Expert Review of Pharmacoeconomics & Outcomes

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Cardiovascular outcome trials of glucose-lowering

therapies

Kamlesh Khunti, Melanie J. Davies & Samuel Seidu

To cite this article: Kamlesh Khunti, Melanie J. Davies & Samuel Seidu (2020): Cardiovascular
outcome trials of glucose-lowering therapies, Expert Review of Pharmacoeconomics & Outcomes
Research, DOI: 10.1080/14737167.2020.1763796

To link to this article: https://doi.org/10.1080/14737167.2020.1763796

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EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
https://doi.org/10.1080/14737167.2020.1763796

REVIEW

Cardiovascular outcome trials of glucose-lowering therapies

Kamlesh Khunti, Melanie J. Davies and Samuel Seidu
Diabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK

ABSTRACT ARTICLE HISTORY

Introduction: Early initiated and long-term sustained intensive glucose control is associated with Received 2 January 2020
a significantly decreased risk of cardiovascular events and all-cause mortality, over and above the well- Accepted 29 April 2020
established decline in the risk of microvascular disease. Based on the recent cardiovascular outcome KEYWORDS
trial (CVOT) data, this review focuses on the various benefits of the newer medications with their Cardiovascular outcome
positioning in the treatment algorithm and explores the place of the older medications in the manage- trials; major adverse
ment of type 2 diabetes mellitus (T2DM). cardiovascular events; type 2
Areas covered: We searched the literature for glucose-lowering therapies for patients with T2DM. We diabetes; glucose lowering
included CVOTs conducted for newer sulphonylureas, thiazolidinediones, insulin degludec, DPP-4 therapies
inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists.
Expert opinion: Selection of glucose-lowering therapy in the management of T2DM should be
individualized and based on patient characteristics, associated comorbidities, patient preference, afford-
ability and adherence to treatment. In view of the benefits seen in the CVOTs with SGLT2 inhibitors and
GLP-1 receptor agonists, these newer classes should be the preferred choice in patients with/without
established atherosclerotic cardiovascular disease and chronic kidney disease.

1. Introduction T2DM is essential as opposed to the historic ‘one drug-fit all’

The 8th edition of the International Diabetes Federation (IDF)
Diabetes Atlas 2017 highlights the continuing growth in rates
of diabetes incidence and prevalence across the globe, with
a particular higher prevalence of type 2 diabetes mellitus
(T2DM) rising across all regions. Worldwide, an estimated
451 million adults aged 18–99 years have diabetes, and is
expected to reach 693 million people by 2045 [1].
The risk of cardiovascular disease (CVD) almost doubles in
individuals with T2DM compared to those without diabetes, in
spite of adjustment for established cardiovascular risk factors [2];
in addition, the probability for cardiovascular events increases
with concomitant T2DM and kidney disease. A recent systematic
review reported an overall prevalence of 32.2% (95% confidence
interval [CI], 30.0–34.4%) of CVD in people with T2DM, with
50.3% (95% CI, 37.0–63.7%) of all deaths in people with T2DM
[3]. The ever-increasing burden of cardiorenal metabolic disease,
in terms of incidence, prevalence and cost, continues to jeopar-
dize the healthcare system [4].
The current American Diabetes Association/European
Association for the Study of Diabetes (ADA/EASD) Consensus
report advocates physicians to consider a history of CVD in the
initial process of selecting a treatment, apart from risk of
hypoglycemia, early consideration of weight, cost of treatment
and other patient-related factors that might impact the selec-
tion [4]. Assessment of overall cardiac function at baseline can
add value in interpreting results [5].
To curb this high rate of cardiovascular mortality and morbid-
ity, an individualized patient-centric approach of management of
attitude. An ideal glucose-lowering agent for T2DM in the pre-
sent era should not just be a ‘glucose-lowering agent’ but also
have validated beneficial macro- or micro-vascular effects and
a positive-to-neutral effect on mortality. Efficacy, durability,
safety, utility, and adherence to treatment are the key considera-
tions attributed to an ‘ideal glucose-lowering agent’ (Table 1).
The search for such an ideal agent continues, as suggested by
the plethora of drugs approved by the regulatory authorities and
becoming available worldwide. The emergence and prompt
acceptance of incretin-based therapies: dipeptidyl peptidase 4
(DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor
agonists [6], and sodium-glucose co-transporter 2 (SGLT2) inhi-
bitors is a validation of this evidence-based pharmacological
treatment selection.
2. Glucose-lowering therapy: general review
With a follow-up of >66,000 person-years of patients with
T2DM, the UK Prospective Diabetes Study (UKPDS) exhibited
that, even after 10 years post-termination of randomized inter-
ventions, benefits of an intensive strategy to control blood
glucose levels continued to persist. Benefits in the post-trial
period persisted regardless of the so-called legacy effect, i.e.
initial loss of within-trial differences in levels of glycated
hemoglobin in the interventional phase between the conven-
tional-therapy group and intensive-therapy group [7].
A significant reduction of 25% in the risk of microvascular
disease observed during the interventional period in patients

