9.4 Diabetes Medications
Diabetes pharmacotherapy aims to maintain glycemic control while minimizing hypoglycemia and cardiovascular risk. Treatment includes insulin, oral agents, and GLP-1 receptor agonists.
Insulin Preparations
Types & Pharmacokinetics
| Type | Examples | Onset | Peak | Duration |
|---|---|---|---|---|
| Rapid-acting | Lispro, aspart, glulisine | 5-15 min | 1-2 h | 4-6 h |
| Short-acting | Regular insulin | 30-60 min | 2-4 h | 6-10 h |
| Intermediate | NPH | 1-2 h | 4-12 h | 16-24 h |
| Long-acting | Glargine, detemir | 1-2 h | No peak | 20-24 h |
| Ultra-long | Degludec | 1-2 h | No peak | >42 h |
Clinical Use
- • Type 1 DM: Required; basal-bolus regimen (glargine + lispro with meals)
- • Type 2 DM: When oral agents insufficient; DKA, HHS
- • Pregnancy: Preferred for gestational DM (safest)
- • Hyperkalemia: IV regular insulin + glucose (shifts K+ intracellularly)
⚠️ Adverse Effects
- • Hypoglycemia: Most serious; tremor, sweating, confusion, seizures
- • Weight gain (anabolic effects)
- • Lipohypertrophy at injection sites (rotate sites)
- • Hypokalemia (especially with DKA treatment)
Oral Antidiabetic Agents
Metformin (Biguanide)
Mechanism:
Activates AMPK → ↓ hepatic gluconeogenesis, ↑ peripheral glucose uptake, ↓ intestinal glucose absorption. Does NOT cause hypoglycemia (euglycemic agent).
Indications:
- • First-line for type 2 DM
- • Polycystic ovary syndrome (PCOS)
- • Weight-neutral or promotes weight loss
Benefits:
- ✓ No hypoglycemia
- ✓ Cardiovascular benefits
- ✓ Weight loss
Adverse:
- • GI upset (diarrhea, nausea; dose-limiting)
- • Vitamin B12 deficiency (long-term)
- • Lactic acidosis (rare but serious)
- ⚠️ Contraindications: CrCl <30, acute kidney injury, contrast dye, severe liver disease
Sulfonylureas
Mechanism:
Bind SUR1 subunit of K-ATP channels on pancreatic β-cells → closes channel → depolarization → Ca²⁺ influx → insulin secretion. Requires functioning β-cells.
Agents:
- • Glyburide: Long-acting; highest hypoglycemia risk
- • Glipizide: Shorter-acting
- • Glimepiride: Once-daily
Adverse Effects:
- • Hypoglycemia: Especially in elderly, renal impairment
- • Weight gain (anabolic)
- • SIADH (hyponatremia)
- • Disulfiram-like reaction with alcohol (chlorpropamide)
- Avoid in CKD, elderly. Use with caution.
Thiazolidinediones (TZDs / Glitazones)
Mechanism:
PPAR-γ agonists → ↑ adiponectin, ↑ insulin sensitivity (muscle, adipose), ↓ hepatic glucose output. Effects take weeks to develop.
Agents:
- • Pioglitazone: Only TZD available (rosiglitazone withdrawn in some countries)
⚠️ Major Toxicities:
- • Fluid retention, edema: Contraindicated in HF (NYHA III/IV)
- • Weight gain (adipogenesis)
- • Bone fractures (especially postmenopausal women)
- • Bladder cancer risk (pioglitazone)
- • Hepatotoxicity (monitor LFTs)
DPP-4 Inhibitors (Gliptins)
Mechanism:
Inhibit dipeptidyl peptidase-4 (DPP-4) → ↑ active GLP-1 and GIP (incretin hormones) → ↑ glucose-dependent insulin secretion, ↓ glucagon. No hypoglycemia.
Agents:
- • Sitagliptin, saxagliptin, linagliptin, alogliptin
- • Well-tolerated, weight-neutral
Adverse Effects:
- • Upper respiratory infections
- • Pancreatitis (rare)
- • Heart failure (saxagliptin, alogliptin)
- • Arthralgia
SGLT-2 Inhibitors (Gliflozins)
Mechanism:
Inhibit sodium-glucose cotransporter-2 in proximal tubule → ↓ renal glucose reabsorption → glucosuria. Insulin-independent mechanism.
Agents:
- • Canagliflozin, dapagliflozin, empagliflozin
- • Benefits: Weight loss, BP reduction, cardiovascular/renal protection
Adverse Effects:
- • Genital mycotic infections (glucosuria)
- • UTIs
- • Euglycemic DKA (especially if insulin-deficient)
- • Volume depletion, hypotension
- • Fournier's gangrene (rare)
- • Amputations (canagliflozin)
Injectable Non-Insulin Agents
GLP-1 Receptor Agonists
Mechanism:
Mimic incretin GLP-1 → ↑ glucose-dependent insulin secretion, ↓ glucagon, ↓ gastric emptying, ↑ satiety. Cardioprotective, weight loss.
Agents:
- • Exenatide: Twice-daily or weekly
- • Liraglutide: Once-daily; CV benefit
- • Dulaglutide, semaglutide: Once-weekly
Benefits:
- ✓ Weight loss (5-10% body weight)
- ✓ Cardiovascular benefit (some agents)
- ✓ No hypoglycemia (monotherapy)
Adverse:
- • GI upset (nausea, vomiting, diarrhea)
- • Pancreatitis (rare)
- • Medullary thyroid cancer (animal studies)
- Contraindicated: Personal/family history of MTC, MEN2
Amylin Analog: Pramlintide
Synthetic analog of amylin (co-secreted with insulin). ↓ Glucagon, ↓ gastric emptying, ↑ satiety. Adjunct to insulin in type 1 or type 2 DM.
Adverse:
- • Hypoglycemia (reduce mealtime insulin dose by 50%)
- • Nausea