Diabetes Mellitus

Clinical Snapshot

Diabetes mellitus is not one disease but a heterogeneous group of conditions defined by a shared endpoint — fasting and/or postprandial hyperglycemia — arising from an absolute or relative lack of insulin, resistance to insulin's action, or both. Type 2 diabetes (T2DM), driven primarily by insulin resistance with progressively worsening beta-cell insufficiency, is the form most Canadian pharmacists manage day to day and is the focus of this chapter. Type 1 diabetes (T1DM) results from autoimmune beta-cell destruction causing an absolute insulin deficiency and requires insulin from diagnosis, always; distinctions from T2DM are noted throughout wherever they change management.^[1]

Diabetes is a vascular disease as much as a glycemic one — heart disease is the leading cause of death in people with diabetes. Modern pharmacotherapy selection is built around this: certain glucose-lowering drug classes, specifically SGLT2 inhibitors and GLP-1 receptor agonists, have demonstrated direct cardiovascular and renal protective effects independent of their glucose-lowering action, and current Canadian guidance now selects second-line therapy primarily by a patient's cardiorenal risk profile rather than by glycemic potency alone.^[2]

This chapter covers diagnosis, glycemic targets, and the non-pharmacologic and pharmacologic management of diabetes mellitus itself. Long-term microvascular and macrovascular complications — retinopathy, nephropathy, neuropathy, and atherosclerotic cardiovascular disease — and their dedicated screening/management pathways are covered in a separate companion chapter, and are referenced here only where they directly change an initial drug-selection decision (e.g., choosing an SGLT2 inhibitor because of established chronic kidney disease).

Recognize the Condition

How T2DM actually presents

Most T2DM is discovered incidentally on routine screening or during an unrelated visit — it is very often entirely asymptomatic at diagnosis. When symptoms are present they are usually nonspecific: fatigue, malaise, or unexplained weight change. Some patients present only once a macrovascular or microvascular complication has already developed (a foot ulcer, erectile dysfunction, vision changes, or a cardiovascular event), which is why opportunistic and scheduled screening in at-risk adults matters as much as symptom-triggered testing.

How T1DM actually presents

T1DM classically presents acutely, over days to a few weeks, with the hallmark osmotic symptoms of marked hyperglycemia — polyuria, polydipsia, and unintentional weight loss, sometimes with blurred vision. Left unrecognized it progresses to diabetic ketoacidosis (DKA); treat any of these symptoms in a child, adolescent, or young adult as a same-day assessment, not a routine follow-up booking.^[3]

Latent autoimmune diabetes of adults (LADA) is a slower-onset variant of T1DM that can initially resemble T2DM in an older adult before progressing to insulin dependence — suspect it in an adult who fails oral therapy unusually quickly, or who is lean with a personal/family history of autoimmune disease. Confirmation requires islet-cell or glutamic acid decarboxylase (GAD65) autoantibody testing.

Classification of diabetes mellitus

Type 1 diabetes

Autoimmune beta-cell destruction causing an absolute insulin deficiency. Most commonly diagnosed in children, adolescents, and young adults, though onset after age 30 (including LADA) occurs. Insulin therapy is required from diagnosis and is never optional.

Type 2 diabetes

Insulin resistance combined with progressive, though initially milder, insulin deficiency. The most common form of diabetes; increasingly diagnosed in adolescents and children living with obesity as well as in adults. May be managed initially with lifestyle alone, non-insulin pharmacotherapy, or insulin depending on presentation.

Gestational diabetes

Glucose intolerance first recognized during pregnancy, driven largely by insulin resistance from placental and gestational hormones. Has its own screening pathway and glycemic targets — see Special Populations.

Other specific types

Monogenic diabetes (e.g., maturity-onset diabetes of the young, MODY), pancreatic disease and post-pancreatectomy diabetes (type 3c), and diabetes secondary to infections, other endocrinopathies, or medications (see Risk Factors for a list of dysglycemia-causing drugs).

Risk Factors

Risk factors for type 2 diabetes

Age 40 years or older.
First-degree relative with T2DM.
Member of a high-risk population (e.g., Indigenous, Hispanic, South Asian, Asian, African, or lower socioeconomic status) — the underlying contributors are a mix of biological and social/economic/health-equity factors, and targeting screening/treatment appropriately to at-risk groups can improve outcomes.
History of prediabetes (impaired fasting glucose, impaired glucose tolerance, or A1c 6.0–6.4%).
History of gestational diabetes.
History of delivering a macrosomic infant.
Existing end-organ damage associated with diabetes (cardiovascular or microvascular).
Vascular risk factors: abdominal obesity, HDL cholesterol below 1 mmol/L (males) or 1.3 mmol/L (females), hypertension, overweight, triglycerides ≥1.7 mmol/L, smoking.
Associated conditions: acanthosis nigricans, cystic fibrosis, history of pancreatitis, HIV infection, hyperuricemia/gout, metabolic dysfunction-associated steatotic liver disease, obstructive sleep apnea, polycystic ovary syndrome, and psychiatric disorders (e.g., bipolar disorder, depression, schizophrenia).

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Medications that can cause or worsen dysglycemia

A drug appearing on this list is not automatically a reason to stop it — medication-induced dysglycemia should prompt closer glucose monitoring, not routine discontinuation of an otherwise clinically indicated therapy.

5-fluorouracil
Beta-blockers
Checkpoint inhibitors (e.g., ipilimumab, pembrolizumab)
Corticosteroids
Diazoxide
HMG-CoA reductase inhibitors (statins)
Immunosuppressive agents (e.g., everolimus, sirolimus, tacrolimus, temsirolimus)
Interferon alfa
Isoniazid
Niacin
Pasireotide
Pentamidine
Protease inhibitors
Second-generation antipsychotics (e.g., olanzapine, quetiapine, risperidone)
Thiazide or loop diuretics

Red Flags & Refer

Escalate for same-day or emergency assessment for any of the following:

Diabetic ketoacidosis (DKA) — polyuria, polydipsia, nausea/vomiting, abdominal pain, deep rapid (Kussmaul) breathing, fruity-smelling breath, or altered level of consciousness in a patient with hyperglycemia. Send to emergency care immediately; do not attempt outpatient management.^[1]
Hyperosmolar hyperglycemic state (HHS) — profound dehydration and altered mental status with very high blood glucose, typically in an older patient with T2DM and often with little or no ketosis. Equally urgent as DKA.
Level 3 (severe) hypoglycemia — any low glucose value with impaired physical or cognitive status severe enough to require assistance from another person.^[4]
New suspected T1DM in a child, adolescent, or young adult with polyuria, polydipsia, or unexplained weight loss — same-day assessment; do not trial lifestyle measures while arranging follow-up.
Severe hyperglycemia or clear metabolic decompensation at initial presentation, in either T1DM or T2DM — needs prompt insulin initiation, not a staged lifestyle trial.
New or worsening hyperglycemia (or unexplained GI/malaise symptoms) in a patient taking an SGLT2 inhibitor — consider euglycemic DKA, which can occur with only modest glucose elevation and is easy to miss. Hold the SGLT2 inhibitor and refer for ketone testing.^[2]
Hypoglycemia unawareness (no adrenergic warning symptoms before neuroglycopenic symptoms appear) — needs a structured plan to restore awareness, not just repeated as-needed treatment.
Recurrent severe or otherwise unexplained hypoglycemia despite an apparently appropriate regimen.
Diabetes diagnosed during pregnancy, or pre-existing diabetes in a patient who is pregnant or planning pregnancy — needs prompt specialized care.
Signs of an acute limb-threatening foot infection or ischemia — same-day assessment; routine chronic foot-complication screening is covered separately.