CONTACT Kamlesh Khunti kk22@le.ac.uk Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, University of Leicester, Leicester
LE5 4PW, UK
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 K. KHUNTI ET AL.
Article Highlights
● Early initiated and long-term sustained intensive glucose control is
associated with a significantly decreased risk of cardiovascular events
and all-cause mortality, over and above the well-established decline
in the risk of microvascular disease.
● SGLT2 inhibitors or GLP-1 receptor agonists should be the drugs of
choice in people with CVD; SGLT2 inhibitor should be the preferred
glucose-lowering drug in the presence of heart failure or chronic
kidney disease.
● These drug classes safely reduce glycated hemoglobin with few or no
hypoglycemic episodes, particularly if not combined with insulin or
sulphonylureas.
● Macrovascular events such as myocardial infarction and stroke, risk of
hospitalization due to heart failure or unstable angina pectoris, and
progression of renal disease are consistently lowered with SGLT2
inhibitors, across a broad spectrum of people with T2DM.
● The long-acting GLP-1 receptor agonists, viz. liraglutide, exenatide
long-acting release, albiglutide, and semaglutide, demonstrated con-
sistent reduction in 3-point MACE.
in the intensive-therapy group persisted throughout the post-
trial period among patients in the sulphonylurea–insulin
group; in spite of the rapid convergence of glycated hemo-
globin (HbA1c) levels in the groups and a similar use of
glucose-lowering therapies, the decline in the risk of any
diabetes-related end point also persisted. Clinically relevant
post-trial risk reductions appeared over time for myocardial
infarction (MI) (15%; p = 0.01) and death from any cause (13%;
p = 0.007), even though differences during the interventional
phase of the trial were not significant [8].
Even though the UKPDS revealed the advantage of
improved glycemic control in decreasing the risk of microvas-
cular disease, only extended post-trial follow-up revealed risk
reductions for MI and death from any cause [7].
3. CVOTS: safety driven with demonstrated
atherosclerotic cardiovascular disease (ASCVD)
outcome benefit
3.1. Regulatory status
3.1.1. US Food and Drug Administration
Since 2008, the US Food and Drug Administration (FDA) has
mandated new diabetes drugs to establish cardiovascular safety,
ensuing large and lengthy clinical trials. As per the new regula-
tions, the newer glucose-lowering therapies such as SGLT2 inhi-
bitors, DPP-4 inhibitors, insulin degludec and GLP-1 receptor
agonists have validated cardiovascular safety, with some
Table 1. Characteristics of an ideal glucose-lowering agent.
Efficacy Durability Safety
● Reduces plasma glucose/ ● Sustained effect ● Decreased or no
glycated hemoglobin over time hypoglycemic episodes
● Reduces weight ● Prevents/delays ● Good safety profile
● Reduces macrovascular complications
long-term risk
● Reduces microvascular
long-term risk
representing superior cardiovascular efficacy. In 2016, empagli-
flozin, an SGLT2i, came to be the first FDA approved diabetes
drug for a clinical outcome indication, i.e. to decrease the risk of
cardiovascular death based on data from EMPA-REG trial [9].
In addition to major adverse cardiovascular events (MACE)
defined as cardiovascular death, stroke, and non-fatal MI (3-point
MACE) in T2DM, heart failure is an outcome that can no longer be
ignored. Observational studies and clinical trials have shown the
occurrence of heart failure to be associated with a poor subse-
quent cardiovascular prognosis. Two major outcome trials with
rosiglitazone (RECORD) and pioglitazone (PROACTIVE) identified
a significant increase in risk of heart failure. Consequently, in
addition to the primary composite outcome of MACE, heart fail-
ure should be assessed whenever a cardiovascular outcome trial
(CVOT; either pre-authorization regulatory authority mandated
or post-authorization safety assessment) for a glucose-lowering
drug is deemed obligatory, subject to the safety signals identified
in former developmental phases [10].
Valuable information on adverse events, inclusive of a signal
for congestive heart failure with DPP-4 inhibitors saxagliptin and
alogliptin and an observed increased risk for lower-limb amputa-
tions with SGLT2 inhibitors have been acquired [11].
3.1.2. European Medicines Agency
With reference to cardiovascular safety, the European
Medicines Agency states that, in addition to 3-point MACE,
hospitalization for unstable angina (4-point MACE) may possi-
bly be added as a composite endpoint, when the main objec-
tive is to eliminate a safety signal. It is imperative to make
certain that they are adjudicated events, apart from assess-
ment of other events like worsening of heart failure and/or
revascularization. Other safety outcomes, such as malignan-
cies, need to be selected depending on the mechanism of
action of the investigational drug, known safety profile of the
product class, and/or the non-clinical findings.
Supplementary variables like edema/fluid retention,
increase in body weight, and existence of arrhythmia and
hypertension must also be collected systematically. In case of
an indication of a detrimental effect on cardiac function, there
is a need to evaluate clinically relevant changes in cardiac
function (e.g. using echocardiography) [12].
4. Overview for the various classes
This section summarizes the major CVOTs conducted till date
for these class of drugs compared to placebo. Each trial
Utility Adherence to treatment
● Understandable mode of action ● Simple to administer/good
● Suitable for use at all stages of diabetes concordance
● Suitable across a range of individuals with ● Suitable for use in combina-
a range of comorbidities tion with other agents
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
validated the non-inferiority of their respective agents in their
MACE primary composite end point to placebo (Figure 1).
4.1. Metformin
Universally, metformin is the most prescribed first-line glu-
cose-lowering agent. However, there have been conflicting
findings of the efficacy of metformin in lowering the risk of
cardiovascular complications [13,14].
One meta-analysis of randomized-controlled trials evalu-
ated metformin effects in T2DM patients on cardiovascular
morbidity or mortality as primary outcomes, secondary out-
comes, or adverse events in 13,110 patients with T2DM.
Treatment with metformin did not have a significant effect
on primary outcomes of cardiovascular mortality (Relative risk
[RR], 1.05; 95% CI, 0.67–1.64), and all-cause mortality (RR, 0.99;
95% CI, 0.75–1.31). Additionally, metformin did not affect
secondary outcomes of heart failure, all myocardial infarctions,
all strokes, peripheral vascular disease, leg amputations, and
microvascular complications. The authors concluded that
a 25% reduction or a 31% increase in all-cause mortality, and
a 33% reduction or a 64% increase in cardiovascular mortality
cannot be excluded [14].
Another meta-analysis by Griffin SJ et al. evaluated 2,079
T2DM patients from 13 trials (including the extended follow-
up data from the UKPDS) treated with metformin. The authors
found no statistically significant effect of metformin on risk of
cardiovascular death, all-cause mortality, MI, and stroke (RR,
1.04; 95% CI, 0.73–1.48; χ2 = 0.36; I2 = 0%; p = 0.84) [15].
There continues to remain an uncertainty whether metfor-
min, as first-line therapy in patients with T2DM, lowers CVD
risk particularly with recent data from CVOTs of SGLT2 inhibi-
tors and GLP-1 receptor agonists [16].
4.2. Sulphonylureas
In 2017, the pragmatic trial TOSCA.IT assessed the effects of
the addition of pioglitazone vs. sulphonylureas on the
Figure 1. Timeline representing cardiovascular outcome trials conducted within the newer classes of glucose-lowering agents.
3
incidence of cardiovascular events in patients with T2DM
inadequately controlled with metformin (2–3 g/day). Three
thousand twenty-eight patients were randomly assigned in
a 1:1 ratio, stratified by site and previous cardiovascular events
(noted in 11% individuals at baseline), to add-on pioglitazone
(15–45 mg) or a sulphonylurea (5–15 mg glibenclamide,
2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance
with local practice). The study was terminated early on the
basis of a futility analysis after a median follow-up of
57.3 months. There was no significant difference in the pri-
mary outcome of a composite of first occurrence of all-cause
death, non-fatal MI, non-fatal stroke, or urgent coronary revas-
cularization in those administered sulphonylureas (Hazard
ratio [HR], 0.96; 95% CI, 0.74–1.26, p = 0.79) compared to
those given pioglitazone. Hypoglycemias occurred in fewer
patients in the pioglitazone group than in the sulphonylureas
group (10% vs. 34%; p < 0.0001). Rates of heart failure, bladder
cancer, and fractures were not significantly different between
treatment groups. The TOSCA.IT trial reported a similar inci-
dence of cardiovascular events with sulphonylureas (mostly
glimepiride and gliclazide) and pioglitazone as add-on treat-
ments to metformin. The authors concluded both these widely
available and affordable treatments to be suitable options
with respect to efficacy and adverse events, although piogli-
tazone was associated with fewer hypoglycemia events [17].
The CARdiovascular Outcome Trial of LINAgliptin Versus
Glimepiride in Type 2 Diabetes (CAROLINA) trial was
a multicenter, randomized, double-blind, active-controlled trial
designed to evaluate the effect of linagliptin compared with
glimepiride, in addition to standard of care, on cardiovascular
events in adults with relatively early T2DM at increased cardiovas-
cular risk or established cardiovascular complications and less than
optimized glycemic control [18]. The results of this trial were
recently presented in the latest ADA meet. A total of 6,033 patients
were randomly assigned to receive either linagliptin 5 mg
(n = 3,023), or glimepiride 1–4 mg (n = 3,010), for a median
duration of 6.3 years. For the primary composite outcome
of 3-point MACE, a HR of 0.98 (95% CI, 0.84–1.14; p < 0.0001 for
4 K. KHUNTI ET AL.
non-inferiority) was noted, while that for the 4-point MACE was
