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Glucose Lowering Strategies and 561
Cardiovascular Outcomes

Cv Safety Studies of New Antihyperglycemic Sitagliptin
Agents Sitagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor
CV safety studies have been completed for three which increases the level of glucagon-like peptide1
dipeptidyl peptidase-4 (DPP-4) inhibitors, three glu- and glucose-dependent insulinotropic polypeptide.
cagon-like peptide 1 (GLP-1) receptor agonists, two The Trial Evaluating Cardiovascular Outcomes with
sodium/glucose cotransporter 2 (SGLT-2) inhibitors Sitagliptin (TECOS) randomized 14,671 patients with
and one long acting insulin analogue. All three of the type 2 diabetes (T2DM) and cardiovascular (CV) dis-
DPP-4 inhibitors demonstrated CV safety, but did not ease to receive either sitagliptin or placebo added to
show any CV benefit over placebo [12-14]. their existing therapy [14].The primary outcome of the
trial is the composite of CV mortality, nonfatal MI,
Saxagliptin nonfatal stroke, or hospitalization for unstable an-
gina. The primary outcome occurred in 11.4% of pa-
Saxagliptin is a selective dipeptidyl peptidase 4 tients in the sitagliptin group as compared to 11.6% in
(DPP-4) inhibitor that lowers glucose. Saxagliptin placebo (HR 0.98; 95% CI 0.89-1.08). Sitagliptin was
therapy did not increase the risk of the composite non-inferior to placebo for the primary outcome (HR
Major Cardiovascular Event (MACE) endpoint of CV 0.98; 95% CI 0.88-1.09). Additionally, sitagliptin did
death, non-fatal myocardial infarction (MI), or nonfa- not increase the rate of hospitalization due to heart
tal ischemic stroke, meeting the primary safety ob- failure, or other adverse outcomes including pancre-
jective of SAVOR-TIMI 53 (The Saxagliptin Assess- atitis and pancreatic cancer.
ment of Vascular Outcomes Recorded in Patients
with Diabetes Mellitus–Thrombolysis in Myocardial Lixisenatide
Infarction 53) study [12]. Additionally, saxagliptin did Lixisenatide is an injectable glucagonlike peptide
not increase the risk of an expanded CV composite (GLP-1) agonist used for the treatment of type 2 di-
endpoint, which also included hospitalization for HF, abetes. The first of the GLP-1 CV safety studies to
hospitalization for unstable angina, or hospitalization report was ELIXA, which demonstrated that in com-
for coronary revascularization. An increased risk for parison to placebo, treatment with lixisenatide did
hospitalization for HF, a component of the balanced not show a benefit on cardiovascular outcomes in
secondary endpoint, was observed with saxagliptin the 6000 high-risk patients with diabetes in the Eval-
treatment. This finding was most relevant for patients uation of Lixisenatide in Acute Coronary Syndrome
at increased risk for heart failure (HF), such as those trial [15]. But the agent did not cause any harm in
with a history of HF or renal impairment.
these patients, who had recently suffered a coronary
Alogliptin event and there was no increased incidence of heart
failure or hospitalization for heart failure.
Alogliptin is a potent and highly selective DPP-4 in-
hibitor. In EXAMINE (The Examination of Cardiovas- Liraglutide
cular Outcomes With Alogliptin Versus Standard of
Care in patients with type 2 diabetes mellitus and Liraglutide is an FDA-approved, injectable, long-act-
acute coronary syndrome) study,[13] alogliptin once ing GLP-1 receptor agonist that lowers blood sugar,
daily was compared with placebo once daily in com- reduces BP, and promotes weight loss. LEADER (The
bination with standard of care among individuals Liraglutide Effect and Action in Diabetes: Evaluation
with type 2 diabetes mellitus and acute coronary of Cardiovascular Outcome Results) trial randomized
syndrome (ACS). It randomized 5380 patients with 9,340 patients with type 2 diabetes and high CV risk
T2DM who had either a MI or unstable angina requir- to receive liraglutide or placebo [16]. With a median
ing hospitalization in the previous 15 to 90 days. The follow-up of 3.8 years, liraglutide was associated with
purpose was to address concern regarding elevated a significant reduction in CV mortality, nonfatal MI,
cardiovascular risk related to new antihyperglycemic or nonfatal stroke (13.0% vs. 14.9%, P<0.001) as well
drugs used to treat T2DM. The primary outcome end as a reduction in all-cause mortality (8.2% vs. 9.6%,
point was a composite of death from cardiovascular P=0.02). There was no reduction in hospitalizations
causes, non-fatal myocardial infarction, or non-fatal for CHF with liraglutide versus placebo. The mecha-
stroke, in which alogliptin proved to be non-inferior nism leading to improved CV outcomes with liraglu-
vs. placebo (11.8% vs. 11.3%) with a median trial duration tide is uncertain.
of 18 months. There were no statistically significant
findings on other safety or outcome endpoints. Semaglutide
The Trial to Evaluate Cardiovascular and Other Long-

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