Antidiabetic Medication Adjustment in Type 2 Diabetes · loss): start insulin treatment with or without metformin. INESSS | Quebec’s National Medical Protocol – Antidiabetics

INESSS | Quebec’s National Medical Protocol – Antidiabetics 1 November 2019

Antidiabetic Medication Adjustment in Type 2 Diabetes

No 628004

Developed in collaboration with an advisory committee consisting of Québec clinicians and experts. Validated by the Comité d’excellence clinique en usage optimal du médicament, des protocoles médicaux nationaux et ordonnances de l’Institut national d’excellence en santé et en services sociaux (INESSS).

CLINICAL SITUATION OR TARGET POPULATION

Person 18 years of age or older receiving an antidiabetic treatment following a diagnosis of type 2 diabetes.

CONTRAINDICATIONS TO THE APPLICATION OF THIS PROTOCOL

Type 1 diabetes Gestational diabetes Pregnancy or breastfeeding in women with type 2 diabetes Acute-care hospitalization, or acute phase of ketoacidosis or hyperosmolar hyperglycemic syndrome

INSTRUCTIONS

1. HEALTH STATUS ASSESSMENT AT TIME OF ADJUSTMENT

During each follow-up visit for the antidiabetic medication:

► Reinforce the importance of adopting a healthy lifestyle. o Optimizing healthy eating, physical activity or smoking cessation may take over several weeks or months

and involve various health professionals, including nurses, pharmacists, nutritionists and physical activity specialists.

► Ask about the most recent changes in the factors listed below and, if applicable, consider a dosage reduction,

substitution or reassessment of the drug therapy: o intolerable adverse effects; o symptoms of hypoglycemia (see Appendix I); o an HbA1c level regularly below 6.5% (or consistently below the individual target) if there is a risk of

hypoglycemia; o a recent hospitalization, frailty, functional dependence, onset of neurocognitive disorders, deteriorating

health, reduced life expectancy; o presence of comorbidities (onset or progression of cardiovascular diseases, renal failure, heart failure or

liver failure);

GENERAL TREATMENT INFORMATION

• Immediately promote the adoption of healthy lifestyle habits. • In individuals with a glycated hemoglobin (HbA1c) level at diagnosis that is less than 1.5% above their individual

target: introduce metformin monotherapy if the glycemic targets are not achieved within two or three months of the lifestyle changes.

• In asymptomatic individuals diagnosed with an HbA1c level that is 1.5% or more above their individual target: consider bitherapy with metformin plus another antidiabetic medication selected based on the individual’s clinical characteristics.

• In individuals with symptomatic hyperglycemia or metabolic decompensation (e.g., ketosis, unintentional weight loss): start insulin treatment with or without metformin.

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o personal situation or preferences (e.g., cumbersome treatment, medication that is too expensive or not covered by the insurance plan), or frequently noted medication non-compliance;

o modified glycemic targets or treatment goals.

► Look for symptoms or signs of hyperglycemia (see Appendix I); if any are reported, check medication compliance and persistence, investigate other possible causes of hyperglycemia (see Appendix II); then consider intensifying the treatment.

► Review the results of recent laboratory tests and any available capillary blood or interstitial glucose values. o Check medication compliance and persistence (if not already done) and the glucose measurement

technique. If necessary, educate the individual on the importance of continuously adhere to treatment or provide him/her with technical support;

o Inquire about any changes or factors that can affect blood glucose or HbA1c values, including the use of new medications or natural products (see Appendix II for a list of these factors);

o Adjust antidiabetic medication dosage accordingly and assess the relevance of adding, ceasing or substituting an antidiabetic agent if required.

2. ADJUSTMENT-RELATED LABORATORY TESTING

► Plan the following laboratory tests for the adjustment of the various classes of antidiabetic medications:

! For vitamin B12 dosage, provide a justification for the request; otherwise, the laboratory may deny the request. The vitamin B12 dosage is indicated when symptoms or risk factors, such as the use of biguanides, are present.

LABORATORY TESTS

Tests Before the start of pharmacological treatment1 Every 3 months Every 6 months Once a year

All categories of antidiabetic medications, including insulin

HbA1c2 √ √ 3 √ 4

Serum creatinine (eGFR) √ √

Urine ACR √ √

Biguanides

CBC √

! Vitamin B12 √

Alpha-glucosidase inhibitors; Thiazolidinediones

ALT √ √ 1 A test performed within the 3 month-period preceding treatment is acceptable. 2 If there is discrepancy between HbA1c and blood glucose values, see Appendix II for factors that may affect HbA1c or blood glucose levels. 3 When the capillary blood or interstitial glucose targets and HbA1c targets are not achieved. 4 When the capillary blood or interstitial glucose targets and HbA1c targets are achieved. Acronyms and abbreviations: ALT= alanine aminotransferase; eGFR = estimated glomerular filtration rate; CBC = complete blood count; HbA1c = glycated hemoglobin; ACR = urine albumin/creatinine ratio.


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3. GLYCEMIC TARGETS

► Individualize the glycemic targets based on individual-specific clinical factors, such as the presence of cardiovascular diseases and comorbidities, the person’s life expectancy, anticipated benefits versus the risks of hypoglycemia, weight gain and other adverse effects, and then based on the person’s values and preferences.

► Regularly reassess glycemic targets to ensure that they are still appropriate.

GLYCATED HEMOGLOBIN AND CAPILLARY BLOOD OR INTERSTITIAL GLUCOSE TARGETS

Details

Glycated hemoglobin (HbA1c) (%)

Preprandial (AC); fasting glucose (mmol/L)

Postprandial (PC) glucose at 2 hours (mmol/L)

General target for most people with diabetes to minimize the risk of retinopathy, nephropathy and neuropathy

≤ 7 4.0 to 7.01 5.0 to 10.01

Life expectancy of at least 10 to 15 years; recent diagnosis; no significant cardiovascular disease, and use of antidiabetics with a low risk of hypoglycemia

≤ 6.5 4.0 to 7.01 5.0 to 10.01

History of severe hypoglycemia or hypoglycemia unawareness; or presence of advanced micro or macrovascular complications; or multiple comorbidities; or reduced life expectancy (less than 10 years); or long-standing diabetes with difficult glycemic control; or frail elderly persons; or persons with functional dependence

7.1 to 8.5 5.0 to 10.02 6.0 to 14.02

End of life No target Treat to prevent symptoms of hypo- and hyperglycemia

1 When the HbA1c target is not achieved, aim for a preprandial glucose value between 4.0 and 5.5 mmol/L and a postprandial value between 5.0 and 8.0 mmol/L. 2 Or according to the clinical judgment.

Blood glucose monitoring

• The measurement of capillary blood or interstitial fluid glucose complements the measurement of the glycated hemoglobin level.

• Compliance with the procedures of the Régie de l’assurance maladie du Québec (RAMQ) for test strip reimbursement requires that the recommended times and frequency of blood glucose measurements be individualized based on the prescribed treatment, the risk of hypoglycemia, whether or not glycemic targets are achieved, the desired blood glucose information and the possibility of altering behaviour or medication following the outcomes. (See Self-Monitoring of Blood Glucose in Adults with Type 2 Diabetes not Treated with Insulin.) Additional test strips can be reimbursed by using a reason code after the health professional in charge of follow-up has forwarded the clinical rationale to the pharmacist.