0.99 (95% CI, 0.86–1.14). In terms of HbA1c, there was no overall
difference between the groups, while an average between-group
difference in weight of – 1.5 kg (95% CI, –1.8 to –1.3) favoring
linagliptin was noted. There were significantly lesser ≥1 investiga-
tor-reported episodes of hypoglycemia (10.6% vs. 37.7%; HR, 0.23;
95% CI, 0.21–0.26) reported with linagliptin than glimepiride. The
CAROLINA trial helped resolve the decades-long uncertainty on
the cardiovascular safety of sulphonylureas, particularly glimepir-
ide, with no difference seen in the incidence of cardiovascular
events compared with linagliptin [19].
Sulphonylureas have been associated with good efficacy as
well as durability, without excessive weight gain. The newer
generations of sulphonylureas additionally appear to have
reduced episodes of hypoglycemia; their favorable ratio of cost,
efficacy, and safety confers them affordable for most health-care
economies. However, sulphonylureas can be considered an
essential part of diabetes therapy when not crucial to add
a drug with proven cardiovascular prevention properties [20].
4.3. Thiazolidinediones (TZDs)
The CVOTs evaluating TZDs included the PROspective
pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE
Study) (2005), and Rosiglitazone Evaluated for Cardiac Outcomes
and Regulation of glycemia in Diabetes (RECORD) (2009).
The PROACTIVE study evaluated oral pioglitazone, titrated
from 15 mg to 45 mg or matching placebo, in addition to
glucose-lowering drugs and other medications, in 5238
patients with T2DM with evidence of macrovascular disease
(48% had ≥2 macrovascular disease criteria, defined as MI or
stroke at least 6 months before entry, percutaneous coronary
intervention or coronary artery bypass surgery at least
6 months before recruitment, acute coronary syndrome at
least 3 months before recruitment, or objective evidence of
coronary artery disease or obstructive arterial disease in the
leg) to ascertain whether pioglitazone reduces macrovascular
morbidity and mortality in high-risk patients with T2DM. The
mean follow-up duration was 34.5 months. A total of 514 out
of 2605 patients in the pioglitazone group and 572 out of
2633 patients in the placebo group had at least one event in
the primary composite endpoint defined as time from rando-
mization to: all-cause mortality, non-fatal MI (including silent
MI), stroke, acute coronary syndrome, endovascular or surgical
intervention on the coronary or leg arteries, or amputation
above the ankle (HR, 0.90; 95% CI, 0.80–1.02, p = 0.095).
A consistency of benefit across the endpoints of MI (HR, 0.83;
95% CI, 0.65–1.06), stroke (HR, 0.81; 95% CI, 0.61–1.07), acute
coronary syndrome (HR, 0.78; 95% CI, 0.55–1.11), and coronary
revascularization (HR, 0.88; 95% CI, 0.72–1.08) was observed.
A statistically significant reduction was noted with pioglita-
zone with the main secondary composite endpoint of all-
cause mortality, non-fatal MI, and stroke (301 events vs. 358
events with placebo; HR, 0.84, 95% CI, 0.72–0.98; p = 0.027).
Despite the rise in reported heart failure in the pioglitazone
group (417 events vs. 302 events in the placebo group;
p < 0.0001), the number of deaths from heart failure was
similar in each group (25 vs. 22; p = 0.634) [21].
In the RECORD study, 4,447 patients with T2DM on metformin
or sulphonylurea monotherapy with mean HbA1c of 7.9% were
randomly assigned to addition of rosiglitazone or to a combination
of metformin and sulphonylurea (active control), to evaluate car-
diovascular outcomes after addition of rosiglitazone to either met-
formin or sulphonylurea compared with the combination of the
two over a mean period of 5.5 years. The primary outcome for
cardiovascular death or cardiovascular hospitalization occurred in
321 people in the rosiglitazone group and 323 in the active control
group (HR, 0.99; 95% CI, 0.85–1.16; p = 0.93). There was no sig-
nificant difference for cardiovascular death (HR, 0.84; 95% CI, 0.-
59–1.18), MI (HR, 1.14; 95% CI, 0.80–1.63), and stroke (HR, 0.72; 95%
CI, 0.49–1.06). However, there was a significant increase in the rate
of heart failure causing admission to hospital or death with rosigli-
tazone (61 vs. 29; HR, 2.10; 95% CI, 1.35–3.27; p = 0.0010) compared
to the active control group. Rosiglitazone was associated with
increased rates of upper (risk ratio [RR], 1.57; 95% CI, 1.12–2.19;
p = 0.0095) and distal (RR, 2.60; 95% CI, 1.67–4.04; p < 0.001) lower
limb fracture particularly in women (RR, 1.75 upper limb, 2.93 distal
lower limb). The results of the RECORD study demonstrated that
the addition of rosiglitazone to glucose-lowering therapy in people
with T2DM is confirmed to increase the risk of heart failure and
some fractures, mainly in women. Although inconclusive about
any possible effect on MI, rosiglitazone does not seem to increase
the risk of overall cardiovascular morbidity or mortality compared
with standard glucose-lowering drugs [22,23].
Even though a causal role for rosiglitazone in terms of CVD
continues to be controversial, rosiglitazone should be used as
a last-line glucose-lowering agent or avoided in patients with
or at risk for CVD (considering the broad choice of anti-
hyperglycemic therapies).
4.4. Insulin degludec
Marso et al. conducted a Trial Comparing Cardiovascular
Safety of Insulin Degludec versus Insulin Glargine in Patients
with Type 2 Diabetes at High Risk of Cardiovascular Events
(DEVOTE) to assess the cardiovascular safety of degludec.
A total of 7,637 patients with T2DM (85.2% of whom had
established CVD, CKD, or both) were randomly assigned to
receive either insulin degludec or insulin glargine U100 once
daily between dinner and bedtime. A significantly lower rate
of the primary composite outcome of 3-point MACE was
observed with degludec (8.5% vs. 9.3% with glargine; HR,
0.91; 95% CI, 0.78–1.06; p< 0.001 for non-inferiority).
However, there was no difference between the groups in
terms of the expanded composite cardiovascular outcome
defined as the primary composite outcome or unstable angina
leading to hospitalization (10.1% vs. 11%; HR, 0.92; 95% CI,
0.80–1.05; p = 0.22). In people with T2DM at high risk for
cardiovascular events, the DEVOTE trial demonstrated the
non-inferiority of degludec compared to glargine with respect
to the incidence of MACE [24].
4.5. DPP-4 inhibitors
The CVOTs evaluating DPP-4 inhibitors comprised of the
Saxagliptin Assessment of Vascular Outcomes Recorded in
Patients with Diabetes Mellitus – Thrombolysis in Myocardial
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
Infarction 53 (SAVOR-TIMI 53) (2013), the Examination of
Cardiovascular Outcomes with Alogliptin versus Standard of
Care (EXAMINE) (2013), Trial Evaluating Cardiovascular
Outcomes with Sitagliptin (TECOS) (2015), and Cardiovascular
and Renal Microvascular Outcome Study With Linagliptin
(CARMELINA) (2018).
In the SAVOR-TIMI 53 study, 16,492 patients with T2DM
(with either a history of or those at risk for cardiovascular
events) were randomly assigned to receive 5 mg saxagliptin
daily (or 2.5 mg in patients with an estimated glomerular
filtration rate [GFR] of ≤50 mL/min) or placebo over
a median follow-up period of 2.1 years. A primary endpoint
of 3-point MACE was similar with saxagliptin as placebo (7.3%
vs. 7.2%; HR, 1.00; 95% CI, 0.89–1.12; p for superiority = 0.99;
p for non-inferiority < 0.001). There was a significant increase
in the risk of heart failure with saxagliptin (3.5% vs 2.8%; HR,
1.27; 95% CI, 1.07–1.51; p = 0.007) compared to placebo. The
major secondary endpoint events of cardiovascular death,
nonfatal MI, nonfatal ischemic stroke, hospitalization for
unstable angina or heart failure, coronary revascularization,
occurred in 12.8% patients treated with saxagliptin compared
to 12.4% patients treated with placebo. Results of the SAVOR-
TIMI 53 showed no increase or decrease in the rate of ischemic
events, despite a rise in the rate of hospitalization for heart
failure with saxagliptin [25].
The EXAMINE study randomly assigned 5,380 patients with
T2DM, and either an acute MI or unstable angina requiring
hospitalization within the previous 15–90 days, to receive
alogliptin (25 mg in patients with an estimated glomerular
filtration rate [eGFR] of at least 60 mL/min/1.73 m2, 12.5 mg
in patients with an eGFR of 30 to <60 mL/min/1.73 m2 and
6.25 mg in those with an eGFR of <30 mL/min/1.73 m2), or
placebo, apart from the existing anti-hyperglycemic and car-
diovascular drug therapy. The patients were followed-up for
a median of 18 months. The primary 3-point outcome of MACE
occurred in 11.3% patients assigned to alogliptin vs. 11.8%
patients assigned to placebo (HR, 0.96; upper boundary of
one-sided repeated CI, ≤1.16; p for non-inferiority < 0.001).
Though not statistically significant, there was a reduction in
the death from cardiovascular causes and all-cause mortality
with alogliptin compared to placebo. The EXAMINE trial
revealed no increase in MACE with alogliptin, compared to
placebo, in patients with T2DM and a recent acute coronary
syndrome [26].
In the TECOS study, 14,671 patients were randomly
assigned to treatment with either sitagliptin at a dose of
100 mg daily (or 50 mg daily if baseline eGFR was ≥30 and
<50 mL/min/1.73 m2) or placebo and followed up for median
3.0 years. For the primary composite 4-point MACE (HR in the
per-protocol analysis, 0.98; 95% CI, 0.88–1.09; p < 0.001; HR in
the intention-to-treat analysis, 0.98; 95% CI, 0.89–1.08; p = 0.65
for superiority) treatment with sitagliptin was non-inferior to
placebo. There was no difference in the rate of hospitalization
due to heart failure, death due to cardiovascular causes and
all-cause mortality between sitagliptin and placebo. Though
uncommon, acute pancreatitis occurred more frequently in
the sitagliptin group (HR in the per-protocol analysis, 1.80;
95% CI, 0.86–3.76; p = 0.12; HR in the intention-to-treat ana-
lysis, 1.93; 95% CI, 0.96–3.88; p = 0.07), but the difference was
5
not significant. In patients with T2DM and established CVD,
addition of sitagliptin did not result in any significant effect on
MACE or hospitalization for heart failure [27].
The CARMELINA study assessed 6,979 patients with T2DM
and high cardiovascular and renal risk treated with either 5 mg
