Cardiovascular and Renal Benefits of Novel Diabetes Drugs by

Baseline Cardiovascular Risk: A Systematic Review, Meta-analysis,

and Meta-regression

M. Rodriguez-Valadez, Malak Tahsin, Kirsten E. Fleischmann, Umesh Masharani, Joseph Yeboah, Meyeon Park,
Jose
Lihua Li, Ellerie Weber, Yan Li, Asem Berkalieva, Wendy Max, M.G. Myriam Hunink, and Bart S. Ferket

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Diabetes Care 2023;46(6):1300–1310 | https://doi.org/10.2337/dc22-0772

years

5-year Absolute risk reduction

Largest 5-year absolute risk reduction for heart failure

GLP-1RA, glucagon-like peptide-1 receptor agonists; MACE, major adverse cardiovascular event; NNT, number
needed to treat; tRCT, randomized controlled trial; SGLT2i, sodium–glucose cotransporter 2 inhibitors

ARTICLE HIGHLIGHTS

• Eligibility for glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter 2 inhibitors
(SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but whether expected treat-
ment benefits differ by risk levels is not clear.
• We investigated whether relative and absolute cardiovascular and renal benefits from GLP-1RA and SGLT2i var-
ied by baseline cardiovascular mortality risk.
• Relative treatment effects of both drugs did not depend on baseline cardiovascular mortality risk. However,
5-year absolute risk differences were associated with baseline cardiovascular risk for heart failure for SGLT2i.
• Baseline risk assessment tools are needed to improve decision-making for GLP-1RA and SGLT2i.
 1300 Diabetes Care Volume 46, June 2023

Cardiovascular and Renal Jos
e M. Rodriguez-Valadez,1

Malak Tahsin,1 Kirsten E. Fleischmann,2
Benefits of Novel Diabetes Drugs Umesh Masharani,3 Joseph Yeboah,4
Meyeon Park,3 Lihua Li,1 Ellerie Weber,5
by Baseline Cardiovascular Risk: Yan Li,5 Asem Berkalieva,1 Wendy Max,6
M.G. Myriam Hunink,7,8 and
A Systematic Review, Meta-analysis, Bart S. Ferket 1

and Meta-regression

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Diabetes Care 2023;46:1300–1310 | https://doi.org/10.2337/dc22-0772

BACKGROUND
Eligibility for glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium–glucose
cotransporter 2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower
cardiovascular risk, but whether treatment benefits differ by risk levels is not clear.

PURPOSE
To investigate whether patients with varying risks differ in cardiovascular and renal
benefits from GLP-1RA and SGLT2i with use of meta-analysis and meta-regression. 1
Institute for Healthcare Delivery Science, Depar-
tment of Population Health Science and Policy,
DATA SOURCES
Icahn School of Medicine at Mount Sinai, New York,
META-ANALYSIS

We performed a systematic review using PubMed through 7 November 2022. NY

2
Division of Cardiology, Department of Medicine,
STUDY SELECTION University of California San Francisco, San Francisco,
We included reports of GLP-1RA and SGLT2i confirmatory randomized trials in CA
3
Department of Medicine, University of California,
adult patients with safety or efficacy end point data. San Francisco, CA
4
Section of Cardiovascular Medicine, Internal
DATA EXTRACTION Medicine, Wake Forest University School of
Hazard ratio (HR) and event rate data were extracted for mortality, cardiovascu- Medicine, Winston Salem, NC
5
Department of Population Health Science and
lar, and renal outcomes. Policy, Icahn School of Medicine at Mount Sinai,
New York, NY
DATA SYNTHESIS 6
Institute for Health & Aging and Department
We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary of Social and Behavioral Sciences, University of
HRs were significant for cardiovascular mortality (GLP-1RA 0.87 and SGLT2i 0.86), California, San Francisco, CA
7
Departments of Epidemiology and Radiology,
major adverse cardiovascular events (0.87 and 0.88), heart failure (0.89 and 0.70),
Erasmus MC, Rotterdam, the Netherlands
and renal (0.84 and 0.65) outcomes. For stroke, efficacy was significant for GLP-1RA 8
Center for Health Decision Science, Harvard
(0.84) but not for SGLT2i (0.92). Associations between control arm cardiovascular T.H. Chan School of Public Health, Boston, MA
mortality rates and HRs were nonsignificant. Five-year absolute risk reductions Corresponding authors: Jos
e M. Rodriguez-Valadez,
(0.80–4.25%) increased to 11.6% for heart failure in SGLT2i trials in patients with jm.rodriguez@mountsinai.org, and Bart S. Ferket,
bart.ferket@mountsinai.org
high risk (Pslope < 0.001). For GLP1-RAs, associations were nonsignificant.
Received 19 April 2022 and accepted 27 February
LIMITATIONS 2023