Assessment & Diagnosis

Differentiating type 1 from type 2 diabetes at presentation

Feature	Type 1 diabetes	Type 2 diabetes
Typical age at onset	Childhood, adolescence, young adulthood (LADA: later adulthood)	Adulthood, increasingly adolescents/children living with obesity
Onset	Acute, over days to weeks	Gradual, often years of unrecognized hyperglycemia
Body habitus	Normal weight or underweight typical	Overweight or obesity typical, though not universal
Ketosis risk	High — DKA may be the presenting event	Lower, but possible, especially with SGLT2 inhibitor use
Endogenous insulin	Absent or minimal	Present, often elevated (insulin resistance)
Autoantibodies (islet-cell, GAD65)	Usually positive	Negative
Family history pattern	Less commonly a first-degree relative with diabetes	Commonly a first-degree relative with T2DM
Initial treatment requirement	Insulin required immediately, always	May start with lifestyle alone or non-insulin pharmacotherapy

Occasionally the picture overlaps (e.g., an adolescent living with obesity who presents with new insulin-dependent, antibody-positive diabetes, or LADA in a lean older adult who initially appears to have T2DM) — when the presentation is ambiguous, test autoantibodies and do not delay insulin while waiting for the distinction to become clear.

Diagnostic criteria

Diagnose diabetes in Canada using any ONE of the following:

Random plasma glucose ≥11.1 mmol/L (any time of day, without regard to timing of the last meal), or
Fasting plasma glucose (FPG) ≥7.0 mmol/L (no caloric intake for at least 8 hours), or
Plasma glucose ≥11.1 mmol/L 2 hours after a 75 g oral glucose load (OGTT), or
A1c ≥6.5% (adults), using a standardized, validated assay, in the absence of a condition that affects A1c accuracy (e.g., anemias, hemodialysis, pregnancy) — A1c should not be used as the sole test for suspected T1DM.

^[1]

In a patient without symptoms of hyperglycemia, confirm the diagnosis with a repeat test on another day before treating — with the exception of a random plasma glucose, use the same test to confirm the initial result whenever possible; if 2 different tests are both above their diagnostic cut-points, the diagnosis is confirmed without needing a repeat. In a patient with symptoms of hyperglycemia, a single result in the diabetic range is sufficient to make the diagnosis — no confirmatory test is needed.

Prediabetes

Impaired fasting glucose (IFG): FPG 6.1–6.9 mmol/L.
Impaired glucose tolerance (IGT): OGTT 2-hour plasma glucose 7.8–11.0 mmol/L.
A1c 6.0–6.4%.

Screening

Screen for T2DM every 3 years starting at age 40, or earlier and more often in anyone meeting 1 or more of the risk factors above, using either FPG or A1c (a validated risk calculator such as CANRISK can help identify who needs earlier screening, though it is a weighted scoring tool rather than a simple point-sum and is best used as a screening-eligibility aid, not a diagnostic score). Screening for T1DM in people with normal glucose levels is not recommended — autoantibody positivity does not guarantee the disease will develop, and no long-term preventive therapy is in routine Canadian use.^[1]

When not to rely on A1c, and how to handle discordant results

Do not rely on A1c in a condition known to distort the result — hemolytic or other anemias, hemoglobinopathies, recent transfusion, hemodialysis, pregnancy, or rapidly changing red-cell turnover — use a plasma-glucose-based test instead. If both an FPG and an A1c are available and discordant, use whichever result sits farther into the diabetic range, and confirm per the rules above rather than defaulting to one test type automatically.

Treatment Targets

A1c ≤7.0% for most adults with T1DM or T2DM — the threshold with the strongest evidence for reducing microvascular complications.
A1c ≤6.5% may be targeted in select patients with T2DM if achievable without significant hypoglycemia, to further reduce nephropathy/retinopathy risk.
A1c 7.1–8.5% is an appropriate, deliberately relaxed target for frail older adults, those with limited life expectancy, or a history of recurrent severe hypoglycemia or hypoglycemia unawareness — 7.1–8.0% specifically for functionally dependent patients.
Fasting/preprandial glucose 4–7 mmol/L and 2-hour postprandial glucose 5–10 mmol/L for most patients once at target A1c; tighten to 4–5.5 mmol/L fasting/preprandial and 5–8 mmol/L 2-hour postprandial if the A1c goal has not yet been reached.
For patients using continuous glucose monitoring (CGM), a time-in-range around 70% corresponds approximately to an A1c near 7% — use time-in-range and glucose-variability data alongside A1c, not instead of it.
Individualize every target to the patient — balance the microvascular/macrovascular benefit of tighter control against hypoglycemia risk, functional status, and life expectancy.
Treat blood pressure, lipids, and body weight to their own guideline-specific targets as part of the same vascular-protection strategy — comprehensive dyslipidemia and hypertension management in diabetes is covered in the companion chronic-complications chapter.

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Choose Initial Treatment

Direct treatment rule

Type 2 diabetes — first pharmacologic step

Reasonable in most patients at diagnosis, a shared decision-making trial of nonpharmacologic therapy alone (diet and exercise) is reasonable; if glycemic targets are not met within 3 months, start pharmacotherapy without further delay.

1st-line drug metformin — started alone, or in combination with a second agent as below, metformin is the initial drug of choice for essentially every patient with T2DM unless a contraindication or intolerance is present.^[2]

Start combination therapy instead of metformin monotherapy when the A1c is more than 1.5% above target at diagnosis — metformin monotherapy alone is unlikely to reach target, so add a second agent (selected per the cardiorenal criteria below) from the outset rather than waiting to see metformin fail first.

Second-agent selection — driven by cardiorenal risk, not glycemic potency alone

Established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease — add an agent with proven cardiorenal benefit (an SGLT2 inhibitor, a GLP-1 receptor agonist, or both) at the time the comorbidity is identified, regardless of current A1c. The goal here is organ protection, not just glucose lowering — do not wait for metformin to fail first.^[2]^[5]

Heart failure specifically — prefer an SGLT2 inhibitor; the GLP-1 receptor agonist evidence base is built primarily around atherosclerotic disease rather than heart-failure outcomes.

