Type 2 diabetes: non-insulin pharmacotherapy

Last Updated: June 23, 2023

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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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Diagnosis

Diagnostic criteria for diabetes 1

  • 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
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.

* = 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

Individualizing A1C targets

Factors that affect A1C:1
  • 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)

A1C targets and considerations for glycemic control 1,3-12

Individualize (and reassess) targets

Use this practice aid to individualize the patient’s A1C target

Consider potential benefits and harms to the patient 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

 

 

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

*Lower limit may not be necessary in patients using low-intensity treatment. Consider risks and expected benefits on a case-by-case basis.

Approach to selecting antihyperglycemic agents

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.24 Shared decision-making aims to bridge the information gap between patients and providers while prioritizing patient autonomy.24

Engage patients in a discussion regarding which of the following factors are most important to them:25,26

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

cost Affordability of therapy for 100 day supply
  • Green = < $100
  • Yellow = $100-$400
  • Red = > $400
IV Avoiding therapy that requires injections
  • Yellow = weekly injection
  • Red = daily injection
cost Avoiding therapy that increases risk of hypoglycemia
  • Red = risk of hypoglycemia
Heart Therapy that provides cardiovascular benefits
  • Green = cardiovascular benefit
  • Red = cardiovascular risk (e.g., worsening MI or heart failure)
cost Therapy that fits with daily routine
  • Green = once daily or less administration
  • Yellow = ranges from once daily to 3+ daily
  • Red = 3+ administration per day, inconvenient
cost Avoiding therapy that has gastrointestinal side effects
  • Red = gastrointestinal side effects are common
weight Therapy that impacts weight change
  • Green = decreases weight
  • Red = increases weight
Lung Therapy that provides kidney protection
  • Green = provides kidney protection
  • Red = may cause acute renal injury

Non-insulin pharmacotherapy options

Non-insulin pharmacotherapy

First line options13,29-32

Scroll (left-right) for details
  • Biguanides
    Metformin HCL / Glucophage®
    Agent with evidence-based outcome benefits

    500mg tab, 850mg tab and generic available

    Coverage

    • ODB ✓: 500mg tab
    • ODB X: 850mg tab
    • NIHB✓

    A1C reduction (%):

    • 1.0

    Dose:

    • 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:

    • 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):

    • Generic: $20 (1g bid) to $80 (850mg tid)
    • Trade: $140
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Metformin HCL / Glucophage®

    Other benefits, CVD outcomes
    • Reduced MI in overweight (>120% IBW) patients
    • Reduced all-cause mortality
    • Reduced insulin requirements
    Weight
    • Loss of up to 2.9kg in 5 years
    Harms, hypoglycemic risk (negligible risk as monotherapy unless stated otherwise)
    • GI intolerance
    • Vitamin B12 deficiency
    Comments (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 list
  • Biguanides
    Metformin HCL / Glumetza®
    Agent with evidence-based outcome benefits

    500 mg extended release tab, 1000mg extended release tab and generic available

    Coverage: 

    • ODB X
    • NIHB X

    A1C reduction (%):

    • 1.0

    Dose:

    • Initial: 250–500mg po daily cc
    • Usual: 1000–2000mg po cc pm
    • Max: 2500mg daily

    Renal dose:

    • 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):

    • Generic: $120 (1g/d) to $235 (2g/d)
    • Trade: $300 (2g/d)
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Metformin HCL / Glumetza®

    Other benefits, CVD outcomes
    • Reduced MI in overweight (>120% IBW) patients
    • Reduced all-cause mortality
    • Reduced insulin requirements
    Weight
    • Loss of up to 2.9kg in 5 years
    Harms, hypoglycemic risk (negligible risk as monotherapy unless stated otherwise)
    • GI intolerance
    • Vitamin B12 deficiency
    Comments (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 list

Second line options1,13,15-19,29,30,32,33-37,38

  • 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
Alpha-glucosidase inhibitor
Scroll (left-right) for details
  • Acarbose / Glucobay®

    50mg tab, 100mg tab and generic available

    Coverage

    A1C reduction (%):

    • 0.7-0.8

    Dose:

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

    Renal dose:

    • eGFR<25-30mL/min (contraindication)

    Drug cost for usual dose* ($/100 days):

    • Generic: $74 to $100
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Acarbose / Glucobay®

