Oral hypoglycemic agents (oral glucose-lowering drugs)

These drugs are used mainly in type 2 diabetes. Response is best in patients with diabetes for less than 5 years. Long-standing disease often needs combinations, with or without insulin or a GLP-1 agonist (Lippincott Illustrated Reviews: Pharmacology, p. 809).

Classification

Class	Examples	Mechanism	Key adverse effects
Biguanide	Metformin	Lowers hepatic gluconeogenesis, slows intestinal glucose absorption, improves insulin sensitivity. It does not stimulate insulin release.	GI upset, B12 deficiency, rare lactic acidosis. Weight neutral or weight loss.
Sulfonylureas (insulin secretagogues)	Glibenclamide (glyburide), glipizide, glimepiride, gliclazide	Block ATP-sensitive K+ channels on β cells. This causes depolarization, Ca2+ influx and insulin exocytosis.	Hypoglycemia, weight gain, hyperinsulinemia
Meglitinides	Repaglinide, nateglinide	Same K-ATP channel mechanism with rapid onset and short duration. They act as postprandial glucose regulators.	Hypoglycemia (less than with sulfonylureas), weight gain
Thiazolidinediones (insulin sensitizers)	Pioglitazone, rosiglitazone	PPARγ agonists. They increase insulin sensitivity in adipose tissue, liver and muscle.	Weight gain, fluid retention, heart failure, fractures. Rosiglitazone is less used because of cardiovascular concerns.
α-Glucosidase inhibitors	Acarbose, miglitol	Delay intestinal carbohydrate digestion and absorption.	Flatulence, diarrhea
DPP-4 inhibitors (gliptins)	Sitagliptin, linagliptin, saxagliptin	Prolong endogenous incretin (GLP-1, GIP) activity.	Generally well tolerated, weight neutral. Pancreatitis is a rare risk.
SGLT2 inhibitors (gliflozins)	Empagliflozin, dapagliflozin, canagliflozin	Block renal glucose reabsorption, so glucose is lost in the urine.	Genital mycotic infections, UTI, volume depletion, euglycemic DKA

The α-glucosidase, DPP-4 and SGLT2 rows are partly from my own knowledge rather than the textbook passages I read.

Points on the main classes

Metformin

It is the preferred first-line drug and should be started at diagnosis.
Because it does not promote insulin secretion, hypoglycemia is much less likely than with sulfonylureas.
It is not metabolized and is excreted unchanged by the kidneys.
It is contraindicated when eGFR is below 30 mL/min/1.73 m² because of lactic acidosis risk.
Stop it in acute MI, heart failure exacerbation, sepsis or other causes of acute renal failure.
Stop it temporarily around IV radiographic contrast.
Use caution in patients over 80 and in those with alcohol abuse.
Slow dose titration and taking it with meals reduce GI effects.
It also helps in prediabetes and PCOS (Lippincott Illustrated Reviews: Pharmacology, pp. 811-812).

Sulfonylureas

Second-generation agents (glyburide, glipizide, glimepiride) are the ones mostly used.
They are protein bound, metabolized in the liver, and have a duration of 12 to 24 hours.
Use caution in hepatic or renal impairment and in the elderly.
Glyburide is the worst in renal impairment, because its action is prolonged and hypoglycemia risk rises significantly (Lippincott Illustrated Reviews: Pharmacology, pp. 812-813).

Meglitinides

Take them before meals.
Do not combine them with sulfonylureas, because the mechanisms overlap and serious hypoglycemia can result.
Gemfibrozil raises repaglinide levels by inhibiting its metabolism, and the combination is contraindicated (Lippincott Illustrated Reviews: Pharmacology, p. 815).

Thiazolidinediones

Insulin is required for their action, but they do not stimulate its release. They therefore do not cause hyperinsulinemia (Lippincott Illustrated Reviews: Pharmacology, p. 815).

SGLT2 inhibitors

They also reduce mortality and heart failure hospitalizations in patients with or without diabetes, and they slow chronic kidney disease progression. This appears to be a class effect (Katzung's Basic and Clinical Pharmacology, 16th Ed.).

Quick exam pearls

Metformin is the best first-line drug because it causes no hypoglycemia and no weight gain.
Sulfonylureas and meglitinides cause hypoglycemia and weight gain.
Pioglitazone is contraindicated in heart failure.
Acarbose is used for postprandial hyperglycemia. If hypoglycemia occurs while on it, treat with glucose, not sucrose.
Drugs that potentiate sulfonylurea hypoglycemia include alcohol, sulfonamides, warfarin and fluoroquinolones.

Recent evidence check

I ran a quick PubMed search of the last 2 years. Recent meta-analyses do not contradict the textbook framework, but they add detail on newer agents:

A GLP-1 agonist network meta-analysis (BMJ 2024) compared glycemic, weight and lipid effects.
A meta-analysis of first-line SGLT2 inhibitors and GLP-1 agonists (2024) covered type 2 diabetes patients at low cardiovascular risk.
A meta-analysis of dorzagliatin (2024) covered a newer glucokinase activator.

If you want more depth on one class, such as mechanism diagrams, drug interactions or perioperative management, tell me which.

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