Type 2 Diabetes: Non-Insulin Pharmacotherapy

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This tool is designed to support primary care providers to prescribe and manage non-insulin pharmacotherapy for adult patients living with type 2 diabetes. This is an update of the original Achieving glycemic control in type 2 diabetes tool, released in 2012.

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Diagnostic criteria for diabetes

Fasting plasma glucose (FPG) ≥7.0 mmol/L^*; OR
A1C ≥6.5%^†; OR
2-hour plasma glucose (2hPG) in a 75g oral glucose tolerance test (OGTT) ≥11.1 mmol/L; OR
Random^‡ plasma glucose (PG) ≥11.1 mmol/L

* = fasting – no caloric intake for at least 8 hours
† = using a standardized, validated assay in the absence of factors that affect the accuracy of the A1C
‡ = random – anytime of the day, without regard to the interval since the last meal

The decision of which test to use for diabetes diagnosis is left to clinical judgment. Each diagnostic test has advantages and disadvantages.

Diagnosis of diabetes is confirmed if:

Symptomatic hyperglycemia is present (therefore confirmatory tests are not required); OR
The results of two laboratory tests are in the diabetes range (in the absence of symptomatic hyperglycemia)
- The second confirmatory laboratory test must be done on another day, and it is preferable that the same test be repeated for confirmation (in a timely fashion, based on clinical judgment), with the exception of random PG.

Factors that affect A1C:

Factors that can increase A1C: iron deficiency, B12 deficiency, $ erythropoiesis, alcoholism, chronic renal failure, splenectomy
Factors that can decrease A1C: use of erythropoietin, iron or B12, reticulocytosis, chronic liver disease, ingestion of acetylsalicylic acid, vitamin C/E, decreased erythrocyte lifespan (e.g., chronic renal failure, hemoglobinopathies, splenomegaly, rheumatoid arthritis, antiretrovirals, ribavirin, dapsone)

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A1C targets and considerations for glycemic control New

Individualize (and reassess) targets considering potential benefits and harms to the patient, and according to each patient’s:

Age and/or frailty
Comorbidities
Prognosis
Duration of diabetes

Risk of hypoglycemia
Patient preferences resources and support system number
Complexity and burden of medications

Clinical Frailty Scale:¹¹

Score

Target A1C

8.0%
8.5%
Avoid symptomatic hyper/hypoglycemia

A1C targets

Some adults:
If easy/safe to achieve, without hypoglycemia (e.g., with lifestyle modification and metformin). In others, risks of an A1C of ≤6.5% may warrant deintensification of therapy.^3,5

“Most” adults:
Guidelines differ on the target recommended for “most” adults, however they consistently note the need to individualize treatment intensity and therapy based on patient factors. To achieve A1C ≤ 7.0%, target:

FPG 4.0–7.0 mmol/L and/or
PPG 5.0–10.0 mmol/L or if A1C not at target, aim for PPG 5.0–8.0 mmol/L

HOWEVER, this must be balanced against the risk of hypoglycemia.

Functionally dependent adults (Clinical Frailty Scale¹¹ score = 4-5, on a 9 point scale):

Deintensification (e.g., reducing dose, discontinuation) of therapy in older, frail adults is often appropriate to reduce potential harms (e.g., hypoglycemia, risk of polypharmacy, lack of time-to-benefit).

Adults with cardiovascular disease/risk:
Patients with A1Cs in the range of 7.3-7.9% have demonstrated reductions in cardiovascular, renal, and/or mortality outcomes. However studies featured a specific drug (an SGLT2i, GLP1-RA, or metformin) and demographic, rather than merely the intensity of glycemic control.^6-10

Frail older adults (Clinical Frailty Scale¹¹ score = 6-8, on a 9 point scale) and/or adults with dementia, limited life expectancy or a history of recurrent severe hypoglycemia and/or hypoglycemia unawareness.

Note: A1C tends to rise over time, even for patients on stable treatments.

Management of hyperglycemia in type 2 diabetes New

Management of hyperglycemia in type 2 diabetes

At diagnosis of type 2 diabetes Start and support the ongoing maintenance of healthy lifestyle interventions (nutritional therapy, weight management, physical activity) +/- metformin

Lifestyle interventions have a greater potential for A1C lowering than any pharmacotherapy (nutrition A1C 1-2% and exercise A1C 0.5-0.7%)¹³

Select individualized A1C target

A1C less than 1.5% above target

A1C ≥ 1.5% above target

Symptomatic hyperglycemia and/or metabolic decompensation (may include dehydration, diabetic ketoacidosis, hyperosmolar hyperglycemic state)

See A1C targets and considerations for glycemic control

A1C < 1.5% above target

Start metformin plus a second antihyperglycemic agent, and:

Check renal function before starting agent
Monitor for hypoglycemia when on multiple agents of different classes

A1C ≥ 1.5% above target

Start metformin plus a second antihyperglycemic agent, and:

Check renal function before starting agent
Monitor for hypoglycemia when on multiple agents of different classes

Symptomatic hyperglycemia and/or metabolic decompensation

Initiate insulin +/-
See Type 2 diabetes: insulin therapy

If patient is not at A1C target

at 3 months

in 3-6 months and/or change in clinical status

Not at A1C target at 3 months

Start metformin (if not already started)
Adjust or advance therapy

Not at A1C target in 3-6 months and/or change in clinical status

(e.g., changes in cardiovascular or renal status, presence of diabetes complications, side effects, and ability to take current medications).

Does patient have:

Atherosclerotic cardiovascular disease OR
Chronic kidney disease OR
Heart failure OR
Age > 60 years with at least 2 cardiovascular risk factors: smoking (tobacco use), hypertension (untreated BP ≥ 140/95 or current antihypertensive therapy), dyslipidemia (use of lipid-modifying therapy or a documented untreated LDL > 3.4 mmol/L, or HDL-C < 1.0 mmol/L for men and < 1.3 mmol/L for women, or triglycerides > 2.3 mmol/L), central obesity (waist circumference of ≥ 80cm for females, ≥ 90-94cm for males)

Yes

Add or substitute another antihyperglycemic agent based on shared decision-making factors (see Shared decision-making)

Add or substitute another antihyperglycemic agent with demonstrated cardiorenal benefits

Non-insulin pharmacotherapy New

Shared decision-making

Shared decision-making is an approach to clinical decision-making in which patients and providers jointly consider clinical factors and patient preferences to arrive at a mutually agreeable decision.¹⁴ Shared decision-making aims to bridge the information gap between patients and providers while prioritizing patient autonomy.¹⁴

Engage patients in a discussion regarding which of the following factors are most important to them:^15,16

Use this information and a shared decision-making approach to support patients in deciding which diabetes therapy they would prefer.