    Other benefits, CVD outcomes
    • Improved postprandial control
    Weight
    • Neutral effect on weight
    Harms, hypoglycemic risk (negligible risk as monotherapy unless stated otherwise)
    • GI intolerance, flatulence, diarrhea
    Comments (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
Scroll (left-right) for details
  • DPP4i
    Alogliptin / Nesina®

    NOT on Ontario drug formulary

     6.25mg tab, 12.5mg tab and 25mg tab

    Coverage:

    • ODB X
    • NIHB X

    A1C reduction (%):

    • 0.5–0.7

    Dose:

    • 25mg po daily

    Renal dose:

    • eGFR 30-50mL/min (12.5mg po daily)
    • eGFR <30mL/min (6.25mg po daily)

    Drug cost for usual dose* ($/100 days):

    • Trade: $265
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Alogliptin / Nesina®

    Other benefits, CVD outcomes
    • Improved postprandial control
    • Well tolerated option in older adults
    • Neutral effect on CVD outcomes
    Weight
    • Neutral effect on weight
    Harms, hypoglycemic risk  (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 (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®

    5mg tab

    Coverage: 

    • ODB ✓
    • NIHB✓

    A1C reduction (%):

    • 0.5–0.7

    Dose:

    • 5mg po daily

    Renal dose:

    • eGFR <15mL/min (use with caution). No dosage adjustment.

    Drug cost for usual dose* ($/100 days):

    • Trade: $297
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Linagliptin / Trajenta®

    Other benefits, CVD outcomes
    • Improved postprandial control
    • Well tolerated option in older adults
    • Neutral effect on CVD outcomes
    Weight
    • Neutral effect on weight
    Harms, hypoglycemic risk  (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 (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®

    2.5mg tab and 5mg tab

    Coverage: 

    • ODB ✓
    • NIHB ✓

    A1C reduction (%):

    • 0.5–0.7

    Dose:

    • 5mg po daily

    Renal dose:

    • eGFR <50mL/min (2.5mg po daily)
    • eGFR <15mL/min (use alternative agent)

    Drug cost for usual dose* ($/100 days):

    • Trade: $337
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Saxagliptin / Onglyza®

    Other benefits, CVD outcomes
    • Improved postprandial control
    • Well tolerated option in older adults
    • Neutral effect on CVD outcomes
    Weight
    • Neutral effect on weight
    Harms, hypoglycemic risk  (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 (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®

    25mg tab, 50mg tab and 100mg tab

    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 (%):

    • 0.5–0.7

    Dose:

    • 100mg po daily

    Renal dose:

    • 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):

    • Trade: $99
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Sitagliptin / Januvia®

    Other benefits, CVD outcomes
    • Improved postprandial control
    • Well tolerated option in older adults
    • Neutral effect on CVD outcomes
    Weight
    • Neutral effect on weight
    Harms, hypoglycemic risk  (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 (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

     

GIP and GLP1-RA
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  • Tirzepatide (Mounjaro)

    Pre-filled pen 4 (single dose pen): Solution, 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, 15 mg/0.5 mL

    Coverage: 

    • Currently unavailable for ordering. Awaiting supply.

    Dose:

    • Initial: 2.5 mg subcut once weekly x 4 weeks
    • Usual: 5 mg subcut once weekly
      If additional glycemic control is needed, increase the dosage in increments of 2.5 mg after no less than 4 weeks on the current dose, as tolerated
    • Max: 15 mg subcut once weekly

    Renal dose:

    • No dosage adjustment is required in renal impairment. Tirzepatide is not recommended in end stage renal impairment

    Drug cost for usual dose* ($/100 days):

    • Currently unavailable for ordering. Awaiting supply.
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Tirzepatide (Mounjaro)

    Other benefits, CVD outcomes
    • Under investigation
    Weight
    • Loss up to 11.3 kg over 26 weeks
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Subcut injection irritation 
    • GI side effects, acute pancreatitis / gallstone disease (rare)
    • Contraindicated with personal / family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2
    • Increased risk of hypoglycemia when used in combination with SU or insulin treatment. Consider SU or insulin dosage reduction of 10-20%

    • Increased risk of biliary disease, particularly when it is used at higher doses, longer durations, or for weight loss (off-label)

    • Delays gastric emptying; consider holding for 3 weeks before surgery

    Comments (titration, administration, monitoring, notes)
    • Monitor: SCr, weight, and GI tolerability (baseline and periodically)
    • Avoid combining DPP4i with GLP1-RA
    • Caution weight loss in frail older adults
GLP1-RA
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  • GLP1-RA – longer acting
    Dulaglutide / Trulicity®
    Agent with evidence-based outcome benefits

