1. Insulin and insulin analogues

• Hypoglycemia - most important
• Weight gain
• Injection-site lipohypertrophy/lipoatrophy
• Edema
• Hypokalemia, especially with IV insulin
• Allergy is rare

2. Biguanide

• Activates AMP-activated protein kinase (AMPK)
• Mainly decreases hepatic gluconeogenesis
• Also improves peripheral insulin sensitivity and modestly reduces intestinal glucose absorption
• Does not stimulate insulin release, so hypoglycemia is uncommon when used alone.

• Nausea, diarrhea, abdominal discomfort, metallic taste
• Vitamin B12 deficiency with long-term treatment
• Weight neutral or mild weight loss
• Lactic acidosis is very rare but serious. Risk rises with severe renal impairment, hypoxia, sepsis, severe liver disease, or heavy alcohol use.

3. Sulfonylureas

• Bind the SUR1 subunit of ATP-sensitive K⁺ channels on pancreatic beta cells.
• Close K⁺ channels -> membrane depolarization -> Ca²⁺ influx -> insulin release.
• Work only if functioning beta cells are present.

• Hypoglycemia, especially with long-acting agents, missed meals, old age, renal or liver disease
• Weight gain
• GI upset
• Rash/photosensitivity
• Rare: cholestatic jaundice, blood dyscrasias
• Chlorpropamide: SIADH and disulfiram-like reaction with alcohol

4. Meglitinides or glinides

• Close beta-cell ATP-sensitive K⁺ channels at a different binding site from sulfonylureas.
• Cause rapid, short-duration insulin release, mainly controlling post-meal glucose.

• Hypoglycemia, usually less prolonged than with sulfonylureas
• Weight gain
• Headache, upper respiratory symptoms
• Repaglinide interacts significantly with gemfibrozil

5. Thiazolidinediones (TZDs)

• Activate nuclear PPAR-gamma receptors.
• Alter gene transcription to increase insulin sensitivity in adipose tissue, skeletal muscle, and liver.
• Decrease insulin resistance. Onset is slow, over weeks.

• Weight gain
• Fluid retention and edema
• Can precipitate or worsen heart failure
• Increased fracture risk, especially in women
• Anemia/hemodilution
• Pioglitazone: possible bladder-cancer concern with prolonged exposure, so avoid in active bladder cancer
• Rare hepatotoxicity
• May restore ovulation in anovulatory women, increasing pregnancy risk

6. Alpha-glucosidase inhibitors

• Inhibit intestinal brush-border alpha-glucosidase enzymes.
• Delay breakdown and absorption of complex carbohydrates.
• Primarily reduce postprandial hyperglycemia.

• Flatulence, abdominal bloating, diarrhea, abdominal pain
• Mild elevation of liver enzymes with high-dose acarbose
• Hypoglycemia is uncommon alone. If it occurs with insulin or a sulfonylurea, treat with glucose/dextrose, not sucrose, because sucrose digestion is inhibited.

7. DPP-4 inhibitors or gliptins

• Inhibit dipeptidyl peptidase-4, which normally degrades incretin hormones GLP-1 and GIP.
• Increase glucose-dependent insulin secretion and reduce inappropriate glucagon secretion.
• Therefore lower fasting and postprandial glucose.

• Nasopharyngitis, headache
• Mild GI upset
• Rare: pancreatitis
• Severe joint pain is rare
• Hypersensitivity reactions, including angioedema or severe skin reactions, are rare
• Saxagliptin and alogliptin have been associated with increased heart-failure hospitalization in some patients
• Low hypoglycemia risk unless combined with insulin or a secretagogue

8. GLP-1 receptor agonists

• Mimic GLP-1.
• Increase glucose-dependent insulin release
• Decrease glucagon secretion
• Slow gastric emptying
• Increase satiety and reduce food intake
• Usually produce weight loss.

• Nausea, vomiting, diarrhea, constipation
• Reduced appetite
• Gallbladder disease, including cholelithiasis
• Rare pancreatitis
• Risk of dehydration and acute kidney injury due to severe vomiting/diarrhea
• May worsen diabetic retinopathy temporarily when glucose falls rapidly, particularly with semaglutide in high-risk patients
• Avoid in people with personal/family history of medullary thyroid carcinoma or MEN2 due to rodent thyroid C-cell tumor findings

9. Dual GIP/GLP-1 receptor agonist

• Activates both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors.
• Increases glucose-dependent insulin secretion, reduces glucagon, slows gastric emptying, and reduces appetite.

• Similar to GLP-1 receptor agonists: nausea, vomiting, diarrhea, constipation
• Gallbladder disease
• Rare pancreatitis
• Potential dehydration/renal injury with severe GI loss
• Hypoglycemia mainly when used with insulin, sulfonylureas, or meglitinides
• Same thyroid-tumor precaution as GLP-1 receptor agonists

10. SGLT2 inhibitors or gliflozins

• Inhibit sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule.
• Reduce renal glucose reabsorption -> cause glycosuria -> lower plasma glucose.
• Also cause mild osmotic diuresis, weight reduction, and blood-pressure reduction.

• Genital fungal infections, especially candidiasis
• Urinary tract infections
• Polyuria, dehydration, postural hypotension
• Rare but serious: euglycemic diabetic ketoacidosis
• Rare: Fournier gangrene
• Canagliflozin: caution regarding amputation risk and fractures
• Temporary early fall in eGFR may occur because of hemodynamic effects

11. Amylin analogue

• Synthetic analogue of amylin, normally co-secreted with insulin.
• Slows gastric emptying, suppresses post-meal glucagon, and increases satiety.
• Used as an adjunct to mealtime insulin in selected type 1 or type 2 diabetes.

• Nausea
• Hypoglycemia, especially severe hypoglycemia if the insulin dose is not appropriately reduced
• Reduced appetite

12. Bile-acid sequestrant

• Binds bile acids in the intestine. Its exact glucose-lowering mechanism is not fully defined.
• Produces a modest reduction in LDL cholesterol and glucose.

• Constipation, bloating, dyspepsia
• May increase triglycerides
• Can reduce absorption of other oral drugs and fat-soluble vitamins

13. Dopamine agonist

• Dopamine D2 receptor agonist. It is thought to reset hypothalamic dopaminergic tone and reduce insulin resistance, though the exact antidiabetic mechanism remains incompletely understood.

• Nausea, dizziness, fatigue
• Orthostatic hypotension
• Syncope
• Headache
• Rare psychiatric effects such as hallucinations

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