Chronic kidney disease specifically — an SGLT2 inhibitor is preferred for its renal-protective effect once eGFR/albuminuria criteria are met, and should be continued even as its glucose-lowering effect diminishes at lower eGFR, since the organ-protective benefit persists.^[5]

No established ASCVD, heart failure, or CKD — individualize the second agent by hypoglycemia risk, effect on weight, cost/coverage, and patient preference. Reasonable options include an SGLT2 inhibitor, a GLP-1 receptor agonist, a DPP-4 inhibitor, a sulfonylurea (gliclazide or glimepiride preferred over glyburide for lower hypoglycemia risk), or a thiazolidinedione.

When to start with insulin instead

Special situation start insulin (with or without metformin) immediately, rather than a staged oral trial, when the patient presents with markedly elevated glucose, is significantly symptomatic, or shows signs of metabolic decompensation at diagnosis.

Type 1 diabetes insulin is required from diagnosis in every patient — there is no non-insulin or lifestyle-only pathway.^[3]

Escalating beyond 2 agents in T2DM

If glycemic targets are not met on maximum tolerated doses of 2 agents, add a 3rd from a different class — before moving to a basal-bolus insulin regimen, use a GLP-1 receptor agonist and/or an SGLT2 inhibitor if not already on board, since both typically avoid the weight gain and hypoglycemia risk that come with intensifying insulin.^[2]

Non-Pharmacologic Treatment

Self-management education

Structured education is central to diabetes self-management. Ensure every patient understands:

The basics of what diabetes is and how their specific regimen works.
The role of diet, exercise, and medications together.
How and when to self-monitor glucose, and how to interpret the results.
How to manage sick days.
How to recognize and treat hypoglycemia.
Foot care.
Heart-health risk-factor control, including body weight and smoking cessation.
Why regular follow-up for other organs (eyes, kidneys) matters.

Nutrition

Refer to a registered dietitian for individualized dietary planning wherever possible. For patients who are overweight, incorporate total caloric reduction where appropriate. For patients using insulin, link carbohydrate intake to insulin dose — either a consistent carbohydrate pattern meal-to-meal, or carbohydrate counting with a matched insulin dose.

Exercise

Encourage at least 150 minutes per week of aerobic activity plus resistance training at least twice weekly, once cleared as safe (patients with a history of angina or other higher cardiac risk should be cleared by a physician before vigorous exercise). Counsel patients using insulin specifically on how exercise affects glucose — glucose typically falls after moderate-intensity exercise but can rise after very intense activity — and how to time meals or adjust insulin dosing around planned activity.

Glucose monitoring

Capillary blood glucose (CBG) monitoring or continuous glucose monitoring (CGM) is essential for most patients using insulin, ideally combining pre- and postprandial checks; a minimum of 3 checks per day is appropriate on a basal-bolus regimen. CBG may suit patients without CGM coverage or those already achieving good control with fingerstick testing; CGM provides continuous data without repeated fingersticks and can be offered to any patient who wants more information about their glucose patterns, whether or not they use insulin. For patients not on insulin, individualize monitoring frequency to the antihyperglycemic agent's hypoglycemia risk, concurrent illness, and whether a recent medication change needs to be evaluated. Check A1c every 3 months if targets are not met, or every 6 months in a stable patient consistently at target.^[1]

Ongoing surveillance

Blood pressure at every appropriate visit.
Foot examination annually; refer any patient at high risk of ulceration/amputation, or with an existing ulcer, to a foot-care specialist.
Serum creatinine (eGFR) and a random urine albumin-creatinine ratio at least annually to screen for chronic kidney disease — in T2DM, start at diagnosis; in T1DM, start 5 years after diagnosis (or after puberty if onset was prepubertal). More frequent testing is needed once CKD is established.^[5]
Lipid profile at diagnosis, then annually if normal, or every 3–6 months once lipid-lowering treatment is started.
Dilated eye examination at diagnosis for T2DM (repeat every 1–2 years if normal) and 5 years after diagnosis for T1DM age ≥15 (repeat annually) — more often if retinopathy is found.

Immunization

Give annual influenza vaccination and COVID-19 vaccination to every patient with T1DM or T2DM; review Health Canada's current recommendations for other vaccine-preventable diseases relevant to the individual patient.