linagliptin once daily or placebo over a median of 2.2 years. The
primary outcome of 3-point MACE was similar with linagliptin
(12.4% vs. 12.1%; HR, 1.02; 95% CI, 0.89–1.17; p for non-
inferiority < 0.001, p for superiority = 0.74), compared to placebo.
There was no difference in the secondary kidney composite
outcome (sustained end-stage renal disease [ESRD], death due
to kidney failure, or sustained decrease of ≥40% in eGFR from
baseline) among the groups. Linagliptin showed a reduction in
albuminuria progression (35.3 vs. 38.5; HR, 0.86; 95% CI, 0.78–-
0.95; p = 0.003) and composite microvascular endpoint of time to
first ESRD, death due to renal failure, sustained decrease of at
least 50% in eGFR, albuminuria progression, retinal photocoagu-
lation, anti–vascular endothelial growth factor injection therapy
for diabetic retinopathy, vitreous hemorrhage, and diabetes-
related blindness (36.3 vs. 39.6; HR, 0.86; 95% CI, 0.78–0.95;
p = 0.003). These microvascular complications can be explained
by the reduction in albumin excretion. No significant difference
with linagliptin in the rate of death due to any cause, cardiovas-
cular death, hospitalization for unstable angina, coronary revas-
cularization, and hospitalization for heart failure compared to
placebo was noted. There were 9 (0.3%) events with linagliptin
vs 5 (0.1%) events with placebo of adjudication-confirmed acute
pancreatitis. The CARMELINA trial demonstrated a non-inferior
risk of a composite cardiovascular outcome with linagliptin com-
pared to placebo in T2DM patients with high cardiovascular and
renal risk [28].
Though these CVOTs demonstrated consistent results of no
major harm, there seemed to be no cardiovascular benefit for
DPP-4 inhibitors. Progression of albuminuria was the most
prevalent component of the composite renal endpoint,
whereas the other components (doubling of serum creatinine,
ESRD or renal death) did not contribute substantially to the
benefit. In the DPP-4 inhibitors CVOTs, the DPP-4 inhibitors
have been shown to be safe from a renal perspective, with
modest reduction in albuminuria [29].
4.6. SGLT2 inhibitors
The three CVOTs completed till date for SGLT2 inhibitor are
Empagliflozin, Cardiovascular Outcome Event Trial in T2DM
Patients (EMPA-REG OUTCOME) study with empagliflozin (2015),
Canagliflozin Cardiovascular Assessment Study (CANVAS) with
canagliflozin (2017) and Dapagliflozin Effect on Cardiovascular
Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI
58) with dapagliflozin (2018).
In the EMPA-REG OUTCOME study, the SGLT2 inhibitor empa-
gliflozin, in dose of either 10 mg or 25 mg once daily was
compared with placebo in 7020 patients with T2DM and estab-
lished CVD. Patients were followed for a median of 3.1 years.
Compared to placebo, empagliflozin reduced the 3-point MACE
(12.1% vs. 10.5%; HR, 0.86; 95% CI, 0.74–0.99; p < 0.001 for non-
inferiority; p = 0.04 superiority), and the 4-point MACE (14.3% vs.
12.8%; HR, 0.89; 95% CI, 0.78–1.01; p < 0.001 for non-inferiority;
p = 0.08 for superiority). There was lower incidence of
6 K. KHUNTI ET AL.
cardiovascular mortality (3.7% vs. 5.9%; HR, 0.62; 95% CI, 0.49–-
0.77; p < 0.001), all-cause mortality (5.7% vs. 8.3%; HR, 0.68; 95%
CI, 0.57–0.82; p < 0.001), and hospitalization for heart failure
(2.7% vs. 4.1%; HR, 0.65; 95% CI, 0.50–0.85; p = 0.002) observed
with empagliflozin compared with placebo. An important aspect
of empagliflozin to be considered in clinical practice was that
a statistically higher percentage of genital infection among both
males and females was reported in the pooled empagliflozin
group (6.4% vs. 1.8%; p < 0.001). Thus, the EMPA-REG
OUTCOME study found that treatment with empagliflozin in
patients with T2DM at high risk for cardiovascular events resulted
in an unprecedented 38% lower incidence of cardiovascular
mortality, 35% lower incidence of hospitalization due to heart
failure, 32% lower incidence of death from any cause, and 14%
lower rate of the primary composite cardiovascular outcome as
compared to placebo [30].
Altered hemodynamics and diuretic effects might probably
be accountable for the reductions in cardiovascular mortality
in the EMPA-REG OUTCOME trial that ensued within the initial
few months of treatment. Reductions in blood pressure with-
out an increase in heart rate and weight loss may perhaps
exert added early cardiovascular benefits that are not reliant
of glycemic control [31]. Patients with heart failure with mod-
est as well as superior HbA1c reductions benefited equally
from empagliflozin suggesting glycemic control to not be
completely responsible [32]. Empagliflozin demonstrated an
HR of 0.61 (95% CI, 0.53–0.70) for the composite outcome of
new or worsening nephropathy (progression to urine albumin/
creatinine ratio >33.9 mg/mmoL [>300 mg/g], doubling of
serum creatinine and ESRD, or death by ESRD). Compared
with placebo, the most prevalent effect was on the develop-
ment of sustained albuminuria, but the other components
were each significantly reduced [33].
The CANVAS Program compared canagliflozin with placebo
(included two similar trials, CANVAS and CANVAS-Renal;
n = 10,142) in patients with T2DM who had a history of symp-
tomatic ASCVD or were at elevated risk. Participants in the
CANVAS received either canagliflozin 300 mg, canagliflozin
100 mg, or matching placebo, while those in CANVAS-R
received an initial dose of canagliflozin 100 mg daily with an
optional increase to 300 mg starting from week 13, or matching
placebo. The median follow-up duration was 3.6 years. Results
from the combined analysis of these trials as well as the indivi-
dual studies demonstrated a reduction in the primary compo-
site endpoint of 3-point MACE (in terms of participants/1000
patient-year) with canagliflozin (26.9 vs 31.5; HR, 0.86; 95% CI,
0.75–0.97; p = 0.02) compared to placebo. There was a signifi-
cant reduction in the rates of hospitalization for heart failure
(5.5 vs. 8.7; HR, 0.67; 95% CI, 0.52–0.87). Although there were
lower rates of death due to cardiovascular causes (11.6 vs. 12.8;
HR, 0.87; 95% CI, 0.72–1.06), and all-cause mortality (17.3 vs.
19.5; HR, 0.87; 95% CI, 0.74–1.01), with canagliflozin as com-
pared to placebo, they were not statistically significant. The
results showed a possible benefit of canagliflozin with respect
to the composite outcome of a sustained 40% reduction in risk
in eGFR, ESRD, or renal death (5.5 vs 9.0; HR, 0.60; 95% CI,
0.47–0.77). Among those treated with canagliflozin, progression
of albuminuria occurred less frequently (89.4 vs. 128.7; HR, 0.73;
95% CI, 0.67–0.79) compared to placebo, with greater effects
seen in CANVAS-R (HR, 0.64; 95% CI, 0.57–0.73) than in CANVAS
(HR, 0.80; 95% CI, 0.72−0.90) (p for homogeneity = 0.02).
Adverse reactions recorded with canagliflozin were found to
be consistent with those reported previously apart from an
amplified risk of amputation, mostly at the level of the toe or
metatarsal, as compared with placebo. There was an increase in
the rate of all fractures with canagliflozin (HR, 1.26; 95% CI,
1.04–1.52) than with placebo; a similar trend was seen in low-
trauma fracture events (HR, 1.23; 95% CI, 0.99−1.52) [34].
The Canagliflozin and Renal Endpoints in Diabetes with
Established Nephropathy Clinical Evaluation (CREDENCE) trial
evaluated 100 mg oral dose of canagliflozin once daily in 4,401
people with chronic kidney disease (CKD) with proteinuria for
primary composite outcomes of end-stage kidney disease, dou-
bling of serum creatinine level, or death from renal or cardiovas-
cular causes for a median follow-up period of 2.62 years. On the
recommendation of the data and safety monitoring committee,
the trial was stopped early after a planned interim analysis. The
primary outcome occurred in 43.2 events/1000 patients-years in
the canagliflozin group as compared to 61.2 events/1000
patients-years in the placebo group (HR, 0.70; 95% CI, 0.59–0.82;
p < 0.0001). Canagliflozin group had lower cardiovascular deaths
than placebo (19.0 vs. 24.4; HR, 0.78; 95% CI, 0.61–1.0; p = 0.05).
The rate of end-stage kidney disease, doubling of serum creati-
nine level, or renal death was comparatively lower with canagli-
flozin (27 vs. 40.4; HR, 0.66; 95% CI, 0.53–0.81; p < 0.0001)
compared to placebo. Canagliflozin lowered the risk of kidney
failure and cardiovascular events in patients with T2DM and CKD
compared with placebo [35,36].
The DECLARE-TIMI 58 was a randomized, double-blind, pla-
cebo-controlled trial designed to assess the SGLT2 inhibitor
dapagliflozin (10 mg daily) for cardiovascular safety/efficacy. Of
the 17,160 T2DM patients included, 41% had established CVD
and the remaining were at a high-risk for CVD; the cohort eval-
uated in DECLARE-TIMI 58 included patients without established
CVD, which was quite different from the other CVOTs that mostly
included people with established CVD. Overall, though there was
no reduction in the combined MACE outcome on adding dapa-
gliflozin (8.8% vs. 9.4%; HR, 0.93; 95% CI, 0.84–1.03; p = 0.17 for
superiority; p < 0.001 for non-inferiority), a statistically significant
reduction in the co-primary outcome of hospitalization for heart
failure or cardiovascular death (4.9% vs. 5.8%; HR, 0.83; 95% CI,
0.73–0.95; p for superiority = 0.005) was observed in favor of
dapagliflozin. This was principally driven by a lower rate of
hospitalization due to heart failure with no difference in the
rate of cardiovascular death between the groups. Among
patients with established ASCVD, the rate of MACE was 13.9%
and 15.3% in the dapagliflozin and placebo groups, while that
among those with multiple risk factors for ASCVD were 5.3% and
5.2%, respectively. The findings from the DECLARE-TIMI 58 study
showed a lower rate of cardiovascular death or hospitalization
for heart failure in patients with T2DM who had or were at risk for
ASCVD treated with dapagliflozin, though there was no signifi-
cant reduction in MACE as compared to placebo [37,38]. There
seemed to be a greater benefit for MACE within 2 years after last
acute event (p-interaction trend = 0.007). The relative risk reduc-
tions in cardiovascular death or hospitalization due to heart fail-
ure were more similar, but the absolute risk reductions tended to