    NOT on Ontario drug formulary

    Pre-filled pen (single use) 0.75mg/0.5ml, 1.5mg/0.5ml

    Coverage: 

    • ODB X
    • NIHB X

    A1C reduction (%):

    • 0.6-1.4

    Dose:

    • Initial: 0.75mg subcut once weekly
    • Usual: After ≥ 4 weeks at 1.5mg subcut once weekly
    • Max: After ≥ 4 weeks at 1.5mg subcut once weekly consider increase to 3 mg subcut once weekly for additional glycemic control
    • After ≥ 4 weeks at 3 mg subcut once weekly consider 4.5 mg subcut once weekly for additional glycemic control

    Renal dose:

    • eGFR <15mL/min (caution)

    Drug cost for usual dose* ($/100 days):

    • Trade: $720 (12 weeks)
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Dulaglutide / Trulicity®

    Other benefits, CVD outcomes
    • Reduced MACE in patients with clinical CVD or high risk for CVD
    • Reduced insulin requirements
    Weight
    • Loss of 1.6-3kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Subcut injection irritation 
    • GI side effects: nausea, vomiting, diarrhea, abdominal pain, dyspepsia and constipation
      • Less GI side effects with weekly GLP1-RA vs daily
      • More GI side effects during initiation and titration
      • Caution recommended in patients with gastroparesis (not studied)
    • Increase risk of hypoglycemia when administered with sulfonylurea or insulin
    • Increase risk of hypogylcemia with oral semaglutide
    • Contraindicated in pregnancy and breastfeeding. Women of child-bearing potential should be advised to use contraception with taking GLP1s
    • Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (C-cell/thyroid tumours in animals)
    • Rare side effects: increased heart rate, pancreatitis, cholecystitis, acute kidney injury, retinopathy, pancreatic cancer
    • Increased risk of biliary disease, particularly when it is used at higher doses, longer durations, or for weight loss (off-label)
    • Delays gastric emptying; consider holding for 3 weeks before surgery
    Comments (titration, administration, monitoring, notes)
    • Monitor: SCr, weight, HR and GI tolerability (baseline and periodically)
    • Titrate up to 1.5 mg subcut once weekly after 4-8 to minimize AE
    • Caution weight loss in frail older adults
  • GLP1-RA – longer acting
    Liraglutide / Victoza®
    Agent with evidence-based outcome benefits

    NOT on Ontario drug formulary

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

    Coverage:

    • ODB X
    • NIHB X

    A1C reduction (%):

    • 0.6-1.4

    Dose:

    • Initial: 0.6mg subcut daily
    • Usual: After ≥1 week, increase to 1.2mg subcut daily x 1 week, then 1.8mg subcut daily
    • Max: 1.8mg/d

    Renal dose:

    • eGFR <30mL/min (caution) no dosage adjustment
    • eGFR <15 mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Trade : $1095 (1.8mg subcut daily x 100 days)
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
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    Liraglutide / Victoza®

    Other benefits, CVD outcomes
    • Reduced CV death in patients with ASCVD
    • Reduced MACE in patients with ASCVD or high risk for CVD
    • Reduced insulin requirements
    Weight
    • Loss of 1.6-3kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Subcut injection irritation 
    • GI side effects: nausea, vomiting, diarrhea, abdominal pain, dyspepsia and constipation
      • Less GI side effects with weekly GLP1-RA vs daily
      • More GI side effects during initiation and titration
      • Caution recommended in patients with gastroparesis (not studied)
    • Increase risk of hypoglycemia when administered with sulfonylurea or insulin
    • Increase risk of hypogylcemia with oral semaglutide
    • Contraindicated in pregnancy and breastfeeding. Women of child-bearing potential should be advised to use contraception with taking GLP1s
    • Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (C-cell/thyroid tumours in animals)
    • Rare side effects: increased heart rate, pancreatitis, cholecystitis, acute kidney injury, retinopathy, pancreatic cancer
    • Increased risk of biliary disease, particularly when it is used at higher doses, longer durations, or for weight loss (off-label)
    • Delays gastric emptying; consider holding for 3 days before surgery
    Comments (titration, administration, monitoring, notes)
    • 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, weight, HR and GI tolerability (baseline and periodically)
    • Caution weight loss in frail older adults
  • GLP1-RA – longer acting
    Semaglutide / Ozempic®
    Agent with evidence-based outcome benefits