Weight management and the possibility of remission

Significant, sustained weight loss — through structured calorie restriction, medication, or bariatric surgery — can improve glycemic control and insulin resistance, and in some patients returns glucose to normal or prediabetic levels without ongoing medication. Patients with the best chance of remission are generally those who do not require insulin, have had diabetes for a shorter duration, are motivated toward weight loss if living with obesity, and have relatively less-elevated glucose to begin with. When considering deprescribing toward remission, keep any medication with proven cardiovascular, heart-failure, or renal benefit unless there is a specific reason to stop it — the goal is usually to remove agents that promote weight gain or hypoglycemia (insulin, insulin secretagogues) first, not to strip away cardiorenal protection.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Metformin Preferred	1st-line agent, essentially all T2DM	500-2500 mg/day PO divided BID-TID; start low and titrate slowly	GI upset, metallic taste, vitamin B12 deficiency with long-term use	No weight gain, low hypoglycemia risk alone. Hold if acutely ill/unable to maintain fluid intake, or before iodinated contrast if eGFR under 30.
Empagliflozin (SGLT2 inhibitor class) Preferred	Cardiorenal-protective add-on: ASCVD, heart failure, or CKD	10-25 mg PO once daily	Genital mycotic infection, volume depletion/hypotension, rare euglycemic DKA	Preferred when heart failure or CKD is present; continue for organ protection even as glycemic effect wanes at lower eGFR.
Semaglutide, subcutaneous (GLP-1RA class) Preferred	Cardiorenal-protective add-on: established ASCVD; also useful for weight-benefit second-line	0.25 mg SC weekly x4wk, then 0.5 mg weekly, may increase to 1 mg weekly after a further 4wk	Nausea, vomiting, rare pancreatitis	Preferred when established ASCVD is present or weight loss is a goal. Titrate slowly to limit GI effects. Contraindicated with personal/family history of medullary thyroid carcinoma or MEN2.
Tirzepatide Alternative	Potent glycemic/weight-loss option without an established cardiorenal-outcomes indication yet	2.5 mg SC weekly x4wk, then 5 mg weekly; may increase in 2.5 mg increments no sooner than every 4wk to a maximum of 15 mg weekly	Nausea, vomiting, rare pancreatitis	Same contraindications as GLP-1 receptor agonists. Cardiovascular-outcomes evidence is still accumulating.
Sitagliptin (DPP-4 inhibitor class) Alternative	Well-tolerated non-cardioprotective second-line option	25-100 mg PO once daily (reduce dose in renal impairment per product monograph)	Nasopharyngitis, rare pancreatitis, rare severe joint pain	Weight-neutral, low hypoglycemia risk; useful when GI intolerance or hypoglycemia risk with other classes is a concern. Does not alter CV risk.
Gliclazide (sulfonylurea class) Alternative	Cost-sensitive second-line option	40-320 mg/day PO (divide BID if daily dose ≥160 mg); or gliclazide MR 30-120 mg PO once daily	Hypoglycemia, weight gain	Preferred sulfonylurea over glyburide given lower hypoglycemia risk, especially in older adults.
Glyburide Avoid preferentially	Legacy sulfonylurea — avoid as first sulfonylurea choice	2.5-20 mg/day PO (divide BID if daily dose >10 mg)	Weight gain, hypoglycemia (higher risk than gliclazide/glimepiride)	Avoid preferentially in older adults or renal impairment — gliclazide or glimepiride preferred within the sulfonylurea class.
Pioglitazone (thiazolidinedione class) Special situation	Consider specifically when hepatic steatosis benefit is desired	15-45 mg PO once daily	Weight gain, fluid retention/edema, increased fracture risk, rare macular edema	Avoid in heart failure. Ovulation may resume in previously anovulatory patients — counsel on contraception.
Repaglinide (meglitinide class) Special situation	Flexible option for irregular meal timing	0.5-4 mg PO 0-30 min before each meal; omit the dose if the meal is skipped	Hypoglycemia, weight gain	Avoid combining with gemfibrozil — markedly enhanced and prolonged hypoglycemia.
Acarbose (alpha-glucosidase inhibitor) Special situation	Modest add-on when postprandial control is the specific target	25-100 mg PO TID, taken with the first bite of each meal; start low and titrate slowly	Flatulence, diarrhea, abdominal cramps	Modest glucose-lowering effect. Treat any hypoglycemia in a patient on acarbose with glucose, not sucrose.
Basal insulin (glargine or degludec) Special situation	Add when oral/injectable combination therapy fails, or at diagnosis with decompensation	SC once daily; initiate 0.1-0.2 units/kg or an empiric 5-10 units at bedtime, titrate to fasting glucose under 7 mmol/L	Hypoglycemia, weight gain, lipohypertrophy	No dose ceiling. Continue metformin if tolerated — lowers insulin requirement and hypoglycemia risk.
Rapid-acting insulin (aspart or lispro) Special situation	Prandial coverage once basal insulin alone no longer meets targets	SC 0-15 min before, or within 20 min after starting, a meal	Hypoglycemia, weight gain, lipohypertrophy	Start with the largest meal (basal-plus) and expand to all meals (basal-bolus) if needed; dose by carbohydrate counting or a correction scale.

Special Populations

Pregnancy

Prepregnancy planning (pre-existing T1DM or T2DM): begin folic acid 1 mg PO daily at least 3 months before conception, continuing until at least 12 weeks' gestation. Obtain a baseline eye exam (pregnancy can accelerate retinopathy). Aim for A1c ≤7% (≤6.5% if safely achievable) before conceiving. Continue insulin, metformin, or glyburide if already in use; switch to an insulin-based regimen if taking any other antihyperglycemic agent, including SGLT2 inhibitors, DPP-4 inhibitors, or GLP-1 receptor agonists. Screen for cardiovascular disease/risk factors and CKD. Discontinue ACE inhibitors, ARBs, and statins before conception — all are contraindicated in pregnancy. The rapid-acting insulin analogues lispro and aspart, and the basal insulins NPH, insulin degludec, insulin glargine (U100), are considered safe in pregnancy.^[1]

Gestational diabetes: screen every pregnant patient per Diabetes Canada's preferred approach. Start nonpharmacologic therapy (structured diet and exercise) at diagnosis; if fasting and postprandial targets are not met within 2 weeks, start multiple daily injections of a rapid-acting or regular insulin. Insulin glargine (U100) is a reasonable basal option in pregnancy. Glyburide or metformin may be considered when insulin genuinely cannot be used, recognizing both uses are off-label in pregnancy.

Glycemic targets in pregnancy (pre-existing or gestational diabetes): fasting/preprandial glucose <5.3 mmol/L, 1-hour postprandial <7.8 mmol/L, 2-hour postprandial <6.7 mmol/L. For pre-existing diabetes specifically, aim for an A1c during pregnancy of ≤6.5% (≤6.1% if safely achievable), with frequent pre- and postprandial self-monitoring. To reduce preeclampsia risk, start ASA 81 mg PO once daily at 12-16 weeks' gestation and continue to delivery in patients with pre-existing diabetes.

Breastfeeding

Encourage breastfeeding. Insulin transfers into breast milk only minimally and is degraded in the infant's GI tract, so breastfeeding patients using insulin do not need to change their regimen unless their own glycemic pattern requires it — monitor glucose frequently in the first 24 hours postpartum and beyond, since insulin requirements can change quickly after delivery. Glyburide and metformin have both been used in breastfeeding patients with T2DM with reassuring but limited long-term data. All patients diagnosed with gestational diabetes should have a 75 g OGTT between 6 weeks and 6 months postpartum to detect persistent hyperglycemia.

Pediatric

T1DM is the predominant form in children and adolescents, though T2DM is increasingly diagnosed in adolescents and children living with obesity. Pediatric DKA carries a specific risk of cerebral edema from the sodium, pH, and glucose shifts of treatment — manage only with a specialized pediatric diabetes team in a monitored setting, never as a scaled-down adult protocol.^[3]

Renal impairment

Reduce metformin dose with declining renal function and hold below an eGFR of 30 mL/min/1.73m²; also hold before iodinated contrast if eGFR <30. SGLT2 inhibitors have reduced glycemic efficacy at lower eGFR but should be continued for their renal-protective benefit per current guidance — check each product's specific eGFR cut-off for the glycemic-indication versus renal-protection use. Sulfonylureas, especially glyburide, carry a higher hypoglycemia risk in renal impairment — dose-reduce or avoid. Insulin requirements often fall as renal clearance declines — monitor closely and adjust proactively, not reactively.^[5]

Hepatic impairment

Metformin is contraindicated in significant hepatic impairment. Pioglitazone offers a specific hepatic benefit in metabolic dysfunction-associated steatotic liver disease but still requires monitoring given its own adverse-effect profile.

Older adults and frailty

Relax the A1c target (7.1-8.5%, or 7.1-8.0% specifically for functionally dependent patients). Prioritize agents with a low hypoglycemia risk, and simplify regimens (e.g., basal-only insulin or a twice-daily premixed regimen rather than basal-bolus) when self-management capacity is limited.