Analyses were limited by lack of patient-level data, consistency in end point defi- This article contains supplementary material online
at https://doi.org/10.2337/figshare.22186279.
nitions, and variation in cardiovascular mortality rates for GLP-1RA trials.
© 2023 by the American Diabetes Association.
CONCLUSIONS Readers may use this article as long as the
work is properly cited, the use is educational
Relative effects of novel diabetes drugs are preserved across baseline cardiovascular
and not for profit, and the work is not altered.
risk, whereas absolute benefits increase at higher risks, particularly regarding heart fail- More information is available at https://www
ure. Our findings suggest a need for baseline risk assessment tools to identify variation .diabetesjournals.org/journals/pages/license.
in absolute treatment benefits and improve decision-making. See accompanying article, p. 1143.
diabetesjournals.org/care
Globally, diabetes is an increasingly preva-
lent disorder across all regions. In 2021, it
was estimated that 537 million adults
aged 20–79 years (10.5% of this age-
group) live with diabetes, and by 2030,
643 million are projected to have diabe-
tes. Type 2 diabetes accounts for the vast
majority (over 90%) of these diabetes
cases. Type 2 diabetes significantly in-
creases the risk for atherosclerotic cardio-
vascular disease (ASCVD), heart failure,
and end-stage renal disease (ESRD). In
2021,
6.7 million adults were estimated
to have died due to diabetes or its compli-
cations (1). In the U.S., type 2 diabetes has
been estimated to reduce life expectancy
by
4 years, with ASCVD and heart failure
accounting for
31% of all diabetes attrib-
utable death (2). Type 2 diabetes is also a
driver of the growth in treated ESRD inci-
dence across the world. Particularly in
Asia, generally more than one-half of all
ESRD cases were attributed to diabetes.
In the U.S., ESRD has high morbidity and
mortality, with dialysis associated with a
>25-year shorter life span compared with
the general population’s life expectancy
(3). Prevention strategies targeting ASCVD
such as major adverse cardiovascular events
(MACE), heart failure, and adverse renal
outcomes in patients with type 2 diabetes
are thus critically important to reduce dis-
ease burden at the population level.
Two recent meta-analyses (4,5) showed
significant relative risk reductions in these
clinical outcomes with two recently in-
troduced glucose-lowering drug classes:
glucagon-like peptide 1 receptor agonists
(GLP-1RA) and sodium–glucose cotrans-
porter-2 inhibitors (SGLT2i). More re-
cently published trials primarily focusing
on improving heart failure and renal out-
comes were not included in these meta-
analyses (4,5), in part because these tri-
als allowed for inclusion of participants
without diabetes. Yet, the relative efficacy
of both new drug classes for reducing car-
diovascular and renal outcome rates has
generally been shown not to depend on
comorbid diabetes status and glycemic
control at baseline (6). For the latter rea-
son, eligibility for both drugs has now
been expanded to patients with diabetes
and high cardiovascular risk, heart failure,
or chronic kidney disease and HbA1c levels
below recommended targets. Eligible pa-
tients also include those without prior
first-line metformin use (7).
However, to what extent expected treat-
ment benefits of GLP-1RA and SGLT2i differ
by cardiovascular risk levels is not clear. Pri-
ces of both drug classes are much higher
than traditional diabetes medications and
cardiovascular preventive drugs such as sta-
tins. For example, in the U.S., it has been
estimated that prices were up to 360 times
higher than traditional diabetes medica-
tions (8). In other countries, including lower-
and middle-income countries, these price
ratios are more favorable, although prices
of both drug classes remain in general
higher (9–11). Wider use of these expensive
novel glucose-lowering medications may
thus yield uncertain net benefits and cost-
effectiveness at the population level.
We performed an updated systematic
review to include more recently pub-
lished trials, followed by meta-analyses
and meta-regression analyses. We inves-
tigated whether patient populations with
varying risks differed in cardiovascular
and renal benefits received from GLP-
1RA and SGLT2i.
RESEARCH DESIGN AND METHODS
Data Sources and Searches
We updated the search strategies of the
two aforementioned prior meta-analyses
(4,5) that covered trial reports published
through February 2020 using PubMed
with publication dates through 7 November
2022. Screening of titles/abstracts, followed
by full-text reviewing for eligibility, was per-
formed by two independent reviewers
(J.M.R.-V. and B.S.F.). Discrepancies for ex-
cluding articles including reasons for exclu-
sion at full-text review were resolved by
consensus. Eligible articles included reports
of confirmatory randomized controlled tri-
als of GLP-1RA and SGLT2i with ASCVD,
heart failure, and/or adverse renal out-
comes as primary end points to determine
safety or efficacy. Our search strategy is de-
tailed in Supplementary Table 1.
Study Selection
Study selection criteria included trials
with an adult patient population with or