be greater: 1.9% (8.6% vs. 10.5%; HR, 0.81; 95% CI, 0.65–1.00;
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
p = 0.046) in patients with prior MI compared to 0.6% (3.9% vs.
4.5%; HR, 0.85; 95% CI, 0.72–1.00; p= 0.055) in patients without
prior MI [39].
Recently, a systematic review and meta-analysis of rando-
mized, placebo-controlled, CVOTs of SGLT2 inhibitors in
patients with T2DM was performed. This included data
from the above-mentioned three trials involving 34,322
patients (60.2% of whom had established ASCVD), with
3342 MACE, 2028 cardiovascular deaths or hospitalizations
for heart failure events, and 766 renal composite outcomes.
SGLT2 inhibitors demonstrated 11% reduction in MACE (HR,
0.89; 95% CI, 0.83–0.96; p = 0.0014), with benefit recorded
only in people with ASCVD (HR, 0.86; 95% CI, 0.80–0.93) as
compared to those without ASCVD (HR, 1.00; 95% CI, 0.87–-
1.16; p = 0.0501). There was also a 23% reduction in the risk
of hospitalization for heart failure or cardiovascular death
(HR, 0.77; 95% CI, 0.71–0.84; p < 0.0001), with similar bene-
fits seen in those with and without a history of heart failure
and in patients with and without ASCVD. Moreover, a 45%
reduction in the risk of progression of renal disease (HR,
0.55; 95% CI, 0.48–0.64; p < 0.0001), with similar benefits in
those with and without ASCVD, was observed with SGLT2
inhibitors. Nevertheless, the extent of SGLT2 inhibitors ben-
efits varied according to the baseline renal function, with
larger reductions in hospitalizations for heart failure (p for
interaction = 0.0073) and lesser reductions in progression of
renal disease (p for interaction = 0.0258) among those with
more severe kidney disease at baseline. The authors con-
cluded SGLT2 inhibitors to have moderate benefits on ather-
osclerotic MACE in patients with established ASCVD, and
robust benefits on decreasing progression of renal disease
and hospitalization for heart failure regardless of existing
ASCVD or a history of heart failure [40].
SGLT2 inhibitors target different pathophysiological path-
ways in heart failure. The substantial decline in hospitalization
for heart failure shown in the CVOTs suggests that, in the
setting of clinical heart failure, treatment with SGLT2 inhibitors
might provide substantial benefit and must be specially con-
sidered in patients with T2DM and ASCVD and/or heart failure.
The renoprotective effects of SGLT2 inhibitors` in addition to
the induced natriuresis could elucidate the reduction in hos-
pitalization for heart failure.
4.7. GLP-1 receptor agonists
The CVOTs conducted for GLP-1 receptor agonists included
Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA)
study (2015), Liraglutide Effect and Action in Diabetes:
Evaluation of Cardiovascular Outcomes Results (LEADER) trial
(2016), Trial to Evaluate Cardiovascular and Other Long-term
Outcomes with Semaglutide in Subjects with Type 2 Diabetes
(SUSTAIN 6), Exenatide Study of Cardiovascular Event
Lowering (EXSCEL) study (2017), and Albiglutide and cardio-
vascular outcomes in patients with type 2 diabetes and cardi-
ovascular disease (Harmony Outcomes) (2018).
In the ELIXA study, T2DM patients (n = 6,068) with history
of MI or who had been hospitalized for unstable angina within
the previous 180 days were randomly assigned to once daily
lixisenatide starting dose of 10 μg/day or volume-matched
7
placebo during the first 2 weeks and then increased to a max-
imum dose of 20 μg/day or volume-matched placebo (at the
investigator’s discretion), apart from the usual standards of
care. Lixisenatide was found to be non-inferior to placebo for
the primary composite outcomes of death from cardiovascular
causes, nonfatal stroke, nonfatal MI, or unstable angina (13.4%
vs. 13.2%; adjusted HR, 1.02; 95% CI, 0.89–1.17; p = 0.81). No
evidence of an increase in the risk of heart failure events (4.0
vs. 4.2; adjusted HR, 0.96; 95% CI, 0.75–1.23; p = 0.75) and
death from any cause (7.0 vs. 7.4; adjusted HR, 0.94; 95% CI,
0.78–1.13; p = 0.50) was noted. Consequently, lixisenatide
administered within 180 days of an acute coronary syndrome
admission did not demonstrate CVD benefit or harm in T2DM
patients compared to placebo [41].
The LEADER trial evaluated 9,340 patients with T2DM with
CVD or high cardiovascular risk (of which 81.3% had estab-
lished CVD) to randomly assigned 1.8 mg (or maximum toler-
ated dose) liraglutide and placebo groups, once daily as
a subcutaneous injection, in addition to standard care.
Liraglutide revealed a statistically significant lower incidence
of the primary composite outcome of 3-point MACE (13% vs.
14.9%; HR, 0.87; 95% CI, 0.78–0.97; p for superiority = 0.01) and
expanded composite outcome of death from cardiovascular
causes, nonfatal MI, nonfatal stroke, coronary revasculariza-
tion, or hospitalization for unstable angina pectoris or heart
failure (20.3 vs. 22.7; HR, 0.88; 95% CI, 0.81–0.96; p = 0.005)
compared to placebo over a follow-up duration of 3.8 years.
There was a statistically significant reduction in the rate of
death due to cardiovascular events (4.7% vs. 6.0%; HR, 0.78;
95% CI, 0.66–0.93; p = 0.007) and all-cause mortality (8.2% vs.
9.6%; HR, 0.85; 95% CI, 0.74–0.97; p = 0.02) with liraglutide
compared to placebo. Though not statistically significant,
there was a decline in the events of hospitalization for
unstable angina pectoris and hospitalization for heart failure.
Moreover, liraglutide demonstrated a significantly lower rate
of nephropathy events, defined as new onset of macroalbu-
minuria or doubling of serum creatinine level and an eGFR of
≤45 mL/min/1.73 m2, the need for continuous renal-
replacement therapy, or death from renal disease (5.7% vs.
7.2%; HR, 0.78; 95% CI, 0.67–0.92; p = 0.003) compared to
placebo; the plausible explanation for this being a reduction
in albuminuria unlike the outcome seen with SGLT2 inhibitors.
With reference to the significant adverse events, acute gall-
stone disease was found to be more common with liraglutide
than with placebo (3.1% vs. 1.9%; p < 0.001); pancreatic carci-
noma was not statistically increased (0.3% vs. 0.1%; p = 0.06).
Conclusively, among patients with T2DM and high cardiovas-
cular risk, the LEADER trial showed lower MACE with liraglu-
tide when compared to placebo [42].
The SUSTAIN 6 trial compared 3,297 T2DM patients (83% of
which had established CVD, CKD, or both) who were randomly
assigned to receive either 0.5 mg or 1.0 mg of once-weekly
subcutaneous semaglutide or volume-matched placebo over
104 weeks. The primary composite outcome of 3-point MACE
was lower in the semaglutide group (6.6% vs. 8.9%; HR, 0.74; 95%
CI, 0.58–0.95; p for non-inferiority < 0.001, p for superiority = 0.02
[not pre-specified]) compared to placebo; the reduction in MACE
seemed to be a result of the decline in the rate of stroke, rather
than CVD death. The expanded composite outcome of 5-point
8 K. KHUNTI ET AL.
MACE (death from cardiovascular causes, nonfatal MI, nonfatal
stroke, revascularization [coronary or peripheral], and hospitali-
zation for unstable angina or heart failure) was significantly lower
with semaglutide (12.0 vs. 16.0; HR, 0.74; 95% CI, 0.62–0.89;
p = 0.0002). Analogous rates of death from cardiovascular causes,
hospitalization for unstable angina pectoris, hospitalization for
heart failure, and all-cause mortality were recorded in those
administered either semaglutide or placebo. A lower rate of
revascularization was noted with semaglutide (5.0% vs. 7.6%;
HR, 0.65; 95% CI, 0.50–0.86; p = 0.0003) compared to placebo.
Among those treated with semaglutide, a significantly lower rate
of new or worsening nephropathy was seen (3.8% vs. 6.1%; HR,
0.64; 95% CI, 0.46–0.88; p = 0.0005). However, the rate of retino-
pathy complications (including vitreous hemorrhage, onset of
diabetes-related blindness, and the need for treatment with an
intravitreal agent or retinal photocoagulation) were significantly
higher (3.0% vs. 1.8%; HR, 1.76; 95% CI, 1.11–2.78; p = 0.02) with
semaglutide when compared to placebo; 83.5% patients of
which had preexisting retinopathy at baseline. The SUSTAIN 6
CVOT demonstrated the non-inferiority of semaglutide with pla-
cebo in patients with T2DM who were at high cardiovascular
risk [43].
Exenatide (2 mg subcutaneous injection of extended release)
was compared to matching placebo (administered once weekly)
in the EXSCEL study in 14,752 patients with T2DM (73% had
previous CVD) over a median period of 3.2 years. Even though
exenatide was non-inferior to placebo, the rate of MACE was
lower (11.4% vs. 12.2%); HR for MACE in the entire trial was 0.91
(95% CI, 0.83–1.0; p = 0.06) but did not attain the threshold for
demonstrated superiority versus placebo. All-cause mortality as
well as death from cardiovascular causes were lower in the
exenatide arm, but not statistically significant. The rates for
hospitalization for heart failure were almost similar with exena-
tide as placebo. Since the incidence of MACE did not differ
significantly to placebo, the EXSCEL study suggested treatment
with exenatide to be non-inferior to placebo among patients
with T2DM with or without previous CVD [44]. In the subgroup of
patients with known CVD, there was a 10% relative risk reduction
for MACE (HR, 0.90; 95% CI, 0.816–0.999; p = 0.047) with exena-
tide compared to placebo. Each of the secondary end points
including all-cause mortality, demonstrated an HR <1.00 with
exenatide, compared to placebo, with an exception for hospita-
lization due to acute coronary syndrome (HR, 1.03; 95% CI, 0.-
911–1.161), with none meeting statistical significance (all
nominal p > 0.05) [45]. The EXSCEL CVOT had some major issues
in the conduct of trial, such as high rate of premature disconti-
nuation of the trial regimen by the patients due to the complex-
ity of the injection device, and non-standardized usual-care
regimens [44].
The Harmony Outcomes trial randomly assigned 9,463
patients aged ≥40 years with T2DM and established coronary,
cerebrovascular, or peripheral arterial disease to receive either
albiglutide (30 mg once weekly, or increased to a maximum
tolerable dose of 50 mg) or placebo. The primary composite
outcome occurred in 7% vs. 9% patients with an incidence rate