Monitoring & Follow-Up

What to check	Frequency	Notes
A1c	Every 3 months if not at target; every 6 months if stable at target	The core measure of overall control.
Capillary blood glucose or CGM	Individualized; minimum 3x/day on a basal-bolus regimen	Review the log/data at every visit, not just the A1c.
Blood pressure	Every appropriate visit	Vascular protection target, not just a glycemic one.
Foot examination	Annually	Refer high-risk feet or existing ulcers to a foot-care specialist.
Serum creatinine (eGFR) and urine albumin-creatinine ratio	At least annually; more often once CKD is established	Start at diagnosis in T2DM; 5 years after diagnosis in T1DM.^[5]
Lipid profile	At diagnosis, then annually if normal, or every 3-6 months once treated
Dilated eye examination	At diagnosis (T2DM) or 5 years post-diagnosis, age ≥15 (T1DM); repeat per findings	More frequent once retinopathy is found.
Influenza and COVID-19 vaccination	Annually (influenza); per current schedule (COVID-19)

At every visit, review home glucose or CGM records for predictable trends that can be improved, and specifically ask about the occurrence, frequency, and pattern of hypoglycemia — address hypoglycemia before hyperglycemia to keep the patient safe in the short term. Before intensifying any therapy for a rising A1c, assess for and correct a precipitant first — infection, ischemia, a newly added dysglycemic medication, or a change in diet or activity — rather than automatically adding another agent.^[2]

Treatment Failure / Next Step

Confirm adherence to both lifestyle measures and medications, and screen for cost/access barriers that limit adherence.
Assess for and correct a contributing factor before escalating therapy — infection, corticosteroid or other dysglycemic drug use, or intercurrent illness.
If on metformin monotherapy and A1c remains above target after about 3 months, add a second agent chosen per the cardiorenal-risk criteria — don't simply wait longer at the same regimen.
Reassess every 3-6 months, titrating or adding agents until target is reached or 3 non-insulin agents are combined without adequate control.
If triple oral/injectable combination therapy fails, move to insulin — basal insulin first, then intensify per the algorithm below.
For recurrent hypoglycemia despite confirmed adherence, address it before further hyperglycemia treatment: relax the glycemic target temporarily, favour lower-hypoglycemia-risk agents, and consider CGM to identify the pattern.
In an adult who fails oral therapy unusually quickly, especially if lean or with a personal/family history of autoimmune disease, test for islet-cell/GAD65 autoantibodies to rule out LADA and move to insulin earlier if confirmed.

Common Errors to Avoid

Delaying insulin in T1DM, or in a patient with symptomatic metabolic decompensation, while trialing oral agents first.
Continuing metformin unchanged through acute illness with dehydration risk, or before iodinated contrast at eGFR <30.
Defaulting to glyburide as the first sulfonylurea choice — gliclazide or glimepiride carry a lower hypoglycemia risk, especially in older adults or renal impairment.
Missing SGLT2 inhibitor-associated euglycemic DKA because the glucose isn't dramatically elevated — think of it whenever a patient on this class has unexplained GI symptoms or malaise.
Withholding metformin in stable heart failure or liver disease based on outdated lactic-acidosis concerns not supported by current evidence.
Not adding a cardiorenal-protective agent (SGLT2 inhibitor and/or GLP-1 receptor agonist) in a patient with established ASCVD, heart failure, or CKD regardless of A1c control — this is an organ-protection decision, not just a glycemic one.
Treating hypoglycemia with glucose gel as the primary option — it must be swallowed for effect and works slowly; use a fast-acting glucose source instead.
Using sucrose (regular table sugar) to treat hypoglycemia in a patient taking acarbose — its digestion is impaired by acarbose; use glucose instead.
Missing hypoglycemia unawareness and continuing to simply retreat episodes without relaxing targets or re-educating.
In DKA management, stopping the IV insulin infusion before overlapping it with subcutaneous insulin by at least 2 hours — a premature switch is a common, avoidable cause of DKA relapse and readmission.
Waiting until after conception to discontinue ACE inhibitors, ARBs, or statins — these should be stopped during prepregnancy planning, not after a positive pregnancy test.

Clinical Decision Algorithm

Screening and diagnosis

Adult ≥40 years old, or younger with ≥1 risk factor for T2DM

Test FPG and/or A1c (CANRISK can help flag who needs earlier testing)

Diabetic range (random PG ≥11.1, FPG ≥7.0, A1c ≥6.5%, or OGTT 2h ≥11.1 mmol/L)

Symptomatic hyperglycemia present?

Yes

Diagnosis confirmed on this single result — no repeat test needed

Repeat the same test (or an alternative test if random PG) on another day before diagnosing^[1]

Prediabetes range (IFG, IGT, or A1c 6.0-6.4%)

Diagnose prediabetes; counsel on lifestyle intervention and rescreen at a shorter interval

Normal result

Rescreen at the standard 3-year interval, or sooner if new risk factors appear

T2DM — initial pharmacotherapy and escalation

T2DM diagnosed; nonpharmacologic trial not at target within 3 months, or pharmacotherapy indicated immediately

Assess for established ASCVD, heart failure, or CKD

ASCVD, heart failure, or CKD present

Start metformin (unless contraindicated) + an SGLT2 inhibitor and/or GLP-1 receptor agonist with proven cardiorenal benefit, regardless of A1c

Titrate metformin; continue the cardioprotective agent even if its glycemic effect is modest

No ASCVD, heart failure, or CKD

Start metformin alone (or plus a second agent if A1c is >1.5% above target)

If target not met in 3-6 months, add a second agent individualized by hypoglycemia risk, weight effect, cost, and preference

Target still not met on 2 agents at maximum tolerated dose

Add a 3rd agent from a different class — prioritize a GLP-1 receptor agonist and/or SGLT2 inhibitor (if not already used) before basal insulin

Target still not met, or a clear indication for insulin (decompensation, an end-organ issue limiting oral options)

Start basal insulin (glargine, degludec, or icodec); continue metformin. Titrate to fasting glucose under 7 mmol/L

Basal insulin at an adequate dose, A1c still above goal

Add prandial (rapid-acting) insulin — start with the single largest meal (basal-plus), advancing to all meals (basal-bolus) if needed. Stop insulin secretagogues and thiazolidinediones once basal-bolus begins.

Recognizing and treating hypoglycemia

Glucose under 3.9 mmol/L, or symptoms of hypoglycemia in a patient at risk^[4]

Level 1: 3.0-3.9 mmol/L, adrenergic symptoms only

Give 15 g fast-acting glucose (glucose tablets preferred over gel or food); recheck in 15 minutes, repeat if still low

Level 2: under 3.0 mmol/L, neuroglycopenic symptoms, able to safely swallow

Give 20 g fast-acting oral glucose; recheck in 15 minutes, repeat if still low; follow with a snack or meal

Level 3: impaired physical/cognitive status, needs assistance, unsafe to swallow

Give glucagon 1 mg IM/SC, or 3 mg intranasal (age ≥4y); call emergency services. Once conscious, give oral fast-acting sugar, then food.

