Diabetes Mellitus

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).

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.

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).

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

Differentiating type 1 from type 2 diabetes at presentation

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.

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.

• 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.

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.

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.

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]

1. Confirm adherence to both lifestyle measures and medications, and screen for cost/access barriers that limit adherence.
2. Assess for and correct a contributing factor before escalating therapy — infection, corticosteroid or other dysglycemic drug use, or intercurrent illness.
3. 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.
4. Reassess every 3-6 months, titrating or adding agents until target is reached or 3 non-insulin agents are combined without adequate control.
5. If triple oral/injectable combination therapy fails, move to insulin — basal insulin first, then intensify per the algorithm below.
6. 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.
7. 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.

• 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.

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.

Short-acting insulin

Intermediate-acting insulin

Long-acting insulin analogues

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.

Antihyperglycemic Agents

Biguanide

Alpha-glucosidase inhibitor

Dipeptidyl peptidase-4 (DPP-4) inhibitors

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

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.

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

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

Insulin secretagogues — sulfonylureas

Insulin secretagogues — meglitinides

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.

Thiazolidinediones (TZDs)

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

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.

SGLT2 inhibitor / biguanide combinations

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

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.

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.