Current Atherosclerosis Reports

https://doi.org/10.1007/s11883-022-01066-y

EVIDENCE-BASED MEDICINE, CLINICAL TRIALS AND THEIR INTERPRETATIONS​ (K.

NASIR, SECTION EDITOR)

Transitioning to GLP‑1 RAs and SGLT2 Inhibitors as the First Choice

for Managing Cardiometabolic Risk in Type 2 Diabetes
Kunal K. Jha1 · Rishav Adhikari1 · Erfan Tasdighi1 · Ngozi Osuji1 · Tanuja Rajan1 · Michael J. Blaha1

Accepted: 15 August 2022

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract 
Purpose of Review  This forward-looking review summarizes existing evidence from cardiovascular outcome trials on car-
diometabolic risk-reduction in type 2 diabetes (T2DM) management, with attention to updating and personalizing recom-
mendations from recent diabetes practice guidelines issued by cardiology societies.
Recent Findings  T2DM management has shifted towards cardiometabolic outcome improvement rather than purely glycemic
control. According to large clinical trials, sodium-glucose cotransporter-2 inhibitors showed robust results in reducing heart
failure (HF) hospitalization and chronic kidney disease (CKD) progression, while glucagon-like peptide-1 receptor agonists
demonstrated the largest effects on HbA1c reduction, weight loss, and atherosclerotic cardiovascular disease outcomes
prevention, including stroke.
Summary  Considering the distinct features of these new cardiometabolic agents, initial selection of therapy should be tar-
geted to each individual patient, with consideration of combination therapy for the highest risk patients. Moreover, future
studies should investigate the addition of obesity-predominant risk, in conjunction with coronary artery disease, stroke,
CKD, and HF, as a new influential indicator for choosing the optimal cardiometabolic agent.

Keywords  Diabetes · Hyperglycemia · Cardiovascular disease · Sodium-glucose co-transporter-2 · Glucagon-like peptide 1

receptor agonist

Introduction  (CAD), stroke, heart failure (HF), and chronic kidney

Type 2 diabetes mellitus (T2DM) and obesity have been
two of the most concerning non-communicable diseases
in the US and around the world. In 2018, 10.5% of the
adult US population had T2DM, and in 2017–2018,
42.4% were obese. T2DM and obesity are indepen-
dently associated with premature mortality, and lead
to direct healthcare expenditures of $327 and $480 bil-
lion in the USA, respectively [1–3]. Moreover, patients
with T2DM are at higher risk of coronary artery disease
This article is part of the Topical Collection on Evidence-Based
Medicine, Clinical Trials and Their Interpretations
* Michael J. Blaha
mblaha1@jhmi.edu
1
Johns Hopkins Ciccarone Center for the Prevention
of Cardiovascular Diseases, Blalock 524D1 JHH 600 N
Wolfe St, Baltimore, MD 21287, USA
disease (CKD) [4, 5].
Glycated hemoglobin (HbA1c) is nearly universally
measured in patients with cardiometabolic disease and is
a known marker of glycemic status, which helps to estab-
lish the diagnosis of T2DM. However, there is conflicting
evidence regarding the strength of the correlation between
HbA1c and CAD. A prospective study among patients with
T2DM showed that higher HbA1c was modestly, but not
statistically significantly, associated with atherosclerotic
cardiovascular events [6], while a meta-analysis comprising
50,000 patients with no history of T2DM and normal fasting
blood glucose showed that the risk of CAD was increased
20% per 1% higher HbA1c [7]. Therefore, HbA1c alone can-
not explain the majority of cardiometabolic risk, which has
resulted in reorientation of T2DM standards of care towards
cardiometabolic risk management rather than solely glyce-
mic control.