Recurrent or otherwise unexplained hypoglycemia: review the regimen, reassess the glycemic target, and screen for hypoglycemia unawareness

Recognizing DKA and hyperosmolar hyperglycemic state (HHS)

Hyperglycemia with vomiting, abdominal pain, Kussmaul breathing, fruity breath, dehydration, or altered consciousness

Check point-of-care or serum ketones (beta-hydroxybutyrate preferred over urine ketone strips) and blood gas; refer to emergency care immediately — do not attempt outpatient management^[1]

Hospital management: aggressive IV fluid resuscitation, an IV insulin infusion (never stop insulin once started — add dextrose to the IV fluid if glucose falls below 14 mmol/L rather than pausing insulin), and potassium replacement guided by serum potassium (do not give insulin if K+ under 3.3 mmol/L)

Overlap IV insulin with subcutaneous insulin by at least 2 hours before stopping the infusion, once the anion gap has closed and the patient is eating — a premature switch is a common, avoidable cause of DKA relapse and readmission

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Insulin and Analogues

Rapid-acting insulin analogues

Used for prandial/bolus coverage; approximately 60% of total daily insulin requirement when used in a basal-bolus regimen.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Insulin aspart	Standard formulation: SC 0-15 min before, or within 20 min after starting, a meal Faster-acting formulation: SC 0-5 min before, or within 20 min after starting, a meal	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Faster-acting aspart formulations (e.g., Fiasp) may be dosed 0-5 min before a meal or within 20 min after starting one; other aspart products 0-15 min before or within 20 min after.
Insulin lispro	Adults: SC 0-15 min before, or within 20 min after starting, a meal	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Available in 100 units/mL and 200 units/mL concentrations — confirm concentration carefully when converting between products.
Insulin glulisine	Adults: SC 0-15 min before, or within 20 min after starting, a meal	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents

Short-acting insulin

Drug	Dosage	Adverse effects	Drug interactions	Comments
Insulin, regular (human biosynthetic)	Adults: SC 30-45 min before a meal	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Preferred insulin for IV infusion (e.g., DKA management). A concentrated 500 units/mL formulation exists for patients with very large insulin requirements (e.g., immune-mediated insulin resistance) — reserve for specialist-directed use given the overdose risk from measuring/dosing error.

Intermediate-acting insulin

Drug	Dosage	Adverse effects	Drug interactions	Comments
Insulin, NPH (isophane)	Basal-bolus regimen: SC once daily at bedtime, or BID Basal-only initiation (T2DM): 0.1-0.2 units/kg, or an empiric 5-10 units, SC at bedtime; titrate to fasting glucose under 7 mmol/L	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Cloudy appearance — resuspend by gentle rolling before each dose. May be used as the basal component of a basal-bolus regimen, or alone as basal-only therapy in T2DM.

Long-acting insulin analogues

Drug	Dosage	Adverse effects	Drug interactions	Comments
Insulin glargine, U100	Basal-bolus or basal-only regimen: SC once daily, or BID in 2 equal doses Basal-only initiation (T2DM): 0.1-0.2 units/kg, or an empiric 5-10 units, SC at bedtime; titrate to fasting glucose under 7 mmol/L	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Do not mix with other insulins; do not inject IM or IV. Considered safe in pregnancy.
Insulin glargine, U300	Adults: SC once daily	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Flatter, longer profile than U100 glargine. Do not mix with other insulins; do not inject IM or IV.
Insulin degludec	Adults: SC once daily	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Very flat, long duration of action. Available in 100 units/mL and 200 units/mL concentrations — confirm concentration carefully. Do not mix with other insulins; do not inject IM or IV.
Insulin icodec	Adults: SC once weekly, preferably the same day each week, at any time of day	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Once-weekly basal insulin. In an insulin-naive T2DM patient, begin 70 units once weekly. When switching from a daily basal insulin, multiply the total daily dose by 7 and round to the nearest 10 units. A first-dose-only 50% increase may be considered if hyperglycemia is not controlled. Do not mix with other insulins; do not inject IM or IV.

Premixed insulin

For patients who need a simplified regimen at the expense of dosing flexibility — reasonable when day-to-day food/activity is stable, injection assistance is required, or the patient cannot safely self-adjust doses.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Insulin regular/insulin NPH, 30/70	Adults: SC BID, 30 min before a meal; begin 5-10 units BID	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Cloudy appearance — resuspend before each dose.
Insulin (human biosynthetic)/insulin isophane, 30/70	Adults: SC BID, 30 min before a meal; begin 5-10 units BID	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Cloudy appearance — resuspend before each dose.
Insulin aspart protamine/insulin aspart, 30/70	Adults: SC BID, 0-15 min before or within 20 min after starting a meal; begin 5-10 units BID	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Cloudy appearance — resuspend before each dose.
Insulin lispro/insulin lispro protamine, 25 or 50	Adults: SC BID, 0-15 min before or within 20 min after starting a meal; begin 5-10 units BID	Hypoglycemia, lipohypertrophy, local/systemic hypersensitivity (rare)	Additive hypoglycemia with other antihyperglycemic agents	Cloudy appearance — resuspend before each dose. Available as 25% or 50% rapid-acting component.

Antihyperglycemic Agents

Biguanide

Drug	Dosage	Adverse effects	Drug interactions	Comments
Metformin	Adults: 500-2500 mg/day PO divided BID; start low and titrate slowly to minimize GI effects, typically to 1000 mg BID	Nausea, diarrhea, abdominal discomfort, anorexia, metallic taste; vitamin B12 deficiency with long-term use; lactic acidosis (rare) in hepatic/renal disease	Alcohol potentiates the hypoglycemic effect	No weight gain. Contraindicated in significant hepatic impairment, severe renal impairment, or a history of lactic acidosis. Reduced doses can be used down to a ClCr of 45 mL/min. Hold if acutely ill/unable to maintain fluid intake, and hold at eGFR under 30 with iodinated contrast administration.

Alpha-glucosidase inhibitor

Drug	Dosage	Adverse effects	Drug interactions	Comments
Acarbose	Adults: 25-100 mg PO TID with the first bite of each meal; start low and titrate slowly	Flatulence, diarrhea, abdominal cramps, nausea	Potentiates other antihyperglycemic agents; may reduce metformin bioavailability	Not absorbed; does not cause hypoglycemia alone but potentiates hypoglycemia from insulin/secretagogues. Contraindicated in inflammatory bowel disease and irritable bowel syndrome. Because it impairs sucrose digestion, treat hypoglycemia in a patient on acarbose with glucose, not sucrose.