Affordability of therapy for 100 day supply

Green = < $100
Yellow = $100-$400
Red = > $400

Avoiding therapy that requires injections

Yellow = weekly injection
Red = daily injection

Avoiding therapy that increases risk of hypoglycemia

Red = risk of hypoglycemia

Therapy that provides cardiovascular benefits

Green = cardiovascular benefit
Red = cardiovascular risk (e.g., worsening MI or heart failure)

Therapy that fits with daily routine

Green = twice daily or less administration
Yellow = ranges from once daily to 3+ daily
Red = 3+ administration per day, inconvenient

Avoiding therapy that has gastrointestinal side effects

Red = gastrointestinal side effects are common

Therapy that impacts weight change

Green = decreases weight
Red = increases weight

Therapy that provides kidney protection

Green = provides kidney protection
Red = may cause acute renal injury

Non-insulin pharmacotherapy

See definitions of acronyms used throughout the following pharmacotherapy cards

First line options

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Biguanides
Metformin HCL / Glucophage®
Agent with evidence-based outcome benefits

Generic available

Formulations: 500mg tab and 850mg tab

Coverage: 500mg tab ODB 𝙓 NIHB✓; 850mg NIHB✓

A1C reduction (%)^12,18: 1.0

Dose¹⁸: Initial: 250–500mg po daily cc; Usual: 1000mg po bid cc OR 1700mg cc am and 850mg cc pm; Max: 2550mg daily OR 850mg tid

Renal dose^12,18: eGFR 30-45mL/min (≤1000mg daily); eGFR <30mL/min (avoid*)
*Sometimes used at low dose when eGFR between 15-30 mL/min in renally stable patients

Drug cost for usual dose* ($/100 days)¹⁷:
Generic: $20 (1g bid) to $80 (850mg tid); Trade: $140
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Metformin HCL / Glucophage®

Other benefits, CVD outcomes^12,18

Reduced MI in overweight (>120% IBW) patients

Reduced all-cause mortality

Reduced insulin requirements

Reduced risk of lactic acidosis

Weight^12,18

Loss of up to 2.9kg in 5 years²⁰

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

GI intolerance

Vitamin B12 deficiency

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up every 1–2 weeks to avoid GI AE

Take with largest meal to minimize GI AE

85% of max glucose lowering seen at 1500 mg daily

Fewer GI side effects with ER formulation

Monitor: hemoglobin and vitamin B12 deficiency (annually), SCr (baseline and periodically)

On SADMANS list²¹
Biguanides
Metformin HCL / Glumetza®
Agent with evidence-based outcome benefits

Generic available

Formulations: 500mg extended release tab and 1000mg extended release tab

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 1.0

Dose¹⁸: Initial: 250–500mg po daily cc; Usual: 11000–2000mg po cc pm; Max: 2550mg daily

Renal dose^12,18: eGFR 30-45mL/min (≤1000mg daily); eGFR <30mL/min (avoid*)
*Sometimes used at low dose when eGFR between 15-30 mL/min in renally stable patients

Drug cost for usual dose* ($/100 days)¹⁷:
Generic: $120 (1g/d) to $235 (2g/d); Trade: $300 (2g/d)
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Metformin HCL / Glumetza®

Other benefits, CVD outcomes^12,18

Reduced MI in overweight (>120% IBW) patients

Reduced all-cause mortality

Reduced insulin requirements

Reduced risk of lactic acidosis

Weight^12,18

Loss of up to 2.9kg in 5 years²⁰

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

GI intolerance

Vitamin B12 deficiency

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up every 1–2 weeks to avoid GI AE

Take with largest meal to minimize GI AE

85% of max glucose lowering seen at 1500 mg daily

Fewer GI side effects with ER formulation

Monitor: hemoglobin and vitamin B12 deficiency (annually), SCr (baseline and periodically)

On SADMANS list²¹

Second line options

Avoid combining Dipeptidyl peptidase-4 inhibitor (DPP4i) with Glucagon-like peptide-1 receptor agonists (GLP1-RA).
Insulin secretagogues – sulfonylureas: Risk of hypoglycemia: gliclazide < glimepiride < glyburide

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Alpha-glucosidase inhibitor
Acarbose / Glucobay®

Generic available

Formulations: 50mg tab and 100mg tab

Coverage: ODB✓ (LU 175, 176) NIHB ✓

A1C reduction (%)^12,18: 0.7-0.8

Dose¹⁸: Initial: 25mg po daily cc; Usual: 50–100mg po tid cc; Max: 100mg po tid cc

Renal dose^12,18: eGFR<25-30mL/min (contraindication)

Drug cost for usual dose* ($/100 days)¹⁷:
Generic: $74 to $100
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Acarbose / Glucobay®

Other benefits, CVD outcomes^12,18

Improved postprandial control

Weight^12,18

Neutral effect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

GI intolerance, flatulence, diarrhea

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up every 1–2 weeks until 50 mg tid to avoid GI AE; then every 4–8 weeks

Max effect may take weeks

Take with first bite of meal

Monitor: SCr and LFTs (baseline and periodically)
DPP4i
Alogliptin / Nesina®

NOT on Ontario drug formulary

Formulations²³: 6.25mg tab, 12.5mg tab, 25mg tab

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.5–0.7

Dose¹⁸: 25mg po daily

Renal dose^12,18: eGFR 30-50mL/min (12.5mg po daily); eGFR <30mL/min (6.25mg po daily)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $265
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Alogliptin / Nesina®

Other benefits, CVD outcomes^12,18

Improved postprandial control

Well tolerated option in older adults

Neutral effect on CVD outcomes

Weight^12,18

Neutral effect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Pancreatitis (rare), severe joint pain (rare)

Alogliptin: possible worsening of HF in patients with acute coronary syndrome without a history of HF

Saxagliptin: HF

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline, especially for alogliptin)

Alogliptin: may increase LFTs

Linagliptin: no dosage adjustment in renal impairment; Saxagliptin: avoid in HF
DPP4i
Linagliptin / Trajenta®

Formulations: 5mg tab

Coverage: ODB ✓ NIHB✓

A1C reduction (%)^12,18: 0.5–0.7

Dose¹⁸: 5mg po daily

Renal dose^12,18: eGFR <15mL/min (use with caution). No dosage adjustment.

