This commentary provides an interim update to the 2013 Canadian Diabetes Association Clinical Practice Guidelines regarding the pharmacologic management of type 2 diabetes. It discusses the approval of a new class of antihyperglycemic agents, sodium-glucose cotransporter-2 (SGLT2) inhibitors, in Canada since the 2013 guidelines. The commentary summarizes the efficacy, safety considerations, and place in therapy of SGLT2 inhibitors based on current evidence. Metformin remains the initial pharmacologic treatment of choice for type 2 diabetes, and SGLT2 inhibitors can be considered as additional treatment options based on individual patient characteristics.

1. 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-François 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
significant 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 agentsdsodium-
glucose 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: canagliflozin and dapagliflozin
(2). This update was deemed necessary by the steering committee
because the addition of a new class of pharmacologic therapy
represents a significant 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 meta-
analyses show that, when added to metformin, SGLT2
inhibitors generally have similar or slightly better efficacy in
lowering glycated hemoglobin levels than do other anti-
hyperglycemic 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 dapagliflozin 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 difficulty, nausea,
vomiting, abdominal pain, confusion or fatigue, even in the
absence of high blood glucose, should be evaluated for ketoaci-
dosis. If the ketoacidosis is confirmed, 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 sum-
marizes the therapeutic considerations for SGLT2 inhibitor
therapy in the management of type 2 diabetes mellitus. The
efficacy of SGLT2 inhibitors with respect to glucose lowering is
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Can J Diabetes 39 (2015) 250e252

2. 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.
W. Harper / Can J Diabetes 39 (2015) 250e252 251

3. 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 first 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
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mps/prodpharma/notices-avis/index-eng.php. Accessed March 6, 2015.
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ema/index.jspcurl=pages/medicines/human/referrals/SGLT2_inhibitors/human_
referral_prac_000052.jsp&mid=WC0b01ac05805c516f. Accessed 19 June 2015.
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15. Harper W, Clement M, Goldenberg R, et al. Canadian Diabetes
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(Suppl 1):S61e8.
Figure 2. Antihyperglycemic medications and renal function. Based on product monograph precautions. CKD, chronic kidney disease; GFR, glomerular filtration rate;
TZD, thiazolidinedione. Designed by and used with the permission of Jean-François Yale MD CSPQ FRCPC.
W. Harper / Can J Diabetes 39 (2015) 250e252252