Received: 22 March 2022 Revised: 11 October 2022 Accepted: 12 October 2022

DOI: 10.1111/dom.14893

ORIGINAL ARTICLE

Sodium-glucose co-transporter-2 inhibitors in type 2 diabetes:

Are clinical trial benefits for heart failure reflected in real-world
clinical practice? A systematic review and meta-analysis
of observational studies

William Hinton MSc 1,2 | Abdus Samad Ansari FRCOphth 3 |

Martin B. Whyte PhD 2 | Andrew P. McGovern MD 2 | Michael D. Feher MD 1 |
Neil Munro DPhil 2 | Simon de Lusignan MD 1,4

1
Nuffield Department of Primary Care Health
Sciences, University of Oxford, Oxford, UK Abstract
2
Department of Clinical and Experimental Aim: To determine the absolute risk reduction (ARR) of heart failure events in people
Medicine, University of Surrey, Guildford, UK
3
treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors.
Department of Twin Research and Genetic
Epidemiology, King's College London, Materials and Methods: We searched PubMed, EMBASE, CINAHL and ISI Web of
London, UK Science for observational studies published to 9 May 2022 that explored the associa-
4
Royal College of General Practitioners (RCGP)
Research and Surveillance Centre (RSC),
tion between SGLT2 inhibitors and any indication for heart failure (including new
London, UK diagnosis or hospitalization for heart failure) in type 2 diabetes. Identified studies

Correspondence
Simon de Lusignan, MD, Nuffield Department
of Primary Care Health Sciences, University of
Oxford, Oxford, OX2 6GG, UK.
Email: simon.delusignan@phc.ox.ac.uk
Funding information
University of Oxford
were independently screened by two reviewers and assessed for bias using the
Newcastle-Ottawa scale. Eligible studies with comparable outcome data were pooled
for meta-analysis using random-effects models, reporting hazard ratios (HRs) with
95% confidence intervals (CIs). The ARR per 100 person-years was determined over-
all, and in subgroups with and without baseline cardiovascular disease (CVD).
Results: From 43 eligible studies, with a total of 4 818 242 participants from 17 coun-
tries, 21 were included for meta-analysis. SGLT2 inhibitors were associated with a
reduced risk of hospitalization for heart failure (HR 0.65, 95% CI 0.59-0.72) overall
and both in those with CVD (HR 0.78, 95% CI 0.68-0.89) and without CVD (HR 0.53,
95% CI 0.39-0.71). Risk reduction for hospitalization for heart failure in people with a
history of CVD (ARR 1.17, 95% CI 0.78-1.55) was significantly greater than for those
without CVD (ARR 0.39, 95% CI 0.32-0.47). The number-needed-to-treat to prevent
one event of hospitalization for heart failure was 86 (95% CI 65-128) person-years of
treatment for the CVD group and 256 (95% CI 215-316) person-years for those
without CVD.
Conclusions: Real-world SGLT2 inhibitor use supports randomized trial data for the
size effect of reduced hospitalization for heart failure in type 2 diabetes, although
with a much lower ARR in people without CVD.

KEYWORDS
heart failure meta-analysis observational studies sodium-glucose co-transporter-2 inhibitors
systematic review type 2 diabetes

Diabetes Obes Metab. 2023;25:501–515. wileyonlinelibrary.com/journal/dom © 2022 John Wiley & Sons Ltd. 501

