Can J Diabetes 40 (2016) 484486
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Canadian Journal of Diabetes
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w w w. c a n a d i a n j o u r n a l o f d i a b e t e s . c o m
Policies, Guidelines, and Consensus Statements
Pharmacologic Management of Type 2 Diabetes: 2016 Interim Update
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
The initial draft of this commentary was prepared by Gillian Booth MD, FRCPC,
Lorraine Lipscombe MD, MSc, FRCPC, Sonia Butalia MD, MSc, FRCPC, Kaberi Dasgupta MD, MSc, FRCPC,
Dean Eurich PhD, MSc, Ronald Goldenberg MD, FRCPC, FACE, Nadia Khan MD, MSc, FRCPC,
Lori MacCallum BScPhm, PharmD, CDE, Baiju Shah MD, PhD, FRCPC, Scot Simpson BScPhm, PharmD, MSc,
Robyn L. Houlden MD, FRCPC on behalf of the Steering Committee for the Canadian Diabetes Association
2018 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 19 September 2016
Accepted 19 September 2016
The Canadian Diabetes Association Clinical Practice Guidelines
(CPGs) for the Prevention and Management of Diabetes in Canada
are formally updated in a 5-year cycle in order to provide compre-
hensive, evidence-based recommendations for healthcare profes-
sionals (1). However, interim updates are published in light of new
evidence that is considered to be practice changing, as was the case
following the publication of the Empagliozin Cardiovascular
Outcome Event (EMPA-REG OUTCOME) trial (2), which demon-
strated the cardioprotective effect of empagliozin in patients with
type 2 diabetes and clinical cardiovascular disease. This interim
update provides a revised recommendation based on the Liraglutide
Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome
Results (LEADER) trial (3).
Since the last update (4), a second publication from the EMPA-
REG OUTCOME trial has been published, rearming the clinical ben-
ets of empagliozin in patients with pre-existing cardiovascular
disease (5). The rst publication, in 2015, reported signicantly fewer
major adverse cardiovascular events in those taking empagliozin
compared to placebo, including lower rates of hospitalizations due
to heart failure as well as to cardiovascular death and death from
any cause (2). In a secondary analysis, empagliozin was also
associated with a signicant reduction in hospitalizations for
congestive heart failure (4.1% vs. 2.7%) (HR 0.65; 95% CI 0.50 to
0.85; p<0.002), corresponding to a number-needed-to-treat of 71
over 3 years or 213 per year (5). Although this nding is compel-
ling, we await results from further trials of sodium/glucose
co-transporter 2 (SGLT2) inhibitors to conrm this benet.
Further analyses published in June 2016 now show a signi-
cantly lower risk for major adverse renal outcomes in those who
received empagliozin (6). After a median observation period of
3.1 years, participants in the pooled empagliozin group had sig-
1499-2671 2016 Canadian Diabetes Association.
http://dx.doi.org/10.1016/j.jcjd.2016.09.003
nicantly fewer microvascular outcomes than those allocated to
placebo, driven primarily by a reduction in progression to
macroalbuminuria, a doubling of serum creatinine and initiation of
renal replacement therapy, with relative risk reductions ranging from
38% to 55% (6).
The LEADER trial, published in June 2016, also demonstrated the
benets of the glucagon-like peptide 1 receptor agonist (GLP1 recep-
tor agonist) liraglutide in a high-risk population of patients with
type 2 diabetes similar to that of the EMPA-REG OUTCOME trial (3).
The LEADER trial enrolled 9340 patients with long-standing type 2
diabetes (median duration 12.8 years) and glycated hemoglobin
(A1C) levels 7%. The majority of participants (81%) were at least
50 years of age or older and had at least 1 co-existing cardiovas-
cular condition (coronary heart disease, cerebrovascular disease,
peripheral arterial disease, chronic heart failure or stage 3 or higher
chronic kidney disease). The remaining participants were 60 years
of age or older and had at least 1 co-existing cardiovascular risk
factor. Participants were randomized to receive liraglutide 1.8 mg
(or the maximally tolerated dose) or a matched placebo adminis-
tered subcutaneously once daily in addition to standard care. Over
a median follow up of 3.8 years, fewer patients in the liraglutide
arm compared to placebo had the primary endpoint of nonfatal myo-
cardial infarction, nonfatal stroke or cardiovascular death (14.9% vs.
13%, respectively; HR 0.87, 95% CI 0.78 to 0.97), fullling both the
statistical criteria for noninferiority (p<0.001) and for superiority
(p=0.01). This nding corresponds to a number-needed-to-treat of
66 over 3 years or 198 per year. The rate of cardiovascular death
and death from any cause was also signicantly lower in the group
receiving liraglutide compared with the group receiving placebo
(4.7% vs. 6%; HR 0.78, 95% CI 0.66 to 0.93; and 8.2% vs. 9.6%; HR 0.85,
95% CI 0.74 to 0.97, respectively) as was the rate of microvascular
 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee / Can J Diabetes 40 (2016) 484486
endpoints, primarily because of fewer nephropathy events. Unlike
the EMPA-REG OUTCOME trial, there was no signicant reduction
in hospitalizations for heart failure for people taking liraglutide.
Intermediary endpoints were also more favourable in the group
receiving liraglutide; compared to placebo, the treatment group
had a 0.4% lower mean A1C level, a 2.3 kg greater weight loss and a
1.2 mm Hg lower systolic blood pressure. A greater number of par-
ticipants in the liraglutide than the placebo group discontinued their
medication due to adverse side effects (largely gastrointestinal). Acute
gallstone disease was also more common in patients receiving
liraglutide, whereas severe hypoglycemia was more common in the
placebo group, likely due to greater use of insulin and sulfonylureas
in this group.
The many strengths of the LEADER trial include its random-
ized, double-blinded placebo-controlled study design and near com-
plete assessment of participants for study outcomes. Vital status
was known in virtually all (99.7%) participants, and 96.8% had a nal
visit or study outcome or died. One limitation is that the studys
duration was insucient to make conclusions about long-term safety.
For example, the study was not powered to evaluate the effects of
liraglutide on cancer risk. There was a nonsignicantly higher