• In some individuals, the use of a flash glucose monitoring system or a continuous glucose monitoring device may be indicated rather than the use of a conventional blood glucose meter.

• When adjusting a medication, capillary blood or interstitial glucose levels for the past 3 to 7 days should be taken into consideration.

4. THERAPEUTIC APPROACH TO MAKING AN ADJUSTMENT

General principles for antidiabetic medication adjustment

All medication additions and adjustments, combined with lifestyle interventions, have the goal of achieving glycemic targets within 3 to 6 months.

Diet and antidiabetic dosage should be adjusted to achieve the glycemic targets; however, hypoglycemia must be avoided and weight gain minimized.

Generally, it is preferable to increase the dosage of only one antidiabetic agent at a time. When insulin is used in combination with an oral or injectable antidiabetic agent and a treatment intensification

is required, proceed first with the antidiabetic drug presenting a lower risk of hypoglycemia. In the case of a

https://www.inesss.qc.ca/fileadmin/doc/INESSS/Rapports/MaladiesChroniques/INESSS_Guide_usage_EN_ASG.pdf


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downwards adjustment of the treatment regimen, give priority to the antidiabetic drug presenting a higher risk of hypoglycemia.

Principles relating to oral or injectable antidiabetics

All antidiabetic medications should generally be introduced at the starting doses, which can then be gradually

increased, in order to avoid hypoglycemia and adverse effects (see tables in Section 5 for procedures). When making dose increment, return to the previous dose level if intolerance or hypoglycemic episodes occur. Combining antidiabetics at submaximal doses helps achieve glycemic targets faster and possibly with fewer

adverse effects than maximum-dose monotherapy. However, when certain antidabetics are being taken because of their cardiovascular or renal benefits, doses for which such protection has been demonstrated should be used (provided they are tolerated).

The choice of the antidiabetic medication to be added is based on its mechanism of action (to ensure that this mechanism is different from that of the antidiabetics already administered) and according to clinical considerations relating to the person, with priority being given to cardiovascular and renal protection (see Appendix III).

Principles relating to insulin

When insulin is added to the drug treatment regimen, it is best to start with daily basal insulin in order to

normalize fasting blood glucose. If the HbA1c targets have still not been achieved, multiple injection therapy1 (basal and prandial insulin) can be

introduced gradually. When dose adjustment is being made, priority must be given to correcting hypoglycemic episodes by

decreasing the responsible insulin. Then, the fasting hyperglycemic episodes can be corrected by adjusting the basal insulin, and the postprandial hyperglycemic episodes by modifying the prandial insulins.

Do not take into account a hypoglycemic or hyperglycemic episode associated with an exceptional or readily explicable one-time situation (see Appendix II).

5. GENERAL INFORMATION ON THE DRUGS AND ADJUSTMENT PROCEDURES

The general information on the antidiabetic drugs presented below is not exhaustive. When adding or modifying a treatment regimen, the potential for drug interaction must be assessed.

A summary table showing the various classes of antidiabetic drugs, including in particular such additional information as their relative cost, coverage by the RAMQ and mechanism of action, can be found in Appendix III. The list of antidiabetic drugs available in Canada is given in Appendix IV.

The starting doses and adjustment frequencies presented in the tables below are generally appropriate for elderly or frail persons. Where a dosing or frequency range is provided, it may be desirable to choose the smallest dose and adjust the dosage to the lowest frequency for elderly or frail individuals.

1 Metformin should not be discontinued when a multiple insulin injection therapy is introduced. However, sulfonylureas and meglitinides should be stopped when two or more injections of prandial insulin are administered per day.


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5.1 Biguanides

GENERAL INFORMATION FOR THE CLASS OF BIGUANIDES

Contraindications - History of allergic reaction to biguanides - History of lactic acidosis - Acute diabetic ketoacidosis - Severe renal failure: eGFR < 30 ml/min/1.73 m2 - Severe liver failure - Severe respiratory failure and conditions associated with hypoxemia - Stress conditions: severe infection, trauma or surgery

Precautions - Renal failure: • eGFR 30-44 ml/min/1.73 m2: use caution, adjustment recommended

- Severe dehydration: can exacerbate renal failure - Radiological examination with contrast agent, surgery (cease 48 hours before and resume 48 to 72 hours after,

unless otherwise indicated by the medical team) - Presence of risk factors for lactic acidosis (acute or unstable heart failure, recent myocardial infarction, respiratory

failure, dehydration (diarrhea, vomiting), alcohol abuse, renal failure, acute liver failure) - Decompensated heart failure - Pregnancy or breastfeeding

Most frequent or severe adverse drug effects

- Gastrointestinal effects (e.g., nausea, diarrhea, abdominal cramps) - Vitamin B12 deficiency

- Lactic acidosis (rare) Most significant drug interactions

- Drugs that can impair renal function in acute context (e.g., non-steroidal anti-inflammatories (NSAIDs), antihypertensives of the class of angiotensin conversion enzyme inhibitors (ACEIs) or angiotensin receptor antagonists (ARA), diuretics, iodized contrast agents, type 2 sodium-glucose transporter inhibitors (iSGLT2))

DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF BIGUANIDES

Drug Starting dose and

administration schedule

Maximum dose Adjustment procedures Adjustment for intolerance

Metformin

500 and 850 mg scored tablets

250 to 500 mg PO BID at meals

2550 mg/day

• eGFR 30-44 ml/min/1.73 m2: max 1000 mg/day

↑ by 250 to 500 mg every 1 to 2 weeks

or depending on tolerance.

The daily dose can be split into 2 or 3 doses (BID or

TID), depending on tolerance and compliance.

↓ the dose to the lower adjustment step or try a

temporary halt for 1 week or until symptom resolution.

Resume at the starting dose or at the tolerated lower step (if halted).

Resume with a smaller dosage adjustment:

↑ the dose by 250 mg (maximum: 1 dose/day) or ↑ the adjustment

interval1.

Extended-release metformin

500 and 1000 mg unscored tablets

500 to 1000 mg PO QD (at dinner)

2000 mg/day

• eGFR 30-44 ml/min/1.73 m2: max 1000 mg/day

↑ the dose by 500 mg every

1 to 2 weeks.



Resume at the starting dose or at the tolerated lower step (if halted). Resume with a slower adjustment pace by ↑ the adjustment interval.

1 Extended-release metformin can be considered for individuals presenting a gastrointestinal intolerance when using the regular form. Abbreviation: eGFR = estimated glomerular filtration rate.


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5.2 Secretagogues-sulfonylureas

GENERAL INFORMATION FOR THE CLASS OF SECRETAGOGUES-SULFONYLUREAS Contraindications - History of allergic reaction to sulfonylureas

- Acute diabetic ketoacidosis - Severe liver failure - Renal failure:

• Gliclazide, glimepiride: eGFR < 15 ml/min/1.73 m2 • Glyburide: eGFR < 30 ml/min/1.73 m2

- Stress conditions: severe infection, trauma or surgery

Precautions - History of allergic reaction to sulfa drugs - Renal failure (↑ the risk of hypoglycemic episodes):

• Gliclazide, glimepiride: eGFR 15-29 ml/min/1.73 m2 • Glyburide: eGFR 30-49 ml/min/1.73 m2

- Elderly persons, malnutrition, liver or renal failure, intense or prolonged exercise, consumption of alcohol – especially without food (↑ the risk of hypoglycemic episodes)

- G6PD deficiency (↑ the risk of hemolytic anemia) - Pregnancy and breastfeeding

Most frequent adverse drug effects

- Weight gain - Frequent hypoglycemic episodes (especially with glyburide)

Most significant drug interactions

- Under the influence of sympatholytic drugs (e.g., β-blockers, clonidine), symptoms of hypoglycemia may be ↓ or absent.

