Table 1.

Antihyperglycemic agents for use in type 2 diabetes

EXPECTED RELATIVE HYPO- EFFECT IN OTHER
DRUG DECREASE A1C GLYCEMIA CV OUTCOME THERAPEUTIC
IN A1C LOWERING TRIAL CONSIDERATIONS

Class* and Mechanism of Action

ALPHA-GLUCOSIDASE INHIBITOR: inhibits pancreatic alpha-amylase and intestinal alpha-glucosidase

Not recommended as initial

therapy in people with marked
Negligible risk hyperglycemia
Acarbose (Glucobay) 0.6% as (A1C 8.5%)
monotherapy Weight neutral as monotherapy
GI side effects

Class* and Mechanism of Action

DPP-4 INHIBITOR: amplifies incretin pathway activation by inhibition of enzymatic breakdown of endogenous GLP-1 and GIP

Weight neutral
Alogliptin (Nesina) Neutral
Improved post-prandial control
Rare cases of pancreatitis
Linagliptin (Trajenta) Negligible
Caution with saxagliptin in heart
0.7% risk as
failure
Sitagliptin (Januvia) monotherapy Neutral

Saxagliptin (Onglyza) Neutral

Class* and Mechanism of Action

GLP-1 RECEPTOR AGONIST: activates incretin pathway by utilizing DPP-4 resistant analogue to GLP-1

Improved postprandial control

Albiglutide (Eperzan)
Significant weight loss
Nausea and vomiting
Dulaglutide (Trulicity)
Administration parenteral
Rare cases of pancreatitis
Exenatide (Byetta) Negligible Parafollicular cell hyperplasia
1.0% to risk as
Contraindicated with personal/
Exenatide QW (Bydureon) monotherapy family history of medullary thyroid
cancer or multiple endocrine
Superiority in neoplasia syndrome type 2
Liraglutide (Victoza) T2DM patients
with clinical CVD

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 EXPECTED RELATIVE HYPO- EFFECT IN OTHER
DRUG DECREASE A1C GLYCEMIA CV OUTCOME THERAPEUTIC
IN A1C LOWERING TRIAL CONSIDERATIONS

Class* and Mechanism of Action

INSULIN: activates insulin receptors to regulate metabolism of carbohydrate, fat, and protein

Bolus (prandial) Insulins Potentially greatest A1C reduction

Rapid-acting analogues and no maximal dose
Aspart (NovoRapid) Numerous formulations and
Glulisine (Apidra) delivery systems (including
Lispro (Humalog) subcutaneous-injectable)
Lispro U200 Allows for regimen flexibility
(Humalog U200) When initiating insulin, consider
Short-acting adding bedtime long-acting
Regular (Humulin-R, basal analogue or intermediate-
Novolin geToronto) acting NPH to daytime oral
antihyperglycemic agents
(Note: Pork regular insulin (although other regimens
[Hypurin Regular Insulin can be used)
Pork] and pork isophane Basal-bolus regimen recommended
insulin [Hypurin NPH Insulin if above fails to attain glycemic
Isophane] are available but Significant targets
rarely used) 0.9 1.1% risk Increased risk of weight gain
relative to sulfonylureas and
Basal Insulins metformin
Intermediate-acting
NPH (Humulin-N,
Novolin ge NPH)
Long-acting basal
analogues
Detemir (Levemir) Neutral (glargine)
Glargine (Basaglar, Lantus) (detemir)
Glargine U300 (Toujeo)

(Note: Pork isophane insulin

[Hypurin NPH Insulin
Isophane] is available but
rarely used)
Premixed Insulins
Premixed Regular-NPH
(Humulin 30/70; Novolin ge
30/70, 40/60, 50/50)
Biphasic insulin aspart Significant
0.9 1.1% risk

(NovoMix 30)
Insulin lispro/lispro
protamine suspension
(Humalog Mix25, Mix50)

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 EXPECTED RELATIVE HYPO- EFFECT IN OTHER
DRUG DECREASE A1C GLYCEMIA CV OUTCOME THERAPEUTIC
IN A1C LOWERING TRIAL CONSIDERATIONS

Class* and Mechanism of Action

INSULIN SECRETAGOGUE: activates sulfonylurea receptor on beta cell to stimulate endogenous insulin secretion

Sulfonylureas Relatively rapid BG-lowering

response
Gliclazide Minimal/
All insulin secretagogues reduce
(Diamicron, Diamicron MR, moderate
glycemia similarly (except
generic) risk
nateglinide, which is less effective)
Post-prandial glycemia is especially
Glimepiride Moderate
reduced by meglitinides
(Amaryl) risk
Hypoglycemia and weight gain are
especially common with glyburide
0.8% Consider using other class(es)
Glyburide of antihyperglycemic agents
(Diabeta, Euglucon, generic) first in patients at high risk of
Significant
(Note: Chlorpropamide and hypoglycemia (e.g. the elderly,
risk
Tolbutamide are available renal/hepatic failure)
but rarely used) If a sulfonylurea must be used
in such individuals, gliclazide
is associated with the lowest
Meglitinides incidence of hypoglycemia
and glimepiride is associated
with less hypoglycemia than
Nateglinide
(Starlix)
glyburide
Minimal/ Nateglinide and repaglinide are
0.7% moderate associated with less hypoglycemia
risk than sulfonylureas due to their
Repaglinide shorter duration of action allowing
(GlucoNorm)
medication to be held when
forgoing a meal