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $297
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Linagliptin / Trajenta®

Other benefits, CVD outcomes^12,18

Improved postprandial control

Well tolerated option in older adults

Neutral effect on CVD outcomes

Weight^12,18

Neutral effect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Pancreatitis (rare), severe joint pain (rare)

Alogliptin: possible worsening of HF in patients with acute coronary syndrome without a history of HF

Saxagliptin: HF

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline, especially for alogliptin)

Alogliptin: may increase LFTs

Linagliptin: no dosage adjustment in renal impairment; Saxagliptin: avoid in HF
DPP4i
Saxagliptin / Onglyza®

Formulations: 2.5mg tab and 5mg tab

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 0.5–0.7

Dose¹⁸: 5mg po daily

Renal dose^12,18: eGFR <50mL/min (2.5mg po daily) eGFR <15mL/min (use alternative agent)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $337
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Saxagliptin / Onglyza®

Other benefits, CVD outcomes^12,18

Improved postprandial control

Well tolerated option in older adults

Neutral effect on CVD outcomes

Weight^12,18

Neutral effect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Pancreatitis (rare), severe joint pain (rare)

Alogliptin: possible worsening of HF in patients with acute coronary syndrome without a history of HF

Saxagliptin: HF

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline, especially for alogliptin)

Alogliptin: may increase LFTs

Linagliptin: no dosage adjustment in renal impairment; Saxagliptin: avoid in HF
DPP4i
Sitagliptin / Januvia®

Formulations: 25mg tab, 50mg tab, 100mg tab

Coverage: ODB ✓ NIHB ✓ (for patients who did not achieve glycemic control or who demonstrated intolerance to an adequate trial of metformin and a sulfonylurea)

A1C reduction (%)^12,18: 0.5–0.7

Dose¹⁸: 100mg po daily

Renal dose^12,18: eGFR 30-49mL/min (50mg po daily); eGFR <30mL/min, hemodialysis, peritoneal dialysis, chronic kidney disease (25mg po daily)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $354
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Sitagliptin / Januvia®

Other benefits, CVD outcomes^12,18

Improved postprandial control

Well tolerated option in older adults

Neutral effect on CVD outcomes

Weight^12,18

Neutral effect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Pancreatitis (rare), severe joint pain (rare)

Alogliptin: possible worsening of HF in patients with acute coronary syndrome without a history of HF

Saxagliptin: HF

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline, especially for alogliptin)

Alogliptin: may increase LFTs

Linagliptin: no dosage adjustment in renal impairment; Saxagliptin: avoid in HF
GLP1-RA – short acting
Exenatide / Byetta®

NOT on Ontario drug formulary

Formulations²⁴: Pre-filled pen (multiuse) 250μg/mL, 1.2mL, 2.4mL Pk

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.4

Dose¹⁸: Initial/Usual: 5μg SC bid ac, prior to main meals ≥6 hour apart; Max: 10μg SC bid ac

Renal dose^12,18: eGFR <50mL/ min (caution), <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $510
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Exenatide / Byetta®

Other benefits, CVD outcomes^12,18

Unknown

Weight^12,18

Loss of 1.6-3kg1

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects acute pancreatitis/gallstone disease (rare)

Contraindicated with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Comments^12,18 (titration, administration, monitoring, notes)

Administer within 60 minutes before meal

Injection daily or once weekly

Initiate 5ug SC bid within 60 mins ac x 1 month, then 10ug bid

If no improvement in blood glucose control after 3-4 months, consider alternatives

Monitor: SCr (baseline and periodically)

Less A1C lowering with short-acting agents than long-acting agents
GLP1-RA – short acting
Lixisenatide / Adlyxine®

Formulations²⁴: Pre-filled pen (multiuse) 0.05mg/mL, 0.1mg/mL; 3mL Pk

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 0.6-1.4

Dose¹⁸: Initial: 10mcg SC daily ac x 2 weeks; Usual/Max: 20mcg SC daily ac

Renal dose^12,18: eGFR <15-20mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $419
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Lixisenatide / Adlyxine®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes

Weight^12,18

Loss of 1.6-3kg1

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects acute pancreatitis/gallstone disease (rare)

Contraindicated with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Comments^12,18 (titration, administration, monitoring, notes)

Start 10ug SC daily within the hour prior to any meal of the day x 2 weeks then 20ug SC daily

If not tolerated, the dose can be temporarily reduced to 10ug SC daily and consider increasing the dose to 20ug SC once daily within 4 weeks

Monitor: SCr (baseline and periodically)
GLP1-RA – longer acting
Dulaglutide / Trulicity®
Agent with evidence-based outcome benefits

NOT on Ontario drug formulary

Formulations²⁵: Pre-filled pen(single use) 0.75mg/0.5ml; 1.5mg/0.5ml

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.4

Dose¹⁸: Initial: 0.75mg SC once weekly; Usual/Max: 1.5mg SC once weekly

Renal dose^12,18: eGFR <15mL/min (caution)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $720 (12 weeks)
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Dulaglutide / Trulicity®

Other benefits, CVD outcomes^12,18

Decreased MACE in patients with clinical CVD

Weight^12,18

Loss of 1.6-3kg¹

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects (less GI side effects with weekly GLP1-RA vs daily), acute pancreatitis/ gallstone disease (rare)

Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 C-cell/thyroid tumors in animals)

SC semaglutide: Increased retinopathy complications seen in 1 trial in those with retinopathy history (3.0% vs. 1.8% placebo in 2 year trial)

Although similar:

Saxenda® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes or dyslipidemia) and who have failed a previous weight management intervention

Victoza® is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control

Comments^12,18 (titration, administration, monitoring, notes)

With or without meals

Monitor: SCr (baseline and periodically)

Single use disposable (environmental impact)
GLP1-RA – longer acting
Exenatide / Bydureon®

NOT on Ontario drug formulary

Formulations²⁶: ER pen (powder, single use) 2mg

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.4

Dose¹⁸: 2mg SC once weekly (must reconstitute)

Renal dose^12,18: eGFR <50mL/min (caution), <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $775 (12 weeks)
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Exenatide / Bydureon®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes

Weight^12,18

Loss of 1.6-3kg¹

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects (less GI side effects with weekly GLP1-RA vs daily), acute pancreatitis/ gallstone disease (rare)

Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 C-cell/thyroid tumors in animals)

SC semaglutide: Increased retinopathy complications seen in 1 trial in those with retinopathy history (3.0% vs. 1.8% placebo in 2 year trial)

Although similar:

Saxenda® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes or dyslipidemia) and who have failed a previous weight management intervention

Victoza® is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control

Comments^12,18 (titration, administration, monitoring, notes)

