Can J Diabetes 48 (2024) 415e424

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Canadian Journal of Diabetes

journal homepage:
www.canadianjournalofdiabetes.com

Special Article

Pharmacologic Glycemic Management of Type 2 Diabetes in

Adults—2024 Update
Diabetes Canada Clinical Practice Guidelines Expert Working Group:
Baiju R. Shah MD, FRCPC, PhD; Harpreet S. Bajaj MD, MPH, FACE;
Sonia Butalia MD, FRCPC, MSc; Kaberi Dasgupta MD, CM, MSc; Dean T. Eurich BSP, PhD;
Rahul Jain MD, CCFP, MScCH; Karen Leung MD, MSc, CCFP(COE);
Kerry Mansell BSP, PharmD, MBA; Scot Simpson BSP, PharmD, MSc

Key Messages medications to use depends on many factors, including glucose

levels, other health problems, and medication costs.
 Metformin should be the initial agent of choice in most people  Certain medications have specific benefits on the heart and the
with type 2 diabetes who require pharmacotherapy to reach kidneys for people who have these problems already. There-
glycemic targets. fore, these medications should be used by anybody with these
 Insulin should be initiated immediately, with or without met- problems, even if their glucose levels are already good.
formin, in individuals with metabolic decompensation and/or  Sometimes, people with type 2 diabetes also need insulin.
severe symptomatic hyperglycemia. Different types of insulin may be needed at different times of
 When glycated hemoglobin (A1C) is more than 1.5% above day. Other glucose-lowering medications are usually continued
target, other antihyperglycemic agents in combination with because they can reduce the amount of insulin needed.
metformin may be needed.  People with type 2 diabetes should discuss the pros and cons of
 Certain glucagon-like peptide-1 receptor agonists (GLP1-RAs) different treatment plans with their health-care providers to
and sodium-glucose cotransporter-2 (SGLT2) inhibitors should decide together on what approach is best.
be used for cardiorenal protection in people with high cardio-
vascular (CV) risk, heart failure (HF), or chronic kidney disease
Introduction
(CKD). These medications should be initiated if these comorbid-
ities or complications are already present at diagnosis or if they
The United Kingdom Prospective Diabetes Study (UKPDS)
develop over the person’s lifetime, even if the A1C is in target.
established the importance of glycemic management to reduce the
 Choice of additional antihyperglycemic agents, when treat-
risk of long-term complications in people with type 2 diabetes [1].
ment intensification is required to improve glycemia, should
More recently, clinical trials have demonstrated that certain
consider individual priorities, preferences, and comorbidities.
glucose-lowering medications can reduce cardiac and renal com-
Clinical priorities may include weight loss, avoidance of
plications of diabetes in certain populations, beyond the effects of
hypoglycemia, desired magnitude of glucose lowering, cost,
glucose lowering alone. We conducted a thorough review of the
side-effect profile, possibility of pregnancy, and comorbidities.
existing evidence to support people living with type 2 diabetes and
 Insulin regimens in type 2 diabetes should be tailored to the
their health-care providers in the selection of glucose-lowering
individual to reach individualized glycemic levels and mini-
agents. This review spanned the period from June 2020 to
mize the risk of hypoglycemia. Insulin should be introduced in
February 2023, and updates the last guideline published in 2020.
a stepwise approach, and other antihyperglycemic agents
This chapter focusses exclusively on pharmacologic glycemic
should be continued and/or initiated to further improve gly-
management for type 2 diabetes in adults. Physical activity [2], nutri-
cemia and reduce insulin dose requirements.
tion therapy [3], self-management education and support [4], and
weight management [5] are other important components of glycemic
Key Messages for People Living With Diabetes management for type 2 diabetes, and are discussed in their own
chapters. Similarly, related topics, such as targets for glycemic man-
 Most people who have type 2 diabetes will need glucose- agement [6], glucose monitoring [7], management of hypoglycemia [8],
lowering medications to reach their personal glucose targets. and remission of type 2 diabetes [9], are addressed in other chapters.
 Metformin is generally the first choice because of its
effectiveness, mild side effects, safety track record, and low cost. Initiating Pharmacotherapy
 Multiple medications that work in different ways may be
needed if glucose levels are very high, or if they remain high After counselling and support for health behaviour modification
with just 1 medication. The decision about which other is provided, pharmacotherapy may be required to reach glycemic
1499-2671/Ó 2024 Canadian Diabetes Association.
The Canadian Diabetes Association is the registered owner of the name Diabetes Canada.
https://doi.org/10.1016/j.jcjd.2024.08.002
416 B.R. Shah et al. / Can J Diabetes 48 (2024) 415e424

