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Oral Antidiabetic Drugs

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Overview of Classes

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1. Biguanides - Metformin

• Primarily reduces hepatic gluconeogenesis (targets excess fasting glucose)
• Slows intestinal glucose absorption
• Improves peripheral glucose uptake and insulin sensitivity
• Does not stimulate insulin secretion → minimal hypoglycemia risk

• Well absorbed orally, not bound to plasma proteins, not metabolized
• Excreted unchanged by the kidneys

• GI: diarrhea, nausea, vomiting (most common; alleviated by slow titration and taking with meals)
• Lactic acidosis - rare but serious; risk increases with renal impairment
• Vitamin B12 malabsorption with chronic use
• Weight loss (decreases appetite)

• eGFR < 30 mL/min (hold if eGFR 30-45)
• IV contrast procedures (hold for 48 hours)
• Hepatic impairment, alcoholism, heart failure

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2. Sulfonylureas

• Bind SUR1 subunit of ATP-sensitive K⁺ channels on β cells → channel closure → membrane depolarization → Ca²⁺ influx → insulin release
• Action is glucose-independent (hence hypoglycemia risk)

• 1st generation (older, more side effects): Tolbutamide, Chlorpropamide
• 2nd generation (preferred): Glipizide, Glyburide (Glibenclamide), Glimepiride

• All well absorbed orally; extensively protein-bound
• Metabolized by liver; renal excretion of metabolites

• Hypoglycemia (most important - especially glyburide, which has active metabolites and is long-acting; avoid in elderly and renal impairment)
• Weight gain
• Disulfiram-like reaction with alcohol (especially chlorpropamide)
• Drug interactions: NSAIDs, sulfonamides, warfarin can potentiate hypoglycemia

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3. Meglitinides

• Same target as sulfonylureas (K⁺-ATP channels) but faster onset and shorter duration
• Particularly effective for postprandial glucose control

• Taken before each meal
• Repaglinide: metabolized by CYP2C8/CYP3A4, excreted in feces
• Nateglinide: metabolized by CYP2C9/CYP3A4, excreted in urine
• Gemfibrozil (a CYP2C8 inhibitor) markedly increases repaglinide levels - combination is contraindicated

• Hypoglycemia and weight gain, but less than sulfonylureas
• Do NOT combine with sulfonylureas (overlapping mechanism, high hypoglycemia risk)
• Use with caution in hepatic impairment

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4. Thiazolidinediones (TZDs) - "Glitazones"

• Agonists at PPARγ (peroxisome proliferator-activated receptor-γ), a nuclear receptor
• PPARγ activation regulates transcription of insulin-responsive genes
• Increases insulin sensitivity in adipose tissue, liver, and skeletal muscle
• Do NOT cause hyperinsulinemia (no direct insulin secretion)

• Well absorbed; extensively bound to serum albumin
• Metabolized primarily by CYP2C8
• Pioglitazone: excreted in bile/feces; no dose adjustment in renal impairment
• Rosiglitazone: urinary excretion of metabolites

• Weight gain (increased subcutaneous fat)
• Fluid retention → worsen or precipitate heart failure (avoid in symptomatic HF)
• Osteopenia and fracture risk (especially in women)
• Pioglitazone: possible association with bladder cancer (avoid in bladder cancer history)
• Rosiglitazone: cardiovascular concerns limit its use

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5. Alpha-Glucosidase Inhibitors

• Inhibit alpha-glucosidase enzymes in the brush border of the small intestine
• Delay digestion and absorption of complex carbohydrates
• Reduce postprandial glucose spikes
• Taken with the first bite of each meal

• GI: flatulence, bloating, diarrhea, abdominal cramps (most common; limits use)
• Very low hypoglycemia risk as monotherapy
• If hypoglycemia occurs while on alpha-glucosidase inhibitors (in combination), treat with glucose (dextrose), not sucrose - sucrose digestion is blocked

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6. DPP-4 Inhibitors ("Gliptins")

• Inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme that inactivates incretin hormones (GLP-1 and GIP)
• Result: prolonged action of endogenous GLP-1 and GIP
• Effect is glucose-dependent → stimulates insulin secretion only when glucose is elevated; also suppresses glucagon

• Generally well tolerated; weight neutral
• Nasopharyngitis, upper respiratory tract infections
• Rare: pancreatitis; urticaria/angioedema
• Saxagliptin and alogliptin: possible association with increased heart failure hospitalization
• Linagliptin: non-renal elimination (safest in CKD)

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7. SGLT-2 Inhibitors ("Gliflozins")

• Inhibit sodium-glucose cotransporter 2 (SGLT-2) in the proximal renal tubule
• Block renal glucose reabsorption → glycosuria → lower blood glucose
• Mechanism is entirely insulin-independent
• Also reduce blood pressure, weight, and have direct cardiac and renal protective effects

• Empagliflozin (EMPA-REG OUTCOME) and canagliflozin (CANVAS): reduced MACE, CV death, HF hospitalization
• Preferred as add-on to metformin in patients with established ASCVD, heart failure, or diabetic nephropathy

• Genital mycotic infections (most common - due to glycosuria)
• UTIs
• Euglycemic DKA (rare but serious; drug must be held before surgery/prolonged fasting)
• Fournier's gangrene (necrotizing fasciitis of perineum) - rare
• Canagliflozin: increased risk of lower limb amputation and bone fractures
• Polyuria, dehydration, hypotension
• Avoid if eGFR < 30 (reduced efficacy; though some agents allowed down to eGFR 20 for HF/renal protection)

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8. Bile Acid Sequestrant

• Approved as add-on for type 2 diabetes; mechanism of glucose lowering is unclear
• Reduces A1c by ~0.5% when added to metformin, sulfonylurea, or insulin
• Also lowers LDL cholesterol

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9. Oral Semaglutide (GLP-1 Receptor Agonist)

• Only oral GLP-1 receptor agonist currently available
• Same mechanism as injectable GLP-1 RAs: stimulates GLP-1 receptor in a glucose-dependent manner
• Slows gastric emptying, reduces appetite, promotes weight loss
• Requires specific administration: taken fasting with a small amount of water, no food for 30 minutes after

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Treatment Algorithm for Type 2 Diabetes

1. Start: Metformin + lifestyle modification at diagnosis
2. If A1c target not achieved in 2-3 months: add a second agent
   • Established ASCVD/high CV risk: add GLP-1 RA or SGLT-2 inhibitor
   • Heart failure or CKD: prefer SGLT-2 inhibitor
   • Need for weight loss: prefer GLP-1 RA or SGLT-2 inhibitor
   • Cost is a concern: add sulfonylurea
3. Further escalation: Triple therapy (metformin + two agents) or add basal insulin
4. Reinforce lifestyle at every visit; check A1c every 3 months

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Key Comparison Points for Exams

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Metformin and Glibenclamide - Mechanism, Uses & Adverse Effects

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METFORMIN (Biguanide)

Mechanism of Action

• Metformin inhibits mitochondrial Complex I in hepatocytes, raising the AMP:ATP ratio
• This activates AMP-activated protein kinase (AMPK), which suppresses expression of gluconeogenic enzymes (PEPCK, G6Pase)
• Excess hepatic glucose output is the main driver of fasting hyperglycemia in type 2 diabetes - metformin directly tackles this

• Delays carbohydrate absorption from the gut, blunting postprandial glucose spikes

• Increases glucose uptake and utilization in skeletal muscle
• Does NOT stimulate insulin secretion from β cells → no hyperinsulinemia, minimal hypoglycemia risk as monotherapy

Uses

Pharmacokinetics

• Absorption: Well absorbed orally; bioavailability ~50-60%
• Protein binding: None (not bound to plasma proteins)
• Metabolism: Not metabolized - excreted unchanged
• Excretion: Renal (unchanged drug) - explains why renal impairment is dangerous

