12.2 Insulin & Noninsulin Glycemic Agents
Key Takeaways
Rapid-acting insulin analogs (lispro, aspart, glulisine) start working within about 15 minutes, regular insulin within 30–60 minutes, NPH peaks at about 4–10 hours, and glargine and degludec provide basal coverage without a pronounced peak.
Metformin lowers hepatic gluconeogenesis without causing hypoglycemia on its own; it is contraindicated below an eGFR of 30 mL/min/1.73 m² and long-term use can cause vitamin B12 deficiency that worsens neuropathy.
SGLT2 inhibitors cause glycosuria and can precipitate euglycemic ketoacidosis around surgery, so they are held about 3 days beforehand (4 days for ertugliflozin); they also cause genital mycotic infections and carry a Fournier gangrene warning.
GLP-1 receptor agonists and tirzepatide slow gastric emptying, promote weight loss and carry a boxed warning for thyroid C-cell tumors; DPP-4 inhibitors have warnings for severe arthralgia and bullous pemphigoid.
Sulfonylureas close beta-cell K-ATP channels and cause hypoglycemia; pioglitazone causes edema, can worsen heart failure and increases distal fracture risk, including in the foot.
12.2 Insulin & Noninsulin Glycemic Agents
The pharmacology outline lists glycemic agents: insulin and the oral, inhaled and injected hypoglycemic agents. Most patients with diabetic foot disease take several of these drugs. Their adverse effects (hypoglycemia, ketoacidosis, edema, fractures, B12 deficiency) and perioperative handling come up often in podiatric practice. The physiology of insulin secretion is in 16.3 and the second-messenger pathways in 17.4.
Insulin
| Category | Agents | Onset | Peak | Duration |
|---|---|---|---|---|
| Rapid-acting | Lispro, aspart, glulisine | About 15 minutes | 1–2 hours | 3–5 hours |
| Short-acting | Regular insulin | 30–60 minutes | 2–4 hours | 5–8 hours |
| Intermediate | NPH | 1–2 hours | 4–10 hours | 10–18 hours |
| Long-acting | Glargine | 1–2 hours | Minimal peak | About 24 hours |
| Ultra-long-acting | Degludec | 1–2 hours | Minimal peak | More than 40 hours |
| Inhaled | Technosphere insulin | About 12 minutes | About 1 hour | 2–3 hours |
Durations vary with dose and site. Inhaled insulin is rapid-acting and contraindicated in chronic lung disease (asthma, COPD) because it can cause acute bronchospasm; spirometry is required before starting it.
Mechanism. Insulin binds a receptor tyrosine kinase, which signals through IRS-1 and PI3K/Akt to move GLUT4 to muscle and fat membranes. It also stimulates glycogen, fat and protein synthesis and drives potassium into cells.
Adverse effects:
- Hypoglycemia is the most important, more likely with renal impairment, missed meals and exercise
- Weight gain
- Lipohypertrophy at overused injection sites
- Hypokalemia (which is why insulin is part of hyperkalemia treatment)
Hypoglycemia treatment. A conscious patient takes about 15 g of fast-acting carbohydrate and rechecks in 15 minutes. Severe hypoglycemia is treated with IV dextrose or with intramuscular, subcutaneous or intranasal glucagon. Patients on beta-blockers may have blunted warning symptoms, and sweating (sympathetic cholinergic) is often the remaining clue (10.3).
