Insulin and Oral Hypoglycemics
Diabetes pharmacotherapy spans injectable insulins and multiple oral drug classes targeting different pathophysiological mechanisms. Modern treatment emphasizes individualized glycemic targets, cardiovascular and renal benefits, and hypoglycemia avoidance.
## Insulin Therapy
Insulin is essential for type 1 diabetes and is used in type 2 diabetes when oral agents are insufficient. Preparations are classified by onset and duration:
| Type | Examples | Onset | Peak | Duration |
|------|---------|-------|------|----------|
| Rapid-acting | Lispro, aspart, glulisine | 10-15 min | 1-2 h | 3-5 h |
| Short-acting | Regular insulin | 30-60 min | 2-4 h | 6-8 h |
| Intermediate | NPH | 1-2 h | 4-12 h | 12-18 h |
| Long-acting | Glargine (U-100, U-300), detemir | 1-2 h | Minimal | 20-24+ h |
| Ultra-long | Degludec | 30-90 min | None | >42 h |
Basal-bolus regimens mimic physiological insulin secretion: a long-acting basal insulin provides background coverage, and rapid-acting boluses cover meals. Insulin pumps provide continuous subcutaneous delivery with programmable basal rates.
## Metformin
First-line for type 2 diabetes. Activates AMP-activated protein kinase (AMPK), reducing hepatic glucose production and improving insulin sensitivity. Does not cause hypoglycemia or weight gain. GI side effects (nausea, diarrhea) are common initially and improve with extended-release formulations. Contraindicated in severe renal impairment (eGFR <30) due to lactic acidosis risk, though this risk is lower than historically believed.
## SGLT2 Inhibitors
Empagliflozin, dapagliflozin, canagliflozin block sodium-glucose cotransporter 2 in the proximal renal tubule, causing glycosuria (glucose excretion in urine). Beyond glucose lowering, they provide:
- **Cardiovascular benefit** -- Reduced major adverse cardiovascular events and heart failure hospitalization (EMPA-REG, DAPA-HF trials).
- **Renal protection** -- Slow CKD progression independent of diabetes (DAPA-CKD, EMPA-KIDNEY).
- **Weight loss** -- 2-3 kg via caloric loss through glycosuria.
Risks include genital mycotic infections, euglycemic DKA (rare), volume depletion, and Fournier's gangrene (extremely rare).
## GLP-1 Receptor Agonists
Semaglutide, liraglutide, dulaglutide, exenatide mimic incretin hormones, stimulating glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. They produce significant weight loss (semaglutide: up to 15% body weight) and cardiovascular benefit. GI side effects (nausea, vomiting) are the main limitation. Available as weekly injectables; oral semaglutide is also approved.
## Other Oral Agents
- **Sulfonylureas** (glipizide, glyburide, glimepiride) -- Stimulate insulin secretion from beta cells. Cheap and effective but cause hypoglycemia and weight gain. Declining use.
- **DPP-4 inhibitors** (sitagliptin, linagliptin) -- Prevent incretin degradation. Modest A1c reduction, weight-neutral, low hypoglycemia risk. Expensive relative to efficacy.
- **Thiazolidinediones** (pioglitazone) -- PPAR-gamma agonists that improve insulin sensitivity. Effective but cause fluid retention, weight gain, fracture risk, and possible bladder cancer concern.
## Modern Treatment Algorithm
Current ADA/EASD guidelines recommend metformin as initial therapy, then adding an SGLT2 inhibitor or GLP-1 agonist based on the patient's cardiovascular and renal risk profile -- not just A1c. For patients with established ASCVD, heart failure, or CKD, these classes are now recommended regardless of A1c level.
## Key Takeaways
- Metformin remains first-line for type 2 diabetes due to efficacy, safety, and cost.
- SGLT2 inhibitors and GLP-1 agonists offer benefits beyond glucose lowering -- cardiovascular and renal protection.
- Insulin therapy requires individualized regimens; basal-bolus best mimics physiology.
- Treatment selection should be driven by comorbidities, not just hemoglobin A1c.