502
1 | I N T RO DU CT I O N
Randomized controlled trials have shown that empagliflozin and cana-
gliflozin from the sodium-glucose co-transporter-2 (SGLT2) inhibitor
class significantly reduce the risk of major adverse cardiovascular
events, independently of glucose-lowering effects.1,2 In addition,
there appears to be a class effect for this drug for reduced risk of hos-
pitalization for heart failure.1-4 In light of these findings, the European
Association for the Study of Diabetes and American Diabetes Associa-
tion currently recommend SGLT2 inhibitors as a preferred second-line
option for high cardiovascular risk groups but no clear preference is
given to SGLT2 inhibitors in people at low risk.5,6
Real-world evidence suggests that the cardiovascular benefits of
SGLT2 inhibitors translate to effectiveness in people without cardio-
7-11
vascular disease (CVD) at initiation. However, it is unclear whether
these medications should be used in lower risk groups,12-14 particu-
larly because the cost-effectiveness of cardiovascular risk reduction
of SGLT2 inhibitors in low cardiovascular risk groups is unknown. To
determine this, an understanding of the overall risk reduction for this
medication class is needed.
In this systematic review, we explored the effectiveness of SGLT2
inhibitors on the risk of heart failure events in people with type
2 diabetes, compared with other glucose-lowering drugs, in real-
world clinical practice. Furthermore, we determined the absolute
risk reduction (ARR) of SGLT2 inhibitors compared with other
glucose-lowering drugs in the type 2 diabetes population, in those
with and without CVD.
2 | MATERIALS AND METHODS
2.1 | Study design
This study was designed in accordance with the Meta-analysis Of
15
Observational Studies in Epidemiology. The protocol was registered
(CRD42020182593) with the International Prospective Register of
Systematic Reviews, PROSPERO.16
2.2 | Eligibility criteria
We included observational studies for adults (age ≥ 18 years) with
type 2 diabetes. We required one of the study groups to include peo-
ple treated with SGLT2 inhibitors. Drugs considered within the SGLT2
inhibitor class were those with approval for use for the management
of type 2 diabetes: empagliflozin, dapagliflozin, canagliflozin, ertugli-
flozin, ipragliflozin, tofogliflozin, luseogliflozin and remogliflozin. All
non-SGLT2 inhibitor classes of glucose-lowering medications were eli-
gible for comparison (metformin, sulphonylureas, meglitinides, thiazo-
lidinediones, alpha glucosidase inhibitors, dipeptidyl peptidase-4
[DPP-4] inhibitors, glucagon-like peptide 1 [GLP-1] receptor agonists
and insulin). Studies that did not include a comparator group were
excluded from the review.
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HINTON ET AL.
The outcome of interest was any new diagnosis of heart failure or
hospitalization for heart failure. Studies were limited to those in the
English language, and those published after 2012, the year SGLT2
inhibitors were first licenced.17 We also excluded systematic reviews,
clinical trials, conference abstracts, letters and case reports.
2.3 | Search strategy and study selection
We searched PubMed, EMBASE, CINAHL and ISI Web of Science
for the period 1 January 2012 to 9 May 2022 using a comprehen-
sive search strategy (Appendix S1). Duplicates were removed
before the studies went through a two-stage screening process to
determine suitability for inclusion. In the first stage, two reviewers
(WH and ASA) independently reviewed the titles and abstracts
against the inclusion criteria, using Rayyan software.18 Studies
were retained if they met all of the inclusion criteria. Rejection of
studies was dependent on agreement between both reviewers.
Any instances of disagreement between the reviewers for any
studies were retained for full-text screening: the second stage of
screening. In the second stage of screening, the full-text articles of
each study retained from stage 1 were independently reviewed by
each reviewer. Studies were once again, retained or rejected
according to consensus between the two reviewers. Any disagree-
ments between the reviewers were resolved by discussion. In
instances where consensus could not be reached, advice was
sought from a third reviewer (MW). We additionally searched the
references of the included studies to identify any further studies
for screening and inclusion.
2.4 | Data extraction
Information extracted from the studies included the study design,
details about the study population (inclusion criteria), sample size
and population characteristics (age, gender and ethnicity), the defi-
nition and measure for the outcome measure, and results relevant
to our review. Multiple reports from the same studies were
grouped during the data collection process to avoid duplication of
data. These were identified from duplicate author names and
shared study populations. We identified primary studies for inclu-
sion according to the earliest year of publication. However, we
used data from secondary studies that were not reported in the
primary studies, such as data reported from subgroup analysis
(e.g. groups with and without established CVD). In addition, we
contacted authors of studies to request additional data based upon
analysis referred to in the methodology, but not reported in the
manuscript.
The data were extracted by the first reviewer (WH) and were
assessed by the second reviewer (ASA) to ensure all relevant data
were accurately captured. Any discrepancies were discussed, and the
third reviewer (MW) was consulted when consensus could not be
reached.

