figure 6. Weighted mean difference in change in uric acid. SGLT-2 inhibitors
versus placebo or other antidiabetic agents.
13
Supplementary Figure 7. The effect of SGLT-2 inhibitors on eGFR compared to placebo or
active control.
14
Supplementary Figure 8. The effect of the SGLT-2 inhibitors on AKI.
15
Supplementary Figure 9. Subgroup analysis based on type of comparator (placebo versus
active control).
16
Supplementary Figure 10. Subgroup analysis based on type of SGLT-2 inhibitor utilized.
17