- Concurrent use of other antidiabetic agents: risks of hypoglycemic episodes (a ↓ in the secretagogue dose may be required)

DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF SECRETAGOGUES-SULFONYLUREAS1

Drug Starting dose and administration schedule

Maximum dose Adjustment procedures

Adjustment for intolerance or hypoglycemia

Gliclazide

80 mg scored tablets

40 to 80 mg PO BID at meals. If the daily dose is ≥ 160 mg, administer the medication in

2 doses (BID)

320 mg/day ↑ each dose by 40 to 80 mg every 1 to 2 weeks

↓ the dose to the lower adjustment step or try a temporary halt for

1 week or until symptom resolution.

Resume at the starting dose or at the tolerated lower step (if

halted). Resume with a smaller dosage adjustment or

↑ the adjustment interval.

Gliclazide (modified-release)

30 mg (unscored) and 60 mg (scored) tablets

30 mg PO QD at breakfast OR at the first main meal of the day 120 mg/day ↑ the dose by 30 mg every

1 to 2 weeks

Glimepiride

1, 2 and 4 mg tablets

0.5 to 1 mg PO QD at breakfast OR at the first main meal of the

day 8 mg/day ↑ the dose by 0.5 to 1 mg every

1 to 2 weeks

Glyburide

2.5 and 5 mg scored tablets

1.25 to 5 mg PO per day at meals

(in 1 or 2 doses QD or BID). If administered QD, give at the

first main meal of the day.

20 mg/day (max. 10 mg

per dose)

↑ each dose by 1.25 to 2.5 mg every 1 to 2 weeks

The daily dose can be split into 2 doses (BID) if the AC capillary blood

or interstitial glucose levels at breakfast remain > 7 mmol/L

1 Tolbutamide has not been included because it is used infrequently. Acronyms and abbreviations: eGFR = estimated glomerular filtration rate; G6PD: glucose-6-phosphate dehydrogenase.


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5.3 Secretagogues-meglitinides

GENERAL INFORMATION FOR THE CLASS OF SECRETAGOGUES-MEGLITINIDES

Contraindications - History of allergic reaction to meglitinides - Acute diabetic ketoacidosis - Liver failure - Co-administration of gemfibrozil or clopidogrel1

- Pregnancy and breastfeeding

Precautions - Do not take repaglinide if a meal is missed; delay taking repaglinide if the meal is delayed - Elderly persons, malnutrition, liver or renal failure, intense or prolonged exercise, consumption of alcohol –

especially without food (↑ the risk of hypoglycemic episodes)

Most frequent adverse drug effects - Hypoglycemic episodes - Weight gain - Headaches

Most significant drug interactions - CYP3A4 and/or CYP2C8 inhibitors: (e.g., gemfibrozil, clopidogrel1, clarithromycin, ketoconazole, cyclosporine, trimethoprim): ↑ of the plasma repaglinide concentration (↑ the risk of hypoglycemic episodes)

- Concurrent use of other antidiabetic agents: risks of hypoglycemic episodes (a ↓ of the secretagogue dose may be required)

1 Clopidogrel is contraindicated with repaglinide because it can increase the active concentration of this antidiabetic drug, thereby potentially raising the risk of hypoglycemic episodes; in practice, repaglinide can be taken as long as caution is exercised by using the weakest doses possible and ensuring that no hypoglycemic episodes are present.

DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF SECRETAGOGUES-MEGLITINIDES



Maximum dose Adjustment procedures Adjustment for intolerance or

hypoglycemia

Repaglinide

0.5, 1 and 2 mg tablets

0.5 to 1 mg per meal PO QD-TID

0-15 minutes before meal

12 mg/day (max 4 mg per dose)

If the average mealtime capillary blood glucose level is high (> 7 mmol/L or >

target set by the physician), double the dose that was given at the previous meal.

Adjustment interval: each week

The daily dose can be split into 3 doses

(TID).




halted). Resume with a smaller dosage adjustment or ↑ the adjustment

interval.


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5.4 Glucagon-like peptide-1 (GLP-1) receptor agonists

GENERAL INFORMATION FOR THE CLASS OF GLP-1 RECEPTOR AGONISTS Contraindications - History of allergic reaction to GLP-1

- Acute diabetic ketoacidosis - Pregnancy or breastfeeding - Personal or family history of medullary thyroid carcinoma - Multiple endocrine neoplasia syndrome type 2 - Renal failure: • Exenatide, lixisenatide: eGFR < 30 ml/min/1.73 m2 • Liraglutide, semaglutide: eGFR < 15 ml/min/1.73 m2

Precautions - Renal failure: • eGFR < 50 ml/min/1.73 m2: adjust carefully to avoid nausea/vomiting that may cause dehydration • Dulaglutide: eGFR < 30 ml/min/1.73 m2: exercise caution (limited data) • Semaglutide: eGFR between 15 and 29 ml/min/1.73 m2: exercise caution (limited data)

- Liver failure - History of or risk factors for pancreatitis (cholelithiasis, alcoholism, hypertriglyceridemia): halt if symptoms of pancreatitis

appear - Semaglutide1: ↑ in rate of complications from diabetic retinopathies in individuals with a history of retinopathy - Heart diseases that may be exacerbated by an ↑ in heart rate or an extension of the PR interval (e.g., congestive heart

failure, auricular fibrillation, tachyarrhythmia or marked 1st degree or 2nd or 3rd degree atrioventricular blocks) - Gastroparesis

Most frequent adverse drug effects

- Gastrointestinal effects (e.g., nausea, vomiting, diarrhea: ↓ of effects after a few weeks) - ↑ in heart rate (2 to 4 beats/minute) - Injection site reaction

Most significant drug interactions

- Insulin or secretagogues: risk of hypoglycemic episodes (a ↓ in the insulin or secretagogue dose may be required) - Short-acting GLP-1 (short-acting exenatide, lixisenatide): take oral drugs (e.g., antibiotics) at least 1 hour before or 4 hours

after (because of a possible delay in absorption) - Warfarin (exenatide): possible ↑ INR - Drugs that may extend the PR interval (including antiarrhythmic drugs, nondihydropyridine calcium channel blockers, beta

blockers, digitalis glycosides, HIV protease inhibitors, somatostatin analogues) - Drugs that ↑ heart rate (e.g., sympathomimetic, anticholinergic)

1 Appropriate ophthalmological follow-up and a gradual increase in the semaglutide doses are recommended for individuals with a history of retinopathy. Acronyms and abbreviations: CVA = cerebrovascular accident; eGFR = estimated glomerular filtration rate; INR = International Normalized Ratio; HIV = human immunodeficiency virus.


