Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Canagliflozin and cardiovascular and renal events

in type 2 diabetes

Robert Guthrie

To cite this article: Robert Guthrie (2018): Canagliflozin and cardiovascular and renal events in
type 2 diabetes, Postgraduate Medicine, DOI: 10.1080/00325481.2018.1423852

To link to this article: https://doi.org/10.1080/00325481.2018.1423852

Accepted author version posted online: 03

Jan 2018.

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 1

Publisher: Taylor & Francis

Journal: Postgraduate Medicine

DOI: 10.1080/00325481.2018.1423852
Canagliflozin and cardiovascular and renal events in type 2 diabetes

Robert Guthrie

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Professor Emeritus of Emergency Medicine
The Ohio State University

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5939 Dunabbey Loop
Dublin, Ohio 43017
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USA

Email: robertguthriemd@gmail.com
Telephone: 614-371-3321
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Abstract:
Review of: Neal B, Perkovic V, Mahaffey K, et al. Canagliflozin and
Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017:
377; 644-657.
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The report combines the data from two trials, CANVAS and CANVAS-
Renal, which were designed to evaluate the safety and effect of canagliflozin,
an SGLT-2 inhibitor, on the appearance of cardiovascular and renal events
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in patients with type 2 diabetes. Enrollees were patients with type 2 diabetes
of at least 30 years of age, with a glycated hemoglobin of > or equal to 7.0%
and < or equal to 10.5%. Patients either had to have preexisting
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cardiovascular disease or to be at elevated risk for cardiovascular disease,

and to have an estimated glomerular filtration rate (eGFR) of > 30 ml/min.
Patients were randomized to canagliflozin at doses of either 100 mg or 300
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mg or matching placebo in CANVAS, and to canagliflozin 100 mg with a

possible increase to 300 mg, or placebo, in CANVAS-Renal. Physicians
were instructed to continue appropriate diabetic management and other
therapies in accordance with the best practices in their community. There
was a significant 14% reduction in the combined endpoint of cardiovascular
events of death from cardiovascular causes, nonfatal myocardial infarction,
or nonfatal stroke in the canagliflozin treated patients. There was also a
pattern of improvement in markers of renal disease, including the change in
 2

the level and nature of albuminuria, a 40% decrease in the glomerular

filtration rate, the need for renal replacement therapy, or death from renal
causes. This study expands the scope of SGLT-2 inhibitor therapy to prevent
cardiovascular disease in diabetic patients beyond those with preexisting
cardiovascular disease studied in the previous empagliflozin study, raising
the question as to whether SGLT-2 inhibitor therapy should be considered
appropriate for most, if not all, type 2 diabetes patients, not only to control
hyperglycemia but also to reduce cardiovascular and renal events.

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Keywords: Type 2 Diabetes Mellitus, Canagliflozin, Cardiovascualr Events,

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Renal Events
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Practice Pearl
Canagliflozin was the first of the new class of antidiabetic agents called the
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SGLT-2 Inhibitors, or sodium-glucose cotransporter 2 inhibitors, to reach
the US market in April of 2013. Two other agents, empagliflozin and
dapagliflozin, are now on the market. In 2015, a pioneering study showed
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that empagliflozin reduced cardiovascular (CV) events in Type 2 diabetic
patients. (1) This study, EMPA-REG, was limited to Type 2 diabetics with
previously diagnosed cardiovascular disease. While very promising, this
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patient group was somewhat limited in scope. The canagliflozin study

described here included those patients with known CV disease, but also
included Type 2 diabetics without known CV disease but with increased risk
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factors for CV disease, including age greater than 50, along with two other
risk factors including diabetes for > 10 years, systolic blood pressure > 140
while on one or more antihypertensive agents, current smoking,
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microalbuminuria or macroalbuminuria, or high-density lipoprotein (HDL)

less than 1 mmo.per liter or 38.7 mg/dl. Therefore, this canagliflozin study
will expand the patients who should be considered for this therapy to reduce
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the risk of CV disease. (2)

History of Condition
While diabetes has long been recognized to increase the development of
cardiovascular disease, previous studies had not been able to demonstrate
clearly the benefit of a reduction in cardiovascular events with antidiabetic
therapy. (3,4,5,6) While there have been a series of studies to try to
determine if specific antidiabetic therapies might reduce this elevated
 3

cardiovascular risk, prior to the empagliflozin trial published in 2015, the

results had been quite limited. The large UKPDS trial used insulin and the
sulphonylureas agents but failed to demonstrate a reduction in
cardiovascular events. (6) There was a reduction in CV events with
metformin in a sub study of the UKPDS trial, but this type of result is not
definitive as an independent study. (7)
The initial trial showing a reduction in CV events with an anti-diabetic
therapy was the previously mentioned EMPA-REG trial. (1) Using

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empagliflozin in doses of either 10 or 25 mg doses or matching placebo, this

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study showed a reduction in CV events in the range of 14% in patients
treated with either dose of empagliflozin versus the placebo treated patients.