13
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Metformin: Still a Primary Tool for Effective
Diabetes Management?
Metformin is a safe, effective, and well-tolerated antidia-
betic therapy. Metformin monotherapy lowers HbA1c by
1.12% with neutral to slightly beneficial impact on weight
[8, 9]. It exerts its antihyperglycemic effects by decreasing
hepatic glucose production, decreasing intestinal absorp-
tion of glucose, and improving insulin sensitivity. Poten-
tial cardioprotective benefits of metformin have been sug-
gested by the UKPDS sub-study of overweight patients
with newly diagnosed T2DM, randomized to metformin
versus insulin/sulfonylurea. Metformin was associated
with a relative risk reduction (RRR) of 39% and 36%
for myocardial infarction (MI) and all-cause mortality,
respectively [10]. A 2011 meta-analysis of 35 randomized
clinical trials comparing metformin to placebo and other
conventional therapy (insulin, sulfonylurea, alpha-glucosi-
dase inhibitor and thiazolidinedione) demonstrated that
metformin reduced major adverse cardiovascular events
(MACE), MI, stroke, peripheral artery disease, and car-
diovascular (CV) death against placebo (OR = 0.79, 95%
CI, [0.64–0.98]) but not compared to other conventional
therapies (OR = 1.03, 95% CI, [0.72–1.77]) [11], suggest
that metformin has potentially modest but uncertain cardi-
oprotective benefits. Results of the ongoing VA-IMPACT
trial enrolling veterans with prediabetes and atheroscle-
rotic cardiovascular disease will give more clarity regard-
ing the CV benefit of metformin compared to placebo [12].
Metformin continues to be the most prescribed medi-
cine in patients with T2DM. Despite a lack of evidence
of clear CV benefit, its low cost, wide availability, and
favorable safety profile are reason why metformin remains
so commonly used [13]. However, there are several limi-
tations to the routine use of metformin. For example,
metformin is contraindicated in patients with estimated
glomerular filtration rate (eGFR) < 30 mL/min/1.73 ­m2
and acute decompensated HF because of the risk of lactic
acidosis [14]. In addition, metformin commonly requires
discontinuation during acute renal failure and from 24 h
prior to until 48 h following administration of iodinated
contrast agents [14]. Moreover, recent dedicated cardio-
vascular outcome trials (CVOTs) have clearly shown that
sodium-glucose cotransporter-2 inhibitors (SGLT2is) and
glucagon-like peptide-1 receptor agonists (GLP-1RAs)
have a stronger evidence base for preventing adverse car-
diovascular outcomes, irrespective of HbA1c decrement
(Fig. 1) [15–20]. In contrast, neither metformin nor life-
style interventions reduced the first occurrence of nonfatal
MI, stroke, or CV deaths among participants of Diabetes
Prevention Program Outcomes Study [21•]. On this basis,
SGLT2is and GLP-1 RAs have rightlfully challenged the
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Current Atherosclerosis Reports
dominance of metformin as the first choice of treatment in
patients with T2DM as cardiorenal protection has become
the new focus.
Sodium‑Glucose Cotransporter‑2 Inhibitors:
a Novel Therapy with Unexpected
Cardiovascular Benefit
Sodium-glucose cotransporter-2 receptors are located in
the proximal convoluted tubules, where they mediate reab-
sorption of glucose and sodium [22]. Blocking these recep-
tors by SGLT2is leads to significant glucosuria and natriu-
resis, improving glycemic and hemodynamic parameters.
Numerous other mechanisms have also been proposed by
which SGLT2is exert their cardiorenal benefits, includ-
ing (1) decreasing blood pressure; (2) modest weight loss;
(3) improving cardiac energy metabolism; (4) preventing
inflammation, ischemic/reperfusion injury, and adverse
cardiac remodeling; and (5) inhibiting the sympathetic
nervous system [23]. Currently, four SGLT2is (empagliflo-
zin, dapagliflozin, canagliflozin, and ertugliflozin) are food
and drug administration (FDA) approved. They were eval-
uated in first-generation CVOTs designed to demonstrate
CV safety, and also in several second-generation clinical
trials specific for HF and kidney disease [19, 20, 24–30].
SGLT2is cause HbA1c reduction of 0.7–1% [31]. The anti-
glycemic efficacy of SGLT2is varies widely, and depends
on medication, dose, baseline eGFR, and concomitant use
with other blood glucose-lowering therapies. Additionally,
SGLT2is reduce systolic blood pressure by 4–6 mmHg,
diastolic blood pressure by 1–2 mmHg [20], and weight
by 4–6lbs [31].
Generally, SGLT2is are safe and well-tolerated but clini-
cians should be aware of a few adverse events, including
genital mycotic infection, volume depletion, dehydration,
and orthostatic hypotension. Therefore, these drugs should
be used with caution in elderly and frail individuals [19,
20, 24–30]. SGLT2is cause HbA1c reduction of 0.7–1%
[31]. Additionally, euglycemic diabetic ketoacidosis (DKA)
is a rare but serious adverse event which is more probable if
the patient has a lower body mass index and decreased gly-
cogen stores. Euglycemic DKA can be triggered in patients
using SGLT2is in the setting of surgery, infection, trauma,
a major illness, reduced food intake, persistent vomiting,
gastroparesis, dehydration, and reduced insulin dosages
[32, 33]. As SGLT2is are filtered by the glomerulus, they
are contraindicated in patients with advanced renal disease
(eGFR < 20–30 ml/min/1.73 m2). Nonetheless, patients who
are already receiving SGLT2is can safely continue them if
eGFR ultimately falls below this range.
Current Atherosclerosis Reports
Fig. 1  Timeline of cardiovascular outcome trials investigating cardio-
metabolic agents as the new antidiabetic therapies. CV, cardiovascu-
lar; CVOT, cardiovascular outcome trial; FDA, US Food and Drug
Administration; GLP, glucagon-like peptide; MACE, major adverse
First‑Generation SGLT2i CVOTs
Since 2008, CVOTs have been mandated by the FDA
to ensure the cardiovascular safety of new therapies to
treat T2DM. In the pivotal EMPA-REG OUTCOME trial,
empagliflozin (N = 7020, 63  years old, mean HbA1c:
8%, median follow-up: 3.1  years) demonstrated 14%
CV events; MARE, major adverse renal events; MARCE, major
adverse renal and CV events; SGLT, sodium-glucose cotransporter.
HHF, Hospitalization for HF is included as part of the trial primary
end point
reduction in a 3-point composite MACE (HR = 0.86,
95% CI, [0.754–0.99]) in patients with T2DM and estab-
lished cardiovascular disease (CVD), primarily driven
by a 38% reduction in CV mortality [20]. Empagliflozin
also reduced HF hospitalizations (35% RRR), all-cause
mortality (32% RRR), and CKD progression, and these
benefits were independent of baseline HbA1c status. The
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CANVAS trial (N = 10,142, 63.3 years old, mean HbA1c:
8.2%, mean T2DM duration:13.5 years, mean follow-up:
3.5 years) evaluating canagliflozin showed 14% RRR in
MACE, which was driven by HF hospitalization reduc-
tion (HR = 0.67, 95% CI, [0.52–0.87]). Like empagliflozin,
canagliflozin improved kidney outcomes (44% RRR) [19].
In DECLARE-TIMI58 (N = 17,160, 64 years old, mean
HbA1c: 8.3%, median T2DM duration: 11 years, median
follow-up: 4.2 years), dapagliflozin reduced a dual end-
point of CV mortality or HF hospitalization, primarily
driven by a reduction in HF hospitalization (HR = 0.73,
[0.61–0.88]) [30]. This benefit in HF outcomes was inde-
pendent of baseline ASCVD or HF history. This trial also
demonstrated reduced incidence of a renal composite,
comprised of ≥ 40% decrease in eGFR, new end-stage
renal disease, renal or cardiovascular death (4.3 vs. 5.6%,
HR = 0.76; 95% CI, [0.67 to 0.87]). Finally, the VER-
TIS-CV trial (N = 8246, 64.4  years old, mean HbA1c:
8.2%, T2DM mean duration: 13 years, mean follow-up:
3.5 years) of ertugliflozin showed non-inferiority to pla-
cebo for 3-point MACE (HR = 0.97; 95% CI, [0.85–1.11],
p < 0.001). It also demonstrated reduction in hospitaliza-
tion due to HF (HR = 0.70; 95% CI, [0.54–0.90]) [25].
Second‑Generation SGLT2i CVOTs
(Dedicated Heart Failure) and Chronic
Kidney Disease Trials
Because first-generation SGLT2i CVOTs were designed
only to evaluate the cardiovascular non-inferiority among
patients with diabetes, they prompted new trials specifi-
cally evaluating the beneficial effects of SGLT2is on CV
and renal outcomes regardless of diabetes status, i.e., the
second-generation CVOTs.
HF SGLT2i CVOTs
DAPA-HF (N = 4744, 66.6 years old, median follow-up:
18.2 months) included participants with ejection fraction
(EF) < 40% with or without T2DM. In this trial, dapagli-
flozin reduced the risk of HF hospitalization, urgent visit
due to HF, and cardiovascular death compared to placebo
(16.3 vs. 21.2%, HR = 0.74; 95% CI, [0.65 to 0.85]); the
magnitude of this benefit was independent of T2DM status
[27]. In EMPEROR-REDUCED (N = 3730, 67 years old,
median follow-up: 16.2 months), which recruited patients
with class II, III, or IV HF with EF ≤ 40%, empagliflozin
demonstrated 25% RRR (HR =  0.75; 95% CI, [0.65–0.86];
p < 0.001) in CV mortality and hospitalization from
HF regardless of baseline T2DM status. The SOLOIST-
WHF Trial (N = 1222, 69.5 years old, median follow-up:
9 months) evaluated the effect of sotagliflozin, a novel dual
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Current Atherosclerosis Reports
SGLT1 and SGLT2 inhibitor in patients with T2DM who
were recently hospitalized for heart failure, showing a 22%
RRR in composite of CV death and HF-related hospitaliza-
tion or urgent care visits [34]. The EMPEROR-Preserved
trial (N = 5988, 71.9 years old, class II–IV HF, mean EF of
54.3% with median follow-up of 26.2 months) evaluating
empagliflozin in patients with heart failure with preserved
ejection fraction (HFpEF) was the first trial in the history
of any drug to show beneficial CV outcomes in HFpEF
patients. The trial included participants with EF > 40% with
or without T2DM, and empagliflozin showed 21% RRR in
a composite of CV death or HF hospitalization (HR = 0.79;
95% CI, [0.69–0.9]), driven by a decreased risk of hos-
pitalization of HF (HR = 0.73, 95% CI, [0.76–1.09]) [24].
This evidence collectively shows that SGLT2is improve HF
outcomes across the entire range of ejection fractions.
Renal SGLT2i Trials
The FDA’s 2008 guidance did not mandate evaluation
of renal safety of new antidiabetic therapies. Nonethe-
less, most CVOTs investigated secondary renal endpoints.
Similar to the unexpected HF outcome, several first-gen-
eration CVOTs revealed that SGLT2is appear to reduce
major adverse renal events (MAREs). The EMPA-REG
OUTCOME and CANVAS trials showed 46% and 40%
RRR in the secondary MARE outcomes (> 40% eGFR
reduction, initiation of dialysis, and renal death), respec-
tively [19, 20]. DECLARE-TIMI58 demonstrated 47%
RRR in the composite outcome of major adverse cardiac
and renal events (MARCEs) [30]. However, first-gener-
ation SGLT2i trials recruited low-risk CKD patients and
there was substantial variation in inclusion criteria and
secondary outcomes (MARE vs. MARCE). These obser-
vations led to the design of structured second-generation
renal-specific SGLT2i trials in which the MACE was
replaced with MARCE.
The CREDENCE trial of canagliflozin (N = 4401,
63 years old, HbA1c: 8.3%, T2DM duration: 15.8 years,
median follow-up: 2.62 years), the first structured renal
trial, was terminated early due to overwhelmingly positive
outcomes. It showed 30% reduction in the primary compos-
ite MARCE. The DAPA-CKD (N = 4304, 61.8 years old,
median follow-up: 2.4 years) trial of dapagliflozin dem-
onstrated similar outcomes; 39% RRR in MARCE, and
subgroup analysis revealed that renal benefit was T2DM-
independent [29]. A recent meta-analysis of nine SGLT2i
trials, which included 25,749 participants with CKD
(eGFR < 60 mL/min/1.73m2) and 12,863 participants with
macroalbuminuria, evaluated the effect of SGLT2is on renal
outcomes [35]. SGLT2is reduced the primary renal out-
come by 30% in participants with CKD and 43% in partici-
pants with macroalbuminuria. Importantly, the cumulative
Current Atherosclerosis Reports
evidence demonstrates that SGLT2is improve renal out-
comes in patients with CKD even without T2DM [35].
Real‑World Evidence and Generic SGLT2i
Randomized clinical trials often have strict entry criteria
and their practical applicability might be limited for the
larger real-world population. CVD-REAL I & II (Com-
parative Effectiveness of Cardiovascular Outcomes in New
Users of SGLT-2 Inhibitors) were real-world studies which
both evaluated the effects of newly prescribed SGLT2is on
HF hospitalization and mortality outcomes (Supplemen-
tary Table 1). Moreover, CVD-REAL II evaluated MI and
stroke as additional outcomes and strongly suggests that
SGLT2is have class effects and their benefits are consistent
across geographic regions [36, 37].
GLP‑1RA Therapy—Jointly Tackling Obesity,
Diabetes, Metabolism, and ASCVD
GLP-1RAs are incretin-based therapies for the management
of T2DM and obesity, with demonstrated CV risk reduction
in patients with T2DM. These medications work by activating
GLP-1 receptors, which in the pancreas enhances glucose-
dependent insulin release and reduces glucagon release, in the
stomach delays gastric emptying, and in the brain suppresses
appetite. GLP-1 RAs exert their antihyperglycemic effects
without causing significant hypoglycemia. Non-glycemic
effects of GLP-1 RAs include significant weight loss, reduced
lipid parameters and blood pressure, decreased inflammation,
and renal protection. There are two types of GLP-1 RAs:
short- and long-acting agents. Eight CVOTs of seven GLP-1
RAs have been reported, with several long-acting agents dem-
onstrating superior CV outcomes [15–18, 38–41].
Currently, five GLP-1 RAs are FDA-approved for glycemic
control: dulaglutide, exenatide, liraglutide, lixisenatide, and
semaglutide. Albiglutide was approved by the FDA but was
withdrawn for commercial reasons [16]. Two GLP-1RAs are
approved for weight loss: injectable liraglutide and semaglutide.
Most GLP-1 RAs are administered by subcutaneous injections,
although oral semaglutide recently became available. Liraglu-
tide, dulaglutide, and injectable semaglutide have received addi-
tional indications for cardioprotection in patients with T2DM
with CV risk factors. The main adverse events associated with
GLP-1 RAs are GI-related: nausea, vomiting, constipation, and
diarrhea. These symptoms are consistent with the mechanism of
action of the drug, variable in severity, and commonly self-lim-
iting. Slower titration or lowering the dose of GLP-1 RAs miti-
gates these side effects [42]. Other rare adverse events include
pancreatitis, worsening gall bladder disease, and increased risk
of medullary thyroid cancer. However, these associations were
called into question in the SUSTAIN-6 [17] and LEADER [18]
trials and a meta-analysis of four CVOTs [43].
GLP‑1 RA CVOTs
LEADER, the first CVOT to evaluate a long acting
GLP-1 RA, liraglutide, (N = 9340, 64 years old, mean
HbA1c 8.7%, mean duration of T2DM 12.8 years, median
follow-up of 3.8 years), showed that 3-point MACE (CV
death, MI, or non-fatal stroke) incidence decreased by
13%, driven primarily by reduction in CV mortality
(HR = 0.78, 95% CI, [0.66–0.93]) [18]. In SUSTAIN-6
(N = 3297, 64 years old, mean HbA1c: 8.7%, mean T2DM
duration: 13.9 years and median follow-up: 2.1 years), a
CVOT of once-weekly injectable semaglutide in patients
with T2DM, semaglutide reduced the composite 3-point
MACE by 26%, which was largely driven by lower risk
of nonfatal stroke (HR = 0.61, 95% CI, [0.38–0.99]) [17].
The next CVOT, EXSCEL (N = 14,752, 62  years old,
with median follow-up: 3.2 years), evaluated the effect
of once-weekly administration of exenatide in patients
with T2DM, with or without established CVD, on three-
point MACE. It reported that exenatide was noninferior to
placebo in terms of safety, but did not significantly reduce
MACE (p = 0.06 for superiority). The HARMONY OUT-
COMES trial of albiglutide (N = 9463, 64.1 years old,
mean HbA1c: 8.7%, T2DM duration: 14.1 years, median
follow-up: 1.5 years) showed decreased 3-point MACE
(HR = 0.78, 95% CI, [0.68–0.90]), driven by reduction in
nonfatal MI (HR =  0.75, 95% CI, [0.61–0.90], p = 0.003)
[39]. The REWIND trial (N = 9901, 66 years old, median
HbA1c: 7.2%, median T2DM duration: 9.5  years,
median follow-up: 5.4  years) of dulaglutide resulted
in 12% reduction of a 3-point MACE (HR = 0.88, 95%
CI, [0.79–0.99]), driven by reduction in nonfatal stroke
(HR = 0.76, 95% CI, [0.61–0.95]) [15]. Importantly, the
REWIND trial was focused on primary prevention, utiliz-
ing a cohort with well controlled HbA1c, and the median
follow-up term was significantly longer than other GLP-1
RA CVOTs. PIONEER-6 (N = 3183, 66 years old, mean
HbA1c: 8.2%, mean T2DM duration: 14.9 years, median
follow-up: 1.32 years) was the first CVOT of oral sema-
glutide and demonstrated non-inferiority for the 3-point
MACE (HR = 0.79, 95% CI, [0.57–1.11]). Interestingly,
all-cause mortality was lower in the intervention group
(HR = 0.51, 95% CI, [0.31—0.84]). Finally, the AMPLI-
TUDE-O trial (N = 4076, 64  years old, mean HbA1c:
8.94%, mean T2DM duration: 15.1 years, median follow-
up: 1.81 years) of efpeglenatide demonstrated 27% reduc-
tion in a 3-point MACE and 32% reduction in composite
renal outcomes [38].
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Metanalysis of GLP‑1RA Trials
In a recent meta-analysis of eight CVOTs examining the
effects of GLP-1RAs on cardiorenal outcomes in T2DM
patients, investigators found a 14% reduction in a 3-point
MACE (HR = 0.86, 95% CI, [0.79–0.94]) with greatest ben-
efit in participants with established CVD [44]. GLP-1RAs
also reduced CV mortality by 13%, HF hospitalization by
10%, nonfatal stroke by 16%, all-cause mortality by 12%,
and composite renal endpoints by 17% [44]. Improvement
in renal outcomes was mostly due to reduction of new-
onset macroalbuminuria (HR = 0.74, 95% CI, [0.67–0.82],
p < 0.001) [44], suggesting that GLP-1 RAs have both CV
benefits and renal protective effects.
FDA Prescription Label Expansion
for SGLT2is and GLP‑1RAs
Based on the EMPA-REG OUTCOME trial, in 2016,
empagliflozin became the first antidiabetic to receive an
FDA indication for reduction of CV events in adults with
T2DM and CVD [45]. Likewise, in 2017, based on the
LEADER trial, the FDA granted a similar indication to
the first injectable long-acting GLP-1RA, liraglutide [46].
In 2020, the FDA approved dapagliflozin for reduction in
Fig. 2  Updated algorithm to choose the optimum antidiabetic therapy
between GLP-1 RA and SGLT2is. SGLT2is, sodium-glucose cotrans-
porter-2 inhibitors; GLP-1RAs, glucagon-like peptide-1 receptor ago-
nists; CVD, cardiovascular disease; HbA1c, glycated hemoglobin;
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Current Atherosclerosis Reports
CV death and hospitalization for HF events in adults with
heart failure with reduced ejection fraction (HFrEF) irre-
spective of their T2DM status, the first time an antidiabetic
therapy was repurposed to treat HF even in the absence of
T2DM [47]. In February 2020, the FDA approved dula-
glutide for the reduction of MACE in adults with T2DM
who have established cardiovascular disease or multiple
cardiovascular risk factors, opening the door for using
GLP-1 RAs for primary prevention [48]. Last but not
least, in February 2022, the FDA approved empagliflozin
for wider range of patients with HF including those with
preserved ejection fraction, which has a poor prognosis
and few treatment options [49].
Key Takeaways Comparing Various
Guidelines and Expert Consensus
Several society guidelines and expert consensus statements
strongly recommend prescribing SGLT2is/GLP-1RAs in
patients with T2DM with established CVD or at high CV
risk, but each takes a slightly distinct approach to achieve
this aim. Regardless, all guidelines agree on the following:
when HF or CKD predominate, SGLT2is are preferred,
but when SGLT2is are contraindicated, GLP-1RAs are
recommended. Likewise, if ASCVD predominates, either
eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-
creatinine ratio; BNP, B-type natriuretic peptide; ECHO, echocardi-
ography; EF, ejection fraction, CKD, chronic kidney disease; CAD,
coronary artery disease; OSA, obesity sleep apnea
Current Atherosclerosis Reports