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

    Coverage:

    • ODB ✓
    • NIHB ✓

    A1C reduction (%):

    • 1.5-2.0

    Dose:

    • Initial: 0.25mg subcut once weekly
    • Usual: After ≥4 weeks increase to 0.5mg subcut once weekly x 4 weeks, then titrate up to 1mg subcut weekly as tolerated
    • Max: 1-2 mg subcut once weekly

    Renal dose:

    • eGRF <15 mL/min (contraindicated)
    • eGFR <30mL/min (caution) no dosage adjustment

    Drug cost for usual dose* ($/100 days):

    • 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
    • Reduced MACE in patients with ASCVD or high for CVD
    Weight
    • Loss of up to 4kg in 2 years
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Subcut injection irritation 
    • GI side effects: nausea, vomiting, diarrhea, abdominal pain, dyspepsia and constipation
      • Less GI side effects with weekly GLP1-RA vs daily
      • More GI side effects during initiation and titration
      • Caution recommended in patients with gastroparesis (not studied)
    • Increase risk of hypoglycemia when administered with sulfonylurea or insulin
    • Increase risk of hypogylcemia with oral semaglutide
    • Contraindicated in pregnancy and breastfeeding. Women of child-bearing potential should be advised to use contraception with taking GLP1s
    • Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (C-cell/thyroid tumours in animals)
    • Rare side effects: increased heart rate, pancreatitis, cholecystitis, acute kidney injury, retinopathy, pancreatic cancer
    • Increased risk of biliary disease, particularly when it is used at higher doses, longer durations, or for weight loss (off-label)
    • Delays gastric emptying; consider holding for 3 weeks before surgery
    Comments (titration, administration, monitoring, notes)
    • Titrate after ≥ 4 weeks to minimize GI AE (see usual dose)
    • Monitor: SCr, weight, HR and GI tolerability (baseline and periodically)
  • GLP1-RA – longer acting
    Semaglutide / Rybelsus®
    Agent with evidence-based outcome benefits

    3mg tab, 7mg tab and 14mg tab

    Coverage: 

    A1C reduction (%):

    • 1.1

    Dose:

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

    Renal dose:

    • Not studied in eGFR < 30mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Trade : $818
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    Semaglutide / Rybelsus®

    Other benefits, CVD outcomes
    • Neutral effect on CVD outcomes or MACE
    • Reduced insulin requirements
    Weight
    • Loss of up to 5kg in 1 years
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • GI side effects: nausea, vomiting, diarrhea, abdominal pain, dyspepsia and constipation
      • More GI side effects during initiation and titration
      • Caution recommended in patients with gastroparesis (not studied)
    • Increase risk of hypoglycemia when administered with sulfonylurea or insulin
    • Increase risk of hypogylcemia with oral semaglutide
    • Contraindicated in pregnancy and breastfeeding. Women of child-bearing potential should be advised to use contraception with taking GLP1s
    • Contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (C-cell/thyroid tumours in animals)
    • Rare side effects: increased heart rate, pancreatitis, cholecystitis, acute kidney injury, retinopathy, pancreatic cancer
    • Increased risk of biliary disease, particularly when it is used at higher doses, longer durations, or for weight loss (off-label)
    • Delays gastric emptying; consider holding for 3 weeks before surgery
    Comments (titration, administration, monitoring, notes)
    • Increase dose ≥ 30 days apart to reduce GI AE (see usual dose)
    • To be taken with 120mL of water
    • Monitor: SCr, HR, hypoglycemia, weight and GI tolerability (baseline and periodically)
    • Caution weight loss in frail older adults
Insulin secretagogues
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  • Insulin secretagogues – meglitinides
    Repaglinide / Gluconorm®

    0.5mg tab, 1mg tab, 2mg tab and generic available

    Coverage:

    • ODB X EAP
    • NIHB ✓

    A1C reduction (%):

    • 0.7-1.1

    Dose:

    • Initial: A1C <8% 0.5mg po tid ac, A1C ≥8% 1-2mg po tid ac
    • Usual: 1-4mg po bid-qid ac
    • Max: 16mg daily

    Renal dose:

    • eGFR <30mL/min (caution)

    Drug cost for usual dose* ($/100 days):