With or without meals

Monitor: SCr (baseline and periodically)

Supplied as a powder suspension to be reconstituted into a solution
GLP1-RA – longer acting
Liraglutide / Victoza®
Agent with evidence-based outcome benefits

NOT on Ontario drug formulary

Formulations²⁷: Pre-filled pen (multiuse): 6mg/mL; 3mL Pk

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.4

Dose¹⁸: Initial: 0.6mg SC daily; Usual: After ≥1 week, increase 1.2mg SC daily x 1 week, then 1.8mg SC daily; Max: 1.8mg/d

Renal dose^12,18: eGFR <15-30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade : $1095 (1.8mg SC daily x 100 days)
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Liraglutide / Victoza®

Other benefits, CVD outcomes^12,18

Decreased CV death in patients with clinical CVD

Decreased MACE in patients with clinical CVD

Decreased nephropathy progression

Weight^12,18

Loss of 1.6-3kg¹

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects (less GI side effects with weekly GLP1-RA vs daily), acute pancreatitis/ gallstone disease (rare)

Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 C-cell/thyroid tumors in animals)

SC semaglutide: Increased retinopathy complications seen in 1 trial in those with retinopathy history (3.0% vs. 1.8% placebo in 2 year trial)

Although similar:

Saxenda® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes or dyslipidemia) and who have failed a previous weight management intervention

Victoza® is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control

Comments^12,18 (titration, administration, monitoring, notes)

Administer without regard for meals

Titrate up after 1 week to reduce GI AE (see usual dose)

If >3 missed doses, restart at 0.6mg daily and titrate

Monitor: SCr (baseline and periodically)
GLP1-RA – longer acting
Liraglutide / Saxenda®

Formulations²⁷: Pre-filled 6mg/mL, Pen 5x3mL

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.4

Dose¹⁸: Initial: 0.6mg SC daily; Usual:After ≥1 week, increase 1.2mg SC daily x 1 week, then 1.8mg SC daily x 1 week, then 2.4mg SC daily x 1 week, then 3.0mg; Max: 3.0mg/d

Renal dose^12,18: eGFR <15-30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade : $1095 (1.8mg SC daily x 100 days)
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Liraglutide / Saxenda®

Other benefits, CVD outcomes^12,18

Decreased CV death in patients with clinical CVD

Decreased MACE in patients with clinical CVD

Decreased nephropathy progression

Weight^12,18

Loss of 1.6-3kg¹

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects (less GI side effects with weekly GLP1-RA vs daily), acute pancreatitis/ gallstone disease (rare)

Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 C-cell/thyroid tumors in animals)

SC semaglutide: Increased retinopathy complications seen in 1 trial in those with retinopathy history (3.0% vs. 1.8% placebo in 2 year trial)

Although similar:

Saxenda® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes or dyslipidemia) and who have failed a previous weight management intervention

Victoza® is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control

Comments^12,18 (titration, administration, monitoring, notes)

Administer without regard for meals

Titrate up after 1 week to reduce GI AE (see usual dose)

If >3 missed doses, restart at 0.6mg daily and titrate

Monitor: SCr (baseline and periodically)
GLP1-RA – longer acting
Semaglutide / Ozempic®
Agent with evidence-based outcome benefits

Formulations: Pre-filled pen (multiuse): 1.34mg/mL; 1.5mL, 3mL Pk

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 1.5-2.0¹⁰

Dose¹⁸: Initial: 0.25mg SC once weekly; Usual: After ≥4 weeks increase 0.5mg SC once weekly x 4 weeks, then titrate up to 1mg SC weekly as tolerated; Max: 1mg SC once weekly

Renal dose^12,18: eGFR <30mL/min (caution)

Drug cost for usual dose* ($/100 days)¹⁷: Trade : $390-$772
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Semaglutide / Ozempic®

Other benefits, CVD outcomes^12,18

Decreased MACE in patients with clinical CVD

Weight^12,18

Loss of up to 4kg in 2 years

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects (less GI side effects with weekly GLP1-RA vs daily), acute pancreatitis/ gallstone disease (rare)

Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 C-cell/thyroid tumors in animals)

SC semaglutide: Increased retinopathy complications seen in 1 trial in those with retinopathy history (3.0% vs. 1.8% placebo in 2 year trial)

Although similar:

Saxenda® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes or dyslipidemia) and who have failed a previous weight management intervention

Victoza® is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control

Comments^12,18 (titration, administration, monitoring, notes)

Titrate after ≥ 4 weeks to minimize GI AE (see usual dose)

Monitor: SCr (baseline and periodically)
GLP1-RA – longer acting
Semaglutide / Rybelsus®
Agent with evidence-based outcome benefits

NOT on Ontario drug formulary

Formulations²⁸: Tab: 3mg, 7mg, 14mg

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 1.1

Dose¹⁸: Initial: 3mg po daily 30 mins ac; Usual: After 30 days increase 7mg daily 30 mins ac; Max: 14mg daily

Renal dose^12,18: Not studied in eGFR < 30mL/min

Drug cost for usual dose* ($/100 days)¹⁷: Trade : $818
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Semaglutide / Rybelsus®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes or MACE

Weight^12,18

Loss of up to 5kg in 1 years

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

SC injection

GI side effects (less GI side effects with weekly GLP1-RA vs daily), acute pancreatitis/ gallstone disease (rare)

Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 C-cell/thyroid tumors in animals)

SC semaglutide: Increased retinopathy complications seen in 1 trial in those with retinopathy history (3.0% vs. 1.8% placebo in 2 year trial)

Although similar:

Saxenda® is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes or dyslipidemia) and who have failed a previous weight management intervention

Victoza® is indicated for once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control

Comments^12,18 (titration, administration, monitoring, notes)

Increase dose ≥ 30 days apart to reduce GI AE (see usual dose)

No dose adjustment for hepatic or renal impairment

To be taken with 120mL of water

Monitor: SCr (baseline and periodically)
Insulin secretagogues – meglitinides
Repaglinide / Gluconorm®

Generic available

Formulations²⁸: Tab: 0.5mg, 1mg, 2mg

Coverage: ODB 𝙓 EAP²⁹ NIHB ✓

A1C reduction (%)^12,18: 0.7-1.1

Dose¹⁸: Initial: A1C <8% 0.5mg po tid ac, A1C ≥8% 1-2mg po tid ac; Usual: 1-4mg po bidqid ac; Max: 16mg daily

Renal dose^12,18:eGFR <30mL/min (caution)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $79-$167
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Repaglinide / Gluconorm®