Table 1  Patient and physician Preferences/priorities SGLT2is Long-acting GLP-1RA

preferences and priorities
for considering SGLT2is vs.
GLP-1 RA with established
cardiovascular benefits
MI reduction  +  +   +  + 
Stroke reduction  +   +  +  + 
Primary ASCVD prevention (diabetes)  +   +  + 
HF hospitalization reduction  +  +  + 
All cause mortality reduction  +  +  +   +  + 
Weight loss  +   +  +  + 
HbA1C reduction  +   +  +  + 
CKD progression reduction  +  +  +   + 
Mode of administration Oral Subcutaneous or oral
(less CVOT evi-
dence)
Consideration for administration • eGFR < 20 mL/min/1.73 • Nausea despite
­m2 (contraindication) dietary restrictions
• History of recurrent genital • History of gastropa-
candidiasis resis
• History of diabetic ketoaci- • Active gallbladder
dosis disease
• History of fracture (cana- • History of MEN2 or
gliflozin) medullary thyroid
• Pregnancy and breast carcinoma
feeding • Pregnancy and breast
feeding
Adverse events • Mycotic genital infections • Nausea and vomiting
• Increased appetite • Decreasing appetite
• Dehydration, hypotension, • Pancreatitis
and AKI
• Euglycemic diabetic
ketoacidosis