Figure 1. Pharmacotherapy for type 2 diabetes, to reach glycemic targets and optimize cardiorenal risk. A1C, glycated hemoglobin.

targets and to optimize cardiorenal risk (Figure 1). Metformin is the slow increase minimizes the risk of gastrointestinal side effects.
recommended first-line antihyperglycemic medication for most Minimal improvements in glucose occur at doses above this level.
people. The preference for metformin as the initial agent is based However, metformin cannot be used in everyone, such as those
on its durable efficacy in lowering A1C, absence of risk for hypo- with a history of lactic acidosis, an estimated glomerular filtration
glycemia or weight gain, relatively mild side-effect profile, long- rate (eGFR) <15 mL/min/1.73 m2, or severe hepatic dysfunction.
term safety track record, and affordability. Further, metformin People who have evidence of metabolic decompensation (e.g.
monotherapy in newly-diagnosed participants who had over- marked hyperglycemia, ketosis, hyperosmolar state or uninten-
weight in the UKPDS demonstrated CV and all-cause mortality tional weight loss related to hyperglycemia) and/or severe
benefits [10]. Metformin monotherapy has comparable A1C- symptomatic hyperglycemia (e.g. polyuria, polydipsia, or visual
lowering effects to sulfonylureas, but better glycemic durability blurring) should be started immediately on insulin, with or
[11], negligible risk of hypoglycemia [12], no weight gain [12,13], without metformin, regardless of A1C level. Once stable, it may be
and lower CV risk [13]. Metformin has better A1C lowering and possible to taper or discontinue insulin and replace it with other
weight loss than dipeptidyl peptidase-4 (DPP4) inhibitors [12,14]. agents as required. Even in the absence of metabolic decompen-
To date, no studies have demonstrated superiority of SGLT2 sation, people with marked hyperglycemia (e.g. A1C more than
inhibitors, GLP1-RAs, or glucose-dependent insulinotropic 1.5% above target) may require the initiation of other anti-
polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP1- hyperglycemic agents in combination with metformin at diag-
RAs) over metformin as first-line therapy in people newly diag- nosis for faster and greater improvements in glucose [15e20].
nosed with type 2 diabetes. Metformin should be started at a low These additional agents may be able to be reduced or withdrawn
dose (i.e. 250 mg or 500 mg twice daily with meals) and gradually over time if glycemia improves. Combining metformin with
increased over several weeks to a target dose of 2,000 mg daily. This another agent at the outset lowers average A1C values by 0.4% to
 B.R. Shah et al. / Can J Diabetes 48 (2024) 415e424 417

Table 1 1% more than metformin alone and increases the chances of

Antihyperglycemic agents for use in type 2 diabetes having an A1C <7% at 6 months by 40% [14e16,20]. The initial use
of multiple agents at submaximal doses has also been shown to
result in fewer side effects than monotherapy at maximal doses
[21e25].
Certain GLP1-RAs and SGLT2 inhibitors are demonstrated in
clinical trials to have specific benefits in people with high CV risk,
HF, or CKD, as discussed below. These agents should be used as
initial pharmacotherapy for individuals who already have these
comorbidities or complications at the time of type 2 diabetes
diagnosis. In general, initiating combination therapy of these
agents with metformin is recommended because the majority of
participants in these trials were on concomitant metformin
therapy.
A1C will typically decrease by about 0.5% to 1.5% with mono-
therapy, varying with the baseline A1C level and the specific agent
used. In general, the higher the baseline A1C, the greater the A1C
reduction observed for any given agent. However, the A1C-
lowering efficacy of SGLT2 inhibitors declines with decreasing
eGFR. The maximum effect of non-insulin antihyperglycemic agent
monotherapy generally occurs within 3 to 6 months [26,27].