without type 2 diabetes but not exclu-
sively enrolling patients with type 1 dia-
betes or gestational diabetes mellitus.
We required trial designs randomizing
patients to an intervention arm in which
GLP-1RA or SGLT2i were administered
as a single drug added to existing ther-
apy/standard of care. We required that
the trials’ control arm be defined as ex-
isting therapy/standard of care with or
without placebo. Furthermore, we required
Rodriguez-Valadez and Associates 1301
reporting of efficacy data for at least one of
our primary or secondary outcomes. Pri-
mary outcomes were defined as cardiovas-
cular mortality, MACE, hospitalization for
heart failure, and/or a composite end point
of adverse renal outcomes. The latter was
based on first occurrence of worsening
kidney function, ESRD, or death from re-
nal causes. All-cause mortality, fatal or
nonfatal myocardial infarction (MI), and
fatal or nonfatal any stroke were defined
as secondary outcomes.
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Data Extraction and Quality
Assessment
Two reviewers (J.M.R.-V. and M.T.) inde-
pendently extracted data from selected
full-text reports. Disagreements were re-
solved through discussion or arbitration
with a third reviewer (B.S.F.). We extracted
hazard ratio (HR) and crude event rate
data including 95% CIs for each outcome
of interest. When HRs or event rates were
reported not for the total group but,
rather, by subgroup, we combined these
data using fixed-effects meta-analysis. For
stroke, we prioritized data extraction for
events of any subtype of stroke to avoid
heterogeneity due to combining efficacy
data on different event types such as any
stroke with ischemic stroke. In Dapagliflo-
zin Effect on Cardiovascular Events trial
(DECLARE-TIMI 58) investigators used is-
chemic stroke (12), and we used the HR for
any stroke (13), as also used by McGuire
et al. (5). For our heart failure outcome, we
ignored the reported recurrent event HR
data from the Effect of Sotagliflozin on Car-
diovascular Events in Patients with Type 2
Diabetes Post Worsening Heart Failure
(SOLOIST-WHF) trial in the meta-analysis of
HRs. For the Effect of Sotagliflozin on Car-
diovascular and Renal Events in Patients
with Type 2 Diabetes and Moderate Renal
Impairment Who Are at Cardiovascular
Risk (SCORED) trial, however, we used re-
ported binomial count data on first heart
failure readmissions to obtain an HR esti-
mate for time to first event (14). For the
composite renal outcome, we prioritized
extraction of efficacy data using the rec-
ommended definition of sustained $40%
reduction in estimated glomerular filtration
rate (eGFR) (15), need for renal-replacement
therapy, or renal death (Supplementary
Table 2). When study reports used a dif-
ferent end point definition, we made at-
tempts to identify secondary analyses by
additional trial-specific PubMed searches
using a combination of search terms for
1302 Novel Diabetes Drug Benefits by Baseline Risk
trial and drug names. Otherwise, we used
reported data on sustained $50% reduc-
tion in eGFR from baseline (16–23) or dou-
bling of serum creatinine from baseline
(24–30). A doubling of serum creatinine from
baseline is assumed equivalent to a sustained
57% reduction in eGFR from baseline (15).
In addition, we extracted data on study
characteristics, intervention characteristics,
and patient characteristics, as well as glu-
cose-lowering medications used at baseline.
We assessed risk of bias using version 2 of
the Cochrane risk-of-bias tool for random-
ized trials (31).
Data Synthesis and Analysis
Summary log HRs and their 95% CIs for
time-to-event outcomes were calculated
for GLP-1RA and SGLT2i trials separately
with use of meta-analysis with a random-
effects model, in which the reported ef-
fect size of every study was weighted by
the inverse of its variance.
For estimation of absolute treatment
benefits, we computed 5-year absolute
risk differences (ARDs). A 5-year time ho-
rizon was chosen for each trial because
absolute risks and therefore differences
in risk across study arms depend on
follow-up duration. For each outcome,
we first extracted the event rate per 100
person-years of the control arm and its
SE. Subsequently, we computed the rate
ratio comparing the intervention arm
with the control arm and its SE. Finally,
we used an exponential distribution for
calculating cumulative 5-year risks in each
arm. For estimation of summary ARDs for
each drug class, we conducted random re-
sampling for variance estimation of risk
differences (32,33). Then we performed
meta-analyses of risk differences using
random-effects models weighted by the
inverse of the variance. SCORED and
SOLOIST-WHF, with use of recurrent
events for the heart failure end point,
were ignored for estimation of ARDs of
hospitalization for heart failure.
We assessed interstudy heterogeneity
with the Cochran Q and I2 statistics. The
Cochran Q test is based on a x2 distribu-
tion with a null hypothesis that is used to
evaluate a common effect size shared by
all trials. With the I2 statistic one estimates
the proportion of the total observed vari-
ance that reflects real differences in effect
size. Commonly used I2 thresholds for