    • Generic: $79-$167
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    Repaglinide / Gluconorm®

    Other benefits, CVD outcomes
    • Neutral CVD events and mortality
    • Postprandial glycemia is especially reduced by meglitinides
    • Meglitinides good for patients who skip meals
    Weight
    • Gain of 1.4-3.3 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Repaglinide contraindicated when co-administered with clopidogrel or with gemfibrozil
    • Minimal to moderate risk of hypoglycemia
    Comments (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®

    SR tab: 30mg; ER tab: 60mg; generic available

    Coverage: 

    • ODB ✓
    • NIHB ✓

    A1C reduction (%):

    •  0.6-1.2

    Dose:

    • Initial: 30mg MR po daily
    • Usual: 60mg MR daily
    • Max: 120mg MR daily

    Renal dose:

    • eGFR <30mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Generic: $16
    • Trade: $37
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    Gliclazide / Diamicron MR®

    Other benefits, CVD outcomes
    • Neutral effect on CVD outcomes
    • Increase in all-cause mortality
    • Relatively rapid BG lowering response
    • Gliclazide preferred over glyburide due to potential lower hypoglycemic risk
    Weight
    • Gain of 1.2-3.2 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Minimal to moderate risk of hypoglycemia
    • Caution in older adults
    Comments (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®

    80mg tab and generic available

    Coverage: 

    • ODB ✓
    • NIHB ✓

    A1C reduction (%):

    • 0.6-1.2

    Dose:

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

    Renal dose:

    • eGFR <30mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Generic: $29
    • Trade: $94
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Gliclazide / Diamicron®

    Other benefits, CVD outcomes
    • Neutral effect on CVD outcomes
    • Increase in all-cause mortality
    • Relatively rapid BG lowering response
    • Gliclazide preferred over glyburide due to potential lower hypoglycemic risk
    Weight
    • Gain of 1.2-3.2 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Minimal to moderate risk of hypoglycemia
    Comments (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®

    1mg tab, 2mg tab, 4mg tab and generic available

    Coverage: 

    • ODB X
    • NIHB X

    A1C reduction (%):

    • 0.6-1.2

    Dose:

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

    Renal dose:

    • eGFR <30mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Generic: $62
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Glimepiride / Amaryl®

    Other benefits, CVD outcomes
    • Neutral effect on CVD outcomes
    • Increase in all-cause mortality
    • Relatively rapid BG lowering response
    • Gliclazide preferred over glyburide due to potential lower hypoglycemic risk
    Weight
    • Gain of 1.2-3.2 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Moderate risk of hypoglycemia
    • Caution in older adults with poor renal function
    Comments (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
    Glyburide / Diabeta®Ø

    2.5mg tab, 5mg tab and generic available

    Coverage: 

    • ODB ✓
    • NIHB X

    A1C reduction (%):

    • 0.6-1.2

    Dose:

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

    Renal dose:

    • eGFR <60 (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Generic: $15
    • Trade: $37
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Glyburide / Diabeta®Ø

    Other benefits, CVD outcomes
    • Neutral effect on CVD outcomes
    • Increase in all-cause mortality
    • Relatively rapid BG lowering response
    • Gliclazide preferred over glyburide due to potential lower hypoglycemic risk
    Weight
    • Gain of 1.2-3.2 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Moderate risk of hypoglycemia
    • Caution in older adults with poor renal function
    Comments (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
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  • SGLT2i or gliflozins
    Canagliflozin / Invokana®
    Agent with evidence-based outcome benefits

    100mg tab and 300mg tab

    Coverage:

    • ODB ✓
    • NIHB ✓ LU

    A1C reduction (%):

    • 0.5-0.7

    Dose:

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

    Renal dose:

    • 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):

    • Trade: $321
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Canagliflozin / Invokana®

    Other benefits, CVD outcomes
    • Reduced nephropathy progression and HHF in patients with ASCVD, CKD or high cardiovascular risk
    • Reduced MACE in patients with ASCVD or CKD
    • Reduced HHF in patients with HF
    Weight
    • Loss of 2-3 kg
    Harms, hypoglycemic risk  (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, orthostatic hypotension, increased urinary frequency
    • Caution with renal dysfunction, loop diuretics and older adults
    • Withhold treatment prior to major surgery or with serious illness/infections
    • Fracture risk, lower extremity amputation – avoid if prior amputation
    • Caution in acute dehydrating illness: On SADMANS list
    • Increase risk of hypoglycemia when in combination with sulfonylurea or insulin
    Comments (titration, administration, monitoring, notes)
    • 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