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DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF GLP-1 RECEPTOR AGONISTS Lo

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Drug Starting dose and administration schedule Maximum dose Adjustment procedures Adjustment for

intolerance

Dulaglutide

Single-dose injector pens prefilled with 0.75 mg/0.5 mL and 1.5 mg/0.5 ml

0.75 mg SC each week1 1.5 mg/week ↑ the dose by 0.75 mg SC after 4 weeks

↓ the dose to the lower

adjustment step or try a

temporary halt for 1 week or until symptom

resolution.


halted).

Resume with a smaller dosage adjustment or ↑ the adjustment

interval.

Exenatide extended-release

Single-dose injector prefilled with 2 mg for reconstitution with provided diluent

2 mg SC each week1 2 mg/week --

Liraglutide

Multi-dose injector pen prefilled with 6 mg/ml: doses of 0.6 mg, 1.2 mg

or 1.8 mg

0.6 mg SC QD If significant nausea, the

dose can be administered at bedtime (HS).

1.8 mg/day ↑ the dose by 0.6 mg SC QD every 1 to 2 weeks

Semaglutide

Single-dose injector pens prefilled with 1.34 mg/ml

1.5 ml pen: doses of 0.25 mg or 0.5 mg

3 ml pen: doses of 1 mg

0.25 mg SC each week2 1 mg/week

↑ the dose to 0.5 mg SC after 4 weeks.

If blood glucose is not under control after

4 weeks, the dose can be ↑ to 1 mg.

Shor

t-act

ing

Exenatide

Multi-dose injector pens filled with 250 mcg/ml:

1.2 ml pen: doses of 5 mcg 2.4 ml pen: doses of 10 mcg

5 mcg SC BID in the 60-minute period

preceding the morning and evening meals

(or the 2 main meals of the day, separating the doses

by at least 6 hours).

20 mcg/day (max. 10 mcg

per dose)

↑ to 10 mcg SC BID after 4 weeks of treatment

Lixisenatide

Multi-dose prefilled injector pens 0.05 mg/ml pen: doses of 10 mcg 0.1 mg/ml pen: doses of 20 mcg

10 mcg SC QD in the 60-minute period preceding a meal

(the same each day)

20 mcg/day ↑ to 20 mcg SC QD after 14 days

1 The administration schedule can be modified: wait at least 72 hours between doses. 2 The administration schedule can be modified: wait at least 48 hours between doses.


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5.5 Sodium-glucose cotransporter type-2 (iSGLT2) inhibitors

GENERAL INFORMATION FOR THE CLASS OF ISGLT2 Contraindications - History of allergic reaction to iSGLT2

- Acute diabetic ketoacidosis - Pregnancy and breastfeeding - Dapagliflozin: active bladder cancer - Renal failure: • Dapagliflozin, canagliflozin, empagliflozin: if eGFR < 30 ml/min/1.73 m2 • Ertugliflozin: if eGFR < 45 ml/min/1.73 m2

Precautions - Renal failure1: monitor renal function more often if eGFR < 60 ml/min/1.73 m2 - Dehydration: can impair renal function - Severe liver failure - Risk of diabetic ketoacidosis even if with euglycemia.

Risk factors2: recent bariatric surgery or other surgery, reduced carbohydrate intake (e.g., ketogenic diet), fasting periods, alcohol, intense or prolonged exercise, insulin deficiency, dehydration, infections.

- Surgery, infections, dehydration, vomiting or diarrhea: discontinue (in advance when possible), then resume when the individual’s clinical condition allows

- Elderly persons (risk of dehydration, hypotension, volume depletion) - Dapagliflozin: history of bladder cancer - Canagliflozin, ertugliflozin: individuals with risk factors for amputation of a lower limb (history of amputation,

peripheral vascular disease, neuropathy, diabetic foot) - Canagliflozin: individuals presenting a risk of fractures

Most frequent adverse drug effects - Diabetic ketoacidosis - Hypotension - Urinary tract infection - Genital yeast infection - Pollakiuria - Polyuria

Most significant drug interactions - Digoxin (canagliflozin): ↑ in the plasma digoxin concentration - Loop diuretics (especially furosemide): risk of volume depletion (a ↓ in the dose of the loop diuretic can be

considered and blood pressure should be closely monitored) - Antihypertensives: risk of hypotension (a ↓ in the antihypertensive dose can be considered and blood pressure

should be closely monitored) - Insulin or secretagogues: risk of hypoglycemic episodes (a ↓ in the insulin or secretagogue dose may be

required) 1 Dapagliflozin, canagliflozin, empagliflozin: research-based evidence shows that cardiovascular and renal protection is effective for eGFRs below

45 ml/min/1.73m2. 2 This list is not exhaustive.

DOSAGE ADJUSTMENT PROCEDURES FOR THE SGLT2 CLASS



Maximum dose Adjustment procedures Adjustment for intolerance

Canagliflozin

100 and 300 mg tablets

100 or 300 mg PO QD in the morning

300 mg/day

• 100 mg/day (if eGFR is between 30 and

59 ml/min/1.73 m2)

↑ the dose to 300 mg after 4 weeks (if eGFR

> 60 ml/min/1.73 m2) ↓ the dose to the lower adjustment step or try a


Resume at the starting dose or at the tolerated lower step

(if halted). Resume with a smaller

dosage adjustment or ↑ the adjustment interval.

Dapagliflozin

5 and 10 mg tablets

5 or 10 mg PO QD in the morning 10 mg/day ↑ the dose to 10 mg after

4 weeks

Empagliflozin

10 and 25 mg tablets

10 or 25 mg PO QD in the morning

25 mg/day ↑ the dose to 25 mg after

4 weeks

Ertugliflozin

5 and 15 mg tablets

5 or 15 mg PO QD in the morning 15 mg/day ↑ the dose to 15 mg after

4 weeks

Abbreviation: eGFR = estimated glomerular filtration rate.


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5.6 Dipeptidylpeptidase-4 (iDPP-4) inhibitors

GENERAL INFORMATION FOR THE CLASS OF IDPP-4

Contraindications - History of allergic reaction to DPP-4 inhibitors - Acute diabetic ketoacidosis - Pregnancy and breastfeeding

Precautions - Renal failure: • Linagliptin: if eGFR < 15 ml/min/1.73 m2 • Saxagliptin: if eGFR < 15 ml/min/1.73 m2

- Moderate-to-severe liver failure - Pancreatitis - Saxagliptin: individuals with a history of congestive heart failure

Most frequent or severe adverse drug effects

- Headaches - Rhinopharyngitis, URTI - Rare: • Pancreatitis • Arthralgia (especially with saxagliptin)

Most significant drug interactions - Insulin or secretagogues: risk of hypoglycemic episodes (a ↓ in the insulin or secretagogue dose may be required)

- CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, protease inhibitors): possible increase in the effect of saxagliptin

DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF IDPP-4

Drug Starting dose Maximum dose Adjustment based on renal function

Alogliptin

6.25, 12.5 and 25 mg tablets 25 mg PO QD 25 mg/day

• eGFR between 30 and 59 ml/min/1.73 m2: 12.5 mg PO QD

• eGFR < 30 ml/min/1.73 m2:

6.25 mg PO QD

Linagliptin

5 mg tablets 5 mg PO QD 5 mg/day No adjustment required1

Saxagliptin

2.5 and 5 mg tablets

5 mg PO QD 5 mg/day • eGFR < 45 ml/min/1.73 m2: 2.5 mg PO QD

Sitagliptin


100 mg PO QD 100 mg/day

• eGFR between 30 and 44 ml/min/1.73 m2: 50 mg PO QD

• eGFR < 30 ml/min/1.73 m2:

25 mg PO QD 1 Little data is available when eGFR < 15 ml/min/1.73 m2; exercise caution. Acronyms and abbreviations: eGFR = estimated glomerular filtration rate; URTI: upper respiratory tract infection.


