Metformin
Biguanide; first-line T2D; inhibits hepatic gluconeogenesis; weight-neutral; hold before iodinated contrast (lactic acidosis risk).
GLP-1 RAs
Semaglutide, Liraglutide; slows gastric emptying, promotes weight loss, CV mortality benefit; thyroid C-cell tumor & pancreatitis warning.
Type 2 Diabetes Pharmacotherapy Master Grid
| Drug Class | Mechanism of Action | A1c Effect & Weight | Key Adverse Effects & Warnings |
|---|---|---|---|
| Metformin | Activates AMPK, inhibits hepatic gluconeogenesis, enhances insulin sensitivity | A1c ↓ 1.0-1.5%; Weight neutral | GI upset, Vitamin B12 deficiency; Lactic acidosis (contraindicated if eGFR < 30 mL/min) |
| GLP-1 Agonists (Semaglutide) | Mimics incretin hormone; glucose-dependent insulin secretion, slows gastric emptying | A1c ↓ 1.0-1.5%; Weight loss (↓↓) | Nausea, vomiting; Pancreatitis; Medullary thyroid cancer history is contraindication |
| SGLT-2 Inhibitors (Empagliflozin) | Blocks proximal tubule SGLT2 transporter; promotes glucosuria | A1c ↓ 0.5-1.0%; Weight loss (↓) | Vulvovaginal candidiasis, UTIs, hypotension, euglycemic DKA, Fournier gangrene |
| Sulfonylureas (Glipizide) | Closes beta-cell KATP channels, stimulating endogenous insulin release | A1c ↓ 1.0-1.5%; Weight gain (↑) | Hypoglycemia (especially in renal impairment or skipped meals) |
| TZDs (Pioglitazone) | PPAR-γ agonist; increases peripheral insulin sensitivity in adipose/muscle | A1c ↓ 0.5-1.0%; Weight gain (↑) | Fluid retention, edema, heart failure exacerbation (contraindicated in NYHA Class III/IV), osteoporotic fractures |
Insulin Pharmacokinetics & Clinical Regimens
Standard physiological insulin replacement consists of basal insulin (50% of total daily dose) plus bolus prandial insulin (50% divided among 3 meals):
- Rapid-Acting (Lispro, Aspart, Glulisine): Onset 10-15 min, peak 1 hour, duration 3-4 hours. Injected immediately prior to meals.
- Short-Acting (Regular Insulin): Onset 30-60 min, peak 2-3 hours, duration 5-8 hours. Only formulation administered IV in DKA and HHS protocols.
- Intermediate-Acting (NPH): Onset 1-2 hours, peak 4-10 hours, duration 12-18 hours. Cloud suspension; prone to nocturnal hypoglycemia.
- Long-Acting / Basal (Glargine, Detemir, Degludec): Peakless basal profile lasting 24 to > 42 hours (Degludec). Provides steady background glycemic suppression.
OMM Board Correlate: Pancreatic & Endocrine Autonomics
- Pancreas Autonomics: Sympathetic preganglionics T5-T9 pass through the greater splanchnic nerve to the celiac and superior mesenteric ganglia. Sympathetic hyperactivity decreases insulin secretion and promotes glycogenolysis.
- Chapman Points: Anterior point: right 7th intercostal space near the cartilage. Posterior point: intertransverse space between T7 and T8 on the right.
- Diabetic Neuropathy & Gait: Peripheral sensory neuropathy alters lower extremity biomechanics, causing calf hypertonicity, pronated feet, and sacroiliac somatic dysfunctions.
Board Traps & Common Distractors
- Always discontinue Metformin 48 hours before iodinated IV contrast procedures in patients with eGFR < 60 mL/min or acute illness to prevent contrast-induced nephropathy leading to fatal lactic acidosis.
- SGLT-2 inhibitors can precipitate Euglycemic DKA (blood glucose < 250 mg/dL with severe ketoacidosis) during periods of fasting, surgery, or acute infection; check blood ketones if patient feels unwell.
- Thiazolidinediones (Pioglitazone, Rosiglitazone) promote fluid retention and are strictly contraindicated in symptomatic heart failure (NYHA Class III or IV).