JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES

2018, VOL. 8, NO. 5, 267–268

https://doi.org/10.1080/20009666.2018.1521245

Canagliflozin and Cardiovascular disease- results of the CANVAS trial

Syed Raza Shaha, Najla Issa Najimb, Zainab Abbasic, Mazia Fatimad, Ayesha Altaf Jangdae, Waqas Shahnawazf,
Maira Shahidc and Syed Arbab Shahe
a
Department of Internal Medicine, North Florida Regional Medical Center, University of Central Florida, Gainesville, FL, USA;
b
Department of Internal Medicine, National Children Hospital, Washington DC, USA; cDepartment of Internal Medicine, Dow University
of Health Sciences (DUHS), Karachi, Pakistan; dDepartment of Internal Medicine, Post Doc Fellow Cardiology at Beth Israel Deaconess
Medical Center, Boston, USA; eDepartment of Internal Medicine, Ziauddin Medical University Hospital, Karachi, Pakistan; fDepartment of
Internal Medicine, Agha Khan University Hospital, Karachi, Pakistan

ABSTRACT ARTICLE HISTORY

Canagliflozin is a new novel oral antidiabetic agent belonging to the class of sodium–glucose Received 25 March 2018
co-transporter 2 (SGLT2) inhibitors, inhibiting glucose reabsorption in the proximal tubule, Accepted 31 August 2018
leading to increased urinary glucose excretion and subsequently to reduction in plasma
glucose concentration, in individuals with hyperglycemia. Before the approval of canagliflozin KEYWORDS
by the Food and Drug Administration (FDA) in 2013, a pair-wise meta-analyses of trials Canaglifozin; CANVAS trial;
involving canagliflozin did not differ from control in terms of all-cause mortality, cardiovas- cardiovascular
cular death, myocardial infarction, and stroke. However, no large, randomized-controlled trials
were available for comparison until the results of the CANVAS (Canagliflozin Cardiovascular
Assessment Study) trial were published. The CANVAS Trial was designed to assess the
cardiovascular safety and efficacy of canagliflozin. Recently, results of the completed
CANVAS Trial were released which showed patients with type 2 diabetes and established
cardiovascular disease or at high risk for cardiovascular events who were treated with
canagliflozin had significantly lower rates of the primary cardiovascular outcome than
patients assigned to placebo. All three components of the primary outcome – death from
cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke – showed point
estimates of effect that suggested benefit .These results may represent a significant additional
therapeutic tool in the clinical prevention and management of cardiovascular mortality and
morbidity. However, data on the long-term efficacy on the use of Canagliflozin is still
incomplete and their use in patients with type 2 diabetes should be carefully considered.

By 2030, it is estimated that diabetes will affect
440 million people [1]. Currently, 90% of the popula-
tion is affected by type 2 variant of diabetes which is
associated with higher morbidity rate given that the
risk for developing cardiovascular disease is twofold
in diabetic patients [2]. Newer novel agents have been
around the market to control glucose levels to accep-
table range. Canaglifozin, a sodium–glucose co-
transporter 2 (SGLT2) inhibitor, is one of the newer
novel agents [3]. It inhibits glucose reabsorption in
the kidneys via the proximal tubules and subse-
quently leads to reduction in plasma glucose concen-
tration [4]. In addition, the mechanism of action of
SGLT2 inhibitors is complementary and not alterna-
tive to the mechanisms of other antidiabetic agents.
Thus, SGLT2 inhibitors are suitable for use in a
combination of approaches.
Before the approval of canagliflozin by the Food
and Drug Administration (FDA) in 2013, a pair-wise
meta-analyses of trials involving canagliflozin did not
differ significantly from control in terms of all-cause
mortality and myocardial infarction while results
were similar in sensitivity analyses including only
placebo-controlled trials [5]. Furthermore, no signifi-
cant risk reduction was seen in cardiovascular death
and non-fatal infarctions as compared to other agents
[6]. However, no large, randomized-controlled trials
were available for comparison until the results of the
CANVAS (Canagliflozin Cardiovascular Assessment
Study) trial were published.
The CANVAS Trial, comprising 10,142 partici-
pants, was designed to assess the cardiovascular safety
and efficacy of canagliflozin. CANVAS trial was
initiated in 2009 with the goal to evaluate cardiovas-
cular safety, however, the first approval from the
Food and Drug Administration (FDA) was not avail-
able until 2013. Owing to the inclusion of unmasked
interim cardiovascular outcome data in the regulatory
filing documents, a planned expansion of the sample
size to enable a test of cardiovascular protection was
not undertaken.
Recently, results of the completed CANVAS Trial
were released. These results are encouraging–patients
with type 2 diabetes and established cardiovascular