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Well tolerated, weight-neutral, low hypoglycemia risk; do not alter cardiovascular risk.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Alogliptin	Adults: 6.25-25 mg PO once daily	Nasopharyngitis, hypersensitivity reactions, rare pancreatitis, rare severe joint pain	Low potential for drug interactions; does not inhibit cytochrome P450 isozymes	May be taken with or without food.
Linagliptin	Adults: 5 mg PO once daily	Nasopharyngitis, hypersensitivity reactions, rare pancreatitis, rare severe joint pain	Clearance enhanced by strong CYP3A4 inducers (e.g., rifampin)	May be taken with or without food. No renal dose adjustment required.
Saxagliptin	Adults: 2.5-5 mg PO once daily	Nasopharyngitis, hypersensitivity reactions, rare pancreatitis, rare severe joint pain	Clearance reduced by strong CYP3A4/5 inhibitors (e.g., imidazole antifungals, macrolides); clearance enhanced by strong CYP3A4/5 inducers (e.g., rifampin)	Avoid in patients with heart failure.
Sitagliptin	Adults: 25-100 mg PO once daily	Nasopharyngitis, hypersensitivity reactions, rare pancreatitis, rare severe joint pain	Low potential for drug interactions; does not inhibit cytochrome P450 isozymes	May be taken with or without food. Reduce dose in renal impairment per product monograph.

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

Cause weight loss; caution in patients with cardiac rhythm disturbances or severe renal impairment. Contraindicated in pregnancy and in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Dulaglutide	Initial: 0.75 mg SC once weekly Maintenance: Typically increased to 1.5 mg SC once weekly	Nausea, vomiting, diarrhea, injection-site reactions, rare acute pancreatitis	May reduce the absorption rate of some oral medications
Liraglutide	Initial: 0.6 mg SC once daily Maintenance: Increase to 1.2-1.8 mg SC once daily	Nausea, vomiting, diarrhea, injection-site reactions, rare acute pancreatitis	May reduce the absorption rate of some oral medications
Semaglutide, subcutaneous	Initial: 0.25 mg SC once weekly for 4 weeks Titration: 0.5 mg SC once weekly from week 5 Further titration: May increase to 1 mg SC once weekly after a further 4 weeks	Nausea, vomiting, diarrhea, injection-site reactions, rare acute pancreatitis	May reduce the absorption rate of some oral medications
Semaglutide, oral	Initial: 3 mg PO once daily for 30 days Titration: Increase to 7 mg PO once daily after 30 days Further titration: May increase to 14 mg PO once daily after a further 30 days	Nausea, vomiting, diarrhea, rare acute pancreatitis	May reduce the absorption rate of some oral medications	Take on an empty stomach immediately on waking with no more than 120 mL plain water; no other food, drink, or oral medication for at least 30 minutes afterward.

Glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Same weight-loss profile, cautions, and contraindications as the GLP-1 receptor agonist class.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Tirzepatide	Initial: 2.5 mg SC once weekly for 4 weeks (starter dose, not intended for glycemic efficacy) Titration: Increase to 5 mg SC once weekly after 4 weeks Further titration: May increase in 2.5 mg increments no sooner than every 4 weeks, to a maximum of 15 mg SC once weekly	Nausea, vomiting, diarrhea, injection-site reactions, rare acute pancreatitis	May reduce the absorption rate of some oral medications; may increase heart rate — caution combining with other agents that do the same

Insulin secretagogues — sulfonylureas

Drug	Dosage	Adverse effects	Drug interactions	Comments
Gliclazide	Adults: 40-320 mg/day PO	Hypoglycemia, weight gain	Hypoglycemic effect potentiated by salicylates, sulfonamides, and MAO inhibitors; beta-blockers may mask hypoglycemic symptoms	Divide the daily dose BID once it reaches 160 mg/day or higher.
Gliclazide, modified-release	Adults: 30-120 mg PO once daily	Hypoglycemia (may be prolonged with this formulation), weight gain	Hypoglycemic effect potentiated by salicylates, sulfonamides, and MAO inhibitors; beta-blockers may mask hypoglycemic symptoms
Glimepiride	Adults: 1-4 mg PO once daily	Hypoglycemia (may be prolonged), weight gain	Hypoglycemic effect potentiated by salicylates, sulfonamides, and MAO inhibitors; beta-blockers may mask hypoglycemic symptoms
Glyburide	Adults: 2.5-20 mg/day PO	Weight gain; hypoglycemia, generally higher risk than gliclazide/glimepiride, especially in older adults or renal impairment	Hypoglycemic effect potentiated by salicylates, sulfonamides, and MAO inhibitors; beta-blockers may mask hypoglycemic symptoms	Divide the daily dose BID once it exceeds 10 mg/day. Prefer gliclazide or glimepiride when starting a new sulfonylurea.

Insulin secretagogues — meglitinides

Drug	Dosage	Adverse effects	Drug interactions	Comments
Repaglinide	Adults: 0.5-4 mg PO, 0-30 min before each meal	Hypoglycemia, especially if a meal is skipped; weight gain	Clearance reduced by strong CYP3A4 inhibitors (e.g., imidazole antifungals, macrolides, protease inhibitors) and strong CYP2C8 inhibitors (e.g., atazanavir, ritonavir); clearance enhanced by strong CYP3A4 inducers (e.g., rifampin, carbamazepine); combination with gemfibrozil markedly enhances and prolongs hypoglycemia and should be avoided	Omit the dose if the associated meal is skipped.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Small BP reduction; low hypoglycemia risk alone; reduced glycemic efficacy at lower eGFR but continued for cardiorenal protection per current guidance.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Canagliflozin	Adults: 100-300 mg PO once daily	Genitourinary mycotic infection, volume depletion/hypotension, hyperkalemia, rare diabetic ketoacidosis	Strong enzyme inducers (rifampin, phenytoin, carbamazepine) reduce plasma levels; loop diuretics increase hypotension risk	Less effective, and eventually ineffective, at reduced eGFR for glycemic purposes.
Dapagliflozin	Adults: 5-10 mg PO once daily	Genitourinary mycotic infection, volume depletion/hypotension, hyperkalemia, rare diabetic ketoacidosis	Loop diuretics increase hypotension risk	Less effective, and eventually ineffective, at reduced eGFR for glycemic purposes.
Empagliflozin	Adults: 10-25 mg PO once daily	Genitourinary mycotic infection, volume depletion/hypotension, hyperkalemia, rare diabetic ketoacidosis	Loop diuretics increase hypotension risk	Less effective, and eventually ineffective, at reduced eGFR for glycemic purposes.

Thiazolidinediones (TZDs)

Both agents are contraindicated/avoided in heart failure given fluid retention and worsening heart failure risk.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Pioglitazone	Adults: 15-45 mg PO once daily	Weight gain, fluid retention/edema, worsening heart failure, macular edema, increased fracture risk, possible bladder-cancer association	Potentiates other antihyperglycemic agents; gemfibrozil inhibits metabolism and increases plasma levels	Ovulation may resume in previously anovulatory patients (e.g., PCOS) — counsel on contraception. May offer a hepatic benefit in metabolic dysfunction-associated steatotic liver disease.
Rosiglitazone	Adults: 4-8 mg/day PO in 1-2 doses	Weight gain, fluid retention/edema, worsening heart failure, macular edema, increased fracture risk, possible bladder-cancer association	Potentiates other antihyperglycemic agents; gemfibrozil inhibits metabolism and increases plasma levels	Health Canada requires documented patient consent for every new and renewed rosiglitazone prescription given its cardiovascular-safety history. Ovulation may resume in previously anovulatory patients — counsel on contraception.