Treatment Intensification or Modification

Over time, the function and number of beta cells can decline in
those with type 2 diabetes, which results in higher glucose levels
[28]. Thus, people with diabetes and their health-care providers
need to continually monitor glycemia and consider stepwise
intensification of pharmacotherapy when glycemic values rise
above targets.
When considering pharmacotherapy intensification, health-
care providers should first assess for and address potential pre-
cipitants of increasing A1C (e.g. infection, ischemia, concomitant
medications, changes in eating or physical activity). They should
also explore medication adherence and barriers to adherence,
such as adverse drug effects, costs, beliefs, and preferences. After
these assessments, dose adjustments and/or additional anti-
hyperglycemic medications may be considered, with a goal of
meeting the glycemic target within 3 to 6 months [29]. Health
behaviour interventions, including nutritional therapy and physical
activity, should continue to be optimized while pharmacotherapy is
being intensified. When new agents are added to improve glycemic
levels, existing glucose-lowering medications should generally be
continued unless contraindicated.
When selecting additional antihyperglycemic agents, agent-
specific advantages and disadvantages should be considered from
an individualized person-centred perspective. Factors to consider
include need and desire for weight loss, risks and importance of
preventing hypoglycemia, the magnitude of glucose lowering
required, costs and insurance coverage, adverse effect profiles, and
comorbidities (Table 1). Maximum doses are often determined by
renal function (eGFR), as indicated in Table 2. Simultaneous use of
agents within the same class or with similar mechanisms of action
(e.g. sulfonylureas and meglitinides; or DPP4 inhibitors, GIP/GLP1-
RAs and GLP1-RAs) is not recommended.
Several meta-analyses have summarized head-to-head com-
parisons of metformin-based combinations [12,14,30e32]. These
studies showed that combinations of metformin with sulfonyl-
ureas, thiazolidinediones, SGLT2 inhibitors, DPP4 inhibitors, or
GLP1-RAs have broadly comparable A1C-lowering benefits
[12,30e36]. In contrast, insulin does not have a dose limit and
would therefore be expected to have the greatest potential for A1C
lowering, although dose increases may be limited by hypoglycemia.
418 B.R. Shah et al. / Can J Diabetes 48 (2024) 415e424

Table 2
Maximum daily dose of glucose-lowering medications (regular release formulations unless specified with footnotes)

While glucose lowering is broadly similar across agents in Individuals at high CV risk
combination with metformin, impacts on hypoglycemia and weight
change differ. The risk of hypoglycemia is lower with incretins, Randomized trials [44e50] and meta-analyses of these trials
SGLT2 inhibitors, and thiazolidinediones compared to sulfonylureas [51e57] have demonstrated the benefits of certain GLP1-RAs and
and insulin [12,14,30e32,37,38]. Insulin, sulfonylureas, and thia- SGLT2 inhibitors in people with type 2 diabetes at high CV risk. The
zolidinediones are associated with the most weight gain (1.5 to 5.0 GLP1-RAs dulaglutide [44], liraglutide [45], and subcutaneous
kg), DPP4 inhibitors have a neutral effect on weight, while GIP/ semaglutide [46] reduce major adverse CV events (MACE) in people
GLP1-RAs, GLP1-RAs, and SGLT2 inhibitors lead to weight loss at high CV risk. Alongside CV disease benefits, there is evidence for
[12,14,30e32,39e42]. For the majority of people living with type 2 reductions in microvascular disease, including renal and retinal
diabetes, for whom weight loss is a priority, treatment intensifi- events, with these agents. Other GLP1-RAs, such as lixisenatide
cation with a GIP/GLP1-RA or GLP1-RA may be preferred as they can [58], long-acting exenatide [59], and oral semaglutide [60], have
induce weight loss and have negligible risk for hypoglycemia. not been shown to impact cardiorenal outcomes. Similarly, 4
SGLT2 inhibitors may also be preferred as they can also lead to some landmark trials have been completed with SGLT2 inhibitors in
weight loss and have negligible risk for hypoglycemia. Where people at high CV risk: CANVAS and CANVAS-R [47], EMPA-REG
financial barriers exist, sulfonylureas are the least expensive alter- OUTCOME [48], DECLARE-TIMI 58 [49], and VERTIS-CV [50]. Both
native. The safety of incretin agents or SGLT2 inhibitors in preg- canagliflozin and empagliflozin reduce MACE outcomes in this
nancy is unknown; therefore, these agents should be avoided or population; dapagliflozin and ertugliflozin do not. Individual
discontinued in women who are pregnant, planning a pregnancy, or components of the MACE composite endpoint have shown incon-
not using a reliable contraceptive method [43]. sistent effects between trials owing to low event rates, heteroge-
In some subgroups of people with type 2 diabetes, individual neity of study populations, and methodological decisions. Beyond
SGLT2 inhibitors and GLP1-RAs offer specific cardiorenal benefits. MACE, SGLT2 inhibitors have also shown reductions in HF and renal
These medications should be prioritized for individuals from these outcomes for individuals at high CV risk.
subgroups, and are indicated even if the A1C is in target. Evidence Importantly, however, the definition of “high CV risk” was quite
and recommendations for these subgroups are summarized below variable between these trials. Some recruited only people with
and in Figure 1. established CV disease, while most enrolled both those with
 B.R. Shah et al. / Can J Diabetes 48 (2024) 415e424 419