CONTACT Syed Raza Shah syedraza91shah@live.com Department of Internal Medicine, North Florida Regional Medical Center, University of
Central Florida, Gainesville, FL, USA
© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/),
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
268 S. R. SHAH
disease or at high risk for cardiovascular events who
were treated with canagliflozin had significantly lower
rates of the primary cardiovascular outcome than
patients assigned to placebo [7]. All the components
of the primary outcome including death from cardi-
ovascular causes and nonfatal myocardial infarction
showed point estimates of effect that suggested [7].
The results also showed that patients treated with
canagliflozin had a lower risk of hospitalization for
heart failure than patients who received placebo [7].
Robust long-term cardiovascular evidence for
canagliflozin from the CANVAS trial showed a sig-
nificant benefit of the use of the drug in cardiovas-
cular patients. The study benefits from the large size
of the combined trials, the long duration of the trials,
the randomized design, the breadth of included par-
ticipants, and the high standard to which the conduct
of the trials was held. They may represent a signifi-
cant additional therapeutic tool in the clinical pre-
vention and management of cardiovascular mortality
and morbidity. However, data on the long-term effi-
cacy on the use of Canagliflozin is still incomplete, as
the drug is relatively new, and their use in patients
with type 2 diabetes should be carefully considered.
However, while advances in technologies have helped
elucidate many aspects of these diseases, many mys-
teries still remain. With continued research, we can
expect more cost- effective and patient-friendly drug
therapies to be developed in the near future. Besides,
side effects of particular newer novel drugs in post-
marketing surveillance should be highlighted and well
documented, especially in regions where these proto-
cols are routinely followed. It is anticipated that the
results of the CANVAS trial will soon be implemen-
ted in international guidelines.
Acknowledgments
None declared.
Disclosure statement
No potential conflict of interest was reported by the author.
References
[1] Farag YM, Gaballa MR. Diabesity: an overview of a
rising epidemic. Nephrol Dial Transplant. 2011;26
(1):28–35.
[2] Sarwar N, Gao P, Sarwar N, et al. Emerging risk factors
collaboration diabetes mellitus, fasting blood glucose
concentration, and risk of vascular disease: a collabora-
tive meta-analysis of 102 prospective studies. Lancet.
2010;375(9733):2215–2222.
[3] Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin
and progression of kidney disease in type 2 diabetes. N
Engl J Med. 2016;375:323–334.
[4] Neal B, Perkovic V, de Zeeuw D, et al. Rationale,
design, and baseline characteristics of the
Canagliflozin Cardiovascular Assessment Study
(CANVAS) — a randomized placebo-controlled trial.
Am Heart J. 2013;166:217–223.e11.
[5] Monami M, Dicembrini I, Mannucci E. Effects of
SGLT-2 inhibitors on mortality and cardiovascular
events: a comprehensive meta-analysis of rando-
mized controlled trials. Acta Diabetol. 2017;54
(1):19–36.
[6] Tang H, Fang Z, Wang T, et al. Meta-analysis of effects
of sodium-glucose cotransporter 2 inhibitors on cardi-
ovascular outcomes and all-cause mortality among
patients with type 2 diabetes mellitus. Am J Cardiol.
2016;118(11):1774–1780.
[7] Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS
Program Collaborative Group. Canagliflozin and cardi-
ovascular and renal events in type 2 diabetes. N Engl J
Med. 2017 Jun 12;377:644–657.