of 4.6 vs. 5.9 events/100 person-years in the albiglutide group
(HR, 0.78; 95% CI, 0.68–0.90; p for non-inferiority < 0.0001; p for
superiority = 0.0006) compared to placebo, indicating the super-
iority of albiglutide to placebo. The secondary cardiovascular
outcomes of the 4-point composite MACE (the primary compo-
site, with the addition of urgent revascularization for unstable
angina) were significantly lower with albiglutide (8% vs. 10%; HR,
0.78; 95% CI, 0.69–0.90; p = 0.0005). Death from any cause and
death from cardiovascular causes was similar between the
groups. The incidence of acute pancreatitis, pancreatic cancer,
including other serious adverse events did not differ between
the albiglutide and placebo groups. The Harmony Outcomes
study demonstrated the superiority of albiglutide, in terms of
MACE, to placebo in patients with T2DM and CVD, when added
to standard care [46].
Conclusively, some GLP-1 receptor agonists offer cardiovas-
cular benefit among patients with established CVD, but no
benefit in reduction in cardiovascular mortality. There is no
evidence of cardiovascular benefit with lixisenatide.
4.8. Comparative inter-class efficacy
None of the randomized clinical trials with cardiovascular out-
comes or mortality have head-on compared the efficacy of the
drugs from these classes. Contained by the confines of observa-
tional studies, the CVD-REAL propensity-matched study revealed
an association of SGLT2 inhibitors with comparatively lower rates
of all-cause mortality (HR, 0.49; 95% CI, 0.41–0.57; p < 0.001),
hospitalization for heart failure (HR, 0.61; 95% CI, 0.51–0.73;
p < 0.001), than other glucose-lowering drugs [38,47]. The empa-
gliflozin and liraglutide trials further demonstrated significant
reductions in cardiovascular death [48]. Presently, empagliflozin
is the only glucose-lowering drug indicated not only to improve
glycemic control in adults with T2DM, but also to reduce the risk
of cardiovascular death in this population with established CVD
[49]; and liraglutide to reduce the risk of MACE in adults with
T2DM and established CVD [50].
Though CVOTs were designed to evaluate cardiovascular
safety (i.e. statistical non-inferiority compared to placebo), var-
ious trials demonstrated ASCVD outcome benefit (i.e. statistical
superiority compared to placebo) and comprised of mortality in
some cases. A significant number of patients with an eGFR of
30–60 mL/min/1.73 m2 (stage 3 CKD) were involved in EMPA-REG
OUTCOME, CANVAS, LEADER, and SUSTAIN 6 trials. In these
studies, there was an imperative finding of decrease in the
primary ASCVD outcome even in participants with stage 3 CKD.
Besides the primary cardiovascular endpoints, most CVOTs of
SGLT2 inhibitors and GLP-1 receptor agonists, although as sec-
ondary outcomes, conveyed benefits in renal endpoints. The
renal outcome benefit for SGLT2 inhibitors has been most pro-
minent and reliable.
In a recent systematic review and network meta-analysis by
Zheng SL et al., the clinical efficacy of SGLT2 inhibitors, GLP-1
receptor agonists, and DPP-4 inhibitors for treatment of T2DM,
was compared. A total of 236 trials that randomized 176,310
participants established SGLT2 inhibitors (absolute risk differ-
ence [RD], −1.0%; HR, 0.80 [95%credible interval {CrI}, 0.71–0.89])
and GLP-1 receptor agonists (absolute RD, −0.6%; HR, 0.88 [95%
CrI, 0.81–0.94]) to be associated with significantly lower all-cause
mortality than the control groups. As compared to DPP-4 inhibi-
tors, lower mortality was associated with SGLT2 inhibitors (abso-
lute RD, −0.9%; HR, 0.78 [95%CrI, 0.68–0.90]) and GLP-1 receptor
agonists (absolute RD, −0.5%; HR, 0.86 [95%CrI, 0.77–0.96]). No
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
significant association of DPP-4 inhibitors with lower all-cause
mortality than the control groups was noted. Lower cardiovas-
cular mortality was significantly associated with SGLT2 inhibitors
(absolute RD, −0.8%; HR, 0.79 [95%CrI, 0.69–0.91]) and GLP-1
receptor agonists (absolute RD, −0.5%; HR, 0.85 [95%CrI, 0.77
−0.94]) than the control groups. Moreover, there was
a significant association of SGLT2 inhibitors with lower rates of
heart failure events (absolute RD, −1.1%; HR, 0.62 [95%CrI, 0.54–-
0.72]) and MI (absolute RD, −0.6%; HR, 0.86 [95%CrI, 0.77–0.97])
than their control counterparts. Whereas GLP-1 receptor agonists
were associated with a higher risk of adverse events resulting in
trial withdrawal than SGLT2 inhibitors (absolute RD, 5.8%; HR,
1.80 [95%CrI, 1.44–2.25]) and DPP-4 inhibitors (absolute RD, 3.1%;
HR, 1.93 [95%CrI, 1.59–2.35]). The network meta-analyses rein-
forced the beneficial effects of SGLT2 inhibitors on heart failure
by indicating a lower risk than DPP-4 inhibitors (HR, 0.55; abso-
lute RD, −1.1%) and GLP-1 receptor agonists (HR, 0.67; absolute
RD, −0.9%) [51].
4.9. Safety outcomes
A recent network meta-analysis found no evidence of differ-
ences in the effect of SGLT2 inhibitors and GLP-1 receptor
agonists for hypoglycemic events, amputations, bone frac-
tures, pancreatitis, diabetic ketoacidosis, and urinary tract
infection. However, data collected on some of these outcomes
in the included trials were very sparse, thereby precluding
a steady conclusion [52].
Safety outcomes analysis from CVOTs revealed an association
of increased risk of genital infections (but not urinary tract infec-
tions) with SGLT2 inhibitors. A higher degree of heterogeneity for
lower-limb amputations reported were determined by the sub-
stantial upsurge in events with canagliflozin (CANVAS), though
this was neither observed in the CREDENCE trial nor with empa-
gliflozin or dapagliflozin. The probability of a clinically mean-
ingful safety signal for SGLT2 inhibitors and amputation could
not be ruled out. These CVOTs also pointed out the link between
increased risk of acute pancreatitis and DPP4 inhibitors. Vigilant
selection of treatment is essential to minimalize such conse-
quences among at-risk patients.
5. Recommendations by international agencies
The chief amendment from preceding guidelines and consen-
sus reports is centered around newer evidences regarding
particular SGLT2 inhibitors or GLP-1 receptor agonists with
proven cardiovascular outcomes, in addition to secondary
outcomes like progression of renal disease and heart failure,
in cases of established CKD or CVD.
In a recent Joint Consensus Statement issued in
September 2018 from the ADA/EASD, based on results from
the CVOTs, the organizations endorsed new drugs that exhibit
reduced cardiovascular risk, namely SGLT2 inhibitors and GLP-1
receptor agonists, to be introduced earlier in high-risk patients.
Trials demonstrate evidence for cardiovascular event reduc-
tion in T2DM patients with clinical CVD those not meeting
glycemic targets at baseline (HbA1c ≥ 53 mmoL/mol [≥7%]).
Moreover, across trials at baseline, nearly 70% patients were on
treatment with metformin. As a result, the consensus report
9
recommends addition of an SGLT2 inhibitor or GLP-1 receptor
agonist with proven benefit for cardiovascular risk reduction in
patients with clinical CVD not achieving individualized glycemic
targets with ongoing treatment with metformin (or in cases
where metformin is not tolerated or contraindicated).
There is a need to not only achieve glycemic targets but
also to implement blood pressure, lipid, antiplatelet, antith-
rombotic therapies, and tobacco cessation guidelines, since
such efforts have been found to be fundamental in studies
that show cardiovascular benefit of these medications [4].
The most recent ADA Standards of Medical Care in Diabetes
2019 recommend either an SGLT2 inhibitor, or GLP-1 receptor
agonist, with verified CVD benefit, as part of the anti-
hyperglycemic dual therapy regimen in those with T2DM
and established ASCVD. In patients with ASCVD at high risk
of heart failure or coexistence of heart failure, SGLT2 inhibitors
are to be preferred. Among those with T2DM and CKD, an
SGLT2 inhibitor or GLP-1 receptor agonist demonstrated to
decrease the risk of cardiovascular events, CKD progression,
or both could be considered. In patients without ASCVD or
CKD, any one of the preferred six treatment options could be
considered; the choice of which should be based on patient
factors and drug-specific effects [53].
The recently published 2019 European Society of
Cardiology (ESC) Guidelines on diabetes, pre-diabetes, and
cardiovascular diseases developed in collaboration with the
EASD advocate a paradigm shift in the management of drug-
naive T2DM patients with either ASCVD or high/very high
cardiovascular risk. The risk of CVD has now been classified
as: moderate risk (diabetes with risk factors, but duration of
diabetes <10 years), high risk (long duration >10 years and risk
factors), and very high risk (established CVD).
SGLT2 inhibitors or GLP-1 receptor agonists’ monotherapy
with proven CVD benefit is now recommended as a first-line
therapy in these patient subgroups, with metformin displaced
as a second-line drug in the management, if HbA1c remains
above target with monotherapy. This will further facilitate and
provide clarity to healthcare professionals in appropriate deci-
sion-making regarding the use of SGLT2 inhibitors or GLP-1
receptor agonists in clinical practice. The guidelines further
consolidate the position of empagliflozin, canagliflozin, dapa-
gliflozin, liraglutide, semaglutide, and dulaglutide to reduce
cardiovascular events and empagliflozin and liraglutide to
reduce the risk of death in T2DM patients. Based on the
promising recent data, empagliflozin, canagliflozin, and dapa-
gliflozin are recommended to reduce the risk of heart failure
and prevention and management of CKD [54].
6. Conclusion
Despite the fact that the new evidence supporting specific
drugs in patients with established CVD or are at high risk of
CVD is obtained from large CVOTs indicating substantial ben-
efits over a period of 2–5 years, we need to remember that
each trial institutes a solitary investigation. Whether to include
heart failure as a stand-alone co-primary endpoint or a key
secondary endpoint can depend on the mechanism of action
of the study drug and the study population. There are
ongoing trials with heart failure as primary end point in
10 K. KHUNTI ET AL.

