6.2 Endocrine and Metabolic Pharmacotherapy

Type 2 Diabetes Mellitus: Diagnostic Criteria and Therapeutic Targets

Diabetes Canada clinical practice guidelines establish diagnostic thresholds and evidence-based management frameworks designed to optimize glycemic control while preventing microvascular and macrovascular complications.

Diagnostic Criteria for Diabetes Mellitus

Diagnosis requires one of the following laboratory criteria, confirmed with a repeat test on a separate day in the absence of unequivocal symptomatic hyperglycemia:

• Fasting Plasma Glucose (FPG): $\ge 7.0\text{ mmol/L}$ (fasting $\ge 8\text{ hours}$).
• Glycated Hemoglobin (HbA1c): $\ge 6.5%$ (standardized, validated assay).
• Two-Hour Plasma Glucose (2hPG) in 75g OGTT: $\ge 11.1\text{ mmol/L}$.
• Random Plasma Glucose: $\ge 11.1\text{ mmol/L}$ accompanied by classic symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, unexplained weight loss).

Prediabetes: Defined by Impaired Fasting Glucose (FPG $6.1-6.9\text{ mmol/L}$), Impaired Glucose Tolerance (2hPG $7.8-11.0\text{ mmol/L}$), or $\text{HbA1c } 6.0-6.4%$.

Glycemic Targets

• General Adult Target: $\text{HbA1c} \le 7.0%$ (FPG / preprandial $4.0-7.0\text{ mmol/L}$; 2-hour postprandial $5.0-10.0\text{ mmol/L}$). This target balances long-term microvascular risk reduction against hypoglycemia risk.
• Intensive Target: $\text{HbA1c} \le 6.5%$ in younger patients with newly diagnosed diabetes, long life expectancy, and low hypoglycemia risk.
• Relaxed Target: $\text{HbA1c } 7.1-8.5%$ in frail elderly individuals, patients with limited life expectancy, high risk of severe hypoglycemia, or extensive comorbid conditions.

---

Antihyperglycemic Selection Algorithm and Cardiorenal Protection

Diabetes Canada emphasizes organ-protection-guided pharmacotherapy. When choosing antihyperglycemic agents, the presence of established atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD) dictates treatment selection independent of baseline HbA1c.

+-------------------------------------------------------------------------+
|            DIABETES CANADA ORGAN-PROTECTIVE SELECTION ALGORITHM         |
+-------------------------------------------------------------------------+
|  FOUNDATION: Metformin (titrated to 2000 mg daily) + Lifestyle          |
|                                |                                        |
|  ASSESS CLINICAL COMORBIDITIES (REGARDLESS OF BASELINE HbA1c):          |
|                                                                         |
|  1. CLINICAL ASCVD (Prior MI, CAD, Stroke, PAD, Age >= 60 + Risk)       |
|     --> Add GLP-1 RECEPTOR AGONIST with proven CV benefit               |
|         (Semaglutide, Liraglutide, Dulaglutide)                         |
|         OR SGLT2 INHIBITOR (Empagliflozin, Canagliflozin, Dapagliflozin)|
|                                                                         |
|  2. HEART FAILURE (HFrEF or HFpEF, LVEF <= 40% or Preserved)            |
|     --> Add SGLT2 INHIBITOR (Empagliflozin, Dapagliflozin)              |
|                                                                         |
|  3. CHRONIC KIDNEY DISEASE (eGFR 20-60 mL/min or ACR > 3.0 mg/mmol)    |
|     --> Add SGLT2 INHIBITOR (Empagliflozin, Dapagliflozin, Canagliflozin|
|         If SGLT2i not tolerated/contraindicated -> Add GLP-1 RA        |
|                                                                         |
|  4. IF GLYCEMIC TARGET NOT MET & NO HIGH-RISK CARDIORENAL COMORBIDITY:  |
|     --> Choose based on Weight Loss priority (GLP-1 RA, Tirzepatide,    |
|         SGLT2i), Hypoglycemia Avoidance (DPP-4i, GLP-1 RA, SGLT2i),     |
|         or Cost (Gliclazide, Pioglitazone, Biosimilar Insulin)         |
+-------------------------------------------------------------------------+