SGLT2is, sodium-glucose co-transporter-2 inhibitors; GLP-1 RA, glucagon like peptide 1 receptor agonists;
MI, myocardial infarction; ASCVD, atherosclerotic cardiovascular disease; HF, heart failure; HbA1C, gly-
cated hemoglobin; CKD, chronic kidney disease; CVOT, cardiovascular outcome trials; eGFR, estimated
glomerular filtration rate; MEN2, multiple endocrine neoplasia type 2

a GLP-1RA or an SGLT-2i with proven CV benefits is
recommended.
The 2019 European Society of Cardiology (ESC)/Euro-
pean Association for the Study of Diabetes (EASD) guideline
stratified CV risk among patients with T2DM into three levels
(i.e., moderate, high, and very high risk) [50]. For patients
with T2DM who have no ASCVD or high/very high CV risk
metformin is the first-line therapy. In patients with T2DM
who have ASCVD or high/very high CV risk, SGLT2is and
GLP-1RAs are the first-line therapies. In 2020, the American
College of Cardiology consensus pathway on management
of T2DM advised the combination of lifestyle intervention
and pharmacotherapy with SGLT2is or GLP-1RAs, inde-
pendent of baseline HbA1c status, in patients with estab-
lished ASCVD, HF, CKD, or at high risk of ASCVD (i.e.,
patients with end organ damage or multiple risk factors) [51].
In the ESC 2021 CVD prevention guidelines, for individu-
als with T2DM and ASCVD or high risk of ASCVD (i.e.,
no established ASCVD and end organ damage with poor
glycemic control or > 10 years of DM), CKD, or HF, the use
of SGLT2is or GLP-1RAs are recommended over metformin
[52]. The recently published American Diabetes Association
2022 Standards of Medical Care for T2DM patients with
established ASCVD or CKD endorses prescribing SGLT2is
or GLP-1RAs with demonstrated CV benefits as the first-line
therapy for comprehensive glycemic control and/or CV risk
modification [53••]. Taken together, all major evidence-based
guidelines confer SGLT2is and GLP-1RAs with class I rec-
ommendations for patients with high CV risk, regardless of
HbA1c, while metformin is considered class IIA.
Combination Therapy
SGLT2is and GLP-1RAs have different mechanisms of
action and adverse event profiles. Therefore, there is poten-
tial for combined use to simultaneously combat ASCVD,
HF, and CKD risk. Small trials that evaluated the feasibil-
ity of co-initiation of SGLT2is and GLP-1RAs revealed that