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Also, the data showed an early and very dramatic reduction in
hospitalization for heart failure, suggesting an unknown but interesting
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potential mechanism. (1) However, this study had enrolled only patients
with previous CV disease, which leads to the question as to whether the
same improvement would be seen in a broader diabetic patient base without
diagnosed CV disease. (1)
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Following the EMPA-REG study, a new study was published showing that
therapy with liraglutide, an analogue of human glucagon-like peptide (GLP-
1), when used in Type 2 diabetes patients with cardiovascular or renal
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disease, similar to the patients treated in the empagliflozin study, showed a

reduction in CV mortality over the placebo treated patients. (8) However,
the study did not show the dramatic, rapid reduction of heart failure
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admissions seen in the EMPA-REG study. Also, the liraglutide study

produced non-significant improvements in non-fatal myocardial infarctions
and non-fatal stroke, issues not consistently seen in EMPA-REG. (8) This
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suggests that there were different mechanisms at work to produce the

different benefits seen in these two studies.
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Objective
The CANVAS program involved two similar studies on canagliflozin, an
inhibitor of the SGLT-2 receptor located in the proximal tubule of the renal
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collecting system. By inhibiting this receptor, the SGLT-2 inhibitors reduce

the renal reabsorption of glucose, increasing glucose excretion in the urine
and lowering serum glucose. (2) The CANVAS studies included two related
studies. CANVAS was initially designed to monitor CV safety in patients
treated with canagliflozin versus matching placebo, while CANVAS-R
evaluated canagliflozin in patients with diabetes and renal dysfunction. The
two CANVAS studies were merged for this report.
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Research Design
The CANVAS program was originally developed in the time before
canagliflozin was marketed to assess the cardiovascular safety of
canagliflozin prior to its arrival on the US market. After canagliflozin was
approved by the US FDA in March of 2013, the CANVAS-Renal study was
developed to add to the cardiovascular end point determinations and to
evaluate the effect of canagliflozin on albuminuria. (2) Patients were
recruited from 30 countries, and the participants were men and women with

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Type 2 diabetes, with glycated hemoglobin levels >7.0% and <10.5%, and

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with a history of symptomatic atherosclerotic CV disease, or age 50 or older
with two or more risk factors for CV disease, including a duration of

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diabetes for > 10 years, systolic blood pressure greater than 140 mm Hg
while on one or more antihypertensive medications, current smoking,
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microalbuminuria or macroalbuminuria, or high-density lipoprotein (HDL)
cholesterol of less than 38.7 mg per deciliter or 1 mmol per liter.(2)
After a two-week single-blind, placebo run-in period, CANVAS participants
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were randomized to 1:1:1 to canagliflozin 100 mg, 300 mg, or placebo.
CANVAS-R patients were randomized 1:1 to a canagliflozin 100 mg
starting dose, with possible titration to 300 mg at week 13 or later, or
matching placebo. Patients were seen three times in the first year and then
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every six months afterwards. (2) Patients were to be managed with

appropriate diabetic management and management of other risk factors in
accordance with the best practices in their communities. (2)
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Outcomes measures
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Cardiovascular (CV) outcomes included a composite of death from CV

outcomes, nonfatal myocardial infarction, or nonfatal stroke. Secondary
outcomes included death from any cause, CV death, progression of
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albuminuria, and a composite of CV death and hospitalization for heart

failure. Other outcomes included regression of albuminuria and a renal
composite of a 40% reduction in EGFR, the need for renal-replacement
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therapy, or death from renal causes. (2)

Findings
The cardiovascular primary endpoint (composite of death from
cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke)
was 14% lower in the canagliflozin group than the placebo patients ( 26.9 vs.
31.5 patients, per 1000 patient years; HR 0.86; 95% CI, 0.75 to 0.97;
P<0.001. (2) These effects were seen across the wide range of patient
 5

groups. The fatal secondary outcomes of death from any cause and
cardiovascular deaths had positive trends of HR’s of 0.87 for both endpoints,
but these were not statistically significant. There were similar outcomes
seen in both CANVAS and CANVAS-R. (2) As in the previous
empagliflozin trial, there was a very significant reduction in admission for
heart failure that began early in the trial (HR 0.76; 95% CI, 0.52-0.87). (1,2)
The renal outcomes were also positive, with a reduction in the progression of
albuminuria for the canagliflozin patients compared to the placebo patients,

