Can J Diabetes 39 (2015) 250e252

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Canadian Journal of Diabetes

journal homepage:
www.canadianjournalofdiabetes.com

Commentary

Policies, Guidelines and Consensus Statements: Pharmacologic

Management of Type 2 Diabetese2015 Interim Update
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
The initial draft of this commentary was prepared by William Harper MD, FRCPC, Maureen Clement MD,
CCFP, Ronald Goldenberg MD, FRCPC, FACE, Amir Hanna MB, BCh, FRCPC, FACP, Andrea Main BScPhm,
CDE, Ravi Retnakaran MD, MSc, FRCPC, Diana Sherifali RN, PhD, CDE, Vincent Woo MD, FRCPC,
Jean-Franois Yale MD, CSPQ, FRCPC, and Alice Y.Y. Cheng MD, FRCPC on behalf of the Steering
Committee for the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention
and Management of Diabetes in Canada
a r t i c l e i n f o
Article history:
Received 13 May 2015
Accepted 13 May 2015

The process of the development of the Canadian Diabetes

Association 2013 Clinical Practice Guidelines for the Prevention and
Management of Diabetes in Canada included provisions to update
individual chapters prior to the planned published revision in 2018
(1). An updated literature search that focused on new evidence
published since the development of the 2013 guidelines yielded
1787 citations. After review of these citations, the chapter authors
advised the steering and executive committees that there were no
signicant changes in evidence to warrant the formulation of
any new recommendations or the revision of any current
recommendations. As such, it was recommended that a full update
of the chapter be deferred until the planned revision of the entire
Clinical Practice Guidelines in 2018.
However, the steering committee decided it was warranted to
publish an interim commentary addressing the approval, in
Canada, of a new class of antihyperglycemic agentsdsodiumglucose linked transporter 2 (SGLT2) inhibitorsdfor the
pharmacologic management of diabetes. Two agents from this class
have received notice of compliance by Health Canada since the
publication of the 2013 guidelines: canagliozin and dapagliozin
(2). This update was deemed necessary by the steering committee
because the addition of a new class of pharmacologic therapy
represents a signicant change in the management options for
diabetes, yet the next complete update of the guidelines is still 3
years away.
SGLT2 inhibitors block glucose transport in the proximal renal
tubule, which results in the urinary excretion of glucose, thereby
lowering blood glucose and body weight (3,4). Network metaanalyses show that, when added to metformin, SGLT2
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inhibitors generally have similar or slightly better efcacy in

lowering glycated hemoglobin levels than do other antihyperglycemic agents (5,6). The incidence of hypoglycemia with
SGLT2 inhibitors is rare unless they are used in combination with
insulin or sulfonylureas (3). Because of the glycosuria resulting
from the use of these agents, there is an increased risk for urinary
tract infections, genital mycotic infections and hypotension
caused by osmotic diuresis (3). Although SGLT2 inhibitors lower
blood pressure (3) and raise high-density lipoprotein cholesterol,
they elevate low-density lipoprotein cholesterol modestly (7,8),
and their cardiovascular safety remains unknown and awaits
long-term clinical trials. An imbalance in bladder cancer was
noted with dapagliozin in early clinical trials; however, many of
the subjects with bladder cancer had pre-existing hematuria (9).
There have been reported cases of diabetic ketoacidosis, without
the usual elevated blood glucose, in patients with type 2 diabetes
being treated with SGLT2 inhibitors (10e13). These cases are rare
and further details await ongoing reviews. Patients on an SGLT2
inhibitor with symptoms of breathing difculty, nausea,
vomiting, abdominal pain, confusion or fatigue, even in the
absence of high blood glucose, should be evaluated for ketoacidosis. If the ketoacidosis is conrmed, appropriate measures
should be undertaken to correct the acidosis. The SGLT2
inhibitor therapy should be interrupted and its subsequent long
term use should be reassessed (10,13). Use of SGLT2 inhibitors
is not currently approved for type 1 diabetes. Figure 1 summarizes the therapeutic considerations for SGLT2 inhibitor
therapy in the management of type 2 diabetes mellitus. The
efcacy of SGLT2 inhibitors with respect to glucose lowering is

W. Harper / Can J Diabetes 39 (2015) 250e252

251

Figure 1. Management of hyperglycemia in type 2 diabetes. A1C, glycated hemoglobin; BG, blood glucose; CHF, congestive heart failure; DPP-4, dipeptidyl peptidase 4;
GI, gastrointestinal; GLP-1, glucagon-like peptide 1; SGLT2, sodium glucose linked transporter 2; TZD, thiazolidinedione; UTI, urinary tract infection.

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W. Harper / Can J Diabetes 39 (2015) 250e252

Figure 2. Antihyperglycemic medications and renal function. Based on product monograph precautions. CKD, chronic kidney disease; GFR, glomerular ltration rate;
TZD, thiazolidinedione. Designed by and used with the permission of Jean-Franois Yale MD CSPQ FRCPC.

dependent on their effects on urinary glucose excretion, which

is attenuated in patients with renal dysfunction (14). Figure 2
summarizes the contraindications to use of SGLT2 inhibitors
in patients with declining renal function based on product
monographs.
In the pharmacologic management of type 2 diabetes,
metformin remains the rst agent of choice (15). SGLT2 inhibitors
are a new class of antihyperglycemic agents available for the
treatment of diabetes in Canada, and their use can be considered in
management plans individualized to meet patients characteristics,
as outlined in Figure 1.
References
1. Booth G, Cheng AYY. Canadian Diabetes Association 2013 Clinical Practice
Guidelines for the Prevention and Management of Diabetes in Canada:
Methods. Can J Diabetes 2013;37(Supp l1):S4e7.
2. Health Canada Notice of Compliance Database. http://www.hc-sc.gc.ca/dhpmps/prodpharma/notices-avis/index-eng.php. Accessed March 6, 2015.
3. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose
cotransporter 2 inhibitors for type 2 diabetes. A systematic review and
meta-analysis. Ann Intern Med 2013;159:262e74.
4. Bolinder J, Ljunggren O, Johansson L, et al. Dapagliozin maintains glycaemic
control while reducing weight and body fat mass over 2 years in patients with
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6. Pacou M, Taieb V, Abrams KR, et al. Bayesian network meta-analysis to assess

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10. U.S. Food and Drug Administration Drug Safety Communication. FDA warns
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much acid in the blood. Available from http://www.fda.gov/Drugs/DrugSafety/
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delivery. Accessed 15 May 2015.
11. European Medicines Agency Review Notice. Review of diabetes medicines
called SGLT2 inhibitors started. Available from http://www.ema.europa.eu/
ema/index.jspcurl=pages/medicines/human/referrals/SGLT2_inhibitors/human_
referral_prac_000052.jsp&mid=WC0b01ac05805c516f. Accessed 19 June 2015.
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advisories-avis/forxiga-invokana-eng.php. Accessed June 22, 2015.
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weeks in patients with type 2 diabetes mellitus and chronic kidney disease.
Diabetes Obes Metab 2014;16:1016e27.
15. Harper W, Clement M, Goldenberg R, et al. Canadian Diabetes
Association 2013 Clinical Practice Guidelines for the Prevention and
Management of Diabetes in Canada: Methods. Can J Diabetes 2013;37(Suppl 1):S61e8.