Other benefits, CVD outcomes^12,18

Neutral CVD events and mortality

Postprandial glycemia is especially reduced by meglitinides

Meglitinides good for patients who skip meals

Weight^12,18

Gain of 1.4-3.3 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Repaglinide contraindicated when co-administered with clopidogrel or with gemfibrozil

Minimal to moderate risk of hypoglycemia

Comments^12,18 (titration, administration, monitoring, notes)

Dose given within 30 minutes of meal (not taken if meal skipped)

A minimum of 1 week should elapse between titration steps to assess response after each dose adjustment

Dosage adjustment usually determined by fasting BG

The preprandial dose can be doubled or increased up to 4mg (e.g., 0.5mg increase to 1mg, 1mg increase to 2mg or 2mg increase to 4mg)

Monitor: SCr and LFTs (baseline and periodically)
Insulin secretagogues – sulfonylureas
Gliclazide / Diamicron MR®

Generic available

Formulations²⁸: SR tab: 30mg; ER tab: 60mg

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 0.6-1.2

Dose¹⁸: Initial: 30mg MR po daily; Usual: 60mg MR daily; Max: 120mg MR daily

Renal dose^12,18: eGFR <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $16; Trade: $37
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Gliclazide / Diamicron MR®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes

Relatively rapid BG lowering response

Gliclazide preferred over glyburide due to potential lower hypoglycemic risk

Weight^12,18

Gain of 1.2-3.2 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Minimal to moderate risk of hypoglycemia

Caution in older adults

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up by 30mg every 2 weeks

Gliclazide MR 30mg = gliclazide 80mg

Gliclazide MR can be given once daily with breakfast

If CrCl < 30mL/min, gliclazide is preferred

Monitor: SCr and LFTs (baseline and periodically)
Insulin secretagogues – sulfonylureas
Gliclazide / Diamicron®

Generic available

Formulations²⁸: Tab: 80mg

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 0.6-1.2

Dose¹⁸: Initial: 40-80mg po daily in am cc; Usual: 80mg bid cc; Max: 160mg bid cc

Renal dose^12,18: eGFR <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $29; Trade: $94
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Gliclazide / Diamicron®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes

Relatively rapid BG lowering response

Gliclazide preferred over glyburide due to potential lower hypoglycemic risk

Weight^12,18

Gain of 1.2-3.2 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Minimal to moderate risk of hypoglycemia

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up by 80mg per week to target BG

For doses of 160mg, administer bid with meals

Monitor: SCr and LFTs (baseline and periodically)
Insulin secretagogues – sulfonylureas
Glimepiride / Amaryl®

Generic available

Formulations²⁸: Tab: 1mg, 2mg, 4mg

Coverage: ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.2

Dose¹⁸: Initial: 1-2mg po daily in am cc; Usual: 1-4mg po daily in am cc; Max: 8mg po daily cc

Renal dose^12,18: eGFR <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $62
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Glimepiride / Amaryl®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes

Relatively rapid BG lowering response

Gliclazide preferred over glyburide due to potential lower hypoglycemic risk

Weight^12,18

Gain of 1.2-3.2 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Minimal to moderate risk of hypoglycemia

Caution in older adults with poor renal function

Comments^12,18 (titration, administration, monitoring, notes)

After reaching a dose of 2mg, dosage increases should be made in increments of no more than 1mg at 1-2 week intervals based on BG response

Monitor: SCr and LFTs (baseline and periodically)
Insulin secretagogues – sulfonylureas
Glimepiride / Diabeta®

Generic available

Formulations²⁸: Tab: 2.5mg, 5mg

Coverage: ODB ✓ NIHB 𝙓

A1C reduction (%)^12,18: 0.6-1.2

Dose¹⁸: Initial: 1.25-2.5 mg po daily cc; Usual: 5mg daily bid cc; Max: 10mg bid cc

Renal dose^12,18: eGFR <60 (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $15; Trade: $37
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Glimepiride / Diabeta®

Other benefits, CVD outcomes^12,18

Neutral effect on CVD outcomes

Relatively rapid BG lowering response

Gliclazide preferred over glyburide due to potential lower hypoglycemic risk

Weight^12,18

Gain of 1.2-3.2 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Minimal to moderate risk of hypoglycemia

Caution in older adults with poor renal function

Comments^12,18 (titration, administration, monitoring, notes)

Continue initial dose for 5-7 days, then titrate by 2.5mg every 1-2 weeks

If patient consumes a light breakfast, defer 1st dose until lunchtime

If more than 10mg daily is required, the excess should be taken with the largest meal (e.g., evening meal)

To prevent hypoglycemia, do not skip meals after taking glyburide

Monitor: SCr and LFTs (baseline and periodically)

Caution in older adults with poor renal function
SGLT2i or gliflozins
Canagliflozin / Invokana®
Agent with evidence-based outcome benefits

Formulations²⁸: Tab: 100mg, 300mg

Coverage: ODB ✓ NIHB ✓ LU (for patients who did not achieve glycemic control or who demonstrated intolerance to an adequate trial of metformin and a sulfonylurea)

A1C reduction (%)^12,18: 0.5-0.7

Dose¹⁸: Initial/Usual: 100mg po od daily am; Max: 300mg daily

Renal dose^12,18: eGFR <60mL/min (max dose 100mg daily); eGFR <60mL/min + UGT inducer (avoid); eGFR <45mL/min (caution); eGFR <30mL/min (contraindicated

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $321
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Canagliflozin / Invokana®

Other benefits, CVD outcomes^12,18

Decreased MACE, decreased nephropathy progression and HF in patients with clinical CVD

Weight^12,18

Loss of 2-3 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Genital mycotic infections, urinary tract infections, hypotension, increased LDL-C, euglycemic diabetic ketoacidosis ± hyperglycemia (rare), fourniere’s gangrene (rare), acute kidney injury

Caution with renal dysfunction, loop diuretics and older adults

Withhold treatment prior to major surgery or with serious illness/infections

Canagliflozin: fracture risk, lower extremity amputation – avoid if prior amputation

On SADMANS list²¹

Comments^12,18 (titration, administration, monitoring, notes)

Once daily dosing, usually in the morning because of increased urinary frequency and volume

Monitor: blood pressure, weight, SCr, potassium, blood ketones if diabetic ketoacidosis symptoms (baseline, within 2-4 weeks of starting, then periodically)
SGLT2i or gliflozins
Dapagliflozin / Forxiga®
Agent with evidence-based outcome benefits