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5.7 Thiazolidinediones (TZD)

GENERAL INFORMATION FOR THE CLASS OF THIAZOLIDINEDIONES (TZD) Contraindications - History of allergic reaction to thiazolidinediones

- Acute diabetic ketoacidosis - Pregnancy or breastfeeding - Pioglitazone: bladder cancer (active or past)

- Pioglitazone: uninvestigated hematuria

- Heart failure (NYHA classes 1 to 4) or left ventricular dysfunction1

- Severe liver failure

Precautions - Renal failure: eGFR < 60 ml/min/1.73 m2:: exercise caution (may cause fluid retention) - Atherosclerotic coronary artery disease (ASCAD) - Peripheral edema - Elderly persons: ↑ in the incidence of edema and congestive heart failure - Osteoporosis - Macular edema - Perimenopause (can restore ovulation: ↑ in the risk of pregnancy)

Most frequent adverse drug effects - Weight gain1

- Heart failure1

- Edema1

- Bone fractures (ankles, wrists): especially in women over long-term use

Most significant drug Interactions - Insulin and other drugs that may increase fluid retention - CYP 2C8 inhibitors (e.g., gemfibrozil): ↑ in the plasma thiazolidinedione concentration

1 Situation requiring special attention, further investigation or a reassessment: weight gain > 3 kg in 2 weeks and presence of the following symptoms: lower limb edema, dyspnea, unusual fatigue; withdraw the drug.

DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF THIAZOLIDINEDIONES (TZD)



Maximum dose Adjustment Adjustment for intolerance

Pioglitazone


15 mg PO QD in the morning 45 mg/day

↑ the dose by 15 mg every 8 to 12 weeks



Resume at the starting dose or at the tolerated lower

step (if halted). Resume with a smaller

dosage adjustment or ↑ the adjustment interval.

Rosiglitazone2


4 mg/day PO, in one or two doses (QD or

BID)

8 mg/day If combined with

sulfonylurea: 4 mg/day

↑ the dose to 8 mg/day after 8 to 12 weeks

2 A patient informed consent form provided by the manufacturer comes with the rosiglitazone prescription. Abbreviation: eGFR = estimated glomerular filtration rate.

https://ca.gsk.com/media/522061/patientinformedconsentform.pdf


November 2019

5.8 Alpha-glucosidase inhibitors

GENERAL INFORMATION ON THE ALPHA-GLUCOSIDASE INHIBITOR CLASS Contraindications - History of allergic reaction to alpha-glucosidase inhibitors

- Acute diabetic ketoacidosis - Pregnancy or breastfeeding - Inflammatory bowel disease - Bowel obstruction - Cirrhosis - Colic ulcer - Renal failure: eGFR < 25 ml/min/1.73 m2

Precautions - Chronic bowel diseases: marked digestive or absorptive disorders or diseases that can be exacerbated by

increased gas production in the intestine (e.g., large hernias, irritable bowel syndrome) - In the event of hypoglycemia, give honey or milk; do not give sucrose (e.g., juice, white sugar).

Most frequent adverse drug effects - Gastrointestinal effects (e.g., diarrhea, flatulence, bloating) - ↑ in transaminases

Most significant drug interactions Digoxin: Acarbose may ↓ the absorption of digoxin

DOSAGE ADJUSTMENT PROCEDURES FOR THE CLASS OF ALPHA-GLUCOSIDASE INHIBITORS



Maximum dose Adjustment procedures Adjustment for Intolerance

Acarbose

50 and 100 mg scored tablets

25 to 50 mg PO QD, BID or TID at the start of the

meal

300 mg/day

Depending on postprandial blood glucose levels and tolerance, ↑ the

dose very slowly by 25 mg, one meal at a time, up to 50 mg TID

every 2 to 4 weeks.

The daily dose can be split into 3 doses (TID).


temporary halt for 1 week or until symptom

resolution. Resume at the starting dose or at the tolerated lower step (if halted).

Resume with a smaller dosage adjustment or ↑ the adjustment interval.

Abbreviation: eGFR = estimated glomerular filtration rate.


November 2019

5.9 Insulin

GENERAL INFORMATION FOR INSULIN

Contraindications - History of allergic reaction to the insulin formulation (rare; if present, use a different insulin type)

Precautions - Pregnancy or breastfeeding: frequent dose adjustments required - Elderly persons, malnutrition, liver failure, renal failure, intense or prolonged exercise, consumption of

alcohol – especially without food (↑ the risk of hypoglycemic episodes): close monitoring of blood glucose levels is required

Most frequent adverse drug effects - Frequent hypoglycemic episodes - Significant weight gain - Injection site reaction

Most significant drug interactions - Thiazolidinediones: risk of heart failure. - Under the influence of sympatholytic drugs (e.g., β-blockers, clonidine), symptoms of hypoglycemia

may be reduced or absent. - Concurrent use of other antidiabetic agents: risk of hypoglycemia ( a ↓ in insulin dose may be required)

STARTING DOSES FOR THE CLASS OF INSULIN1

Basal insulin 4 to 10 units injected QD

Prandial insulin (one injection per day added to the basal insulin) 2 to 4 units or 10% of the basal dose at the main meal or breakfast.

Prandial insulin (several injections per day added to the basal insulin):

Calculate the total dose per day of 0.3 to 0.5 unit/kg, then distribute as follows: • 40% of total insulin as basal insulin, • 20% of total insulin as bolus 3 times per day with prandial insulin

No maximum dose 1 Examples of usually prescribed starting doses.


November 2019

INSULIN TYPES

Insulin Action Insulin type Onset of action

Peak effect

Duration of action

Usual administration

schedule Blood glucose level to consider

when adjusting

BA

SAL

Intermediate- acting

Isophane (NPH)

1 to 3 hours

5 to 8 hours

Up to 18 hours

30 minutes before breakfast AC dinner blood glucose level

30 minutes before dinner

next-day AC breakfast blood glucose level

At bedtime next-day AC breakfast blood glucose level

Long-acting analogues

Detemir 90 minutes

Not applicable

16 to 24 hours At bedtime next-day AC breakfast blood

glucose level

Glargine 90 minutes

Not applicable

Up to 24 hours At bedtime next-day AC breakfast blood

glucose level Glargine

300 units/ml1

Up to 6 hours

Not applicable

More than 30 hours

At the same time every day

following-days AC breakfast blood glucose level

Degludec1 2 hours Not applicable

More than 42 hours

At the same time every day

following-days AC breakfast blood glucose level

PRAN

DIAL

Short-acting Crystalline

zinc (regular)