established CV disease and those at older ages with multiple CV risk lower dose of insulin [74], and may induce less weight gain and less
factors. There was significant heterogeneity across trials in the hypoglycemia than that seen when non-insulin antihyperglycemic
definitions of this latter group: the minimum age threshold ranged agents are stopped and insulin is used alone [75,76].
from 50 to 60; the list of eligible risk factors was variable (including Figure 2 summarizes a stepwise approach to insulin regimens
risk factors like hypertension, dyslipidemia, tobacco use, micro- for people with type 2 diabetes. As a first step, a single daily
albuminuria, left ventricular systolic or diastolic dysfunction, and injection of an intermediate-acting (NPH) [77] or long-acting
longer duration of diabetes); and some trials required 2 risk factors insulin analogue (insulin glargine U-100, insulin glargine U-300,
to be present in addition to age while others only required 1. insulin detemir, or insulin degludec) [78e80] may be added,
Meta-analyses of both the GLP1-RA trials [51e55] and the SGLT2 particularly for people with fasting hyperglycemia. Insulin icodec
inhibitor trials [55e57] found that the benefit of these agents was recently approved in Canada with once-weekly dosing; how-
among those with established CV disease was clear; however, the ever, it was not included in the literature review for this update and
benefit for those with multiple CV risk factors only was less certain. so is not discussed here. Incretins and SGLT2 inhibitors have been
In the absence of multiple CV risk factors, there is no robust shown to be efficacious at further lowering glucose levels when
evidence for the use of any specific second-line antihyperglycemic combined with insulin therapy [81e94]. These agents should
agent for the prevention of MACE. therefore be continued and/or initiated for people starting basal
insulin. The basal insulin dose should be titrated to the fasting
Individuals with HF glucose levels; insulin requirements will likely increase as diabetes
progresses, and higher doses may be needed over time.
Randomized controlled trials of dapagliflozin and empagliflozin If glycemia is suboptimal on treatment regimens that include
have demonstrated cardiorenal benefits for people who have HF basal insulin with other agents, bolus insulin at mealtimes (short-
with either reduced ejection fraction 40% [61,62] or preserved or rapid-acting analogues) may be added. Generally, once bolus
ejection fraction >40% [63,64]. Approximately one-half of individ- insulin is introduced into a treatment regimen, either as a separate
uals in these trials did not have diabetes. The benefits of dapagli- mealtime bolus or as part of a premixed regimen, insulin secreta-
flozin and empagliflozin were observed in the composite outcomes gogues, such as sulfonylureas and meglitinides, should be dis-
of CV death or hospitalization for HF across major subgroups, continued due to an increased risk for hypoglycemia. Concomitant
including those with and without diabetes, HF with reduced or therapy with metformin, incretins, and SGLT2 inhibitors should be
preserved ejection fraction, New York Heart Association functional continued with regimens containing bolus insulin to support gly-
class, and the presence or absence of CKD [65,66]. Furthermore, cemic management with less risk of weight gain and hypoglycemia
SGLT2 inhibitors may reduce MACE and renal outcomes in those [75,76,81e102]. Bolus insulin should be initiated using a stepwise
with a history of HF [67]. approach, starting with 1 injection at the largest meal and then
introducing additional mealtime injections later, if needed. This
Individuals with CKD approach was shown to be as efficacious at A1C lowering as a full