HINTON ET AL.
2.5 | Quality assessment
The quality of each study was assessed using the Newcastle-Ottawa
quality assessment scale for observational studies.19 The tool is used
to assess the quality of studies based on selection of the study groups
(exposed and non-exposed), comparability between the groups and
how the outcome was determined. We adapted the tool to make it
useable for our assessment of the studies (Appendix S2). Studies were
ranked according to low risk (7 to 9), high risk (4 to 6) or very high risk
(1 to 3) of bias.20
2.6 | Data synthesis
A narrative synthesis of the findings from the included studies was
performed. This considered the population characteristics, study
design, data source and assessment of the outcome measure.
For statistical synthesis, we grouped two or more studies that
shared comparable outcome data (e.g. hazard ratios [HRs], odd ratios),
and pooled these data in meta-analysis. The primary comparator was
non-SGLT2 inhibitor glucose-lowering drugs. However, where data
were only reported for individual drug classes, we extracted estimates
for DPP-4 inhibitors as the first choice of comparison group, followed
by sulphonylureas, GLP-1 receptor agonists, thiazolidinediones, megli-
tinides, alpha glucosidase inhibitors, metformin and insulin. Where an
intention-to-treat analysis was conducted, these data were included
in the meta-analysis. For studies where this analysis was not reported,
estimates of effects for on-treatment analyses were included instead.
Pairwise meta-analysis was performed using random-effects models
to account for variation in how the outcome measure was assessed
(heart failure events) and other variations in the study design. For
comparison, we also performed fixed-effects meta-analysis. The
21
meta-analysis was performed using the inverse variance method.
We reported the pooled estimates of effect with 95% confidence
intervals (95% CI).
Heterogeneity among the studies was determined using the
Q-test; a P value of less than 0.1 implies heterogeneity between the
studies. A tau-squared value and I2 statistic with 95% CI were also
reported, where an I2 value of less than 30%, 30-59%, 60-90%
and more than 90% inferred low, moderate, substantial and consid-
erable heterogeneity, respectively. To assess risk of publication bias,
we plotted funnel plots and performed Egger's test (for 10 or more
studies) to test for asymmetry. Data synthesis was performed in
RStudio software, version 1.3.959,22 using the packages meta and
metafor.23,24
To account for overlapping sample populations across studies
that used the same data source, we only included estimates from
studies with the largest sample size. A sensitivity analysis was per-
formed to check for consistency by replacing these data with esti-
mates of sample populations with the second largest sample sizes of
studies that used the same data source. Furthermore, the main analy-
sis was repeated only for studies with large cohorts (N ≥ 10 000) and
those rated as high quality. Finally, we separately pooled the
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503
estimates of studies that applied a new-user design from studies that
did not.
For subgroup analysis, we pooled estimates for people with or
without CVD at baseline. We reported the pooled estimates for stud-
ies conducted within different geographical regions: North America,
Europe and Asia. We also pooled estimates for studies according to
different non-SGLT2 inhibitor drug comparators: DPP-4 inhibitors,
GLP-1 receptor agonists and other glucose-lowering drugs. We then
pooled estimates of studies that provided data for the composite out-
come of hospitalization for heart failure or all-cause death.
For each study, we determined the ARR per 100 person-years for
heart failure events in people treated with SGLT2 inhibitors compared
with other glucose-lowering drugs (Appendix S3). These data were
then pooled, and the number-needed-to-treat (NNT) to prevent one
event per year was determined. This analysis was repeated for studies
that reported data according to the presence of CVD at baseline.
3 | RE SU LT S
3.1 | Included study characteristics
We identified 367 observational studies from title and abstract
screening, and six additional studies from bibliographic searches
(Appendix S4, Figure A1). Of these, the full-text manuscripts of
83 studies were screened for eligibility. After full-text screening,
43 studies were included for the narrative synthesis.
All but one of the 43 studies were cohort studies,25 published
between 2017 and 2022 and conducted across 17 countries (Appendix
S4, Table A1). The smallest study comprised 89 participants,26 but sam-
ple sizes were much higher across other studies, with the largest study
reporting 2 581 980 individuals.10 After accounting for overlapping
populations across multiple studies using the same databases, the total
population size was 4 818 242. Studies were conducted in North Amer-
ica (USA = 14; Canada = 2), Europe (Sweden = 5; Denmark = 4;
Norway = 3; Germany = 3; Italy = 2; Spain = 2; UK = 3; Hungary = 1;
Slovenia = 1) or Asia (South Korea = 5; Taiwan = 5; Japan = 4;
China = 3; Israel = 1; Singapore = 1). Six studies were multinational.
One article reported cardiovascular outcomes data for Australia, but the
country was not included in this review as heart failure data were not
included in the authors' analyses.10 The average (reported as mean or
median) duration of follow-up across the studies was wide ranging, from
2 months to 5.6 years. Despite these differences, however, the studies
overall were similar in design. The data sources used across the studies
included a mixture of medical claims, primary care, hospital (inpatient
and/or outpatient) and national registry databases.
Nine studies comprised only high cardiovascular risk type 2 diabe-
tes populations: three for co-morbid heart failure,27-29 two for estab-
lished CVD,30,31 two for coronary heart disease,26,32 one for
peripheral artery disease33 and one for controlled hypertension.34
Another study only included patients with type 2 diabetes without
established CVD.35 The remaining studies comprised broader popula-
tions of people with or without a history of cardiovascular events.