Noninsulin Agents
| Class | Examples | Mechanism | Key adverse effects and podiatric relevance |
|---|---|---|---|
| Biguanide | Metformin | Activates AMPK; decreases hepatic gluconeogenesis; improves insulin sensitivity | GI upset; rare lactic acidosis; no hypoglycemia alone; vitamin B12 deficiency that can worsen neuropathy; contraindicated below an eGFR of 30, not started at an eGFR of 30–45 |
| Sulfonylureas | Glipizide, glimepiride, glyburide | Close beta-cell K-ATP channels, causing depolarization, Ca2+ entry and insulin release | Hypoglycemia (worst with glyburide in older or CKD patients), weight gain; overdose treated with dextrose plus octreotide |
| Meglitinides | Repaglinide, nateglinide | Same K-ATP target, short acting | Hypoglycemia with skipped meals |
| Thiazolidinedione | Pioglitazone | PPAR-gamma agonist; increases insulin sensitivity | Fluid retention and heart failure (boxed warning), weight gain, fractures (distal limbs, including the foot), possible bladder cancer risk |
| DPP-4 inhibitors | Sitagliptin, linagliptin, saxagliptin | Prevent breakdown of endogenous GLP-1 and GIP | Weight-neutral; severe arthralgia and bullous pemphigoid warnings; pancreatitis; saxagliptin heart failure signal |
| GLP-1 receptor agonists | Semaglutide, dulaglutide, liraglutide, exenatide | Glucose-dependent insulin release, glucagon suppression, slowed gastric emptying, satiety | Nausea, vomiting, weight loss, pancreatitis, gallbladder disease, boxed warning for thyroid C-cell tumors (avoid with medullary thyroid carcinoma or MEN2); some agents have proven cardiovascular benefit |
| Dual GIP/GLP-1 agonist | Tirzepatide | Agonist at both incretin receptors | Similar to GLP-1 receptor agonists with greater weight loss |
| SGLT2 inhibitors | Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin | Block proximal tubule sodium-glucose cotransporter 2, causing glycosuria | Genital mycotic infections, UTI, volume depletion, euglycemic DKA, Fournier gangrene warning; canagliflozin carries a lower-limb amputation warning; proven heart failure and kidney benefit |
| Alpha-glucosidase inhibitors | Acarbose, miglitol | Delay intestinal carbohydrate digestion | Flatulence; treat hypoglycemia with glucose, not sucrose |
| Amylin analog | Pramlintide | Slows gastric emptying, suppresses glucagon | Hypoglycemia when combined with insulin |
Choosing therapy. Current diabetes standards emphasize lifestyle measures and metformin for many patients. They recommend an SGLT2 inhibitor or GLP-1 receptor agonist with proven benefit for people with atherosclerotic cardiovascular disease, heart failure or CKD, regardless of HbA1c. Hypoglycemia risk, weight effects, cost and comorbidities guide the rest.
Perioperative Management in Foot and Ankle Surgery
- SGLT2 inhibitors: hold 3 days before scheduled surgery (4 days for ertugliflozin) to reduce euglycemic DKA risk. Check ketones if the patient is unwell even when glucose is near normal.
- Metformin: commonly held on the day of surgery; hold around iodinated contrast in patients with reduced renal function, and restart when eating and renal function is stable.
- Sulfonylureas: hold on the morning of surgery to avoid fasting hypoglycemia.
- Basal insulin: usually continued at a reduced dose (often about 75–80%) the evening before or morning of surgery; hold prandial insulin while fasting.
- GLP-1 receptor agonists: slowed gastric emptying raises aspiration concern, so follow the current anesthesia guidance on holding doses or using a liquid diet beforehand.
- Glucose targets: perioperative glucose of about 100–180 mg/dL is a common target. Hyperglycemia impairs neutrophil function and raises surgical site infection and nonunion risk.
Glucose and Wound Healing
Chronic hyperglycemia glycates collagen, impairs leukocyte chemotaxis and phagocytosis, and promotes microangiopathy (8.1). Improving glycemic control around surgery and during diabetic foot ulcer treatment supports healing, but aggressive lowering that causes hypoglycemia is also harmful, particularly in older adults.
A patient taking empagliflozin presents two days after a transmetatarsal amputation with nausea, abdominal pain and rapid breathing. Glucose is 168 mg/dL, bicarbonate is 11 mEq/L and serum beta-hydroxybutyrate is markedly elevated. What is the most likely diagnosis?
Lactic acidosis caused by metformin
Euglycemic ketoacidosis linked to SGLT2 inhibition
Respiratory alkalosis from postoperative pain
Hyperosmolar hyperglycemic state from postoperative dehydration
Which glycemic agent acts by closing ATP-sensitive potassium channels in pancreatic beta cells, and which adverse effect follows from that mechanism?
Sitagliptin; severe arthralgia
Metformin; vitamin B12 deficiency
Pioglitazone; fluid retention
Glipizide; hypoglycemia
A patient with type 2 diabetes, heart failure and a history of metatarsal stress fractures asks to start a new oral glycemic agent. Which agent is least appropriate?
Empagliflozin
Linagliptin
Pioglitazone
Metformin, if eGFR is adequate
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