Formulations²⁸: 5mg, 10mg

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 0.5-0.7

Dose¹⁸: Initial/Usual: 5mg po daily am; Max: 10mg po daily am

Renal dose^12,18: eGFR < 45mL/min (not recommended); eGFR <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $304
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Dapagliflozin / Forxiga®

Other benefits, CVD outcomes^12,18

Decreased nephropathy progression and HF or CV death in patients with clinical CVD

Weight^12,18

Loss of 2-3 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Genital mycotic infections, urinary tract infections, hypotension, increased LDL-C, euglycemic diabetic ketoacidosis ± hyperglycemia (rare), fourniere’s gangrene (rare), acute kidney injury

Caution with renal dysfunction, loop diuretics and older adults

Withhold treatment prior to major surgery or with serious illness/infections

Dapagliflozin: avoid in bladder cancer

On SADMANS list²¹

Comments^12,18 (titration, administration, monitoring, notes)

Once daily dosing, usually in the morning because of increased urinary frequency and volume

Monitor: blood pressure, weight, SCr, potassium, blood ketones if diabetic ketoacidosis symptoms (baseline, within 2-4 weeks of starting, then periodically)
SGLT2i or gliflozins
Empagliflozin / Jardiance®
Agent with evidence-based outcome benefits

Formulations²⁸: Tab: 10mg, 25mg

Coverage: ODB ✓ NIHB ✓

A1C reduction (%)^12,18: 0.5-0.7

Dose¹⁸: Initial/Usual: 10mg po daily am; Max: 25mg po daily am

Renal dose^12,18: eGFR <60mL/min (caution); eGFR <30mL/min (contraindicated)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $304
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Empagliflozin / Jardiance®

Other benefits, CVD outcomes^12,18

Decreased MACE and decreased CVD death in patients with clinical CVD

Decreased Nephropathy progression, HF or CV death in patients with HF +/- decreased in all cause mortality

Weight^12,18

Loss of 2-3 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Genital mycotic infections, urinary tract infections, hypotension, increased LDL-C, euglycemic diabetic ketoacidosis ± hyperglycemia (rare), fourniere’s gangrene (rare), acute kidney injury

Caution with renal dysfunction, loop diuretics and older adults

Withhold treatment prior to major surgery or with serious illness/infections

On SADMANS list²¹

Comments^12,18 (titration, administration, monitoring, notes)

Once daily dosing, usually in the morning because of increased urinary frequency and volume

Monitor: blood pressure, weight, SCr, potassium, blood ketones if diabetic ketoacidosis symptoms (baseline, within 2-4 weeks of starting, then periodically)
TZD
Pioglitazone HCL / Actos®

Generic available

Formulations²⁸: Tab: 15mg, 30mg, 45mg

Coverage: ODB 𝙓 EAP²⁹; NIHB ✓

A1C reduction (%)^12,18: 0.7-0.9

Dose¹⁸: Initial: 15mg daily po daily; Usual: 30-45mg po daily; Max: 45mg po daily

Renal dose^12,18: eGFR <60mL/min (caution)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $247–$366; Trade:$388-$578
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Pioglitazone HCL / Actos®

Other benefits, CVD outcomes^12,18

Decreased MACE, decreased MI, decreased stroke

Weight^12,18

Gain of 2-5 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Edema, HF, fractures, increased HDL-C, macular edema (rare), contraindicated in HF

Pioglitazone: possible bladder risk

Comments^12,18 (titration, administration, monitoring, notes)

4–12 weeks for max effect

Pioglitazone: increase by 15mg every 4 weeks

Monitor: SCr and LFTs (baseline and periodically)

Risk of heart failure, which may be higher if combined with insulin (combination not approved in Canada)

Health Canada restrictions: rosiglitazone only to be used when all other oral agents have been tried alone or together and targets not reached³⁰
TZD
Rosiglitazone / Avandia®

Generic available

Formulations: Tab: 2mg, 4mg, 8mg

Coverage: EAP²⁹; ODB 𝙓 NIHB 𝙓

A1C reduction (%)^12,18: 0.7-0.9

Dose¹⁸: Initial: 4mg po daily; Usual: 4mg po daily to bid; Max: 8mg po daily

Renal dose^12,18: eGFR <60mL/min (caution)

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $207; Trade: $292
View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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Rosiglitazone / Avandia®

Other benefits, CVD outcomes^12,18

Possible MI risk

Weight^12,18

Gain of 2-5 kg

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Edema, HF, fractures, increased HDL-C, macular edema (rare), contraindicated in HF

Pioglitazone: possible bladder risk

Comments^12,18 (titration, administration, monitoring, notes)

4–12 weeks for max effect

Rosiglitazone: increase to 8mg daily in 8-12 weeks if BG not at target

Monitor: SCr and LFTs (baseline and periodically)

Risk of heart failure, which may be higher if combined with insulin (combination not approved in Canada)

Rosiglitazone: requires special authorization from patient prior to prescribing

Health Canada restrictions: rosiglitazone only to be used when all other oral agents have been tried alone or together and targets not reached³⁰

Combination products

Refer to individual components in Non-insulin pharmacotherapy table for maximum dose, renal dose, comments

Scroll (left-right) for details

Insulin degludec/liraglutide (Xultophy®)

Formulation¹⁷: 100 units/mL insulin degludec, 3.6mg/mL

Usual dose¹⁸: 16 units/0.58mg – 50 units/1.8mg SC daily (50 units insulin daily)

Coverage: ODB 𝙓¹⁷ or NIHB 𝙓¹⁹

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $370 for 5x3mL
Insulin glargine/lixisenatide (Soliqua®)

Formulation¹⁷: 100U/mL, 33mcg/mL

Usual dose¹⁸: 15 units/5mcg – 60 units/20mcg; SC daily (60 units insulin daily)

Coverage: ODB ✓ NIHB ✓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $215
Linagliptin/empagliflozin (Glyxambi®)

Not on Ontario drug formulary

Formulation¹⁷: Tab: 5/10mg, 5/25mg³¹

Usual dose¹⁸: 1 tab po daily

Coverage: ODB 𝙓 NIHB 𝙓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $563
Metformin/canagliflozin (Invokamet®)

Not on Ontario drug formulary

Formulation¹⁷: Tab: 500/50mg, 850/50mg, 1000/50mg, 500/150mg, 850,150mg, 1000/150mg³²

Usual dose¹⁸: 1 tab po bid cc

Coverage: ODB 𝙓 NIHB 𝙓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $386
Metformin/dapagliflozin (Xigduo®)

Formulation¹⁷: Tab: 850/5mg, 1000/5mg

Usual dose¹⁸: 1 tab po bid cc

Coverage: ODB ✓ NIHB ✓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $273
Metformin/empagliflozin (Synjardy®)