504
One study reported data for people with a history of CVD or at high
risk of cardiovascular events in their primary findings; however, data
were reported for the broader type 2 diabetes population in the sensi-
tivity analysis.36
Almost all of the studies reported data for two or more SGLT2
inhibitors (n = 37). In the majority of studies, empagliflozin (n = 29),
dapagliflozin (n = 28) or canagliflozin (n = 23) were the exposure medi-
cations. Five studies included other types of SGLT2 inhibitors as the
exposure medication (ipragliflozin = 5; tofogliflozin = 3; luseogliflo-
zin = 3; ertugliflozin = 1). Nine studies did not report the specific
25,34,37-43
SGLT2 inhibitor medications included in their analyses. Across
the studies, the exposure was either directly compared with one drug
class (n = 36) or a combination of other non-SGLT2 inhibitor glucose-
lowering drugs (n = 13). The studies most frequently compared SGLT2
inhibitors with DPP-4 inhibitors in one-to-one drug class comparisons
(n = 23), followed by GLP-1 receptor agonists (n = 8), sulphonylureas
(n = 3), metformin (n = 1) and thiazolidinedione (n = 1). In the majority
of studies (n = 35), exposure and comparator groups were matched
using propensity score matching, or used inverse probability weighting
to adjust for patient characteristics at initiation.
The definition used for the outcome measure across all but one
of the studies was hospitalization for heart failure.26 One study
defined the outcome as admission to hospital for heart failure or
death because of heart failure,44 and another as first hospitalization
for heart failure or first initiation of a loop diuretic.45 The majority of
the studies used time-to-event analysis and reported HRs (n = 40),
making it possible to perform meta-analysis.
3.2 | Quality of included studies
The quality of the studies was generally good. The mean quality score
of the studies using the Newcastle-Ottawa quality assessment scale
was 7.8 (median = 8). All but four of the studies scored 7 to 9 for the
quality assessment and had a low risk of bias (Appendix S4, Table A2).
Only 26 studies, however, featured a new-user design to mitigate the
risk of immortal time bias.46 In addition, the majority of studies did not
provide details relating to the loss of individuals during the follow-up
period (n = 36).
After assessing studies that used the same data sources, and
therefore, with overlapping populations, we included 21 studies in the
primary meta-analysis (Table 1).
3.3 | Risk of heart failure events
Compared with other glucose-lowering medications, initiation of
SGLT2 inhibitors was associated with a lower risk of hospitalization
for heart failure (HR 0.65, 95% CI 0.59-0.72) (Figure 1). There was
substantial heterogeneity across the studies (Tau2 = 0.0593;
I2 = 85.0% [95% CI 80.2%; 88.6%]; Q-statistic, P < .0001).
A funnel plot displayed some potential asymmetry (Appendix S4,
Figure A2), however, Egger's test suggested that there was no
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HINTON ET AL.
publication bias (P = 0.069). Results from our sensitivity analysis,
including only studies with large cohorts (N > 10 000) and those rated
as high quality, were consistent with the primary analysis (HR 0.66,
95% CI 0.60-0.73) (Appendix S4, Figure A3). In addition, when we
replaced the largest samples with the second largest samples for stud-
ies with overlapping populations, these results were consistent with
the primary analysis (HR 0.62, 95% CI 0.57-0.68) (Appendix S4,
Figure A4). The pooled HR for studies that featured a new-user design
(HR 0.64, 95% CI 0.57-0.72) was also consistent with the primary
analysis in showing that the use of SGLT2 inhibitors was associated
with a lower risk of hospitalization for heart failure compared with
use of other glucose-lowering medications (Appendix S4, Figure A5).
3.4 | Subgroup analysis
People treated with SGLT2 inhibitors had a significantly lower risk of
hospitalization for heart failure compared with those treated with
other glucose-lowering drugs, regardless of the presence of CVD at
baseline (Figure 2). In subgroup analysis of the different geographical
regions, SGLT2 inhibitors reduced the risk of heart failure events com-
pared with other glucose-lowering drugs to a similar extent in each
region (Figure 3). For subgroup analysis of different comparator drug
classes, SGLT2 inhibitors also decreased the risk of heart failure in
those treated with DPP-4 inhibitors or other glucose-lowering drugs,
but there was no difference compared with participants treated with
GLP-1 receptor agonists (HR 0.97, 95% CI 0.90-1.05) (Appendix S4,
Figure A6). However, to check for consistency with other distinct
samples, we repeated this analysis by including three studies that
were excluded from the main analysis because of repeated use of the
same data source.57-59 This showed that SGLT2 inhibitors were signif-
icantly associated with a reduced risk of heart failure events com-
pared with GLP-1 receptor agonists (HR 0.86, 95% CI 0.77-0.95)
(Appendix S4, Figure A7).
3.5 | Hospitalization for heart failure or all-cause
death
Six studies reported a composite outcome for hospitalization for heart
failure or all-cause death. When these data were pooled, SGLT2 inhib-
itors were associated with a 36% reduced risk of either outcome com-
pared with other glucose-lowering drugs (HR 0.64, 95% CI 0.52-0.80)
(Appendix S4, Figure A8). There was, however, considerable heteroge-
neity between the findings of the studies (Tau2 = 0.0720; I2 = 91.6%
[95% CI 85.4-95.2]; Q-statistic, P < .0001).
3.6 | ARR for heart failure and number needed to
treat
Data for incidence rates were available for 16 of the 21 studies
included in the meta-analysis. For people treated with SGLT2

HINTON ET AL.
TABLE 1 Key features of studies included in meta-analysis
Authors Study population
Baviera et al. (2021)37 Patients with T2D ≥ 50 y
11 683 matched pairs
Birkeland et al. (2021)47 Patients with T2D and
without history of CVD or
renal disease
242 889 matched pairs (vs.
oGLD). 105 130 matched
pairs (vs. DPP-4i)
Filion et al. (2020)48 Patients with T2D ≥ 18 y
209 867 new users in each
group
Garry et al. (2019)49 Patients with T2D ≥ 18 y
SGLT-2i: 3529; DPP-4i:
5232
Kashiwagi et al. (2022)50 Patients with T2D aged
≥ 20 y
SGLT-2i: 57 070; DPP-4i:
568 669
Kosiborod et al. (2017)51 Patients with T2D ≥ 18 y On-treatment: mean
154 528 pairs after matching duration was 239 d in the
SGLT-2i group and 211 d
in the oGLD group
Kosiborod et al. (2018)10 Patients with T2D ≥ 18 y
235 064 episodes each for
SGLT-2i and oGLD
Li et al. (2022)28 Patients > 18 y of age, with
T2D and a diagnosis of
HFpEF
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505
New-user
Adjustment for
Duration of follow-up Comparator drug design:
confounding
Yes/No
Median (ITT approach): oGLD PS matching. Adjusted Yes
SGLT-2i: 1.8 (IQR 1.0-2.7) for age group; sex;
and 1.6 (0.7-2.5) y in index year; prior
Lombardy and 1.6 (0.7-2.2) exposure to insulin;
and 1.5 (0.7-2.3) y in duration of diabetes;
Apulia and Drug Derived
Complexity Index
On-treatment approach: oGLD and DPP-4i PS matching. Adjusted Yes
mean follow-up of 1.5 y for an extensive
number of variables
including age, gender,
diabetes duration,
microvascular
complications, severe
hypoglycaemia, lower
limb amputations,
cancer, frailty, all
separate GLDs, drugs
to prevent CVD, etc.
On-treatment: mean follow- DPP-4i Time-conditional PS Yes
up was 0.9 (SD 0.76) y scores, adjusted for
age, sex, co-
morbidities,
medications,
healthcare use
Average treatment DPP-4i PS score decile No
persistence was 6 mo adjustment for > 20
since initiation (unspecified) variables
Not reported DPP-4i IPW adjusted for age, Yes
sex, BMI, Charlson
Comorbidity Index,
adapted Diabetes
Complications
oGLD PS matching. Adjustment No
included demographics,
frailty, duration of
T2D, CVD history,
smoking status, BMI,
HbA1c, eGFR, CV
conditions,
microvascular disease,
medications
ITT: mean duration of follow- oGLD PS matching with Yes
up in SGLT-2i cohort: adjustment for
374 d. oGLD cohort: 392 d demographics, frailty,
duration of T2D, CVD
history, smoking status,
BMI, HbA1c, eGFR, CV
conditions,
microvascular disease,
medications
ITT: mean follow-up was Sitagliptin (DPP-4i) PS matching including No
295 d age, gender, race/
ethnicity, hypertension,
hyperlipidaemia,
coronary artery
(Continues)