13

Table 2  Clinical case 1
combination therapy was safe, well-tolerated, and provided
improved glycemic control. Accordingly, a recent 2022 meta-
analysis with pooled data from eight CVOTs, evaluating 1895
patients with T2DM, showed that in comparison to monother-
apy, the combination of SGLT2is and GLP-1 RAs results in
higher reduction of HbA1c (0.77% [95% CI: − 1.03, − 0.50]),
SBP (Standardized Mean Difference (SMD) − 0.33 mmHg;
[95% CI: − 0.49, − 0.17]), BMI (SMD − 0.96 kg/m2; [95%
CI: − 1.69, − 0.23]), and LDL-C (SMD − 23.41  mmol/L;
[95% CI: − 33.74, − 13.08]) [54]. A subgroup analysis of the
AMPLITUDE-O trial reported that, among patients who
were already on SGLT2is, adding efpeglenatide reduced the
incidence of 3-point MACE (HR = 0.70, 95% CI [0.37–1.30])
[55]. Several trials are underway to determine whether a GLP-
1RA, SGLT2i, or combination therapy is most effective in
reducing CV and renal outcomes [56–58].
Cardiac Imaging: a Decision Aid Guiding
Prioritization of SGLT2is or GLP‑1 RA
Therapy in Patients with T2DM
Coronary calcium scores (CAC) and coronary computed
tomography angiography (CCTA) improve ASCVD risk strat-
ification in T2DM patients, and can help in precise allocation
13
Current Atherosclerosis Reports
of cardiometabolic medications [59–63]. CCTA could be
instrumental as a decision aid in T2DM patients with angina,
whereas CAC can be helpful in asymptomatic T2DM patients
[59, 63]. A pooled analysis of multiple cohorts showed that
individuals without overt CVD but with CAC > 100 would
benefit from a GLP-1RA, while restricting use in individuals
with CAC = 0 may reduce costs with little impact on CV event
rates [64]. Current ESC guidelines explicitly cite CAC scoring
and identification of obstructive disease on CTA as reasons to
prioritize selection of CV risk-reducing therapies.
Novel FDA‑Approved Cardiometabolic
Therapies
Finerenone
Finerenone, a selective, nonsteroidal mineralocorticoid
antagonist, reduced CV outcomes and improved renal
parameters in the FIGARIO-DKD [65] and FIDELIO-
DKD [66] trials. A pooled analysis of these trials (FIDEL-
ITY study) demonstrated that finerenone improved CV
outcomes by 14% (95% CI, 0.78–0.95; p = 0.0018) and
renal outcomes by 23% (95% CI, 0.67–0.88; p = 0.0002) in
Current Atherosclerosis Reports
Table 3  Clinical case 2
patients with CKD and T2DM [67]. Accordingly, the FDA
has approved finerenone for management of T2DM with
established CKD to further reduce cardiorenal events [68].
Tirzepatide
Tirzepatide, a dual GLP-1 and glucose-dependent insu-
linotrophic polypetide (GIP) receptor agonist, was found
to be safe and effective in the SURPASS trials. Tirze-
patide significantly reduced HbA1c (− 2% from baseline
7.9%) and weight (− 14 to 18lbs from baseline 190lbs)
and was rarely associated with severe hypoglycemia [69].
The SURPASS-CVOT of tirzepatide is ongoing and will
further clarify the impact on glycemic control and CV
outcomes compared to the GLP-1RA dulaglutide. The
FDA has recently approved tirzepatide to improve glyce-
mic control in adults with T2DM [70].
Updated Algorithm for Selecting GLP‑1 RA
Vs. SGLT2i
A challenge for many clinicians remains the nuanced
difficulty in selecting the optimal cardiometabolic
therapy for each patient. Based on our expert opinion,
GLP-1RAs should be considered the superior agent for
improvement of glycemic parameters, weight loss, pri-
mary ASCVD prevention, secondary stroke reduction,
and improvement in obesity-associated comorbidities.
As such, we propose that obesity-predominant risk
should be considered as a new compelling indication in
future guidelines for proper cardiometabolic risk man-
agement, alongside HF, ASCVD, and CKD (Fig. 2). We
anticipate further support for this position from ongoing
CVOTs such as SELECT. In addition, we believe that
prior history of stroke is also a compelling reason to
select GLP-1 RAs (Fig. 2). On the other hand, SGLT2is
are clearly more effective in reducing the incidence of
HF hospitalization and CKD progression (Table  1).
Thus, SGLT2is will almost always be the preferred
agents later in the disease process (i.e., when HF and
CKD has become evident), and older patients with mul-
tiple comorbidities.
Clinical Vignettes
The broad cardiometabolic benefits of SGLT2is and GLP-1
RAs have been well received by the medical community,
leading to a fundamental revision of treatment protocols for
13