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with a HR of 0.73 (95% CI, .67 to .79). The effects were greater in

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CANVAS-R (HR, 0.64; 95% CI 0.57 to 0.73) than CANVAS (HR, 0.80;
95% CI, 0.72 to 0.90). Regression of albuminuria was also greater in the

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canagliflozin than the placebo patients. The composite outcome of a
sustained 40% reduction in eGFR , the need for renal replacement therapy,
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or death from renal disease were also reduced in the canagliflozin treated
patients (HR, 0.60; 95% CI, 0.47 to 0.77) in both CANVAS and
CANVAS-R. (2)
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Serious adverse events were less common in the canagliflozin versus the
placebo patients (HR, 0.93; 95%CI, 0.87 to 1.00), even though adverse
events leading to discontinuation were not different between the groups.
There was a higher rate of amputation in the canagliflozin treated patients,
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(6.3 vs 3.4 patients per 1000 patient years, HR 1.97; 95% CI 1.41 to 2.75)
usually in patients with a history of previous amputation and with the
amputations primarily affecting the toe or metatarsal level. (2) A further
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report examined the absolute amputation risk seen in this study. This report
determined that the excess amputation risk corresponded to a number needed
to harm (NNH) of 277 patients treated with canagliflozin over three years to
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lead to one additional amputation, while also noting that the risk of
ampujtation was higher in patients with a history of a previous amputation or
concomitant peripheral vascular disease (PVD). (9) There was also a higher
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rate of fractures in the canagliflozin treated patients but with a similar rate of
low trauma fractures between groups. There were increased levels of
adverse events typically seen with the SGLT-2 Inhibitor agents, including
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genital infections, volume depletion, and diuresis, but the ketoacidosis rates
were very low in both groups. (2)

Application in practice
This is a very important report for the future of the management of Type 2
Diabetes Mellitus. Prior to the empagliflozin report published in 2015, there
had not been a conclusive report of an antidiabetic therapy reducing
cardiovascular events. (1) This report shows the reduction of cardiovascular
 6

end points was seen in both of the two trials with different SGLT-2 Inhibitor
agents, empagliflozin and canagliflozin. And interestingly, the HR for the
composite endpoint of each of the different studies was 0.86, with the same
14% reduction in the measured cardiovascular events in both studies. A
similar project with the third SGLT-2 Inhibitor, dapagliflozin, is currently
under way. When these two studies are examined carefully, the results are
nearly identical. Also, while the empagliflozin study evaluated only Type 2
diabetic patients with a previous symptomatic CV event, only about 65% of

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the canagliflozin patients had had previous symptomatic CV events, while

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the other 35% had only increased CV risk factors (age above 50 with two of
the following: diabetes > ten years, increased systolic blood pressure > 140

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mm Hg while on one or more antihypertensive agents, current smoking,
microalbuminuria or macroalbuminuria, or a reduced HDL-C cholesterol).
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This additional patient group extends the benefit of SGLT-2 Inhibitors to the
prevention of CV events into primary patients without previous symptomatic
CV disease, a significant extension of patients who will benefit from this
therapy.
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One of the more important aspects of this study, along with the previously
mentioned empagliflozin trial, was the degree of renal protection seen in the
study. The renal improvement markers – improvements in the rate of
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albuminuria, along with an improvement in the rate of decline in the e

GFR, or the need for renal replacement therapy, or death from renal causes,
are also very profound improvements in the care of diabetic patients. With
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renal problems so common in diabetic patients, these very significant renal

protections should be emphasized equally along with the cardiovascular
benefits. The renal protection results reinforce the value of SGLT-2
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Inhibitor therapy as important in the comprehensive management of type 2

diabetes with their well demonstrated reductions in the cardiovascular and
renal problems so common in type 2 diabetes patients.
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Conclusions from the report