Class* and Mechanism of Action

METFORMIN: enhances insulin sensitivity in liver and peripheral tissues by activation of AMP-activated protein kinase

Improved cardiovascular outcomes

in overweight subjects
C  ontraindicated if CrCl/eGFR
<30 mL/min or hepatic failure
Caution if CrCl/eGFR <60 mL/min
Negligible Weight neutral as monotherapy,
Metformin
(Glucophage, Glumetza)
1.0 1.5% risk as promotes less weight gain
monotherapy when combined with other
antihyperglycemic agents,
including insulin
B12 deficiency
GI side effects

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 EXPECTED RELATIVE HYPO- EFFECT IN OTHER
DRUG DECREASE A1C GLYCEMIA CV OUTCOME THERAPEUTIC
IN A1C LOWERING TRIAL CONSIDERATIONS

Class* and Mechanism of Action

SODIUM-GLUCOSE LINKED TRANSPORTER 2 (SGLT2) INHIBITOR: enhances urinary glucose excretion by inhibiting glucose
reabsorption in the proximal renal tubule

Canagliflozin (Invokana) Genital infections, UTI, hypotension,

dose-related changes in LDL-C,
Dapagliflozin (Forxiga) caution with renal dysfunction and

Negligible loop diuretics, dapagliflozin not to be
Empagliflozin (Jardiance) 0.7 1.0% to risk as used if bladder cancer, rare diabetic
monotherapy Superiority in ketoacidosis (may occur with no
T2DM patients hyperglycemia
with clinical CVD

Class* and Mechanism of Action

THIAZOLIDINEDIONE (TZD): enhances insulin sensitivity in peripheral tissues and liver by activation of peroxisome
proliferator-activated receptor-gamma receptors

Pioglitazone (Actos) Longer duration of glycemic control

with monotherapy compared to
metformin or glyburide
Mild BP lowering
Between 6 and 12 weeks required
Neutral to achieve full glycemic effect
Weight gain
May induce edema and/or
congestive heart failure
Contraindicated in patients
Negligible with known clinical heart failure
0.8% risk as or evidence of left ventricular
Rosiglitazone (Avandia) monotherapy dysfunction on echocardiogram or
other heart imaging
Higher rates of heart failure when
combined with insulin
Neutral Rare occurrence of macular edema
Higher occurrence of fractures
Cardiovascular controversy
(rosiglitazone)
Rare risk bladder cancer with
pioglitazone

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 EXPECTED RELATIVE HYPO- EFFECT IN OTHER
DRUG DECREASE A1C GLYCEMIA CV OUTCOME THERAPEUTIC
IN A1C LOWERING TRIAL CONSIDERATIONS

Class* and Mechanism of Action

WEIGHT LOSS AGENT: inhibits lipase

Orlistat (Xenical) Promote weight loss

0.5% None Orlistat can cause diarrhea and
other GI side effects
COMBINED FORMULATIONS

Avandamet See relative See expected See metformin, TZDs, DPP-4

(metformin + rosiglitazone) A1C lowering decrease inhibitors, and sulfonylureas
for each in A1C for Negligible risk
of the each of the as
components components monotherapy
added to added to
metformin metformin

Avandaryl Moderate
(glimepiride + rosiglitazone)
1.6% risk

Janumet/Janumet XR
(metformin/metformin ER
+ sitagliptin)
Jentadueto See relative See expected
(linagliptin + metformin) A1C lowering decrease
for each in A1C for Negligible risk
Kazano of the each of the as
(alogliptin + metformin)
components components monotherapy
Komboglyze added to added to
(metformin + saxagliptin) metformin metformin

Xigduo
(dapagliflozin + metformin)

Oseni Negligible risk

(alogliptin + pioglitazone) 1.5% as
monotherapy

A1C, glycated hemoglobin; BG, blood glucose; BP, blood pressure; CrCl, creatinine clearance; CV, cardiovascular; DPP-4, dipeptidyl peptidase 4;
eGFR, estimated glomerular filtration rate; GI, gastrointestinal; GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide 1; AMP, adenosine monophosphate.
Physicians should refer to the most recent edition of the Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, Ontario, Canada)
for product monographs and detailed prescribing information.
* Listed in alphabetical order.
A1C percentage/relative reduction expected when agent from this class is added to metformin therapy with exception of metformin where A1C
percentage/relative reduction reflects expected monotherapy efficacy.
Combining insulin with a TZD is not an approved indication in Canada.
Adapted from multiple references. See chapters on Pharmacologic Management of T2D for more details:
http://guidelines.diabetes.ca/browse/chapter13
http://guidelines.diabetes.ca/update

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