DPP-4 inhibitor / biguanide combinations

Combination therapy always uses agents from different classes; can be used as initial therapy if hyperglycemia is not expected to respond to a single agent. Contraindicated in hepatic impairment, severe renal impairment, and previous lactic acidosis — see Metformin above.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Alogliptin / metformin	Starting from metformin monotherapy: Continue the metformin dose, add alogliptin 12.5 mg PO BID Maximum: 12.5 mg/1000 mg PO BID	Nasopharyngitis, GI upset, rare pancreatitis, rare lactic acidosis (renal/hepatic disease)	Alcohol potentiates the hypoglycemic effect
Linagliptin / metformin	Starting from metformin monotherapy: Continue the metformin dose, add linagliptin 2.5 mg PO BID Maximum: 2.5 mg/1000 mg PO BID	Nasopharyngitis, GI upset, rare pancreatitis, rare lactic acidosis (renal/hepatic disease)	Alcohol potentiates the hypoglycemic effect
Sitagliptin / metformin (immediate-release)	Starting from metformin monotherapy: Continue the metformin dose, add sitagliptin 50 mg PO BID Maximum: 50 mg/1000 mg PO BID	Nasopharyngitis, GI upset, rare pancreatitis, rare lactic acidosis (renal/hepatic disease)	Alcohol potentiates the hypoglycemic effect	A saxagliptin/metformin fixed-dose combination (Komboglyze) is also marketed in Canada but is not separately tabulated here — dose each component per its own monograph if used.
Sitagliptin / metformin, extended-release	Adults: 50/500 mg, 50/1000 mg, or 100/1000 mg PO once daily Maximum: 100 mg/2000 mg PO once daily	Nasopharyngitis, GI upset, rare pancreatitis, rare lactic acidosis (renal/hepatic disease)	Alcohol potentiates the hypoglycemic effect

SGLT2 inhibitor / biguanide combinations

Same contraindications as the individual components (metformin: hepatic/severe renal impairment, previous lactic acidosis; SGLT2 inhibitor: euglycemic DKA risk).

Drug	Dosage	Adverse effects	Drug interactions	Comments
Canagliflozin / metformin	Starting from metformin monotherapy: Continue the metformin dose, add canagliflozin 50 mg PO BID Maximum: 150 mg/1000 mg PO BID	Genitourinary mycotic infection, volume depletion, rare DKA, GI upset, rare lactic acidosis	Loop diuretics increase hypotension risk; alcohol potentiates the hypoglycemic effect
Dapagliflozin / metformin	Adults: 10 mg/850 mg or 10 mg/1000 mg PO BID	Genitourinary mycotic infection, volume depletion, rare DKA, GI upset, rare lactic acidosis	Loop diuretics increase hypotension risk; alcohol potentiates the hypoglycemic effect	Use the combination strength nearest the patient's existing individual-component doses.
Empagliflozin / metformin	Starting from metformin monotherapy: Continue the metformin dose, add empagliflozin 5 mg PO BID Maximum: 12.5 mg/1000 mg PO BID	Genitourinary mycotic infection, volume depletion, rare DKA, GI upset, rare lactic acidosis	Loop diuretics increase hypotension risk; alcohol potentiates the hypoglycemic effect

Basal insulin / GLP-1 receptor agonist combination

Not for use in type 1 diabetes. Contraindicated in pregnancy and in patients with a personal or family history of medullary thyroid carcinoma or MEN2.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Insulin glargine / lixisenatide	If on under 30 units insulin/day: Initial 15 units/5 mcg SC once daily If on 30-60 units insulin/day: Initial 30 units/10 mcg SC once daily Titration: Adjust by 2-4 units every week per glucose results Maximum: 60 units/20 mcg SC once daily	Hypoglycemia, nausea, vomiting, diarrhea, injection-site reactions, rare pancreatitis	Increased hypokalemia risk with potassium-lowering drugs; may reduce the absorption rate of some oral medications	Give within 1 hour of a meal, preferably the first meal of the day. An insulin degludec/liraglutide combination product (Xultophy) is also marketed in Canada and dosed similarly in principle, but is not separately tabulated here.

Hypoglycemia treatment

Level 1/2 hypoglycemia (patient able to safely swallow) is self-treated with a fast-acting oral glucose source; Level 3 (needs assistance) requires glucagon or emergency IV dextrose.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Glucose, fast-acting oral source	Level 1 (self-treat): 15 g fast-acting glucose; recheck in 15 min, repeat if still low Level 2 (self-treat if able to swallow safely): 20 g fast-acting glucose; recheck in 15 min, repeat if still low, then a snack/meal	None at recommended doses	None significant	Glucose tablets are preferred over gel or juice for reliability of dose; glucose gel works slowly and must be swallowed for effect, so it is not a preferred option.
Glucagon	IM or SC injection: 1 mg, single dose Intranasal powder (age ≥4y): 3 mg, single dose into 1 nostril	Nausea, vomiting, headache	None significant at emergency doses	For Level 3 hypoglycemia when the patient cannot safely take oral glucose. Call emergency services. Once the patient is conscious, give oral fast-acting sugar followed by food.
Dextrose, IV	Adults: Per institutional protocol	Local irritation with extravasation	None significant	Hospital/emergency use when oral glucose is unsafe and glucagon is unavailable or ineffective, or as part of DKA/HHS fluid management.

References

Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada — Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42(Suppl 1):S1-S325
Pharmacologic Glycemic Management of Type 2 Diabetes in Adults — 2024 Update — Diabetes Canada Clinical Practice Guidelines Expert Working Group (Shah BR, Bajaj HS, Butalia S, et al.). Can J Diabetes 2024;48(7):415-424
Glycemic Management Across the Lifespan for People With Type 1 Diabetes: A Clinical Practice Guideline — Diabetes Canada Clinical Practice Guidelines Steering Committee (Halperin IJ, Wicklow B, Amed S, et al.). Can J Diabetes 2025;49(1):5-18
Hypoglycemia in Adults — Diabetes Canada Clinical Practice Guidelines Expert Working Group (Lega IC, Yale JF, Chadha A, et al.). Can J Diabetes 2023;47(7):548-559
Chronic Kidney Disease in Diabetes: A Clinical Practice Guideline — Diabetes Canada Clinical Practice Guidelines Steering Committee (Tobe SW, Bajaj HS, Tangri N, et al.). Can J Diabetes 2025;49(2):73-86.e14

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.