This is an extremely important study, confirming the reduction of CV events
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in patients with Type 2 diabetes when they are treated with an SGLT-2
Inhibitor. Also, as stated above, the risk group of Type 2 diabetic patients
who benefitted for this therapy was expanded in this study. These two
reports, when taken together, indicate a class effect in the reduction of
cardiovascular and renal events when an SGLT-2 Inhibitor is used in higher
risk diabetic patients with Type 2 diabetes. A further more recently
published evaluation of this same data looks at the difference in event
reduction between the less severely ill primary prevention patients and more
 7

complicated secondary disease patients. This analysis shows that while

there is a greater absolute events reduction in the secondary patients, there is
no evidence of heterogenicity in the relative beneficial treatment effects in
the primary and secondary patients. (10)
Several questions accompany this report. The first is whether this benefit is
class effect for all three of the SGLT-2 Inhibitor agents. There has not yet
been a comparable study published with dapagliflozin, the third SGLT-2
Inhibitor in widespread use. However, with these two studies, there is good

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evidence for a class effect, since these two studies had nearly identically

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positive results.
A different study, the CVD-REAL study followed over 350,000 Type 2

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diabetic patients scattered over 6 nations (USA, UK, Germany, Sweden,
Norway, and Denmark). Patients were matched for propensity scores
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divided between those who were initiated on an SGLT-2 Inhibitor or other
glucose lowering therapy by their respective physicians. Over the
monitoring period of less than a year, the patients who were placed on
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SGLT-2 Inhibitor therapy had significant reductions in hospitalizations for
heart failure (HR, 0.61; p<0001). There also was a reduction in all-cause
mortality (HR, 0.49; p<000.1) and in the incidence of hospitalizations for
heart failure or all-cause mortality (HR, 0.54; p<000.1) (11)
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As a non-controlled, observational, community based study, this data is only

suggestive, but it is so strongly suggestive that it points to a very positive
class effect benefit since all three of the SGLT-2 Inhibitors were used in this
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study. (11) A similar retrospective, population based study from the UK

compared more than 22,000 Type 2 diabetic patients, 4444 of whom were on
dapagliflozin, over a 32-month period. The patients with Type 2 diabetes
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and previously diagnosed CV disease who were exposed to dapagliflozin

had a significantly reduced risk of all-cause mortality (HR, 0.50, 95% CI:
0.33 to 0.75; p=0.0001). Those Type 2 patients without previous CV disease
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also had a significant reduction is all-cause mortality (HR, 0.43; 95% CI:
0.25 to 0.74) (12). This is also indirect support for the SGLT-2 Inhibitor
benefit being class effect, and also to be applicable to most, if not all Type 2
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patients.
Along this line, a meta-analysis from 2016 of various studies using SGLT-2
Inhibitors found significant cardiovascular benefits, including a reduction in
major CV events (HR, 0.84; 95% CI 0.75 to 0.95; p=0.006), CV death (HR,
0.63; 95% CI 0.51-0.77; p<0.0001), heart failure (HR, 0.65; 95% CI 0.50 -
0.85;p=0.002) and all-cause mortality (HR 0.71; 95% CI, 0.61-0.83;
p<0.0001). They did not detect a benefit for non-fatal MI or angina, but did
notice an adverse effect on non-fatal stroke (HR 1.30; 95% CI 1.00-1.68;
 8

p=0.049). They did not notice any difference between the effects of the
three SGLT-2 Inhibitors. (13)
A careful examination of the details on both the canagliflozin study and the
previous empagliflozin paper, reveal details that shed significant light on the
mechanisms involved.
Clearly the benefits of the use of canagliflozin were the same across both the
dosage groups of canagliflozin, as were the benefits seen with both
empagliflozin doses used in the EMPA-REG trial. (1,2) Also, since all

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patients were managed by their physicians with other antidiabetic therapy,

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the difference between the glycated hemoglobin values in the two groups,
while marked at the onset of the study, was only about 0.2%- 0.3% in the

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later months of the study, not enough to account for the improvement in
events. (2) This is extremely similar to the changes seen in the EMPA-REG
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trial, raising the question as to the mechanism of the reduction in CV events.
(1)
However, there are a series of unanswered questions around this emerging
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research. The first question asks what is the mechanism for the benefit seen
in this study and the previous empagliflozin study? This author wrote a
similar Practice Pearl for the empagliflozin paper shortly after it came out.
(14) This author speculated that the mechanism was probably not related to
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the degree of glucose control, where the differences were modest, pointing
instead to an influence on the patients’ vascular tone, possibly through an
effect on the renin-angiotensin system, leading to a relaxation of the vascular
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tone and an unloading of the ventricle. (14) This assumption links together
the rapid reduction in heart failure admissions in both studies, along with the
reduction in blood pressure seen with SGLT-2 Inhibitor therapy.
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Other authors have drawn similar conclusions. Abdul-Ghani et al noted the