30 minutes

2 to 3 hours

6.5 hours

15 to 30 minutes before a meal AC next-meal blood glucose level

Fast-acting analogues

Aspart 10 to 15 minutes

1 to 1.5 hours 3 to 5 hours 0 to 15 minutes

before breakfast 0 to 15 minutes

before lunch 0 to 15 minutes before dinner

Pre-breakfast dose: 2-hour PC breakfast blood glucose

level or AC lunch blood glucose level2

Pre-lunch dose:

2-hour PC lunch blood glucose level or AC dinner blood glucose level2

Pre-dinner dose:

2-hour PC dinner blood glucose level or HS blood glucose level

Glulisine 10 to 15 minutes

1 to 1.5 hours 3 to 5 hours

Lispro 10 to 15 minutes

1 to 2 hours

3.5 to 4.75 hours

Ultra-fast-acting

analogue

Fast-acting Aspart 4 minutes 0.5 to 1.5

hour 3 to 5 hours

0 to 2 minutes AC ad 20 minutes after start of breakfast 0 to 2 minutes AC

ad 20 minutes after start of lunch

0 to 2 minutes AC ad 20 minutes after

start of dinner

PRAN

DIAL

-BAS

AL

Short/inter-mediate-acting

(premixed)

Regular/ NPH 30/70 40/60 50/50

Depends on the prandial/basal ratio

15 to 30 minutes before breakfast

15 to 30 minutes

before dinner

Pre-breakfast dose: AC lunch blood glucose level and

AC dinner blood glucose level

Pre-dinner dose: HS blood glucose level and next-day

AC breakfast glucose level

Fast/inter-mediate-acting

analogues (premixed)

Biphasic aspart Mix 30

Depends on the prandial/basal ratio

0 to 15 minutes before breakfast

0 to 15 minutes before dinner

Pre-breakfast dose: 2-hour PC lunch blood glucose level or AC lunch2 and AC dinner blood

glucose level

Pre-dinner dose: 2-hour PC dinner PC blood glucose level or HS blood glucose level2 and

next-day AC breakfast blood glucose level

Lispro/lispro protamine

Mix 25 Mix 50

Fast- and long-acting

Crystalline zinc 500

units/ml1

15 minutes

4 to 8 hours 17 to 24 hours

30 minutes before breakfast

30 minutes before lunch

30 minutes before dinner

Pre-breakfast dose: AC lunch blood glucose level and

AC dinner blood glucose level

Pre-lunch dose: AC dinner blood glucose level and

HS blood glucose level

Pre-dinner dose: HS blood glucose level and next-day

AC breakfast blood glucose level 1 Concentrated insulin (200 units/ml, 300 units/ml and 500 units/ml) must never be transferred from one pre-filled pen to another device, such as a syringe.

The syringe graduations do not provide accurate dose measurements, thus increasing the risk of severe hypoglycemic episodes. 2 If blood glucose level is not measured 2 hours PC.


November 2019

INSULIN ADJUSTMENT PROCEDURES

ADJUSTMENT INTERVAL: EVERY 3 TO 7 DAYS

Time of day Capillary blood glucose results1 Adjustment2, 3, 4 Responsible insulin

NIGHT, BREAKFAST

< 4 mmol/L or

< glycemic targets

↓ the insulin dose by 10% OR

↓ the dose by 2 to 4 units Adjust the basal insulin administered at dinner

or bedtime or

the prandial-basal insulin administered at

dinner

> 7 mmol/L or

> glycemic targets

and absence of nocturnal hypoglycemic episodes

↑ the insulin dose by 10% OR

↑ the dose by 1 to 2 units (↑ the dose by 2 to 4 units if blood glucose level

≥ 10 mmol/L)

LUNCHTIME

< 4 mmol/L or

< glycemic targets


↓ the dose by 2 to 4 units Adjust the prandial or prandial-basal insulin

administered at breakfast

> 7 mmol/L or

> glycemic targets



≥ 10 mmol/L)

AFTERNOON (within 3 hours after lunch)

< 4 mmol/L or

< glycemic targets

↓ the insulin dose by10% OR

↓ the dose by 2 to 4 units Adjust the prandial

insulin administered at lunch > 7 mmol/L

or > glycemic targets



≥ 10 mmol/L)

DINNER (more than 3 hours after lunch)

< 4 mmol/L or

< glycemic targets


↓ the dose by 2 to 4 units

Adjust the basal or prandial-basal insulin

administered at breakfast

or the prandial or short- and long-acting insulin

(crystalline zinc – 500 units/ml)

administered at lunch

> 7 mmol/L or

> glycemic targets


↑ the dose by 1 to 2 units (↑ the dose by 2 to 4 units of blood glucose level

≥ 10 mmol/L)

BEDTIME

< 4 mmol/L or

< glycemic targets


↓ the dose by 2 to 4 units

Adjust the prandial or prandial-basal insulin administered at dinner

or the fast- and long-acting insulin (crystalline zinc -

500 units/ml) administered at lunch

> 7 mmol/L or

> glycemic targets



≥ 10 mmol/L) 1 Calculate, for each time of the day, the average capillary blood or interstitial glucose levels for the past 3 to 7 days. 2 Two insulin adjustment scales: a) % of the insulin dose OR b) number of insulin units. 3 Round off the dose (minimum 1 unit). 4 The adjustment steps may exceed 4 units at the same time in the presence of insulin resistance (total dose exceeding 100 units per 24 hours).


November 2019

6. INFORMATION TO BE CONVEYED

Discuss the followings with the individual:

GENERAL CONCEPTS

- Optimization of lifestyle habits (diet, consumption of alcohol or tobacco, physical activity, weight loss), effect on diabetes and overall health, and available resources to achieve this optimization (refer, if possible)

- Indication, dosage and administration schedule for the antidiabetic medications prescribed

- Adverse effects (managing, preventing)

- Importance of treatment compliance and persistence

- Procedure in the case of a missed or wrong dose (see Appendix V)

- Current blood glucose levels and desired therapeutic target

- Importance of having the person document, analyze and interpret the blood glucose level results himself/herself

- Frequency of follow-up visits

- Preparation for the next follow-up visit: times and frequency of self-monitoring of blood glucose levels, blood collection for laboratory tests

- Self-management of treatment (insulin)

- Quantity of test strips needed and quantity limit reimbursed by the RAMQ depending on the diabetes treatment (if applicable) PRECAUTIONS

- Symptoms of hypoglycemia and hyperglycemia

- Prevention and treatment of hypoglycemic episodes (e.g., while exercising or performing intense or extended physical work)

- Action plan for sick days (which medication to discontinue, increased hydration and self-monitoring)

- Importance of foot care

- Reasons to contact a medical clinic or doctor or to go to emergency

- Potential risks related to other prescription or over-the-counter drugs, natural products or certain diets (e.g., ketogenic diet)

- Importance of carrying a card or wearing a bracelet indicating that the person is taking an antidiabetic drug (if applicable)

- Driving a vehicle: self-monitoring of blood glucose required; strategies to reduce the risks of hypoglycemia (if applicable)

- Pregnancy planning or the use of a contraceptive method (if applicable)


November 2019

7. FOLLOW-UP

Depending on the information gathered during the health status assessment: Plan how the next follow-up visit will be conducted (e.g, telephone call, appointment with the prescriber); Determine whether, and if so, when laboratory tests need to be performed; Specify the appropriate use of self-monitoring blood glucose required for the next follow-up visit.