    5mg tab and 10mg tab

    Coverage: 

    • ODB ✓
    • NIHB ✓

    A1C reduction (%):

    • 0.5-0.7

    Dose:

    • Initial/Usual: 5mg po daily am
    • Max: 10mg po daily am

    Renal dose:

    • eGFR < 25mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Trade: $84
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Dapagliflozin / Forxiga®

    Other benefits, CVD outcomes
    • Reduced nephropathy progression and HHF in patients with ASCVD, CKD or high cardiovascular risk
    • Reduced all-cause death in patient with HF or CKD
    • Reduced HHF and CV death, benefits if patients is comorbid with HFrEF or HFpEF
    Weight
    • Loss of 2-3 kg
    Harms, hypoglycemic risk (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, orthostatic hypotension, increased urinary frequency
    • Caution with renal dysfunction, loop diuretics and older adults
    • Withhold treatment prior to major surgery or with serious illness/infections
    • Avoid in bladder cancer
    • Caution in acute dehydrating illness: On SADMANS list
    • Increase risk of hypoglycemia when in combination with sulfonylurea or insulin
    Comments (titration, administration, monitoring, notes)
    • 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

    10mg tab and 25mg tab

    Coverage: 

    • ODB ✓
    • NIHB ✓

    A1C reduction (%):

    • 0.5-0.7

    Dose:

    • Initial/Usual: 10mg po daily am
    • Max: 10-25mg po daily am

    Renal dose:

    • eGFR <60mL/min (caution)
    • eGFR <20mL/min (contraindicated)

    Drug cost for usual dose* ($/100 days):

    • Trade: $304
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Empagliflozin / Jardiance®

    Other benefits, CVD outcomes
    • Reduced nephropathy, HHF in patients with ASCVD, CKD or HF (HFrEF)
    • Reduced MACE in patients with ASCVD or CKD
    • Reduction of HHF and CV death if patient is comorbid with HFpEF
    Weight
    • Loss of 2-3 kg
    Harms, hypoglycemic risk  (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, orthostatic hypotension, increased urinary frequency
    • Caution with renal dysfunction, loop diuretics and older adults
    • Withhold treatment prior to major surgery or with serious illness/infections
    • Caution in acute dehydrating illness: On SADMANS list
    • Increase risk of hypoglycemia when in combination with sulfonylurea or insulin
    Comments (titration, administration, monitoring, notes)
    • Monitor: blood pressure, weight, SCr, potassium, blood ketones if diabetic ketoacidosis symptoms (baseline, within 2-4 weeks of starting, then periodically)
TZD
Scroll (left-right) for details
  • TZD
    Pioglitazone HCL / Actos®Ø

    15mg tab, 30mg tab, 45mg tab and generic available

    Coverage:

    • ODB X EAP
    •  NIHB ✓

    A1C reduction (%):

    • 0.7-0.9

    Dose:

    • Initial: 15mg daily po daily
    • Usual: 30-45mg po daily
    • Max: 45mg po daily

    Renal dose:

    • eGFR <60mL/min (caution)

    Drug cost for usual dose* ($/100 days):

    • Generic: $247–$366
    • Trade:$388-$578
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Pioglitazone HCL / Actos®Ø

    Other benefits, CVD outcomes
    • Reduced MACE, reduced MI, reduced stroke
    Weight
    • Gain of 2-5 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Edema, HF, fractures, increased HDL-C, macular edema (rare), contraindicated in HF
    • Possible bladder risk
    Comments (titration, administration, monitoring, notes)
    • 4–12 weeks for max effect
    • 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)
  • TZD
    Rosiglitazone / Avandia®Ø

    2mg tab, 4mg tab, 8mg tab and generic available

    Coverage: 

    • ODB X EAP
    • NIHB X

    A1C reduction (%)

    • 0.7-0.9

    Dose:

    • Initial: 4mg po daily
    • Usual: 4mg po daily to bid
    • Max: 8mg po daily

    Renal dose:

    • eGFR <60mL/min (caution)

    Drug cost for usual dose* ($/100 days):

    • Generic: $207
    • Trade: $292
    View benefits and CVD outcome, weight, harms and hypoglycemic risk, and comments
    Close