506
TABLE 1 (Continued)
Authors Study population
SGLT-2i group: 89 patients;
sitagliptin group: 161
patients
Longato et al. (2021)52 Patients with T2D
3216 patients in each group
Martin et al. (2021)29 Patients with T2D with acute Median follow-up time was
heart failure
Canagliflozin group: 45;
control group: 57 patients
Patorno et al. (2019)11 T2D patients aged ≥ 18 y
112 264 individuals in each
group
Real et al. (2021)53 Adults (age ≥ 18 y) with T2D
12 917 new user episodes in
each drug cohort
Rodionov et al. (2021)54 Patients (age > 40 y) with
T2D, with and without
PAD
9299 SGLT-2i and 2453
GLP-1 RA users with PAD
36 222 SGLT-2i and 8893
GLP-1 RA users without
PAD
Ryan et al. (2018)30 Individuals with a diagnosis
of T2D on or before the
index date
142 800 new users of
canagliflozin and 460 885
new users of oGLDs
Suto et al. (2021)40 Patients with T2D (age
≥ 18 y)
18 583 patients in each
group
Thomsen et al. (2021)45 Patients with T2D (age
≥ 18 y)
14 498 incident
empagliflozin users and
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HINTON ET AL.
New-user
Adjustment for
Duration of follow-up Comparator drug design:
confounding
Yes/No
disease, chronic kidney
disease,
cerebrovascular
accident, eGFR, mean
BMI, mean HbA1c and
confounding
medications
ITT: median (IQR) follow-up DPP-4i PS matching. Adjusted Yes
was 18 (10-24) mo for demographics and
co-morbidities (such as
stroke, PAD and
chronic kidney disease)
oGLD IPW-adjusted Cox model No
22 mo adjusted for sex, age,
prior heart failure,
coronary artery
disease, NYHA class,
NT-ProBNP at
discharge
On treatment: mean follow- DPP-4i PS matching with Yes
up was 5.3 mo adjustment for > 140
potential baseline
characteristics
SGLT-2i mean 0.73 (SD oGLD PS matching, with Yes
0.57); oGLD 0.78 (SD adjustment for age at
0.62) study date entry (index
date), gender, CV risk
factors, indicators of
diabetes severity and
use of concomitant
medications
Cohort 2 (postwarning) with GLP-1 RA IPW with adjustment for Yes
PAD—SGLT-2i = 1.92; 35 variables including
GLP-1 RA = 1.79. Cohort age and sex, co-
2 (postwarning) without morbidities, alcohol
PAD—SGLT-2i = 2.12; abuse, smoking and
GLP-1 RA = 2.05 concomitant
medications
Median follow-up time: oGLD PS matching with a broad No
60-100 d (on treatment). range of covariates
Mean/median follow-up (including
not reported for ITT demographics,
approach medications, previous
conditions and
Charlson comorbidity
index)
On treatment: mean follow- DPP-4i PS matching with Yes
up times were 639 and adjustment for 54
596 d for the SGLT-2i and variables
DPP-4i cohorts,
respectively
18 239 person-years Liraglutide (GLP-1 RA) PS IPW to control for Yes
potential confounders.
These comprised an
extensive list of
variables including:

HINTON ET AL.
TABLE 1 (Continued)
Authors Study population
12 706 incident liraglutide
users
Udell et al. (2018)55 Individuals with T2D (age
≥ 18 y) with established
CVD
12 629 matched pairs
Xu et al. (2021)32 Elderly patients (age ≥ 60 y)
with co-morbid coronary
heart disease and T2D
167 patients treated with
SGLT-2i and 334 patients
who did not receive SGLT-2i
Yang et al. (2022)42 T2D patients newly initiated
SGLT-2is or DPP-4is
21 329 matched pairs
Zerovnik et al. (2021)56 T2D patients aged ≥ 40 y
2851 new users of SGLT-2i
and 3817 new users of
DPP-4i
Duration of follow-up
Median time for ITT analysis
was 1.6 y: 1.7 and 1.5 y
with SGLT-2i and oGLDs
Mean follow-up was 13.2 mo oGLD
(SGLT-2i group: 12.7 mo;
control group: 13.5 mo)
Mean follow-up was 1.6 y
(ITT approach)
Median (IQR) duration of
follow-up for ITT analysis
for SGLT-2i and DPP-4i
cohorts: 2.5 (1.8-3.2) and
3.2 (2.1-4.1) y, respectively
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507
New-user
Adjustment for
Comparator drug design:
confounding
Yes/No
age, sex, year of
inclusion, diabetes
duration, number of
diabetes drugs used,
metformin use, insulin
use, diabetes
complications, eGFR,
history of
cardiovascular disease,
heart failure, obesity,
COPD, cancer, other
concomitant
medications
oGLD 1000 variables included Yes
in PS matching, such as
patient demographics,
duration of diabetes,
baseline co-morbidities
and medication use
Cox model adjusted for No
HbA1c only
DPP-4i PS matched with Yes
adjustment for
demographics at the
index date, diabetes-
related complications
in the year prior to the
index date, and
previous exposure to
oGLDs and CVD-
related medications in
the year prior to the
index date
DPP-4i Cox model adjustment Yes
for covariates in two
blocks:
Block 1: patient
demographics, duration
of diabetes therapy,
use of insulin at
baseline,
hospitalization because
of T2D, and hospital
admission because of
different
cardiovascular causes
Block 2: concomitant
antidiabetic medicines
in background therapy,
such as metformin and
SU, and time of cohort
entry
(Continues)
 14631326, 2023, 2, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14893 by Imam Abdulrahman Bin Faisal University, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
508 HINTON ET AL.

TABLE 1 (Continued)

New-user
Adjustment for
Authors Study population Duration of follow-up Comparator drug design:
confounding
Yes/No
Zhou et al. (2022)43 T2D patients without heart ITT approach: median follow- DPP-4i PS matching with No
failure diagnosis or prior up duration of 5.6 (IQR: adjustment for baseline
use of heart failure 5.32-5.82) y age, sex, prior co-
medications morbidities and non–
20 997 matched pairs SGLT-2i/DPP-4i
medications

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; CVD, cardiovascular disease; DPP-4i, dipeptidyl
peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HFpEF, heart failure with preserved
ejection fraction; IPW, inverse probability weighting; ITT, intention-to-treat; NT-pro BNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New
York Heart Association; oGLD, other glucose-lowering drug; PAD, peripheral artery disease; PS, propensity score; SGLT-2i, sodium-glucose co-
transporter-2 inhibitor; SU, sulphonylurea; T2D, type 2 diabetes.

F I G U R E 1 A forest plot of the risk of heart failure events in people initiated sodium-glucose co-transporter-2 inhibitors (SGLT-2is) compared
with other glucose-lowering medications. Both fixed and random-effect pooled estimates favour SGLT-2is. Vertical lines represent the pooled
random-effects estimate (dotted) and fixed-effects estimate (dashed) for all studies combined for comparison. CI, confidence interval; CVD,
cardiovascular disease; HR, hazard ratio; oGLD, other glucose-lowering drug; PAD, peripheral artery disease

inhibitors (with and without CVD combined), events for hospitaliza-
tion for heart failure reduced by 0.70 (95% CI 0.58-0.82) per 100 per-
son-years compared with other glucose-lowering drugs (Appendix S4,
Figure A9). As a sensitivity analysis, we omitted data from three stud-
ies that comprised only high-risk populations of patients with type
28,29,32
2 diabetes and heart failure or coronary heart disease
pooled ARR was consistent with data from the primary analysis
(Appendix S4, Figure A10). To prevent one event of hospitalization for
heart failure per year, 143 (95% CI 122-173) people would need to be
treated with an SGLT2 inhibitor. There was considerable heterogene-
ity between the ARRs of the studies (Tau2 = 0.0817; I2 = 99.4% [95%
; the CI 99.4-99.5]; Q-statistic, P < .0001).
 14631326, 2023, 2, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14893 by Imam Abdulrahman Bin Faisal University, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HINTON ET AL. 509

F I G U R E 2 A forest plot of the risk of heart failure events in people initiated sodium-glucose co-transporter-2 inhibitors (SGLT-2is) compared
with other glucose-lowering medications, stratified by the presence of CVD at baseline. Both fixed and random-effect pooled estimates favour
SGLT-2is. Vertical lines represent the pooled random-effects estimate (dotted) and fixed-effects estimate (dashed) for all studies combined for
comparison. CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; oGLD, other glucose-lowering drug. *Analysis of CVD-REAL
data. Kosiborod et al. (2017)51 did not report data by presence of CVD at baseline. **Data only reported as a composite of HRs for three
databases: Optum, MarketScan and Medicare