patients with or without diabetes mellitus. Data from only the
indexed CVOTs for individual drugs are considered; analysis
and interpretation of the various sub-group analyses for these
CVOTs were beyond the scope of this review.
There is an increased risk of hypoglycemia and weight gain
by sulphonylureas, which are both major risk factors for CVD,
and the FDA label also suggests a potential increased risk for
cardiovascular mortality. Though true in patients without
established CVD, it is particularly important in those with
established CVD and already at high risk for the development
of future cardiac events.
In view of the cardiovascular benefits of SGLT2 inhibitors,
there have been calls for [16,54–56] the use of SGLT2 inhibi-
tors as first line in the treatment of T2DM. In view of the
benefits seen in the CVOTs with SGLT2 inhibitors, this class
of glucose-lowering agents should be the preferred choice in
patients with/without established ASCVD and CKD (with ade-
quate eGFR). In patients with T2DM with/without established
ASCVD and CKD requiring the potency of an injectable ther-
apy for glucose control, GLP-1 receptor agonists can be pre-
ferred; liraglutide is indicated to reduce the risk of MACE in
adults with T2DM and established CVD.
By and large, CVOTs of DPP-4 inhibitors have demonstrated
non-inferiority for the primary MACE endpoint relative to pla-
cebo; there is no cardiovascular benefit, but are safe in a wide
range of patient populations (Table 2; Figure 2).
Selection of appropriate glucose-lowering therapy should be
individualized and tailored to patient characteristics, risk factors,
patient choice, affordability, adherence, and persistence to treat-
ment and goals recommended by the ADA/EASD guidelines.
There is a need to consider additional cardiovascular-related fac-
tors, although the current evidence have shown significant bene-
ficial effects of SGLT2 inhibitors and GLP-1 receptor agonists in
people with established ASCVD and with high cardiovascular risk.
7. Expert opinion
Data from the recently completed CVOTs have yielded
a wealth of information on the characteristics of various glu-
cose-lowering medications, which could be useful in the man-
agement of people with T2DM. Even though the primary
objective of the CVOTs was to demonstrate the safety of
these medications, the diabetes and cardiovascular commu-
nity have now serendipitously been blessed with a wealth of
information required to make individualized decision-making
depending on various patient characteristics.
Metformin still arguably remains the first line of treatment
in most guidelines. This is now however being questioned
given the wealth of information around more attractive drug
options for various patient groups. The main attraction for
Metformin at the moment is the fact that it is very cheap
and prescribers have wealth of experience with it. It is impera-
tive, however, for the diabetes and cardiovascular community
to challenge this status quo and continue to make the chase
for better evidence-based medications for the benefit of
appropriate patients across the globe.
Like Metformin, Sulphonylureas are very cheap and very widely
prescribed across the globe. Over the last decade, there has been
an increased focus on this group because of their association with
a slightly increased weight gain and the more concerning effect of
hypoglycemia. Even though these side effects have always been
known, the heightened discussions around these concerns seem
to have coincided with the proliferation of newer glucose-
lowering drugs, all struggling to establish their position as
the second-line drug for diabetes after metformin. However,
CVOTs that have used sulphonylureas as an active comparator
have failed to link the drugs to adverse cardiovascular outcomes.
Both the PROACTIVE and IRIS studies suggest there may be
some cardiovascular benefits with Pioglitazone; however, the
increased risk of heart failure limits its use in patients with T2DM
and heart failure. Additionally, the increased risk in bone fractures
and tag of bladder cancer risks associated with Pioglitazone
further limits the diabetes subpopulation in whom it can be
used. However, it is our belief that with a clear understanding of
these data, there is still a sizable group of patients with T2DM
where Pioglitazone could be potentially very useful. It is potent,
cheap, and boasts of a long durability in its glycemic reduction.
With regards to DPP-4 inhibitors, it is now generally
accepted that they are some of the safest glucose-lowering
medications available, with the exception of Saxagliptin that
is associated with a 27% increase in hospitalization for heart
failure and probably Alogliptin. They are generally very inert