number of cases of pancreatic cancer in the liraglutide group, but
higher numbers of several nonpancreatic cancers in the placebo
group. Overall, a very low number of pancreatic cancer events were
observed (0.3% and 0.1% for liraglutide and placebo, respectively).
Another limitation is that the study recruited participants over
50 years of age only, with or at high risk for cardiovascular events.
Therefore, the studys ndings may not be generalizable to younger
individuals with type 2 diabetes or those at lower cardiovascular
risk. It is important to acknowledge that although the EMPA-REG
OUTCOME trial permitted recruitment of participants younger than
50 years of age, the age distributions of the 2 studies were similar;
only a small percentage of subjects in the EMPA-REG OUTCOME trial
were younger than 50 years of age (2).
The subgroup analyses in the LEADER trial should be inter-
preted with caution, given the small number of patients and the
few events observed. For example, the subgroup analysis of primary
prevention suggested that this group had less benet than those
with pre-existing cardiovascular disease (3). However, no conclu-
sion can be made about the safety and ecacy of liraglutide in
primary prevention because the subgroup of 1742 subjects without
cardiovascular disease (18.7% of the total) accounted for only 137
of the 1302 (10.5%) primary outcome events in the trial (3). Fur-
thermore, only 8.9% of subjects had chronic kidney disease (glo-
merular ltration rate <60 mL/min/1.73 m2) without cardiovascular
disease, and the rate of events in this small subgroup was not
reported. Also, only 3.9% of the population were antihyperglycemic
agent-naive, accounting for only 4% of primary events, suggesting
that the LEADER trial results are applicable only to patients requir-
ing add-on antihyperglycemic agent therapy.
Given that LEADER was a placebo-controlled trial and did not allow
for head-to-head comparisons of various agents, no conclusions can
be made about how the cardioprotective properties of liraglutide com-
pared to other agents from a different class, such as empagliozin,
or to agents from the same class. The Evaluation of Lixisenatide in
Acute Coronary Syndrome (ELIXA) trial did not demonstrate any car-
diovascular benet of lixisenatide in high-risk patients with type 2
diabetes (7). There were some notable differences in eligibility cri-
teria between the 2 studies, leading to some differences in popula-
tion characteristics. For example, baseline A1C levels were higher in
participants enrolled in the LEADER trial than in those in the ELIXA
trial. It is unknown whether the variation in outcomes across studies
is due to differences in trial design or in the cardiovascular effects of
different drugs within the class of GLP1 receptor agonists. Finally, as
is the case with most CV outcome studies, the ELIXA trial was of insuf-
cient duration to detect longer-term adverse effects, and the inclu-
485
sion of relatively healthier patients in clinical trials may underestimate
potential real-world harms of therapies.
The revised algorithm for the management of hyperglycemia in
type 2 diabetes is summarized in Figure 1, which integrates the
updated ndings from the LEADER and EMPA-REG OUTCOME trials.
As highlighted in the previous update, the presence of clinical car-
diovascular disease and the effect of antihyperglycemic agents on
cardiovascular outcomes should be considered the top priority in
choosing add-on treatment regimens for patients with type 2 dia-
betes. The algorithm for management, as illustrated in the gure,
now recommends that an antihyperglycemic agent with demon-
strated cardiovascular outcome benets, such as empagliozin or
liraglutide, should be added if glycemic targets are not met in
patients with clinical cardiovascular disease. The gure provides
further information about the agents that have cardiovascular
outcome trial data and the results of such trials (superiority, neu-
trality or inferiority). As future cardiovascular outcome trials of
antihyperglycemic agents are published, the guidelines commit-
tee will continue to assess new evidence and update recommen-
dations and the algorithm.
Recommendations (changes from earlier 2016 interim update
are in bold)
1. In people with a new diagnosis of type 2 diabetes:
i. Metformin may be used at the time of diagnosis, in con-
junction with lifestyle management (Grade D, Consensus).
ii. If A1C <8.5% and glycemic targets are not achieved
using lifestyle management within 2 to 3 months,
antihyperglycemic agent therapy with metformin should be
initiated (Grade A, Level 1A) (8).
iii. If A1C levels are 8.5%, antihyperglycemic agents should be
initiated concomitantly with lifestyle management, and con-
sideration should be given to initiating combination therapy
with 2 agents, 1 of which may be insulin (Grade D,
Consensus).
iv. Individuals with symptomatic hyperglycemia and
metabolic decompensation should receive an initial
antihyperglycemic regimen containing insulin with or
without metformin (Grade D, Consensus).
2. Metformin should be the initial drug used in monotherapy
(Grade A, Level 1A) (9,10) for overweight patients (Grade D, Con-
sensus for non-overweight patients).
3. Other classes of antihyperglycemic agents, including insulin,
should be added to metformin, or used in combination with
each other, if glycemic targets are not met, taking into account
the information in the gure and the table available at
http://guidelines.diabetes.ca/update (Grade D, Consensus), and
these adjustments to and/or additions of antihyperglycemic
agents should be made in order to attain target A1C levels within
3 to 6 months (Grade D, Consensus).
4. In adults with type 2 diabetes with clinical cardiovascular
disease in whom glycemic targets are not met, an
antihyperglycemic agent with demonstrated cardiovascu-
lar outcome benet should be added to reduce the risk of
major cardiovascular events (Grade 1, Level 1A for
empagliozin (2); Grade 1, Level 1A for liraglutide if age 50
years (3); Grade D, Consensus for liraglutide if age <50 years).
5. Choice of additional pharmacologic treatment agents should
be individualized by patients characteristics, taking into con-
sideration (Grade D, Consensus):
Degree of hyperglycemia
Risk of hypoglycemia
Overweight or obesity
Cardiovascular disease or multiple risk factors
486 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee / Can J Diabetes 40 (2016) 484486