degree of heterogeneity are #25% (low),
26–50% (moderate), and >50% (high).
To assess heterogeneity of relative and
absolute treatment benefits by baseline
cardiovascular risk, we performed meta-
regression using mixed-effects linear
modeling. We used the reported cardiovas-
cular mortality rate in the control group as
a covariate and the log HR and 5-year ARD
estimates, respectively, for each trial as
outcomes. We chose the control arm’s
cardiovascular mortality rate as covariate
because it can be considered a good proxy
for global cardiovascular risk, includes heart
failure, and was available for all trials.
To assess the potential impact of dif-
ferences in trial design and setting, we
conducted sensitivity analyses for meta-
regressions of 5-year ARDs by excluding
studies with SGLT2i that also included inhi-
bition of sodium–glucose cotransporter 1
(23,34). We also excluded those done in an
acute care setting (25,26,34) and those
that exclusively enrolled patients with es-
tablished heart failure at baseline (18,19,22,
34–37). MACE was generally defined as
death from cardiovascular causes, nonfatal
MI, or any nonfatal stroke. However, in
DECLARE-TIMI 58, ischemic instead of any
stroke was used. For this reason, we per-
formed an additional analysis excluding this
one trial. For similar reasons, we repeated
the meta-regression for the composite renal
outcome after removing trials with a diver-
gent end point definition (16–19,22–26,34).
Finally, we conducted analyses excluding
studies with evaluation of drugs currently
not available on the market (23,34,38–40).
For the analyses, we used the metafor
and meta packages in R, version 4.1.1
(R Foundation for Statistical Computing
[https://www.r-project.org]) and P < 0.05
for statistical significance. The study pro-
tocol was performed according to Pre-
ferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA)
and registered on International pro-
spective register of systematic reviews
(PROSPERO) (CRD42022308907).
Data and Resource Availability
Statistical codes and data sets used for our
analyses can be obtained from https://
github.com/Modeling-NovelDiabetesMeds.
RESULTS
Characteristics of Included Trials
We included 15 reports on 13 trials that
were already selected in the two previous
systematic reviews. In our updated PubMed
search we identified 1,179 citations, and
Diabetes Care Volume 46, June 2023
339 citations were additionally identified
through trial-specific searches. After remov-
ing 134 duplicates, from the total of 1,384
articles, we ultimately included 34 full-text
reports (Supplementary Fig. 1) on 22 trials
(n = 154,649): 9 on GLP-1RAs (n = 64,326)
vs. 13 on SGLT2i (n = 90,413). Although the
Canagliflozin Cardiovascular Assessment
Study (CANVAS) Program comprised an inte-
grated analysis of two sister trials (CANVAS
and CANVAS-Renal), we used its efficacy
data as coming from a single trial. The nine
trials that were not considered in the two
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previous meta-analyses (4,5) included one
GLP-1RA trial (39) and eight SGLT2i trials
(16,19,22,23,34–37,41).
Mean age of the trial participants ranged
between 62 and 72 years, 36% of the trial
participants were women, and mean BMI
varied from 28.2 to 32.8 kg/m2 across trials.
Four trials only enrolled patients with dia-
betes, and in these trials mean duration of
diabetes ranged from 9.2 to 15.8 years.
Thirteen trials also enrolled patients with-
out a history of cardiovascular disease. The
lowest proportion of trial participants with
cardiovascular disease at baseline was
37%, in Dapagliflozin And Prevention of
Adverse outcomes in Chronic Kidney Dis-
ease (DAPA-CKD). Baseline eGFR varied
between 43 and 85 mL/min/1.73 m2, and
the proportion of participants with micro-
or macroalbuminuria ranged from 25 to
100% in Canagliflozin and Renal Events in
Diabetes with Established Nephropathy Clin-
ical Evaluation (CREDENCE) (Table 1). All in-
cluded trials were deemed high quality and
with a low risk of bias (Supplementary Tables
3 and 4).
Meta-analysis of HRs and 5-Year
ARDs
Summary HRs were significant for GLP-1RA
regarding cardiovascular mortality (HR
0.87, 95% CI 0.80–0.96), MACE (HR 0.87,
95% CI 0.79–0.97), hospitalization for
heart failure (HR 0.89, 95% CI 0.81–0.99),
and the composite renal outcome (HR
0.84, 95% CI 0.73–0.97). For SGLT2i, the
summary HR for cardiovascular mortality
was 0.86 (95% CI 0.81–0.92), and for
MACE it was 0.88 (95% CI 0.82–0.95).
The SGLT2i trials’ summary HRs for hospi-
talization for heart failure and the com-
posite renal outcome were 0.70 (95%
CI 0.67–0.74) and 0.65 (95% CI 0.58–0.74),
respectively (Fig. 1). For the secondary out-
comes, among GLP-1RA trials, the summary
HR was 0.89 (95% CI 0.82–0.96) for all-
cause mortality, 0.91 (95% CI 0.82–1.02) for
Table 1—Characteristics of trials
Follow-up Diabetes Hx CV Hx heart
FDA duration, Age, Female, BMI, Diabetes, duration, disease, failure,
Trial (reference no.) (n) Drug Route; dose approval years years N (%) kg/m2 N (%) years N (%) N (%)
GLP-1RA trials
ELIXA (25,26) (n = 6,068) Lixisenatide SQ; 10 mg/day or Yes 2.1 60 (10) 1,861 (31) 30.1 (5.6) 6,068 (100) 9.2 (8.2) 6,068 (100) 1,358 (22)
20 mg/day
diabetesjournals.org/care