In people with a history of CVD at baseline, the ARR for hospitali-
zation for heart failure events was significantly larger than for those
without CVD at baseline (Figure 4). In people with CVD at baseline,
86 (95% CI 65-128) people per year would need to be treated with an
SGLT2 inhibitor to prevent one event of hospitalization for heart fail-
ure. For those without CVD, 256 (95% CI 215-316) people per year
would need to be treated with an SGLT2 inhibitor to prevent one
event of hospitalization for heart failure.
4 | DISCUSSION
This comprehensive review of observational studies explored the risk
of heart failure events in people with type 2 diabetes treated with
SGLT2 inhibitors, compared with those prescribed other glucose-
lowering medications. Our analyses revealed real-world effectiveness
of using SGLT2 inhibitors to prevent hospitalization for heart failure
(pooled HR 0.65, 95% CI 0.59-0.72). Our findings reflected those from
cardiovascular outcome trials (CVOTs). The HR for risk reduction was
consistent across regions, in people with and without baseline CVD,
and for different drug class comparators. However, the ARR for hospi-
talization for heart failure differed depending on baseline risk: for
those with CVD at baseline, the ARR was 1.17 (95% CI 0.78-1.55),
while in those without CVD, the ARR was 0.39 (95% CI 0.32-0.47).
This translates into a NTT of 86 (95% CI 65-128) person-years to pre-
vent one event of hospitalization for heart failure in those with CVD,
and 256 (95% CI 215-316) person-years in those without CVD.
In the CVOTs for SGLT2 inhibitors, the risk of hospitalization for
heart failure was reduced by 27% to 35% for each respective SGLT2
inhibitor drug compared with placebo.1-4 Our meta-analysis of real-
world studies is consistent with these findings for those at high CVD
risk. However, we extended the analysis to a broader population of
people with type 2 diabetes. Previous meta-analyses of clinical trial
data have confirmed that SGLT2 inhibitors reduce the risk of heart
failure events regardless of the presence of CVD at initiation.60,61
However, the participants in the trials without established CVD were
required to have multiple risk factors to be eligible, and thus were at
high risk of these events.1,4 Our systematic review, on the other hand,
included people at low risk, without a history of CVD or risk factors
for cardiovascular events. This is important because SGLT2 inhibitors
were introduced into clinical practice for their glucose-lowering prop-
erties rather than to manage cardiovascular risk. The cardiovascular
risk profile of the type 2 diabetes population treated with these medi-
cations in the real-world clinical setting will, therefore, be broad. Our
 14631326, 2023, 2, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14893 by Imam Abdulrahman Bin Faisal University, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
510 HINTON ET AL.

F I G U R E 3 A forest plot of the risk of heart failure events in people initiated sodium-glucose co-transporter-2 inhibitors (SGLT-2is) compared
with other glucose-lowering medications, stratified by geographical region (North America, Europe, Asia). Both fixed and random-effect pooled
estimates favour SGLT-2is. Vertical lines represent the pooled random-effects estimate (dotted) and fixed-effects estimate (dashed) for all studies
combined for comparison. CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; oGLD, other glucose-lowering drug; PAD,
peripheral artery disease

study also supports the findings of previous meta-analyses of obser-
vational studies, which showed that SGLT2 inhibitors are associated
with reduced odds/risk of heart failure events compared with people
treated with other glucose-lowering medications. However, three of
the previous analyses did not stratify included studies by the presence
of baseline CVD,62-64 while another only reported risk for studies with
65
populations with 20%-30% incidence of CVD. Our review includes
more recently published studies, across more countries, which pro-
vides more data on high and low cardiovascular risk groups, making it
possible for us to explore differences between these groups more
comprehensively. Furthermore, the previous analyses did not report
the ARR across groups, which is more important at the individual level
when making a decision regarding drug selection in type 2 diabetes.
The NNT to prevent cardiovascular events have previously been
assessed for several medications in heart failure. Examples include
eplerenone (NNT 19 [95% CI 15-27] to prevent one death due to car-
diovascular causes or hospitalization for heart failure over 1 year),66
and carvedilol (NNT 23 [95% CI 17-37] to prevent one death over
1 year).67 However, the cohorts in these studies were people with
established heart failure, and were therefore at even higher risk for
their respective endpoints than the cohorts included in the real-world
evidence studies of our review. This is likely to explain the smaller
 14631326, 2023, 2, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14893 by Imam Abdulrahman Bin Faisal University, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HINTON ET AL. 511

F I G U R E 4 A forest plot of the ARR for hospitalization for heart failure event rates per 100 person-years in people sodium-glucose co-
transporter-2 inhibitors (SGLT-2is) compared with those treated with other glucose-lowering medications, stratified by the presence of CVD at
baseline. Both fixed and random-effect pooled estimates favour SGLT-2is. Vertical lines represent the pooled random-effects estimate (dotted)
and fixed-effects estimate (dashed) for all studies combined for comparison. ARR, absolute risk reduction; CI, confidence interval; CVD,
cardiovascular disease. *Data only available as a composite of ARR for three databases: Optum, Truven and Medicare

