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562 Cardio Diabetes Medicine 2017

term Outcomes With Semaglutide in Subjects With overall risk of cardiovascular disease by 14 percent
Type 2 Diabetes (SUSTAIN-6) examines the long- and reduced the risk of heart failure hospitalization
term cardiovascular and other safety outcomes of by 33 percent. The drug also demonstrated potential
0.5-mg and 1.0-mg semaglutide, which was admin- renal protective effects [20].
istered subcutaneously once weekly and compared
with placebo, both in addition to standard of care, Degludec
in approximately 3300 people with type 2 diabetes Insulin degludec is a new-generation injectable basal
treated for 104 weeks. The primary outcome was the insulin that is administered once daily and provides
composite of CV mortality, nonfatal MI, or nonfatal a duration of action lasting at least 24 hours. The
stroke. The outcome was observed in 6.6% and 8.9% goal of the DEVOTE trial (A Trial Comparing Cardio-
of the semaglutide and placebo groups, respectively vascular Safety of Insulin Degludec Versus Insulin
(hazard ratio 0.74). The trial also noted that the sema- Glargine in Subjects With Type 2 Diabetes at High
glutide group had a higher incidence of diabetic reti- Risk of Cardiovascular Events) was to assess the car-
nonpathy as compared to placebo (3 vs. 1.8%, hazard diovascular safety of insulin degludec compared with
ratio 1.76) [17].
insulin glargine in patients with type 2 diabetes at
high risk of cardiovascular events. In DEVOTE, 7637
Empagliflozin patients with T2D who were at high risk of major ad-
Empagliflozin is an inhibitor of the sodium glucose verse cardiovascular events (MACE) were evaluated
co-transporter-2(SGLT-2), which is found almost ex- for approximately 2 years at 436 sites in 20 countries.
clusively in the proximal tubules of nephronic com- Out of the total population, 6506 patients had prior
ponents in the kidneys. SGLT-2 accounts for about cardiovascular disease or chronic kidney disease,
90 percent of glucose reabsorption into the blood. and the remaining patients had multiple cardiovas-
Blocking SGLT-2 reduces blood glucose by block- cular risk factors. The results of this trial indicate that
ing glucose reabsorption in the kidney and thereby degludec is similar to insulin glargine in improving
excreting glucose via the urine. glycemic control and noninferior for reducing cardio-
vascular events in patients with type 2 diabetes and
The EMPA-REG OUTCOME trial was the first of the high cardiovascular risk. The risk of severe hypogly-
modern CV trials to show treatment benefit, in which cemia was lower with degludec. The upper limit of
empagliflozin met the primary endpoint of CV safety, the 95% CI for the HR had to be <1.8 for premarketing
but also showed benefit in the key secondary end- studies and <1.3 for postmarketing studies. This trial
point of 3-point MACE. A 38% reduction in CV death thus establishes the cardiovascular safety profile of
was the primary driver of the outcome. There was no degludec for use in patients with type 2 diabetes,
significant benefit for either MI or stroke. Empagli- compared with insulin glargine [21].
flozin was also associated with a 35% reduction in
hospitalization for CHF, another key secondary end-
point of this study [18]. Recently, despite the fact that Discussion
the mechanism for the improvement in CV outcomes CVOT trials completed after 2008 showed that new
is unknown, the FDA approved the indication of em- glucose lowering agents like the DPP-4 inhibitors
pagliflozin for reduction of CV death in patients with saxagliptin, alogliptin, and sitagliptin and the GLP-
type 2 diabetes and CVD [19]. 1 receptor agonist lixisenatide are safe with respect
to CV outcomes in high CV risk patient populations
Canagliflozin with long T2D duration under standard care for both
CVD and diabetes. In addition, the LEADER study has
Canagliflozin is a sodium–glucose cotransporter 2 in- shown that liraglutide, a GLP-1 receptor agonist, is
hibitor that reduces glycemia as well as blood pres- not only safe but that is also capable of reducing
sure, body weight, and albuminuria in people with CV risk and the incidence of cardiovascular-related
diabetes. The CANVAS Program assessed the effica- death [16]. Furthermore, recently published results
cy, safety, and durability of canagliflozin in more than from SUSTAIN-6 have proven another GLP-1 receptor
10,000 patients with type 2 diabetes, who had either agonist, semaglutide, superior to placebo in reducing
a prior history of CV disease, or at least two CV risk the risk of a cardiovascular composite primary end-
factors. It is composed of two, nearly-identical large point, driven by a significant reduction of stroke risk
outcomes studies: CANVAS (CANagliflozin Cardio- [17]. Moreover, treatment with the SGLT-2 inhibitors
Vascular Assessment Study) and CANVAS-R (Study empagliflozin and canagliflozin were not only non-in-
of the Effects of Canagliflozin on Renal Endpoints). ferior to placebo but also significantly reduced CV
The results showed that canagliflozin reduced the

GCDC 2017