Formulation¹⁷: Tab: 500/5mg, 850/5mg, 1000/5mg, 500/12.5mg, 850/12.5mg, 1000/12.5mg

Usual dose¹⁸: 1 tab po bid cc

Coverage: ODB ✓ NIHB ✓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $307
Metformin/linagliptin (Jentadueto®)

Formulation¹⁷: Tab: 500/2.5mg, 850/2.5mg, 1000/2.5mg

Usual dose¹⁸: 1 tab po bid cc

Coverage: ODB ✓ NIHB ✓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $311
Metformin/saxagliptin (Komboglyze®)

Formulation¹⁷: Tab: 500/2.5mg, 850/2.5mg, 1000/2.5mg³³

Usual dose¹⁸: 1 tab po bid cc

Coverage: ODB ✓ NIHB ✓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $283
Metformin/sitagliptin (Janumet®)

Formulation¹⁷: Tab: 500/50mg, 850/50mg, 1000/50mg

Usual dose¹⁸: 1 tab po bid cc

Coverage: ODB ✓ NIHB ✓

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $383
Metformin/sitagliptin (Janumet XR®)

Formulation¹⁷: ER tab: 500/50mg, 1000/50mg, 1000/100mg

Usual dose¹⁸: 1-2 tab(s) po once daily cc

Coverage: ODB ✓ NIHB ✓ LU (for patients who did not achieve glycemic control or who demonstrated intolerance to an adequate trial of metformin and a sulfonylurea)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $196-$383

DPP4i: Dipeptidyl peptidase-4 inhibitors; GLP1-RA: Glucagon-like peptide-1 receptor agonists; SGLT2i: Sodium-glucose cotransporter-2 inhibitors; TZD: Thiazolidinediones
underlined text: important information, *= prices reflect cost to consumer and include markup and dispensing fee, – = weight neutral, ac = before meals, AE = adverse events, BG = blood glucose, bid = twice daily, cc = with meal, CrCl = creatinine clearance, CV = cardiovascular, CVD = cardiovascular disease, EAP = Exceptional Access Program, eGFR = estimated glomerular filtration rate, ER = extended release, GI = gastrointestinal, HCL = hydrochloric acid, HDL-C = high density lipoprotein cholesterol, HF = heart failure, LDL-C = low density lipoprotein cholesterol, LFTs = liver function tests, LU = limited use, MACE = major adverse cardiovascular event, max = maximum, MI = myocardial infarction, μg = microgram, mg = milligram, mL = milliliter, MR = modified release, NIHB = non-insured health benefits for First Nations and Inuit, ODB = Ontario Drug Benefit, po = by mouth, qid = four times daily, SC = subcutaneous, SCr = serum creatinine, SR = sustained release, Tab = tablets, tid = three times daily, UGT = UDP-glucuronosyltransferase

Resources New

Patient resource

References New

[1]

Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2018;42(Suppl 1):S1–325.
[2]

Punthakee Z, Goldenberg R, Katz P. Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome. 2018;42(Suppl 1): S10–S15. Table 4, Advantages and disadvantages of diagnostic tests for diabetes; p. S12.
[3]

Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA, et al. Hemoglobin A1C targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the American College of Physicians. Ann Intern Med. 2018 Apr 17;168(8):569.
[4]

Rodriguez-Gutierrez R, Gonzalez-Gonzalez JG, Zuñiga-Hernandez JA, McCoy RG. Benefits and harms of intensive glycemic control in patients with type 2 diabetes. BMJ. 2019 Nov 5;l5887.
[5]

The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545–59.
[6]

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). The Lancet. 1998 Sep;352(9131):854–65.
[7]

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):311–22.
[8]

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117–28.
[9]

Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295–306.
[10]

Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016 Nov;375:1834-1844.
[11]

Juma S, Taabazuing M-M, Montero-Odasso M. Clinical frailty scale in an acute medicine unit: a simple tool that predicts length of stay. Can Geriatr J. 2016 Jun 29;19(2):34–9.
[12]

Diabetes Canada Clinical Practice Guidelines Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update. Canadian Journal of Diabetes. 2020 Oct 1;44(7):575-591.
[13]

RxFiles. Update on type 2 diabetes non-insulin pharmacotherapy [Internet]. Winter 2019/2020 [cited 2020 Sept 16]. Available from: https://www.rxfiles.ca
[14]

Saheb Kashaf M, McGill ET, Berger ZD. Shared decision-making and outcomes in type 2 diabetes: A systematic review and meta-analysis. Patient Educ Couns. 2017 Dec;100(12):2159–71.
[15]

RxFiles. Shared decision making in diabetes [Internet]. 2020 [cited 2020 Aug 18]. Available from: https://www.rxfiles.ca
[16]

Mayo Clinic. Diabetes medication choice [Internet]. 2016 [cited 2020 Aug 18]. Available from: https://shareddecisions.mayoclinic.org/decision-aid-information/decision-aids-for-chronicdisease/diabetes-medication-management/
[17]

Government of Ontario, Ministry of Health. Ontario Drug Benefit Formulary [Internet]. [cited 2020 Aug 4]. Available from: https://www.formulary.health.gov.on.ca/formulary
[18]

RxFiles. Anti-hyperglycemic type 2 diabetes agents: Drug comparison chart [Internet]. 2020 [cited 2020 Aug 6]. Available from: https://www.rxfiles.ca/
[19]

Indigenous Services Canada. Non-insured health benefits, First Nations and Inuit Health Branch: Drug benefit list [Internet]. 2020. Available from: https://www.sac-isc.gc.ca/DAM/DAM-ISC-SAC/DAM-HLTH/STAGING/texte-text/nihb_benefits-services_drugs_dbl-index_1573154657223_eng.pdf
[20]

Viberti G, Kahn SE, Greene DA, Herman WH, Zinman B, Holman RR, et al. A Diabetes Outcome Progression Trial (ADOPT): An international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care. 2002 Oct;25(10):1737-1743.
[21]

RxFiles. Type 2 diabetes and sick days medications to pause [Internet]. Available from: https://www.rxfiles.ca/rxfiles/uploads/documents/SADMANS-Rx.pdf
[22]

Government of Ontario, Ministry of Health. Ontario Drug Benefit Formulary: Acarbose limited use notes [Internet]. [cited 2020 Sep 24]. Available from: https://www.formulary.health.gov.on.ca/formulary/limitedUseNotes.xhtml?pcg9Id=682002011
[23]

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[25]