NNT values than in our analysis. The NNT for studies of other cardio-
protective medications, in people with established CVD, provide a
more useful comparison. For instance, the NNT for statins over
4.3 years to prevent a major coronary event (non-fatal myocardial
infarction or death because of coronary heart disease) in people with
a history of CVD was between 40 and 61 (which approximates to
68
172-262 over 1 year). Whilst for aspirin, the NNT (over 1 year) in
those with stable CVD were 229 for non-fatal myocardial infarction,
110 for non-fatal stroke and 196 for all-cause death.69 The NNT for
these drugs have also been reported in people without a history of
CVD. Statins have a NNT (to prevent one event for CVD over
10 years) of 18 to 32 (equivalent to an NNT of 180 to 320 over
1 year)70, and for aspirin, the NNT to prevent one non-fatal myocar-
dial infarction was 361 person-years.71 These data provide some con-
text regarding the effectiveness of SGLT2 inhibitors at preventing
cardiovascular events. Due to contemporary, widespread use of drugs
with proven efficacy for heart failure, the NNT for more recent thera-
peutic additions (including SGLT2 inhibitors) may be greater than his-
72
toric data.
4.1 | Strengths and limitations
Our review comprised studies with large sample sizes that were con-
ducted over a number of different countries. The studies generally
had robust methodologies and adjusted for a wide range of known con-
founders. However, there were several limitations of the review. We
searched for studies reporting any heart failure outcome following initi-
ation of an SGLT2 inhibitor, yet none of the studies reported risk for
new onset of heart failure. The criteria for diagnosis of heart failure,
guidelines for therapy and severity of illness requiring hospitalization all
vary between countries: these contribute to heterogeneity between the
results of the studies. The definitions for baseline CVD were generally
similar across the studies (e.g. myocardial infarction, unstable angina,
atrial fibrillation, heart failure, stroke or peripheral artery disease), but
differences in definitions may have added to the heterogeneity. There
was considerable heterogeneity in the pooled ARR (> 90% heterogene-
ity between the study estimates). As well as differences in the definition
of cohorts, the setting and design of the studies, this likely reflects the
varying degree of risk across multiple independent cardiovascular risk
factors that persisted despite subgroup analysis. Recording of CVD in
real-world clinical settings may also be underestimated and therefore
some of the non-CVD group may have unrecognized CVD. For exam-
ple, asymptomatic coronary artery disease may be present in up to 60%
of people with type 2 diabetes.73-75 Despite this, however, all of our
analyses showed a trend towards heart failure benefit for SGLT2 inhibi-
tors in people with type 2 diabetes, regardless of CVD history.
Unmeasured confounding, or bias by indication, are potential
issues for any observational studies of this nature.76-78 It should be
noted that the NNT and ARR estimates presented here are derived

512
from adjusted risk ratios rather than direct ARR estimates derived
from randomization in a trial setting. It is possible that the effects
observed are attributable to unmeasured confounding rather than
representing true risk reduction. Immortal time bias may have
occurred because of the omission of time between a patient switching
from the comparator to the exposure drug of interest.46,79 In our
review, we found that only just over half of the studies mitigated for
this bias by applying a new-user design. Despite these limitations,
however, the consistency with randomized trial data in those at high
CVD risk supports the reliability of the extension into the lower risk
groups where only observational data are available.
Another limitation was the repeated use of data sources across
different studies. We minimized duplication of data by grouping arti-
cles that came from the same study. Furthermore, in our meta-analy-
sis, we addressed overlap of patient data for different studies with the
same data source by only pooling estimates from studies with the
largest sample size.
All studies were conducted in developed countries. We there-
fore cannot be certain that the findings of these studies are general-
izable to developing countries with different demographics, health
systems and different event rates for heart failure. There were also
limited data to conduct meta-analysis for individual SGLT2 inhibi-
tors. As more data come to light, these will provide further insight
into whether SGLT2 inhibitor action is a class effect or differs by
drug type.
In conclusion, in real-world clinical practice, SGLT2 inhibitors
reduce the risk of hospitalization for heart failure in people with type
2 diabetes compared with those treated with other glucose-lowering
drugs. The risk reduction is comparable with that seen in CVOTs.
Reduction in hospitalization for heart failure was also seen in those
without CVD but with a much smaller ARR.
AUTHOR CONTRIBUTIONS
WH designed the review with input from AMcG, MF and SdeL. WH
and ASA performed the searches and extracted data from the eligible
studies, with adjudication by MW. WH and ASA assessed the quality
of the studies, and WH conducted the statistical analysis with critical
appraisal from AMcG, MW, MF, NM and SdeL. WH led the drafting of
the manuscript, with review and contributions from ASA, AMcG, MW,
MF, NM and SdeL.
ACKNOWLEDGEMEN TS
The authors would like to acknowledge the support of Dr Filipa
Ferreira, Senior Project Manager at the University of Oxford.
FUND ING INFORMATION
The authors did not receive financial support for conducting this
study, authorship, or publication of this article.
CONF LICT OF IN TE RE ST
WH has had part of his academic salary funded from grant awards
with Eli Lilly and Co., Novo Nordisk Ltd and AstraZeneca UK Ltd. ASA
acknowledges funding from a NIHR Academic Clinical Fellowship.
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HINTON ET AL.
AMcG reports research funding from Eli Lilly and Co., AstraZeneca
and Pfizer and consultancy from Boehringer Ingelheim. MW has
received grant funding from Sanofi, Eli Lilly and Co., and speaker fees
from AstraZeneca and MSD. MF receives financial support for
research, speaker meetings and consultancy from AMGEN, MSD,
Merck, AstraZeneca, Pfizer, Novo Nordisk Ltd, Eli Lilly and Co. and
Sanofi-Aventis. NM has received financial support for research,
speaker meetings and consultancy from MSD, Merck, BMS, AstraZe-
neca, Pfizer, Novo Nordisk Ltd, Eli Lilly and Co. and Sanofi-Aventis.
SdeL holds or recently held grants from Eli Lilly and Co., AstraZeneca
and Novo Nordisk Ltd through his university for investigator-led
research in diabetes.
PE ER RE VIEW
The peer review history for this article is available at https://publons.
com/publon/10.1111/dom.14893.
DATA AVAILABILITY STAT EMEN T
All data analysed for this systematic review were published elsewhere.
All relevant collected data are included in this article and the supple-
mentary files.
OR CID
Martin B. Whyte https://orcid.org/0000-0002-2897-2026
Simon de Lusignan https://orcid.org/0000-0002-8553-2641
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