LEADER (27,29,30) (n = 9,340) Liraglutide SQ; 1–8 mg/day Yes 3.8 64 (7) 3,337 (36) 32.5 (6.3) 9,340 (100) 12.8 (8.0) 7,598 (81) 1,667 (18)
SUSTAIN-6 (28,30)(n = 3,297) Semaglutide SQ; 0–5 mg/week or Yes 2.1 65 (7) 1,295 (39) 32.8 (6.2) 3,297 (100) 13.9 (8.1) 2,735 (83) 777 (24)
1 mg/week
EXSCEL (49) (n = 14,752) Exenatide SQ; 2 mg/week Yes 3.2 62 (9) 5,603 (38) 32.7 (6.4) 14,752 (100) 13.1 (8.3) 10,782 (73) 2,389 (16)
FREEDOM-CVO (39) (n = 4,156) Exenatide SQ; continuous osmotic No 1.3 63 (57–68) 1,525 (37) 32.2 (28.7–36.4)* 4,156 (100) 10.3 (5.9–15.4)* 3,159 (76) 668 (16)
mini pump
Harmony Outcomes (40,58) Albiglutide SQ; 30 mg/week or Yes 1.5 64 (7) 2,894 (31) 32.3 (5.9) 9,463 (100) 14.2 (8.8) 9,463 (100) 1,922 (20)
(n = 9,463) 50 mg/week
REWIND (59,60) (n = 9,901) Dulaglutide SQ; 1–5 mg/week Yes 5.4 66 (7) 4,589 (46) 32.3 (5.7) 9,901 (100) 10.5 (7.2) 3,114 (31) 853 (9)
PIONEER 6 (61) (n = 3,183) Semaglutide Oral; 14 mg/day Yes 1.3 66 (7) 1,007 (32) 32.3 (6.5) 3,183 (100) 14.9 (8.5) 2,695 (85) 388 (12)
AMPLITUDE-O (38) (n = 4,076) Efpeglenatide SQ; 4 mg/week or No 1.8 65 (8) 1,344 (33) 32.7 (6.2) 4,076 (100) 15.4 (8.8) 3,650 (90) 737 (18)
6 mg/week
SGLT2i trials
EMPA-REG Outcome (50,51) Empagliflozin Oral; 10 mg daily or Yes 3.1 63 (9) 2,004 (29) 30.6 (5.3) 7,020 (100) 57% > 10† 7,020 (100) 706 (10)
(n = 7,020) 25 mg daily
CANVAS Program (52) (n = 10,142) Canagliflozin Oral; 100 mg daily Yes 2.4 63 (8) 3,632 (36) 31.9 (5.9) 10,142 (100) 13.5 (7.8) 6,656 (66) 1,461 (14)
DECLARE-TIMI 58 (12) (n = 17,160) Dapagliflozin Oral; 10 mg daily Yes 4.2 64 (7) 6,422 (37) 32.1 (6.0) 17,160 (100) 11.8 (7.8) 6,974 (41) 1,724 (10)
CREDENCE (24) (n = 4,401) Canagliflozin Oral; 100 mg daily Yes 2.6 63 (9) 1,494 (34) 31.3 (6.2) 4,401 (100) 15.8 (8.6) 2,220 (50) 652 (15)
VERTIS CV (62,63) (n = 8,246) Ertugliflozin Oral; 5 mg daily or Yes 3.0 64 (8) 2,477 (30) 31.9 (5.4) 8,246 (100) 13.0 (8.3) 8,246 (100) 1,958 (24)
15 mg daily
DAPA-HF (18,19) (n = 4,744) Dapagliflozin Oral; 10 mg Yes 1.3 67 (11) 1,109 (23) 28.2 (5.9) 1,993 (42) 7.4 (2.7–13.5)* NR 4,744 (100)
EMPEROR-Preserved (36) Empagliflozin Oral; 10 mg Yes 2.2 72 (9) 2,676 (45) 29.8 (5.8) 2,934 (49) NR NR 5,987 (100)
(n = 5,988)
DAPA-CKD (16,17) (n = 4,304) Dapagliflozin Oral; 10 mg Yes 2.4 62 (12) 1,425 (33) 29.5 (6.2) 2,888 (67) 13.7 (7.1–20.0)* 1,610 (37) 468 (11)
EMPEROR-Reduced (35,37) Empagliflozin Oral; 10 mg Yes 1.3 67 (11) 893 (24) 27.9 (5.3) 1,865 (50) NR NR 3,730 (100)
(n = 3,730)
SOLOIST-WHF (34) (n = 1,222) Sotagliflozin Oral; 200–400 mg No 0.8 69 (63–76)* 412 (34) 30.7 (26.7–34.4)* 1,222 (100) 10.2 (5.0–16.9)* NR 1,222 (100)
SCORED (23) (n = 10,584) Sotagliflozin Oral; 200–400 mg No 1.3 69 (63–74)* 4,754 (45) 31.8 (28.0–36.2)* 10,584 (100) NR 5,429 (51) 3,283 (31)
DELIVER (20–22) (n = 6,263) Dapagliflozin Oral; 10 mg Yes 2.3 72 (10) 2,747 (44) 29.8 (6.2) 2,806 (45) NR 6,263(100) 6,263 (100)
EMPA-KIDNEY (41) (n = 6,609) Empagliflozin Oral; 10 mg Yes 2.0 64 (10) 2,192 (33) 29.8 (4.8) 3,040 (46) NR 1,765 (26) 658 (9)
Categorical data are presented as N (%) and continuous data are presented as mean (SD) or, where specified with an asterisk, median (IQR). CV, cardiovascular; DAPA-HF, Dapagliflozin and Prevention
of Adverse Outcomes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; DPP-4, dipeptidyl peptidase 4; ELIXA, Evaluation
of Lixisenatide in Acute Coronary Syndrome; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; AMPLITUDE-O, Effect of Efpeglenatide on Cardiovascular Outcomes; EMPA-REG
Outcome, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with
Preserved Ejection Fraction; EMPEROR-Reduced, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure and a Reduced Ejection Fraction; EXSCEL, EXenatide Study of Cardiovascular Event
Lowering; FDA, U.S. Food and Drug Administration; Hx, medical history; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; NR, not reported; PIONEER 6,
Peptide Innovation for Early Diabetes Treatment 6; REWIND, Researching Cardiovascular Events With a Weekly INcretin in Diabetes; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term
Outcomes With Semaglutide in Subjects With Type 2 Diabetes; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial. SQ, subcutaneous. †Approximately 57% of partici-
Rodriguez-Valadez and Associates