At diagnosis of type 2 diabetes

Comorbidities (renal, congestive heart failure, hepatic, etc.)
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin Preferences of the patient
Symptomatic hyperglycemia Access to treatment
A1C <8.5% A1C 8.5%
with metabolic decompensation 6. When basal insulin is added to antihyperglycemic agents, long-
acting analogues (detemir or glargine) may be used instead of
If not at glycemic target
Start metformin immediately.
Initiate intermediate-acting Neutral Protamine Hagedorn (NPH) to
Consider initial combination with
(2-3 mos)
another antihyperglycemic agent.
insulin +/- metformin reduce the risk for nocturnal and symptomatic hypoglycemia
(Grade A, Level 1A) (1113).
Start/Increase metformin If not at glycemic targets 7. When bolus insulin is added to antihyperglycemic agents, rapid-
acting analogues may be used instead of regular insulin to
Add another agent best suited to the individual by prioritizing patient characteristics: improve glycemic control (Grade B, Level 2) (14) and to reduce
PATIENT CHARACTERISTIC CHOICE OF AGENT the risk for hypoglycemia (Grade D, Consensus).
Antihyperglycemic agent with 8. All individuals with type 2 diabetes currently using or start-
Priority:
demonstrated CV outcome benet ing therapy with insulin or insulin secretagogues should be
Clinical cardiovascular disease
(empagliozin, liraglutide)
counselled about the prevention, recognition and treatment of
Degree of hyperglycemia Consider relative A1C lowering
Risk of hypoglycemia Rare hypoglycemia drug-induced hypoglycemia (Grade D, Consensus).
Overweight or obesity Weight loss or weight neutral
Cardiovascular disease or multiple risk factors Effect on cardiovascular outcome
Comorbidities (renal, CHF, hepatic) See therapeutic considerations, consider eGFR
Preferences & access to treatment See cost column; consider access

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alo=alogliptin; empa=empagliozin; glar=glargine; lira=liraglutide
lixi=lixisenatide; saxa=saxagliptin; sita=sitagliptin

If not at glycemic targets

Add another agent from a different class Add/Intensify insulin regimen

Make timely adjustments to attain target A1C within 3-6 months

Figure 1. Revised algorithm for the management of hyperglycemia in type 2 diabetes.