3.1 Insulin & Oral Antidiabetic Agents

3.1 Insulin & Oral Antidiabetic Agents

Diabetes pharmacotherapy sits at the heart of the Clinical Pharmacology & Therapeutic Decision Making domain, the largest content area on the DHA Pharmacist Licensing Assessment. Expect questions on insulin kinetics, renal dose thresholds, class-defining adverse effects, and counseling points.

Insulin Pharmacology

Insulin is essential for all patients with type 1 diabetes mellitus (T1DM) and is used in type 2 diabetes (T2DM) when oral agents are insufficient, during pregnancy, during acute illness, or when glycated hemoglobin (HbA1c) is markedly elevated. Insulins are classified by their time-action profile:

Rapid-acting analogs are injected immediately before (or within 15 minutes of) a meal, whereas regular insulin must be given about 30 minutes before eating. Insulin glargine and degludec provide a flat basal profile and cause less nocturnal hypoglycemia than NPH.

Mixing and storage counseling (frequently examined):

• When mixing two insulins in one syringe, draw the clear (regular or rapid-acting) insulin before the cloudy (NPH) — "clear before cloudy" — to avoid contaminating the rapid-acting vial with protamine. Glargine and degludec must never be mixed in a syringe with other insulins.
• Unopened insulin is refrigerated at 2-8 °C and never frozen; the vial or pen in current use may be kept at room temperature (below 25-30 °C) for up to 28 days.
• Cloudy suspensions (NPH, premixes) are gently rolled between the palms, not shaken.

Metformin

Metformin, a biguanide, is first-line pharmacotherapy for T2DM. It reduces hepatic gluconeogenesis and improves peripheral insulin sensitivity without stimulating insulin secretion, so it does not cause hypoglycemia or weight gain when used alone. Key exam points:

• Lactic acidosis is a rare but serious risk. Metformin is contraindicated when eGFR is below 30 mL/min/1.73 m² and requires dose review and caution between 30-45.
• Withhold metformin at the time of procedures using iodinated contrast media in at-risk patients and restart after 48 hours once renal function is confirmed stable; also withhold during acute illness causing dehydration, hypoxia or sepsis ("sick day rules").
• Long-term therapy causes vitamin B12 deficiency — monitor periodically, especially with anemia or peripheral neuropathy.
• Gastrointestinal upset (nausea, diarrhea, metallic taste) is common; taking doses with food and slow titration improves tolerance.

Sulfonylureas

Sulfonylureas (gliclazide, glimepiride, glibenclamide/glyburide) stimulate insulin release by closing ATP-sensitive potassium channels on pancreatic beta cells. They are potent and inexpensive but cause hypoglycemia and weight gain. Long-acting agents such as glibenclamide should be avoided in the elderly and in renal impairment because of prolonged hypoglycemia; shorter-acting gliclazide is preferred.

DPP-4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, linagliptin, vildagliptin) block degradation of endogenous incretin hormones, increasing glucose-dependent insulin secretion and suppressing glucagon. They are weight-neutral, well tolerated and carry a low intrinsic hypoglycemia risk. Most require renal dose adjustment — linagliptin is the exception. Rare associations include pancreatitis and severe arthralgia.

GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists (exenatide, liraglutide, dulaglutide, semaglutide) enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying and increase satiety — producing clinically useful weight loss, with proven cardiovascular outcome benefit for liraglutide, semaglutide and dulaglutide. Adverse effects are mainly gastrointestinal (nausea, vomiting, diarrhea). Use caution with a history of pancreatitis; liraglutide and semaglutide carry a thyroid C-cell tumor warning and are contraindicated with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2).

SGLT2 Inhibitors

Sodium-glucose cotransporter-2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, canagliflozin) block renal glucose reabsorption, causing glycosuria. Beyond glycemic control they deliver cardiovascular and renal protection — reduced heart-failure hospitalization and slowed progression of chronic kidney disease — plus modest weight and blood-pressure reduction. Adverse effects include genital mycotic infections, urinary tract infections, volume depletion and euglycemic diabetic ketoacidosis (DKA): ketoacidosis with a near-normal blood glucose, which delays recognition. Counsel patients to hold the drug during acute illness, prolonged fasting or the perioperative period.

Thiazolidinediones and Acarbose

Pioglitazone, a thiazolidinedione (TZD), improves insulin sensitivity via peroxisome proliferator-activated receptor gamma (PPAR-gamma). It causes fluid retention and weight gain, is contraindicated in heart failure (NYHA class III-IV), increases fracture risk, and carries a caution regarding bladder cancer — avoid in active or previous bladder cancer and investigate unexplained hematuria. Acarbose, an alpha-glucosidase inhibitor, delays intestinal carbohydrate absorption; it causes flatulence and must be taken with the first bite of each main meal. Hypoglycemia occurring with acarbose must be treated with glucose (dextrose), not sucrose, because acarbose blocks sucrose digestion.

Hypoglycemia: Recognition and Treatment

Symptoms include sweating, tremor, palpitations, hunger, confusion and, if untreated, seizures or coma. For a conscious patient apply the 15-15 rule: give 15 g of fast-acting carbohydrate (for example 3-4 glucose tablets or 150-200 mL of fruit juice or regular soft drink), recheck blood glucose after 15 minutes, and repeat if still below 4 mmol/L; once corrected, follow with a longer-acting carbohydrate snack. Severe hypoglycemia with impaired consciousness requires intramuscular glucagon or intravenous dextrose — never give anything orally to an unconscious patient.