Eli Lilly Canada Inc. Product monograph: Trulicity® [Internet]. 2019 [cited 2020 Aug 10]. Available from: http://pi.lilly.com/ca/trulicity-ca-pm.pdf
[26]

AstraZeneca Canada Inc. Product monograph: Bydureon® [Internet]. 2020 [cited 2020 Aug 10]. Available from: https://www.astrazeneca.ca/content/dam/az-ca/downloads/productinformation/bydureon-product-monograph-en.pdf
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Novo Nordisk Canada Inc. Product monograph: Victoza® [Internet]. 2020 [cited 2020 Aug 10]. Available from: https://www.novonordisk.ca/content/dam/Canada/AFFILIATE/www-novonordisk-ca/OurProducts/PDF/victoza-product-monograph.pdf
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Novo Nordisk Canada Inc. Product monograph: Rybelsus® [Internet]. 2020 [cited 2020 Aug 10]. Available from: https://www.novonordisk.ca/content/dam/Canada/AFFILIATE/www-novonordisk-ca/OurProducts/PDF/Rybelsus-PM-EN-monograph.pdf
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Acknowledgments and legal New

The Type 2 diabetes: Non-insulin pharmacotherapy tool (‘Tool’) was developed as part of the Knowledge Translation in Primary Care Initiative, led by the Centre for Effective Practice, in collaboration with the Nurse Practitioners’ Association of Ontario. Clinical leadership for the development of the Tool was provided by Dr. Risa Bordman and was subject to external review by health care providers and other relevant stakeholders. This Tool was funded by the Government of Ontario as part of the Knowledge Translation in Primary Care Initiative.

This Tool was developed for licensed health care professionals in Ontario as a guide only and does not constitute medical or other professional advice. Health care professionals are required to exercise their own clinical judgement in using this Tool. Neither the Centre for Effective Practice (“CEP”), Government of Ontario, Nurse Practitioners’ Association of Ontario, nor any of their respective agents, appointees, directors, officers, employees, contractors, members or volunteers: (i) are providing medical, diagnostic or treatment services through this Tool; (ii) to the extent permitted by applicable law, accept any responsibility for the use or misuse of this Tool by any individual including, but not limited to, primary care providers or entity, including for any loss, damage or injury (including death) arising from or in connection with the use of this Tool, in whole or in part; or (iii) give or make any representation, warranty or endorsement of any external sources referenced in this Tool (whether specifically named or not) that are owned or operated by their parties, including any information or advice contained therein.

This Tool is a product of the Centre for Effective Practice. Permission to use, copy, and distribute this material is for all noncommercial and research purposes is granted, provided the above disclaimer, this paragraph and the following paragraphs, and appropriate citations appear in all copies, modifications, and distributions. Use of this Tool for commercial purposes or any modifications of the Tool are subject to charge and must be negotiated with the Centre for Effective Practice (Email: info@cep.health).

For statistical and bibliographic purposes, please notify the Centre for Effective Practice (info@cep.health) of any use or reprinting of the Tool. Please use the following citation when referencing the Tool: Reprinted with Permission from Centre for Effective Practice. (October 2020). Type 2 diabetes: Non-insulin pharmacotherapy: Ontario. Toronto: Centre for Effective Practice.

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Type 2 Diabetes: Non-Insulin Pharmacotherapy

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Diagnostic criteria for diabetes

Diagnosis of diabetes is confirmed if:

Factors that affect A1C:

A1C targets and considerations for glycemic control New

Clinical Frailty Scale:11

A1C targets

≤ 6.5% – Some adults

≤ 7.0% – “Most” adults

7.1-8.0% – Functionally dependent adults (Clinical Frailty Scale11 score = 4-5, on a 9 point scale)

7.3-7.9% – Adults with cardiovascular disease/risk

7.1-8.5% – Frail older adults (Clinical Frailty Scale11 score = 6-8, on a 9 point scale)

Management of hyperglycemia in type 2 diabetes New

Management of hyperglycemia in type 2 diabetes

A1C < 1.5% above target

A1C ≥ 1.5% above target

Symptomatic hyperglycemia and/or metabolic decompensation

Not at A1C target at 3 months

Not at A1C target in 3-6 months and/or change in clinical status

Add or substitute another antihyperglycemic agent based on shared decision-making factors (see Shared decision-making)

Add or substitute another antihyperglycemic agent with demonstrated cardiorenal benefits

Non-insulin pharmacotherapy New

Shared decision-making

Engage patients in a discussion regarding which of the following factors are most important to them:15,16

Affordability of therapy for 100 day supply

Avoiding therapy that requires injections

Avoiding therapy that increases risk of hypoglycemia

Therapy that provides cardiovascular benefits

Therapy that fits with daily routine

Avoiding therapy that has gastrointestinal side effects

Therapy that impacts weight change

Therapy that provides kidney protection

Non-insulin pharmacotherapy

First line options

Scroll (left-right) for details

Metformin HCL / Glucophage® Agent with evidence-based outcome benefits

Metformin HCL / Glucophage®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Metformin HCL / Glumetza® Agent with evidence-based outcome benefits

Metformin HCL / Glumetza®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Second line options

Scroll (left-right) for details

Acarbose / Glucobay®

Acarbose / Glucobay®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Alogliptin / Nesina®

Alogliptin / Nesina®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Linagliptin / Trajenta®

Linagliptin / Trajenta®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Saxagliptin / Onglyza®

Saxagliptin / Onglyza®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Sitagliptin / Januvia®

Sitagliptin / Januvia®

Other benefits, CVD outcomes12,18

Weight12,18

Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise)

Comments12,18 (titration, administration, monitoring, notes)

Clinical Frailty Scale:¹¹

7.1-8.0% – Functionally dependent adults (Clinical Frailty Scale¹¹ score = 4-5, on a 9 point scale)

7.1-8.5% – Frail older adults (Clinical Frailty Scale¹¹ score = 6-8, on a 9 point scale)

Engage patients in a discussion regarding which of the following factors are most important to them:^15,16

Metformin HCL / Glucophage®
Agent with evidence-based outcome benefits

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Metformin HCL / Glumetza®
Agent with evidence-based outcome benefits

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Dulaglutide / Trulicity®
Agent with evidence-based outcome benefits

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Liraglutide / Victoza®
Agent with evidence-based outcome benefits

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Semaglutide / Ozempic®
Agent with evidence-based outcome benefits

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Semaglutide / Rybelsus®
Agent with evidence-based outcome benefits

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise)

Comments^12,18 (titration, administration, monitoring, notes)

Other benefits, CVD outcomes^12,18

Weight^12,18