8. SITUATIONS REQUIRING SPECIAL ATTENTION, REASSESSMENT OR FURTHER INVESTIGATION

► Marked hyperglycemic episodes, with or without symptoms or signs of ketoacidosis (see Appendix I); ► Recurrent hypoglycemic episodes that are unexplained or hypoglycemia unawareness; ► Hospitalization or a recent visit to the emergency room; ► Blood glucose targets not achieved after 6 months of treatment adjustment; ► Blood glucose targets not achieved with the maximum dose prescribed, indicated in this Quebec’s National

Medical Protocol, or tolerated; ► Weight gain of more than 3 kg in 2 weeks (for thiazolidinediones); ► Rapid or unexplained decline in renal function, an eGFR result below a precautionary threshold for the

prescribed medication or if the loss of renal function becomes severe (eGFR below 30 ml/min/1.73m2); ► Presence of cardiovascular diseases or heart failure; ► Rise in ALT levels that is more than 2.5 times the upper limit of normal (ULN) (for thiazolidinediones and alpha-

glucosidase inhibitors); ► Vitamin B12 deficiency (for metformin); ► Onset of a contraindication to the application of this protocol or to the medication during treatment; ► Medication non-compliance regularly noted; ► Intolerance to the medication; ► Deteriorating health; ► Additional self-monitoring test strips needed, involving the transmission of the clinical rationale to the RAMQ for

reimbursement (if applicable).


November 2019

REFERENCES This protocol is based on the latest scientific data and best practice recommandations, which were enhanced with contextual information and experiential knowledge provided by clinicians and experts in Quebec. For further details on the process used to develop this medical protocol and to consult the references, see the report in support of this protocol.

https://www.inesss.qc.ca/thematiques/medicaments/protocoles-medicaux-nationaux-et-ordonnances-associees/protocoles-medicaux-nationaux-et-ordonnances-associees/antidiabetique.html


November 2019

APPENDIX I SYMPTOMS OF HYPOGLYCEMIA AND HYPERGLYCEMIA AND WARNING SIGNS

Typical symptoms of hypoglycemia1 - trembling/shaking - palpitations (tachycardia) - sweating - anxiety - hunger - nausea - numbness in the tongue and face - difficulty concentrating, confusion, irritability - weakness, dizziness - problems with vision, speech or coordination - headaches - drowsiness - unconsciousness

Typical symptoms of hyperglycemia1 - tiredness - dizziness - polyuria - polydipsia - polyphagia - exaggerated hunger - unintentional weight loss - irritability

Warning signs of ketoacidosis and hyperosmolar hyperglycemic state1

- polyuria - polydipsia - weakness - nausea, vomiting, abdominal pain - Kussmaul breathing (ketoacidosis) - a sweet or metallic taste in the mouth (ketoacidosis) - acetone breath (ketoacidosis) - volume depletion - ketones in the blood or urine (ketoacidosis)2

1 This list is not exhaustive. 2 Testing ketone level with blood strips (which measure beta-hydroxybutyrate) is preferable to testing with urine strips (which detect acetoacetate).


November 2019

APPENDIX I I IMPACTING FACTORS Blood glucose1 Certain factors can affect blood glucose levels:

• Missing or delaying a meal or snack, malnutrition ( ↓ ) • Gastroparesis ( ↓ ) • Intense or prolonged physical exercise ( ↕ ) • Taking other medications or using alternative treatments (e.g., natural products) ( ↕ ) • Fasting ( ↕ ) • Stress ( ↕ ) • Hormonal changes ( ↕ ) • Cognitive decline ( ↕ ) • Incorrect or missed antidiabetic dose ( ↕ ) • Consumption of alcohol ( ↕ ) • Hospitalization ( ↕ ) • Intercurrent disease, health problems (e.g., infarct, pulmonary embolism, cerebrovascular accident, acute respiratory

failure, pancreatitis, infection, surgery) ( ↑ ) • Reduced level of physical activity (e.g., due to an injury) ( ↑ ) • Corticosteroid treatment ( ↑ ) • Occasional overconsumption of food or carbohydrates ( ↑ ) • Dehydration ( ↑ )

Glycated hemoglobin1 The HbA1c level depends on the average lifespan of the erythrocytes. Since they do not decrease in a linear fashion, the average blood glucose level for the 30 days prior to sampling determines 50% of the HbA1c value. The HbA1c value must be interpreted with caution since it may not reflect the person's actual average blood glucose level, particularly in certain ethnic groups. Other factors can also affect HbA1c values and create a discrepancy with capillary blood glucose values:

↑ HbA1c ↓ HbA1c ↕ HbA1c Advanced age Alcoholism Iron or vitamin B12 deficiency Reduced erythropoiesis High dose of aspirin Ethnic group (Africans, Afro-Americans,

Asians, Hispanics, Amerindians) Hyperbilirubinemia Hypertriglyceridemia Treatment non-compliance Splenectomy Chronic use of opiates

Hemolytic anemia Rheumatoid arthritis Dapsone High doses of vitamins C or E Hemodialysis Hemorrhages Chronic liver failure Erythropoietin treatment (EPO) Reticulocytosis Splenomegaly Iron or B12 supplements Antiretroviral treatments (ribavirin) Recent transfusion

Fetal hemoglobin (pregnancy) Hemoglobinopathies Chronic renal failure Methemoglobinemia

1 This list of factors is not exhaustive. Legend: ↓: decrease ↑: increase ↕: possible increase or decrease


APPENDIX I I I SUMMARY TABLE OF ANTIDIABETIC MEDICATIONS

Hypo-glycemia Weight

Cardiovascular effect1, 2 Renal failure Peculiarities Mechanism of action

Route of adminis--

tration Costs Inclusion in RAMQ List of

Medications1 ASCVD HF Effect on progression1,2 Adjustment based on eGFR1

Biguanides No ↓ ↔

Potentially beneficial Neutral Neutral < 30 ml/min/1.73m2: ,

30 to 44 ml/min/1.73m2: ↓ doses.

Adverse gastrointestinal effects,

↓B12

↑ cell sensitivity to insulin; ↓ glucose

production by the liver PO $

Yes, except for extended-release formulation (not reimbursed under

the PDIP)

Secretagogues (sulfonylureas and

meglitinides) Yes ↑ Neutral Neutral Neutral

Gliclazide, glimepiride: < 15 ml/min/1.73m2: ; 15 to 29 ml/min/1.73m2: (hypo).

Glyburide: < 30 ml/min/1.73m2: ; 30 to 49 ml/min/1.73m2: (hypo).

Repaglinide: safe with RF.

Repaglinide: has a greater effect on

postprandial blood glucose level

Stimulates insulin secretion by the

pancreas PO

SU $

Repaglinide $$

Yes, but glimepiride = exceptional

medication

GLP-1 agonists No ↓

Beneficial: Liraglutide

Semaglutide Dulaglutide

Neutral

Potentially beneficial: Liraglutide

Semaglutide Dulaglutide

Dulaglutide: < 50 ml/min/1.73m2: .

Exenatide, lixisenatide: < 30 ml/min/1.73m2: ; 30 to 49 ml/min/1.73m2: .

Liraglutide, semaglutide: < 15 ml/min/1.73m2: ; 15 to 49 ml/min/1.73m2: .