Comprehensive Antihyperglycemic Drug Classes

Acute Illness Sick-Day Management: The SADMANS Rule

During acute dehydrating illnesses (gastroenteritis, high fever, severe infections, vomiting, diarrhea), specific medications must be temporarily withheld to prevent life-threatening complications:

• S — Sulfonylureas (hypoglycemia during reduced oral intake)
• A — ACE Inhibitors (worsens acute renal hypoperfusion)
• D — Diuretics / Direct Renin Inhibitors (severe volume depletion and dehydration)
• M — Metformin (hypoperfusion and tissue hypoxia precipitate lactic acidosis)
• A — Angiotensin Receptor Blockers (worsens acute kidney injury)
• N — NSAIDs (constricts afferent renal arterioles, precipitating renal failure)
• S — SGLT2 Inhibitors (triggers Euglycemic Diabetic Ketoacidosis [euDKA] during metabolic stress/dehydration)

Hypoglycemia Protocol (The "Rule of 15")

Hypoglycemia is defined clinically as blood glucose $< 4.0\text{ mmol/L}$ with or without autonomic/neuroglycopenic symptoms.

1. Mild-to-Moderate (Conscious, able to swallow): Ingest $15\text{ g}$ of simple, fast-acting carbohydrate (e.g., 4 glucose tablets, $175\text{ mL}$ [3/4 cup] of fruit juice or regular pop, 6 Life Savers, $15\text{ mL}$ [3 teaspoons] of table sugar dissolved in water).
2. Wait 15 Minutes: Recheck capillary blood glucose. If still $< 4.0\text{ mmol/L}$, treat with another $15\text{ g}$ of carbohydrate.
3. Follow-up Snack: Once glucose $> 4.0\text{ mmol/L}$, provide a complex carbohydrate and protein snack (e.g., crackers with cheese, bread with peanut butter) or regular scheduled meal to prevent recurrent hypoglycemia.
4. Severe Hypoglycemia (Unconscious, seizing, or requiring external assistance): Administer Glucagon ($1\text{ mg}$ SC or IM) or Nasal Powder Glucagon (Baqsimi $3\text{ mg}$ intranasally into one nostril). In hospital settings, administer $20-50\text{ mL}$ of IV $50%$ Dextrose ($D_{50}W$) over 1-3 minutes.

---

Thyroid Disorders: Hypothyroidism and Hyperthyroidism

Hypothyroidism

Primary hypothyroidism is characterized by elevated serum thyroid-stimulating hormone (TSH) and low free thyroxine (free $T_4$).

• Pharmacological Treatment: Levothyroxine ($L\text{-thyroxine}, T_4$) is the standard of care.
• Dosing Principles: Full replacement dose is approximately $1.6\text{ }\mu\text{g/kg/day}$ of ideal body weight for young, healthy adults. In elderly patients or those with known coronary artery disease, initiate at a low dose ($25-50\text{ }\mu\text{g/day}$) and titrate slowly by $12.5-25\text{ }\mu\text{g}$ every 6-8 weeks to avoid precipitating myocardial ischemia or tachyarrhythmias.
• Administration Instructions: Take on an empty stomach with a full glass of plain water at least 30 to 60 minutes before breakfast or at bedtime (at least 3-4 hours after the evening meal). Must be separated by at least 4 hours from calcium carbonate, iron supplements, aluminum/magnesium antacids, sucralfate, cholestyramine, and proton pump inhibitors, which significantly impair absorption.
• Therapeutic Monitoring: Serum TSH is the primary monitoring parameter, assessed 6 to 8 weeks after dosage initiation or adjustment (therapeutic target $0.5-4.0\text{ mIU/L}$). In pregnancy, levothyroxine requirements increase by $30-50%$; TSH targets are tighter (trimester 1: $< 2.5\text{ mIU/L}$; trimesters 2-3: $< 3.0\text{ mIU/L}$).