pants with more than 10 years.

1303

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1304 Novel Diabetes Drug Benefits by Baseline Risk Diabetes Care Volume 46, June 2023

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Figure 1—Forest plots of HRs for primary outcomes among GLP-1RA and SGLT2i trials. 95% CIs displayed were computed with use of the natural
 logðlciÞ
logarithm of reported HRs and estimated SEs based on the following formula: logðuciÞ
2 1:96 . uci and lci correspond to the upper and lower limits
of the 95% CIs. Small differences in 95% CIs may have been caused by rounding to two decimals. However, the underlying variance data used for
estimating summary estimates are the same as reported in the studies. DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Fail-
ure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; ELIXA, Evaluation of Lixise-
natide in Acute Coronary Syndrome; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG OUTCOME, BI 10773
(Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, EMPagliflozin outcomE tRial in pa-
tients with chrOnic heaRt failure with Preserved Ejection Fraction; EMPEROR-Reduced, EMPagliflozin outcomE tRial in patients with chrOnic heaRt
diabetesjournals.org/care
MI, and 0.84 (95% CI 0.76–0.92) for any
stroke. For SGLT2i, these HRs were 0.88
(95% CI 0.82–0.94), 0.89 (95% CI 0.78–
1.00), and 0.92 (95% CI 0.75–1.13) (Supple-
mentary Figs. 2–4). I2 statistics generally
remained <50% and Q statistics reached
P < 0.05 only for HRs for MACE among
GLP-1RA trials and for the composite re-
nal outcome among SGLT2i trials.
Summary 5-year ARD estimates for car-
diovascular mortality, MACE, hospitalization
for heart failure, and the composite renal
outcome were statistically significant and
varied from 0.80% (95% CI 1.37 to
0.23) to 4.25% (95% CI 6.39 to 2.10)
(Fig. 2). The largest risk reduction for hospi-
talization for heart failure was estimated
among SGLT2i trials. I2 statistics were >50%
for SGLT2i trials for hospitalization for heart
failure and the composite renal outcome.
Also, Q statistics reached P < 0.01 for these
outcomes among SGLT2i trials.
Five-year absolute risk reductions for all-
cause mortality (1.53%, 95% CI 2.45
to 0.60, for GLP-1RA and 1.84%, 95%
CI 2.90 to 0.77, for SGLT2i) with both
drug classes were larger than for cardiovas-
cular mortality (1.16%, 95% CI 1.92 to
0.40, for GLP-1RA and 1.33%, 95%
CI 2.16 to 0.50, for SGLT2i). For MI and
any stroke, summary 5-year ARDs were
small and only statistically significant for
any stroke with GLP-1RA (0.83%, 95%
CI 1.31 to 0.36) (Supplementary Figs.
5–7). For these secondary outcomes, all I2
statistics were
0 and none of the Q statis-
tics reached P < 0.05.
Meta-regression: Association
Between Cardiovascular Risk and
Treatment Benefits
The cardiovascular mortality rate observed
in the control arm ranged from 0.8 to 2.4
per 100 person-years among GLP-1RA tri-
als and from 0.7 to 12.5 per 100 person-
years among SGLT2i trials. We did not find
any association between the control arm
cardiovascular mortality rate and log-HRs
for both drug classes. Five-year ARDs
generally improved with the control arm
cardiovascular mortality rate and most
prominently for hospitalization for heart
failure with SGLT2i (slope 1.44, P <
0.001), from 0.9% (95% CI 1.7 to 0.1)
failure and a Reduced Ejection Fraction; EXSCEL, EXenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabe-
tes: Evaluation of Cardiovascular Outcome Results; PIONEER 6, Peptide Innovation for Early Diabetes Treatment 6; REWIND, Researching Cardio-
vascular Events With a Weekly INcretin in Diabetes; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide
in Subjects With Type 2 Diabetes; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial.
to a predicted 11.6% (95% CI 14.2 to
9.0) in high-risk populations (Fig. 3, Supp-
lementary Tables 8 and 9, and Supple-
mentary Fig. 8). These risk reductions cor-
respond to number needed to treat (NNT),
defined as the inverse of absolute risk re-
duction, of 109 (95% CI 59–159) and 9
(95% CI 7–11), respectively. For GLP1-RAs,
none of the associations for ARDs were sig-
nificant (Supplementary Table 9).
After removal of trials with investiga-
tion of SGLT2i and sodium–glucose co-
transporter inhibitors (23,34) or acute
setting trials (25,26,34), slopes for the
association between 5-year ARDs and
baseline cardiovascular mortality rates
remained similar (Supplementary Figs. 9
and 10). In analyses omitting SGLT2i tri-
als that exclusively enrolled patients with
established heart failure at baseline, the
slope for 5-year ARD of heart failure
changed from 1.44 (P < 0.001) to
1.67 (P < 0.001). For other main out-
comes, slopes generally steepened but
did not achieve statistical significance
(Supplementary Fig. 11).
In sensitivity analyses excluding trials
with divergent definitions of MACE (12)
or the composite renal outcome (16–19,
22–26,34), as well as excluding trials with
evaluation of drugs currently not available
on the market (23,34,38–40), slopes re-
mained similar (Supplementary Table 9
and Supplementary Figs. 12–14).
CONCLUSIONS
We summarized data from 22 trials
with 154,649 participants including data
from nine newer trials (16–19,22,23,
25,34–37,39,41). The findings from our
updated meta-analyses of HRs augment
the existing evidence on relative cardio-
vascular and renal benefits of GLP-1RA
and SGLT2i. We found statistically signifi-
cant summary HRs for both drug classes
for cardiovascular mortality, MACE, hospi-
talization for heart failure, and the com-
posite renal outcome. For our secondary
end points, all-cause mortality and MI,
hazard rates were statistically significantly
reduced by GLP1-RAs and SGLT2i as well.
For stroke, the hazard rate reduction was
statistically significant for GLP1-RAs. We
generally did not find strong indications
Rodriguez-Valadez and Associates 1305
for heterogeneity in these relative effect
estimates for both drug classes. More-
over, the meta-regression analyses of log
HRs did not reveal important differences in
relative treatment efficacy by baseline car-
diovascular mortality rates. Finally, we esti-
mated absolute benefits achieved with
these agents and generally found more
substantial 5-year absolute risk reductions
for outcomes among high-risk participants.
Statistically significant increasing trends
for reduction of the 5-year risk of hospital-
ization for heart failure were estimated
Downloaded from http://diabetesjournals.org/care/article-pdf/46/6/1300/704600/dc220772.pdf by Research4Life user on 30 May 2023
among SGLT2i trials.
When relative effects remain con-
stant across the participants’ baseline
risk levels, absolute risk reductions with
efficacious treatments are expected to
increase when the control arm’s risk is
high. Thus, the NNT will improve (42).
Indeed, it became apparent that the
SGLT2i trials’ cardiovascular mortality
rates in the control arm were indicative
of rates of heart failure. This resulted in
predictions of significantly larger 5-year
heart failure risk reductions (>10%) in
trials with higher cardiovascular mortal-
ity rates, >12 events per 100 person-
years. Such absolute risk reductions will
translate to lower NNT estimates, reach-
ing levels <10. In comparison, NNT esti-
mates for heart failure were >100 for
SGLT2i trials where low-risk patients were
enrolled.
Our estimates of absolute treatment
benefits with GLP-1RA appear more favor-
able than those reported by Sattar et al.
(4) for cardiovascular and renal outcomes.
First, NNTs in this analysis were calculated
over a weighted average median follow-up
duration of 3.0 years. Second, we addition-
ally included the FREEDOM Cardiovascular
Outcomes (CVO) trial (39), with evaluation
of continuous subcutaneous infusion of an
exendin-4–based agonist (exenatide) but
failure to demonstrate significant relative
reduction of cardiovascular event rates.
We believe that leaving out this trial would
potentially lead to biased estimates of both
summary HRs and ARDs. Moreover, con-
cerns that exendin-4–based agonists are
less effective than human glucagon-like
peptide 1–based molecules have been re-
futed (4).
1306 Novel Diabetes Drug Benefits by Baseline Risk Diabetes Care Volume 46, June 2023