basal-bolus regimen, but is associated with less hypoglycemia and
Several large-scale randomized controlled trials have demon- greater satisfaction after 1 year [103]. Bolus insulin doses are
strated benefits of specific SGLT2 inhibitors on cardiorenal out- titrated to the postprandial glucose levels.
comes among people with CKD. The CREDENCE, DAPA-CKD, and Lower rates of hypoglycemia have been observed in some
EMPA-KIDNEY trials showed that canagliflozin, dapagliflozin, and studies of individuals with type 2 diabetes treated with rapid-
empagliflozin, respectively, are associated with a reduction in the acting insulin analogues compared to those treated with short-
composite outcome of death from renal or CV causes, end-stage acting (regular) insulin [104e107]. Use of long-acting basal insu-
renal disease, or worsening of serum creatinine or eGFR [68e70]. lin analogues reduces the relative risk of symptomatic and
Importantly, one-third of individuals in DAPA-CKD and more than nocturnal hypoglycemia compared to treatment with NPH insulin
one-half of individuals in EMPA-KIDNEY did not have type 2 dia- [104,108-110]. Insulin degludec is associated with lower rates of
betes, and subgroup analysis showed similar results between the overall, symptomatic, nocturnal, and severe hypoglycemia
participants with and without diabetes. These trials also showed compared to glargine U-100 [78,80,111e113]. There is also some
benefits of these agents on CV and HF endpoints among people evidence of lower hypoglycemia rates with glargine U-300
with CKD [71]. Meta-analyses of the CKD subgroups in the compared to glargine U-100 [114]. Efficacy and rates of hypogly-
atherosclerotic CV disease and HF trials of SGLT2 inhibitors simi- cemia are similar between glargine U-100 and detemir [115].
larly demonstrated benefits on CV, HF, and renal outcomes.
Although a similar meta-analysis of the CKD subgroups from GLP1-
RA trials did not demonstrate consistent benefits [72], the recently Recommendations
published FLOW trial specifically examined renal outcomes for
subcutaneous semaglutide in individuals with type 2 diabetes and Initial pharmacologic glycemic management
CKD [73]. However, this trial was not included in the literature
review for this update and so is not discussed here. 1. Physical activity, nutrition therapy, self-management educa-
tion and support, and weight management are important
Insulin Treatment With Type 2 Diabetes components of glycemic management for type 2 diabetes, both
at onset and throughout the course of the disease, and should
A combination of non-insulin antihyperglycemic agents and be incorporated into every person’s individualized care plan
insulin is often effective to manage glucose levels. The insulin [Grade D, Consensus].
regimen in type 2 diabetes should be tailored to the individual to 2. Once the decision to initiate pharmacotherapy is made, met-
reach their individualized glycemic levels and to minimize risk of formin is recommended as the initial antihyperglycemic
hypoglycemia. The mode of insulin administration (injections vs medication because of its durable efficacy in lowering A1C,
continuous subcutaneous infusion), the number of insulin injec- negligible risk for hypoglycemia or weight gain [12] [Grade A,
tions (1 to 4 per day), and the timing of injections will depend on Level 1A], relatively mild side-effect profile, long-term track
each individual’s situation. Adding insulin to non-insulin anti- record, and affordability. Initial dose should be low (250 mg or
hyperglycemic agents may result in better glycemic levels with a 500 mg twice daily with meals) to minimize risk of
420 B.R. Shah et al. / Can J Diabetes 48 (2024) 415e424