Adversegastrointestinal effects

Mimics the effect of incretins (intestinal

hormones involved in the control of blood

glucose levels)

SC $$$$ Exceptional medications, except exenatide and lixisenatide (not reimbursed under the PDIP)

SGLT2 inhibitors No ↓

Beneficial: Canagliflozin Empagliflozin Dapagliflozin



Canagliflozin: < 30 ml/min/1.73m2: ; 30 to 59 ml/min/1.73m2: ↓doses. Dapagliflozin, empagliflozin < 30 ml/min/1.73m2: ; 30 to 59 ml/min/1.73m2:

Ertugliflozin: < 45 ml/min/1.73m2: . 45 to 59 ml/min/1.73m2:

Diabetic ketoacidosis, hypotension, urinary

tract infections, genital yeast infections

Promotes elimination of glucose in the urine PO $$$

Exceptional medications, except ertugliflozin (not reimbursed

under the PDIP)

DPP-4 inhibitors No ↔ Neutral Potentially harmful:

Saxagliptin Neutral

Alogliptin: < 60 ml/min/1.73m2: ↓doses.

Linagliptin: < 15 ml/min/1.73m2: Sitagliptin, saxagliptin: < 45 ml/min/1.73m2: ↓doses.

-

↑ effects of incretins (intestinal hormones

involved in the control of blood glucose

levels)

PO $$$ Exceptional medications

Thiazolidinediones No ↑ Neutral Harmful Neutral < 60 ml/min/1.73m2: . Edema, bladder cancer

(pioglitazone), HF, fractures

↑ insulin action PO $$ Exceptional medications

Alpha-glucosidase inhibitors No ↔ Neutral Neutral Neutral < 25 ml/min/1.73m2: Adverse gastrointestinal

effects

Slow down digestion of carbohydrates in the

intestine PO $$ Yes

Insulin

human

Yes ↑ Neutral Neutral Neutral ↓ doses with a lower eGFR - - SC

$-$$$ Yes, except

crystalline zinc (500-units/ml) (not reimbursed under the PDIP)

analogues $$$

Yes, but Mix 30, Mix 25 and long-acting analogues = exceptional

medications Fast-acting aspart and Mix 50 = not

reimbursed under the PDIP 1 This information may not be up to date in light of the most recent publications. 2 Has not been systematically reviewed. ↓: decrease. ↑: increase. ↔: neutral effect. : contraindicated or not recommended. : exercise caution ou ensure careful titration. Signs and abbreviations: eGFR = estimated glomerular filtration rate; HF = heart failure; RF = renal failure; ASCVD = atherosclerotic cardiovascular disease; RAMQ = Régie de l’assurance maladie du Québec; PDIP = Public Drug Insurance Plan.

http://www.ramq.gouv.qc.ca/SiteCollectionDocuments/professionnels/medicaments/codes-medicaments-exception/codes_medicaments_exception.pdf








APPENDIX IV ORAL OR INJECTABLE ANTIDIABETICS AVAILABLE IN CANADA

Biguanides Secretagogues- sulfonylureas

Secretagogues- meglitinides

GLP-1 receptor agonists

SGLT2 inhibitors

DPP-4 inhibitors Thiazolidinediones

Α-glucosidase

inhibitors Combined formulations1

Metformin Metformin

extended-release

Gliclazide Gliclazide

modified-release

Glimepiride Glyburide Tolbutamide

Repaglinide

Dulaglutide Exenatide

Exenatide extended-release

Liraglutide Lixisenatide Semaglutide

Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin

Alogliptin Linagliptin Saxagliptin Sitagliptin

Pioglitazone1 Rosiglitazone

Acarbose Alogliptin/metformin

Canagliflozin/metformin Dapagliflozin/metformin Dapagliflozin/saxagliptin Empagliflozin/metformin Empagliflozin/linagliptin Ertugliflozin/metformin Ertugliflozin/sitagliptin Linagliptin/metformin Saxagliptin/metformin Sitagliptin/metformin Liraglutide/insulin degludec Lixisenatide/insulin glargine

1 This protocol targets individual formulations.


APPENDIX V PROCEDURE FOR MISSED DOSES1

General principles when a dose is missed:

- Do not take a double dose to make up for the missed dose. - Do not take an additional dose or increase the next day’s dose to make up for the missed dose.

Biguanides

Metformin (regular) - Missed dose is remembered < 2 hours: take the missed dose. - Missed dose is remembered > 2 hours later: do not take the missed dose, but take the next dose at the usual time.

Metformin (extended-release) - Take the missed dose as soon as possible before bedtime.

Sulfonylureas Metiglinides

Glyburide Gliclazide (regular)

Repaglinide - Missed dose is remembered during or just after the meal: take the missed dose. - Missed dose is remembered > 30 minutes after the meal: do not take the missed dose, but take the next dose at the usual time.

Gliclazide (modified-release)

Glimepiride

- Missed dose is remembered during or just after breakfast: take the missed dose. - Missed dose is remembered > 1 hour after breakfast: take the missed dose at noon. - Missed dose is remembered > 1 hour after lunch: do not take the missed dose, but take the next dose at the usual time.

GLP-1 receptor agonists

Dulaglutide

Exenatide (Once weekly)

- If the next dose is in 3 days (72 hours) or more: take the missed injection. - If the next dose is due in less than 3 days (72 hours): do not take the missed dose. - Continue the usual weekly regimen.

Exenatide (regular)

Lixisenatide - Do not take the missed dose. - Take the next dose at the usual time.

Liraglutide - Missed injection is remembered within 12 hours: take the missed injection. - Missed injection is remembered > 12 hours later: do not take the missed injection, but take the next dose at the usual time.

Semaglutide - The missed dose must be administered as soon as possible within 5 days of the oversight. - If more than 5 days have passed since the missed dose, do not take the missed dose. - Continue the usual weekly regimen.

SGLT2 inhibitors Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin - Missed dose is remembered within 12 hours: take the missed dose.

- Missed dose is remembered > 12 hours later: do not take the missed dose, but take the next dose at the usual time.

DPP-4 inhibitors Alogliptin Linagliptin Saxagliptin Sitagliptin

Thiazolidinediones Pioglitazone

Rosiglitazone

If taken QD: - Missed dose is remembered within 12 hours: take the missed dose. - Missed dose is remembered > 12 hours later: do not take the missed dose, but take the following dose at the usual time.

If taken BID: - Missed dose is remembered < 2 hours: take the missed dose. - Missed dose is remembered > 2 hours later: do not take the missed dose, but take the following dose at the usual time.

Alpha-glucosidase inhibitors Acarbose - Do not take the missed dose.

- Take the next dose at the usual time.

Insulin

Degludec - Inject the missed daily dose as soon as possible. - Plan an interval of at least 8 hours between consecutive injections.

Aspart Glulisine

Lispro Fast-acting aspart

- The missed dose can be administered immediately after the meal (aspart) or up to 20 minutes after a meal has begun (fast-acting aspart, glulisine, lispro).

- Resume with the usual schedule with the next meal.

Other insulins - Do not take the missed dose. - Missed doses should be managed on a case-by-case basis in accordance with the clinical judgment.

1 The information provided in this table comes from Canadian monographs and the experience of Advisory Committee members.