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Figure 2—Forest plots of 5-year ARDs for primary outcomes among GLP-1RA and SGLT2i trials. DAPA-HF, Dapagliflozin and Prevention of Adverse Out-
comes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; ELIXA, Evalua-
tion of Lixisenatide in Acute Coronary Syndrome; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG OUTCOME, BI
10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, EMPagliflozin outcomE tRial in pa-
tients with chrOnic heaRt failure with Preserved Ejection Fraction; EMPEROR-Reduced, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure
and a Reduced Ejection Fraction; EXSCEL, EXenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation
of Cardiovascular Outcome Results; PIONEER 6, Peptide Innovation for Early Diabetes Treatment 6; RD, risk difference; REWIND, Researching Cardiovas-
cular Events With a Weekly INcretin in Diabetes; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Sub-
jects With Type 2 Diabetes; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial.
diabetesjournals.org/care Rodriguez-Valadez and Associates 1307

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Figure 3—Relative and absolute treatment benefits for clinical outcomes by baseline cardiovascular mortality rate. Five-year ARDs as computed for
each trial are shown. The size of each trial’s circle is proportional to the inverse of the variance of its ARD. The line and shaded area refer to point
estimates and 95% confidence bands from the meta-regression analyses. MACE is defined as nonfatal MI, nonfatal stroke, or cardiovascular death.
For GLP-1RA trials, 1, AMPLITUDE-O; 2, Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA); 3, EXenatide Study of Cardiovascular Event
Lowering (EXSCEL); 4, FREEDOM-CVO; 5, Harmony Outcomes; 6, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome
Results (LEADER); 7, Peptide Innovation for Early Diabetes Treatment (PIONEER) 6; 8, Researching Cardiovascular Events With a Weekly INcretin in
Diabetes (REWIND); 9, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUS-
TAIN-6). For SGLT2i trials, 1, CANVAS; 2, CREDENCE; 3, DAPA-CKD; 4, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-
1308 Novel Diabetes Drug Benefits by Baseline Risk
In a recent study where investigators
explored absolute benefits for SGLT2i tri-
als, investigators analyzed heart failure in-
cidence rate differences among 10 trials
and found more prominent rate reduc-
tions among trials with higher baseline
risk (43). In another recent study investiga-
tors estimated anticipated absolute effects
using time-specific risk ratios from nine
SGLT2i trials and baseline risks for four the-
oretical populations of patients with heart
failure. The baseline risks were based on
external cohort study data to facilitate the
application of their meta-analysis (44).
They predicted that the number of hospi-
talizations for heart failure and cardiovas-
cular deaths per 1,000 patients over a
2-year period would increase among pa-
tients diagnosed with heart failure at
highest risk. Highest risk was defined ac-
cording to new diagnosis with heart fail-
ure in the hospital.
In agreement with these studies, we be-
lieve that distinguishing between relative
and absolute treatment benefits provides
additional and clinically useful insights.
Absolute treatment benefits can be esti-
mated with an indirect estimation method
combining relative efficacy estimates from
trials and baseline rates derived from ex-
ternal data sources or trial subgroups. This
method would be valid when such base-
line rates are generalizable to clinical prac-
tice and when the trials’ relative effects
are transportable. The latter assumption is
difficult to ascertain. Therefore, we de-
cided for our analyses to estimate ARDs
directly from the reported trial data
(42,45,46) while standardizing for differ-
ences in follow-up duration to a 5-year
time horizon. However, investigators can
still opt to use the summary HRs in combi-
nation with user-defined control event
rates, for example, as incorporated in a
state-transition model, to estimate ARDs.
Some limitations of our analyses need
to be acknowledged. First, the range in
cardiovascular mortality rates among the
control arms of the GLP-1RA trials was
more limited than among SGLT2i trials for
which these rates could be much higher.
The major reason was that trials with
HF); 5, DECLARE-TIMI 58; 6, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER); 7,
The Study of Heart and Kidney Protection With Empagliflozin (EMPA-KIDNEY); 8, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in
Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial; 9, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with Preserved
Ejection Fraction (EMPEROR-Preserved); 10, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure and a Reduced Ejection Fraction
(EMPEROR-Reduced); 11, SCORED; 12, SOLOIST-WHF; 13, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV).
/100 py, per 100 person-years.
enrollment of patients with heart failure
included only evaluation of SGLT2i, and
these trials had the highest cardiovascular
mortality rate. For generalizability of our
results, the variation in baseline risk should
reflect the risks of target patient popula-
tions as recommended in the clinical
guidelines. Because SGLT2i are generally
exclusively recommended for use in pa-
tients with existing heart failure, the 5-year
ARD estimates observed in the high-risk
trial populations could remain generaliz-
able to these patients. On the other hand,
we demonstrated that heart failure hospi-
talization rates can be decreased with GLP-
1RA as well, and efficacy seems to be
maintained in those with established heart
failure (18,19,22,34–37). More research is
needed to assess whether absolute treat-
ment benefits with GLP-1RA for this out-
come could increase to an extent similar to
that observed for SGLT2i. Second, for our
estimates of 5-year ARDs, we could not
incorporate effects of competing death
rates, which may have varied across study
arms and therefore attenuate ARDs. Un-
fortunately, efficacy data for death rates
other than ASCVD and hospitalization for
heart failure are generally not reported.
We recommend that trialists provide such
data to improve estimation of absolute
treatment benefits in meta-analyses. Third,
we could not always estimate summary
HRs and 5-year ARDs while including data
from all trials. This was the case for out-
comes other than all-cause and cardiovas-
cular mortality. However, generally we
obtained a sample size of at least five trials
or more, which is considered reasonable
for performing meta-analysis and meta-