differences between the effects of the benefit of empagliflozin versus the
effects of liraglutide and pioglitazone. (15) Those authors also note the
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limited difference in glucose values, along with a history of other glucose

lowering trials showing no CV benefit, to direct them to look for another
mechanism. They also note the rapid onset of heart failure reductions along
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with the marked reduction in CV mortality with the SGLT-2 agent, and feel
that this indicates marked reduction in the vascular hemodynamics as the
major source of benefit. (15) Indeed, Verma et al have shown that short-
term empagliflozin treatment leads to a significant reduction in left
ventricular mass index and improves diastolic function. (16)
Other authors concur. Kaul also noted the rapid and dramatic hemodynamic
benefits which appear to be very important to the CV hemodynamics, while
noting the very modest differences in glucose measurements. (17) Finally,
 9

research by Januzzi et al evaluated the pattern of certain biomarkers in a post

hoc analysis of patients in an 104 week study of canagliflozin versus placebo.
(18) They found that the biomarkers NT-pro BNP and hsTn1, both of which
are markers of increased CV disease risk, rose over the two years in the
placebo patients but stayed steady in the canagliflozin patients. (18) This
early data points to the need for further research to determine the
mechanism(s) responsible for this benefit.
The trial of the GLP-1 liraglutide showed different benefits than the two

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SGLT-2 Inhibitor trials, suggesting that the mechanism for the benefit is

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probably different between SGLT-2 Inhibitor therapy and liraglutide.
Finally, the question of the apparent increased rate of amputation in the

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canagliflozin patients is difficult to understand. (2) The amputations were
primarily seen in patients with a history of amputation or peripheral vascular
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disease. (2) However, there has not been a proposed credible mechanism
why canagliflozin would lead to an increased rate of amputation, accepting
that the afflicted patients were at high risk for this complication since most
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of them had peripheral vascular disease and/or previous amputation (2) Was
the rate of amputation increased in the canagliflozin patients or was it
unusually low (by some random chance) in the placebo group, especially
since increased rates of amputation were not seen in the other canagliflozin
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trials? That is not clear, and we do not yet have amputation data from the
dapagliflozin or empagliflozin trials, to ascertain more accurately what the
baseline amputation risk in this population is. While the FDA has added an
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amputation warning to the canagliflozin prescribing information, the

European Medicines Agency has added an amputation warning to the
prescribing information of all three of the SGLT-2 Inhibitors. (19) These
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types of unusual and unexplainable adverse events are sometimes seen in

medication trials, like the increased bladder cancer rate noted with Farxiga,
which is also unexplained and probably represents an unusually reduced rate
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of bladder cancer in the placebo patients. (20)

For the practitioner, the CV event benefit is so significant with CV mortality
reductions that the limited risk of amputation can be addressed. Since the
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amputations were seen rarely and primarily in patients with previous

amputation and/or peripheral vascular disease, a cautious clinician could
simply avoid using these agents in this high-risk subgroup until further
research can produce more clarity in this question.
Further research on these agents is indicated, first to see if the CV protection
can be demonstrated in all Type 2 diabetic patients. Also, serious
consideration should be given to studying the SGLT-2 Inhibitors in heart
failure patients without diabetes to see if there is benefit in that disorder.
 10

Also, research comparing the CV events reduction efficacy between

liraglutide and an SGLT-2 Inhibitor, along with a combination arm of those
two therapies together needs to be conducted.
Therefore, as the research around the cardiovascular and renal protective
properties of the SGLT-2 Inhibitors becomes so clear, practitioners should
consider them premier agents in the management of Type 2 Diabetes, since
the risk of cardiovascular disease and renal dysfunction in those patients is
so profound. Concern about the amputation issue might lead careful

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practitioners to be cautious in patients with preexisting amputations or

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significant peripheral vascular disease. It will be interesting to see if the
American Diabetes Association or the endocrinology associations advisory

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panels will adopt the SGLT-2 Inhibitors as recommended therapy for nearly
all Type 2 patients or at least those with increased CV risk like those in the
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CANVAS studies to reduce their risk of CV disease.

Transparency
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Declaration of funding
None.
Declaration of financial/other interests
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R Guthrie has acted as a speaker for Janssen pharmaceuticals. The author
has no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
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the subject matter or materials discussed in the manuscript apart from those
disclosed. One of the peer reviewers of this manuscript had previously
received grant support from Boehringer Ingelheim. Two additional peer
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reviewers on this manuscript had no relevant financial relationships to

disclose.
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