DECISION TO INITIATE INSULIN (from Figure 1)

Glycemic targets not met, or symptomatic hyperglycemia / metabolic decompensation

Basal
If cardiorenal comorbidities change, reassess other antihyperglycemic agents.

• Start basal insulin

• Titrate dose to meet fasting glucose target
• Continue to optimize other antihyperglycemic agents
Educate on prevention and management of hypoglycemia.

B L D bed

IF GLYCEMIC TARGETS NOT MET

Basal-Plus
• Add one injection per day of bolus insulin,
with the largest meal
• Titrate dose to meet postprandial glucose target
• Consider stopping secretagogues to prevent
hypoglycemia
B L D bed

IF GLYCEMIC TARGETS NOT MET

Basal-Bolus or Multiple Daily Injections

• Advance to multiple injections of bolus insulin at all meals

• Titrate doses to meet postprandial glucose target
• Avoid secretagogues

B L D bed

Figure 2. Stepwise approach to insulin regimens for people with type 2 diabetes. B, breakfast; D, dinner; L, lunch.

gastrointestinal side effects, with gradual increase to maximum Ongoing assessment

dose [Grade D, Consensus].
3. Insulin, with or without metformin, is recommended as initial 6. Dose adjustments, substitutions, and/or addition of other
pharmacologic therapy for individuals with metabolic decom- antihyperglycemic medications should be made in order to
pensation (e.g. marked hyperglycemia, ketosis, hyperosmolar reach the target A1C within 3 to 6 months [Grade D,
state, or unintentional weight loss related to hyperglycemia) Consensus].
and/or severe symptomatic hyperglycemia (polyuria, poly- 7. Cardiovascular and renal status should be reviewed at least
dipsia, visual blurring). Once metabolically stable, it may be annually to determine if treatment intensification or modifi-
possible to taper or discontinue insulin and replace it with cation is required [Grade D, Consensus].
other agents, as required [Grade D, Consensus]. 8. Before intensifying pharmacologic therapy, assess for potential
4. Even in the absence of metabolic decompensation, combina- precipitants of increasing A1C, such as infection, ischemia,
tion therapy is recommended as initial pharmacologic therapy concomitant medications, or changes in eating or physical
for people with marked hyperglycemia (e.g. A1C more than activity. Explore medication adherence and barriers to adher-
1.5% above target) [15,17,18] [Grade B, Level 2]. ence, such as adverse drug effects, costs, beliefs, and prefer-
a. Choice of the second agent to start alongside metformin ences [Grade D, Consensus].
should be based on the individual’s priorities, preferences,
and comorbidities [Grade D, Consensus].
5. For individuals with cardiovascular or renal comorbidities at Treatment intensification or modification
the time of diabetes diagnosis, specific GLP1-RAs and/or SGLT2
inhibitors should also be used as initial pharmacotherapy for 9. For individuals who do not have CV or renal comorbidities,
cardiorenal protection (see recommendation #10). choice of an antihyperglycemic medication when treatment
 B.R. Shah et al. / Can J Diabetes 48 (2024) 415e424 421

intensification is required should be based on the individual’s Author Disclosures

priorities, preferences, and comorbidities (see Figure 1 and
Table 1) [12]. Clinical priorities may include weight loss, B.R.S. is funded by the University of Toronto as the Novo Nordisk
avoidance of hypoglycemia, desired magnitude of glucose Research Chair in Equitable Care of Diabetes and Related Condi-
lowering, cost, side-effect profile, possibility of pregnancy, and tions; H.S.B. reports trial fees paid to his institution by Amgen,
comorbidities [Grade D, Consensus]. AstraZeneca, Anji, Biomea, Boehringer Ingelheim, Eli Lilly, Glaxo
10. Priority should be given to medications with specific car- SmithKline, Ionis, Kowa, Novartis, Novo Nordisk, and Pfizer; S.S.
diorenal benefits for certain subgroups of individuals, regard- reports research funding from Merck through their investigator-
less of the A1C level. initiated grant program; S.B., K.D., D.T.E., K.L., K.M., and R.J. have
a. A GLP1-RA and/or SGLT2 inhibitor with demonstrated evi- no conflicts to disclose.
dence of benefit is recommended for individuals at high CV
risk [44e48,51e57] [Grade A, Level 1A for dulaglutide, lir-
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