regression analysis (47). Fourth, we used
combined end point definitions for many
of the outcomes (e.g., mortality, MACE,
stroke, renal outcomes). Heterogeneity
within the distribution of single end points
may have affected our summary effect esti-
mates. For example, we used a combined
stroke end point of fatal and nonfatal stroke
subtypes. Yet, for SGLT2i, it has been estab-
lished that relative effects are generally
only significant for hemorrhagic strokes
(48). As such, it can be expected that in
Diabetes Care Volume 46, June 2023
SGLT2i trials for which the proportion of
hemorrhagic strokes was high, HRs for any
stroke were more protective. In addition,
it should be noted that the 5-year ARD
estimates of combined end points are
sensitive to the baseline risk distribution
of outcome subtypes. For example, for
MACE, the overall ARD is mainly deter-
mined by the risk reduction of cardiovas-
cular mortality, although this contribution
may vary per trial. It was not feasible to
evaluate all potential contributors of inter-
study heterogeneity in our analyses, and
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we chose to focus our analyses on the im-
pact of the cardiovascular mortality rate in
the control arm. We assumed that some
contributors would correlate with this pa-
rameter and that remaining sources of in-
terstudy heterogeneity could be accounted
for by using random effects. Fifth, we used
aggregated data and therefore no causal
inferences could be made about associa-
tions from our meta-regression analyses. As
such, it is not possible to make conclusions
about lack of effect modification across
varying cardiovascular risk factor levels. Fi-
nally, due to limiting our search strategy to
PubMed as defined by prior meta-analyses
(4,5), there is a possibility of incomplete re-
trieval of data from secondary analyses of
included clinical outcome trials (5).
Following the publication of earlier car-
diovascular outcome trials (25–30,49–52),
the American Diabetes Association initially
recommended addition of GLP-1RA and
SGLT2i in those with established ASCVD,
heart failure, or CKD. However, these rec-
ommendations only apply to patients who
have not reached their hemoglobin A1c
(HbA1c) goal on metformin therapy (7).
More recently these recommendations
were expanded to those at elevated
ASCVD risk due to end organ damage or
having multiple cardiovascular risk factors
without established disease. In addition,
recommendations for initiation were made
independent of baseline and individualized
target HbA1c levels, as well as metformin
use (6). Also, in the recently published
Joint American Diabetes Association/Eu-
ropean Association for the Study of Dia-
betes guidelines for the management of
diabetesjournals.org/care
hyperglycemia in type 2 diabetes, similar
recommendations were included. These
guidelines’ recommendations apply for
those with no established disease but
multiple cardiovascular risk factors (such
as age $55 years, obesity, hypertension,
smoking, dyslipidemia, or albuminuria). In
addition, where such high-risk patients
need additional cardiorenal risk reduction,
combination treatment with both a GLP-
1RA and an SGLT2i is suggested, regardless
of background metformin use and HbA1c
levels (53).
The joint impact of multiple risk fac-
tors on expected treatment benefits is
preferably accounted for by estimation of
absolute risks for a scenario with and
without initiation of treatment. When ab-
solute risk or cumulative incidence curves
are expressed over a longer-term hori-
zon, differences in (restricted) event-free
survival time can also be communicated
in a meaningful way. For example, mod-
els have been developed to generate in-
dividualized benefits with lipid-lowering,
blood pressure–lowering, and antithrom-
botic agents (54). Our findings of varying
absolute treatment benefits by cardiovas-
cular risk call for development of such risk
tools to guide trial design and reporting of
results using risk strata. Finally, these tools
can also support more patient-centered
decision-making on these agents.
In conclusion, relative effects of novel
diabetes drugs are preserved across base-
line cardiovascular risk, whereas absolute
benefits increase in those at high cardio-
vascular risk, particularly regarding hospi-
talization for heart failure. Our findings
suggest a need for baseline risk assess-
ment tools to identify variation in abso-
lute treatment benefits with GLP-1RA and
SGLT2i to improve the decision-making
and cost-effectiveness for these agents
(55–57).
Acknowledgments. The authors thank Carrie
Levinson, Reference & Instruction Librarian,
Mount Sinai Health System, who provided ex-
pertise for developing the search strategy.
Funding. Research reported in this publication
was supported by the National Heart, Lung, and
Blood Institute of the National Institutes of
Health under award no. R01HL153456. M.G.M.H.
has received research funding from the Neth-
erlands Organization for Health Research and
Development, the German Innovation Fund,
and Netherlands Educational Grant (“Studie
Voorschot Middelen”), and additional research
funding from the Gordon and Betty Moore
Foundation. K.E.F. is the recipient of an
Innovative Clinical or Translational Science award
from the American Diabetes Association (1-18-
ICTS-041).
The content is solely the responsibility of
the authors and does not necessarily repre-
sent the official views of the National Insti-
tutes of Health.
Duality of Interest. M.G.M.H. receives royal-
ties from Cambridge University Press for a text-
book on medical decision-making, reimbursement
of expenses from the European Society of Radiol-
ogy (ESR) for work on the ESR guidelines for imag-
ing referrals, and reimbursement of expenses
from the European Institute for Biomedical Imag-
ing Research for membership on the Scientific Ad-
visory Board. No other potential conflicts of
interest relevant to this article were reported.
Author Contributions. J.M.R.-V. and B.S.F.
made the analysis plan, performed analyses,
and were involved in writing of the manu-
script. J.M.R.-V. and B.S.F. performed the sys-
tematic search and study selection. J.M.R.-V.
and M.T. conducted data extraction. All other
authors contributed to the discussion and re-
viewed and edited the manuscript. All authors
had full access to all the data and had the fi-
nal responsibility for the decision to submit
for publication.
Prior Presentation. Parts of this study were
presented in abstract form at the 82nd Scien-
tific Sessions of the American Diabetes Associ-
ation, New Orleans, LA, 3–7 June 2022.
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