Table 2. CVOT-based patient-centric approach for selection of first- and second-line glucose-lowering agents.
SGLT2i GLP-1 RA DPP4i Suggested preference
Established ASCVD or High Effect on primary outcome and cardiovascular mortality compared to placebo
cardiovascular risk EMPA-REG: 14% ↓; 38% ↓ LEADER: 13% ↓; 22% ↓ No significant effect SGLT2i or
CANVAS: SUSTAIN 6: 26% ↓; Not significant GLP-1 RA (Oral drug
14% ↓; 13% ↓ HARMONY: 22% ↓; Not significant ELIXA, preferred over
DECLARE-TIMI 58: No EXSCEL: No significant effect injectable)
significant effect
Hospitalization for heart 27%-35% ↓ No significant effect SAVOR-TIMI 53: 27 ↑ SGLT2i
failure No significant effect with
others
Renal Possible benefit seen with Possible benefit of liraglutide and Possible benefit in SGLT2i (canagliflozin
canagliflozin (CREDENCE) semaglutide decreasing 100 mg) or
albuminuria GLP-1 RA (Oral drug
preferred over
injectable)
Weight Decrease Decrease No effect SGLT2i or
GLP-1 RA (Oral drug
preferred over
injectable)
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
Figure 2. Schematic flow for selection of anti-diabetes therapy based on cardiovascular outcome trials.
in terms of their side effect profile and are thereby consid-
ered the safest options, especially in vulnerable populations
where the quality of life is paramount, particularly in the
elderly.
With respect to GLP-1 receptor agonists, the cardiovascular
benefits associated seem to be limited to the long-acting
analogue variants. On the contrary, for SGLT2 inhibitors, car-
diovascular benefits associated with them appear to be a class
effect. Even though Dapagliflozin and Canagliflozin in compar-
ison did not demonstrate the impressive results shown in the
EMPA-REG trial, it is conceivable that either of these drugs
could have replicated the same results if they had been used
instead of Empagliflozin. The derived benefits seem to be
a result of the mechanism of action and not the biology of
the individual molecules.
Finally with basal insulins, in terms of glycemic efficacy,
there is no evidence that there is one superior insulin com-
pared to the other; however, the second generation analogue
basal insulins have consistently demonstrated lower rates of
hypoglycemia and could be considered an option, when avail-
able, for those at particular risk of hypoglycemia.
As impressive as the cardiovascular benefits of the newer
agents in T2DM may seem, they do not address all the con-
cerns faced by frontline clinicians and patients in the manage-
ment of T2DM. For instance, most patients recruited in these
trials are those either with established or at high risk of
cardiovascular disease. The results have shown differential
effects in patients with established cardiovascular disease
compared to those who do not have established cardiovascu-
lar disease. It is only in the REWIND trial that a consistent
benefit was seen across both groups of populations. More
research is therefore needed in populations of patients who
do not have established cardiovascular disease or only at
a low risk of cardiovascular disease.
It is also unclear if the impressive results of CVOTs can be
replicated in populations with well-controlled HbA1c levels.
The results of DAPA-HF trial are a welcome signal that this
assumption could be made. However, more clarity will be
required in these populations as one will have to justify why
expensive newer medications should be prescribed for
patients over and above glycemic control when cheaper
options are available to achieve the same result.
11
Another concern on the findings of CVOTs is the fact that they
are mainly focused on cardiovascular disease prevention. As much
as mortality and morbidity from cardiovascular disease are impor-
tant issues in patients with T2DM, for certain populations, quality
of life is an even better goal of treatment. For instance, in elderly
and frail patients who may be near their end of life, preventing
cardiovascular disease may not be a favored option at all cost.
They may prefer a drug option that may have less adverse effects
such as recurrent genitourinary infections. Even weight loss asso-
ciated with GLP-1 receptor agonists or SGLT2 inhibitors may not
necessarily be the desired outcome in some of these vulnerable
populations. The study populations in the CVOTs have not
included a lot of these frail elderly populations and as a result
extension of these benefits to those populations should only be
considered with extreme caution.
Finally, all CVOTs have mainly focused on cardiovascular out-
comes whereas in patients with T2DM and indeed all chronic
diseases, other considerations such as medication adherence
and persistence, and the management of the condition as well
as other prevalent co-morbidities including respiratory or mus-
culoskeletal conditions could be important. It is therefore crucial
that more research is conducted in the context of multi-
morbidity when considering newer agents for diabetes.
Acknowledgments
We would like to acknowledge the medical writing and editorial assistance
provided by consultant medical writers, Dr. Aafreen Saiyed and Dr. Suraj
Ghag.
Declaration of interest
KK has acted as a consultant and speaker for AstraZeneca, Berlin-Chemie AG/
Menarini Group, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, NAPP, Merck
Sharp & Dohme, Janssen, and Boehringer Ingelheim, has received grants in
support of investigator and investigator-initiated trials from AstraZeneca,
Janssen, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim,
Merck Sharp & Dohme. MJD reports personal fees from Novo Nordisk, Sanofi-
Aventis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca,
Janssen, Mitsubishi Tanabe Pharma Corporation, and Takeda
Pharmaceuticals International and grants from Novo Nordisk, Sanofi-
Aventis, Eli Lilly, Boehringer Ingelheim, and Janssen. SS reports personal
fees from Amgen, personal fees from AstraZeneca, personal fees from
NAPP, personal fees from Lilly, personal fees from Merck Sharp & Dohme,
12 K. KHUNTI ET AL.
personal fees from Novartis, personal fees from Novo Nordisk, personal fees
from Roche, personal fees from Sanofi-Aventis, personal fees from Boehringer
Ingelheim, grants from AstraZeneca, grants from Sanofi-Aventis, grants from
Servier, grants from Janssen, outside the submitted work. The authors have
no other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
Reviewers Disclosure
Peer reviewers on this manuscript have no relevant financial relationships
or otherwise to disclose.
ORCID
Samuel Seidu http://orcid.org/0000-0002-8335-7018
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