Table 4  Clinical case 3
patients with diabetes, CVD, and CKD. Clinical decisions
related to the drug of choice can often be made by assessing
the risk factor profile of each patient and the mechanism of
action of the drug, which we have highlighted in the central
illustration (Fig. 2) and clinical scenarios (Tables 2, 3, 4).
Conclusion
Multiple guidelines and expert consensus pathways have
recommended that SGLT2is/GLP-1 RAs should be con-
sidered as the first agents for high-risk patients including
those with CVD, CKD, T2DM, and HF, irrespective of
HbA1c, baseline medical therapies, or LVEF [14, 50–52].
Despite the significant CV benefits, strong endorsement
by multiple guidelines, and the FDA’s expansion of med-
ication indications, therapeutic inertia remains prominent
among cardiologists. As of December 2020, cardiologists
were responsible for < 2% of total SGLT2i/GLP-1RA pre-
scriptions, and even on a per physician basis, used these
drugs at far lower rates than primary care physicians and
endocrinologists [71, 72]. Lack of prescription ownership
13
Current Atherosclerosis Reports
between physician specialties, frequent changes in the
landscape of T2DM therapies, the need for insurance
prior-authorization, concerns about adverse effects, and
patient specific barriers have engendered therapeutic
hesitancy among cardiologists. Understanding patient,
physician, and healthcare-associated barriers will help
alleviate therapeutic inertia to dramatically improve
patient outcomes. We hope that our review and updated
algorithm (Fig. 2) will assist clinicians and future guide-
lines writers in making the decision to start GLP-1 RAs
vs. SGLT2is more straightforward.
Supplementary Information  The online version contains supplemen-
tary material available at https://​doi.​org/​10.​1007/​s11883-​022-​01066-y.
Declarations 
Conflict of Interest  Dr. Blaha Grants: NIH, FDA, AHA, Amgen, Novo
Nordisk, Bayer. Advisory Boards: Amgen, Novartis, Novo Nordisk,
Bayer, Roche, 89Bio, Kaleido, Inozyme, Agepha. Consulting: Kowa,
emocha
Human and Animal Rights and Informed Consent  This article does not
contain any studies with human or animal subjects performed by any
of the authors.
Current Atherosclerosis Reports
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