Hyperthyroidism

Characterized by suppressed TSH ($< 0.1\text{ mIU/L}$) and elevated free $T_4$ and/or free $T_3$, most commonly caused by Graves' disease (TSH-receptor antibodies) or toxic multinodular goiter.

• Antithyroid Drugs (Thionamides):
  • Methimazole (MMI): Preferred first-line agent due to longer half-life (once-daily dosing), faster euthyroid attainment, and significantly lower risk of severe hepatotoxicity.
  • Propylthiouracil (PTU): Preferred specifically in the first trimester of pregnancy (due to methimazole-associated embryopathy: aplasia cutis, choanal atresia), in thyroid storm (because PTU inhibits peripheral conversion of $T_4$ to $T_3$), and in patients with adverse reactions to methimazole.
  • Black Box Warning & Critical Safety: PTU carries a high risk of severe, fulminant hepatic necrosis. Both thionamides can cause agranulocytosis ($< 0.5%$ incidence; typically within first 3 months). Patients must be educated to immediately report fever, sore throat, or signs of infection, prompt immediate drug cessation, and obtain an urgent Complete Blood Count (CBC) with differential.
• Symptomatic Management: Beta-blockers without intrinsic sympathomimetic activity (e.g., propranolol $10-40\text{ mg}$ TID-QID or atenolol $25-50\text{ mg}$ daily) control adrenergic symptoms (palpitations, tremor, anxiety, heat intolerance) while awaiting thionamide efficacy.

---

Osteoporosis and Bone Health

Osteoporosis Canada (2023 guidelines) focuses on preventing fragility fractures using the CAROC (Canadian Association of Radiologists and Osteoporosis Canada) or FRAX tool to calculate 10-year major osteoporotic fracture risk:

• Low Risk ($< 10%$): Lifestyle, exercise, calcium, and vitamin D.
• Moderate Risk ($10-20%$): Individualized pharmacotherapy based on patient preference and risk factors.
• High Risk ($> 20%$), prior hip/vertebral fragility fracture, or $\ge 2$ fragility fractures: Pharmacological therapy strongly recommended.

Pharmacological Agents for Osteoporosis

---

Obesity Pharmacotherapy

Obesity Canada guidelines recommend pharmacotherapy as an adjunct to medical nutrition therapy and physical activity for adults with $\text{BMI} \ge 30\text{ kg/m}^2$, or $\text{BMI} \ge 27\text{ kg/m}^2$ with weight-related complications (hypertension, T2DM, dyslipidemia, OSA):

• GLP-1 Receptor Agonists: Semaglutide $2.4\text{ mg}$ SC weekly (Wegovy) or Liraglutide $3.0\text{ mg}$ SC daily (Saxenda). Suppress appetite, enhance satiety, and delay gastric emptying.
• Dual GIP/GLP-1 RA: Tirzepatide (Zepbound). Produces average weight reductions of $15-22%$.
• Naltrexone / Bupropion: (Contrave $8/90\text{ mg}$ PO). Synergistic action on hypothalamic appetite centers and dopamine reward pathways. Contraindicated in uncontrolled hypertension, seizure disorders, chronic opioid use, or acute alcohol/benzodiazepine withdrawal.
• Orlistat: (Xenical $120\text{ mg}$ PO TID with fat-containing meals). Reversible gastric and pancreatic lipase inhibitor preventing dietary triglyceride hydrolysis. Adverse effects: fecal urgency, oily spotting, fat-soluble vitamin malabsorption (supplement vitamins A, D, E, K separated by $\ge 2\text{ hours}$).