Diabetes Mellitus Pharmacology: A Detailed Overview

I. Background and Classification

• Fasting plasma glucose ≥ 126 mg/dL
• 2-hr postprandial glucose ≥ 200 mg/dL
• HbA1c ≥ 6.5%
• ADA target for most patients: A1C ≤ 7% (mean glucose ≤ 154 mg/dL)

II. Insulin

Types and Pharmacokinetics

• Insulin lispro, aspart, glulisine - Onset 15-30 min, peak 30-90 min; given 15 min before or within 15-20 min after a meal
• Inhaled insulin - peak within 10-20 min; dry powder absorbed through pulmonary tissue
• Used to mimic prandial insulin release; can also be used in insulin pumps

• Regular insulin - Onset ~30 min, peak 50-120 min; inject 30 min before a meal; used IV in DKA

• NPH (Neutral Protamine Hagedorn) - Formed by adding zinc and protamine to regular insulin; delayed absorption, longer duration; used as basal insulin; given subcutaneously only (never IV)

• Insulin glargine - A "peakless" basal insulin with a flat profile lasting ~24 hours; precipitates at subcutaneous pH
• Insulin detemir - Binds albumin; prolonged action up to ~18 hours
• Insulin degludec - Ultra-long acting (>24 hours); forms multi-hexamers in subcutaneous tissue

Mechanism of Action

Adverse Effects

• Hypoglycemia - most serious and common; risk highest with intensive regimens
• Weight gain
• Lipodystrophy - local atrophy or hypertrophy at injection sites
• Hypokalemia - insulin drives K+ into cells

Intensive vs. Standard Therapy

III. Amylin Analog: Pramlintide

• Reduce mealtime insulin dose by 50% when initiating (risk of severe hypoglycemia)
• Cannot be mixed with insulin in the same syringe
• Contraindicated in diabetic gastroparesis and hypoglycemic unawareness
• Adverse effects: nausea, anorexia, vomiting

IV. Oral Agents for Type 2 Diabetes

A. Biguanides - Metformin (First-line therapy)

1. Reduces hepatic gluconeogenesis (primary effect - addresses the major source of fasting hyperglycemia)
2. Slows intestinal absorption of sugars
3. Improves peripheral glucose uptake and insulin sensitivity

• GI: diarrhea, nausea, vomiting (minimize by slow dose titration, take with food)
• Weight loss (reduces appetite)
• Lactic acidosis (rare but potentially fatal)
• Vitamin B12 deficiency with long-term use - monitor B12 levels, especially with anemia or peripheral neuropathy

• Severe renal dysfunction (eGFR <30 mL/min/1.73 m²) - lactic acidosis risk
• Acute MI, decompensated heart failure, sepsis (acute renal failure risk)
• Caution: age >80 years, alcohol abuse history
• Temporarily hold for IV contrast procedures

B. Sulfonylureas (Insulin Secretagogues)

• Hypoglycemia (most significant - glucose-independent mechanism)
• Hyperinsulinemia
• Weight gain
• Drug interactions: many drugs potentiate hypoglycemia (e.g., sulfonamides, NSAIDs, warfarin) or reduce glycemic control (e.g., thiazides, corticosteroids)

C. Meglitinides (Postprandial Glucose Regulators)

• Take before each meal
• Repaglinide: metabolized via CYP2C8/3A4; excreted in feces
• Nateglinide: metabolized via CYP2C9/3A4; excreted in urine

• Do NOT combine with sulfonylureas (overlapping mechanism, severe hypoglycemia risk)
• Gemfibrozil (lipid-lowering) inhibits CYP2C8, markedly increases repaglinide levels - combination contraindicated

D. Thiazolidinediones (TZDs) - Insulin Sensitizers

• Fluid retention and edema
• Weight gain
• Increased risk of osteoporotic fractures (especially in women)
• Pioglitazone: potential increased risk of bladder cancer
• Contraindicated in symptomatic heart failure (fluid retention worsens heart failure)

E. GLP-1 Receptor Agonists (Incretin Mimetics)

1. Bind and activate GLP-1 receptors on pancreatic beta cells → glucose-dependent insulin secretion
2. Decrease postprandial glucagon secretion
3. Slow gastric emptying (reduce postprandial glucose excursion)
4. Enhance satiety / reduce food intake → weight loss
5. Promote beta-cell proliferation

• Nausea, vomiting, constipation (most common - GI)
• Pancreatitis (rare)
• Thyroid C-cell tumors (seen in animal studies; avoid in personal/family history of MTC or MEN2)

F. DPP-4 Inhibitors (Gliptins)

• Well absorbed orally; food does not affect absorption
• Sitagliptin and alogliptin: renally excreted unchanged
• Saxagliptin: CYP3A4/5 metabolism to active metabolite; renal excretion
• Linagliptin: primarily enterohepatic elimination (no renal dose adjustment needed)
• All except linagliptin require dose adjustment in renal dysfunction

• Generally well tolerated
• Nasopharyngitis, headache
• Rare but serious: hypersensitivity reactions, pancreatitis, severe joint pain
• Saxagliptin increases risk of heart failure hospitalizations - use with caution in heart failure

G. SGLT2 Inhibitors (Gliflozins)

• Canagliflozin and empagliflozin: approved to reduce cardiovascular death in T2DM + CVD
• Canagliflozin and dapagliflozin: reduce heart failure hospitalizations and progression to end-stage kidney disease
• Dapagliflozin and empagliflozin: approved for heart failure with reduced ejection fraction (HFrEF), even without diabetes

• Genital mycotic infections (most common - due to glycosuria)
• Urinary tract infections
• Urinary frequency/polyuria
• Euglycemic DKA (especially in Type 1 DM - not approved for T1DM)
• Canagliflozin: increased risk of lower-limb amputation and fractures

H. Alpha-Glucosidase Inhibitors

V. Drug Class Summary Table

VI. Treatment Strategy

1. Step 1: Metformin at diagnosis (unless contraindicated)
2. Step 2: Add a second agent based on comorbidities:
   • CVD or high CV risk → GLP-1 RA (semaglutide, liraglutide) or SGLT2 inhibitor (empagliflozin, canagliflozin)
   • Heart failure → SGLT2 inhibitor preferred
   • CKD → SGLT2 inhibitor (canagliflozin, dapagliflozin)
   • Weight loss needed → GLP-1 RA or SGLT2 inhibitor
   • Hypoglycemia must be avoided → DPP-4 inhibitor, GLP-1 RA, TZD, SGLT2i
3. Step 3: Add or intensify with additional agents; add basal insulin when needed
4. Insulin: Initiate when A1C remains uncontrolled or in acute illness

VII. Recent Evidence Update