    Rosiglitazone / Avandia®Ø

    Other benefits, CVD outcomes
    • Possible MI risk
    Weight
    • Gain of 2-5 kg
    Harms, hypoglycemic risk  (negligible risk as monotherapy unless stated otherwise)
    • Edema, HF, fractures, increased HDL-C, macular edema (rare), contraindicated in HF
    Comments (titration, administration, monitoring, notes)
    • 4–12 weeks for max effect
    • 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)
    • 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 reached

Combination products29,30,39,40-42

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  • Insulin degludec/liraglutide (Xultophy®)

    100 units/mL insulin degludec, 3.6mg/mL

    Usual dose:

    • 16 units/0.58mg – 50 units/1.8mg subcut daily (50 units insulin daily)

    Coverage:

    • ODB X
    • NIHB X

    Drug cost for usual dose* ($/100 days):

    • Trade: $1065
  • Insulin glargine/lixisenatide (Soliqua®)

    100U/mL, 33mcg/mL

    Usual dose:

    • 15 units/5mcg – 60 units/20mcg; subcut daily (60 units insulin daily)

    Coverage:

    • ODB ✓
    • NIHB ✓

    Drug cost for usual dose* ($/100 days):

    • Trade: $624
  • Metformin/canagliflozin (Invokamet®)

    Not on Ontario drug formulary

    500/50mg, 850/50mg, 1000/50mg, 500/150mg, 850,150mg and 1000/150mg

    Usual dose:

    • 1 tab po bid cc

    Coverage:

    • ODB X
    • NIHB X

    Drug cost for usual dose* ($/100 days):

    • Trade: $386
  • Metformin/dapagliflozin (Xigduo®)

    850/5mg, 1000/5mg and generic available

    Usual dose:

    • 1 tab po bid cc

    Coverage: 

    • ODB ✓
    • NIHB ✓

    Drug cost for usual dose* ($/100 days):

    • G: $148
    • Trade: $273
  • Metformin/empagliflozin (Synjardy®)

    500/5mg, 850/5mg, 1000/5mg, 500/12.5mg, 850/12.5mg and 1000/12.5mg

    Usual dose:

    • 1 tab po bid cc

    Coverage: 

    • ODB ✓
    • NIHB ✓

    Drug cost for usual dose* ($/100 days):

    • Trade: $307
  • Metformin/linagliptin (Jentadueto®)

    500/2.5mg, 850/2.5mg and 1000/2.5mg

    Usual dose:

    • 1 tab po bid cc

    Coverage: 

    • ODB ✓
    • NIHB ✓

    Drug cost for usual dose* ($/100 days):

    • Trade: $311
  • Metformin/saxagliptin (Komboglyze®)

    500/2.5mg, 850/2.5mg and 1000/2.5mg

    Usual dose:

    • 1 tab po bid cc

    Coverage: 

    • ODB ✓
    • NIHB ✓

    Drug cost for usual dose* ($/100 days):

    • Trade: $283
  • Metformin/sitagliptin (Janumet®)

    500/50mg, 850/50mg and 1000/50mg

    Usual dose:

    • 1 tab po bid cc

    Coverage: 

    • ODB ✓
    • NIHB ✓

    Drug cost for usual dose* ($/100 days):

    • Trade: $107
  • Metformin/sitagliptin (Janumet XR®)

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

    Usual dose:

    • 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):

    • Trade: $107
  • Metformin/alogliptin (Kazano)

    1000/12.5mg, 850/12.5mg, 500/12.5mg

    Usual dose:

    • 1 tab po bid cc

    Coverage: 

    • ODB X
    • NIHB X

    Drug cost for usual dose* ($/100 days):

    • Trade: $286

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, Subcut = subcutaneous, SCr = serum creatinine, SR = sustained release, Tab = tablets, tid = three times daily, UGT = UDP-glucuronosyltransferase, Ø = discontinued brand name

Resources

References

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    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.

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    Senior PA, Houlden RL, Kim J, Mackay D, Nagpal S, Rabi D, et al. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update – The users guide. Canadian Journal of Diabetes. 2020 Oct 1;44(7):592–6.

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    Mayo Clinic. Hyperglycemia in diabetes – Symptoms and causes [Internet]. 2020 [cited 2021 Jan 14]. Available from: https://www.mayoclinic.org/diseases-conditions/hyperglycemia/symptomscauses/syc-20373631

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    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.

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