Adverse Effects

• Diarrhea, nausea, vomiting, metallic taste, abdominal cramps
• Minimized by: slow dose titration + taking with meals
• Usually transient; often resolve within weeks

• Occurs because metformin inhibits hepatic lactate clearance (lactate → gluconeogenesis pathway is blocked)
• Risk factors: renal impairment, hepatic failure, sepsis, dehydration, excessive alcohol
• Mortality ~50% when it occurs
• Contraindicated in eGFR < 30 mL/min/1.73 m²; use with caution at eGFR 30-45

• Long-term use reduces B12 absorption (interferes with ileal B12-intrinsic factor complex uptake)
• Periodic monitoring recommended, especially in patients with anemia or peripheral neuropathy

• Weight neutral to slight weight loss (reduces appetite)

Contraindications

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GLIBENCLAMIDE (Glyburide) - 2nd Generation Sulfonylurea

Note: Glibenclamide is the international non-proprietary name (INN); glyburide is the name used in the USA. It is 100-200 times more potent than 1st generation sulfonylureas.

Mechanism of Action

1. Glibenclamide binds to the SUR1 subunit (140-kDa high-affinity sulfonylurea receptor) on the β-cell membrane
2. SUR1 is associated with an inward rectifier ATP-sensitive K⁺ channel (K_ATP channel)
3. Binding inhibits K⁺ efflux through the channel → membrane depolarization
4. Depolarization opens voltage-gated L-type Ca²⁺ channels
5. Ca²⁺ influx triggers exocytosis of preformed insulin granules
6. Net result: increased insulin release

This mechanism mirrors the normal glucose-stimulated insulin secretion pathway, but glibenclamide acts regardless of blood glucose level - this is the basis for its hypoglycemia risk.

• May reduce hepatic glucose output
• May increase peripheral insulin sensitivity (secondary to improved glycemic control)
• Unique property: Glibenclamide also becomes sequestered within the β cell after binding, contributing to its prolonged biologic effect (24 hours) despite a short plasma half-life of 1-2 hours

Uses

Pharmacokinetics

Adverse Effects

• Most serious adverse effect
• Occurs because insulin release is glucose-independent
• Particularly dangerous in: elderly patients, renal impairment (active metabolites accumulate), liver failure, missed meals, excessive exercise, alcohol
• Can be prolonged and severe (lasts 24-36 hours due to active metabolites)
• Glibenclamide has the highest hypoglycemia risk among 2nd generation sulfonylureas

• Due to hyperinsulinemia → increased lipogenesis and appetite
• Average gain: 2-4 kg

• SUR2A receptors on cardiac muscle are also blocked by glibenclamide → may impair ischemic preconditioning of the myocardium (a protective response to ischemia)
• Not recommended in patients with significant cardiovascular disease

• Flushing after ethanol ingestion (more common with chlorpropamide; occurs occasionally with glibenclamide)

• Nausea, vomiting, cholestatic jaundice (rare)

• Leukopenia, thrombocytopenia, hemolytic anemia

• NSAIDs, sulfonamides, warfarin, fluconazole, salicylates (displace from protein binding or inhibit metabolism)
• Beta-blockers (mask tachycardia warning of hypoglycemia; also inhibit glycogenolysis)

Contraindications

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Side-by-Side Comparison

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Regulation of Calcium Levels

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1. Forms of Calcium in Blood

The body contains ~1000-1300 g of calcium total; >99% is stored in bone and teeth. The extracellular Ca²⁺ pool (in ECF/blood) is the tightly regulated compartment.

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2. Overall Calcium Homeostasis - The Big Picture

• 350 mg absorbed from the gut (stimulated by 1,25-(OH)₂ Vitamin D)
• 150 mg secreted back into the gut = net absorption 200 mg/day
• 800 mg excreted in feces
• Kidneys filter ~10,000 mg/day and reabsorb ~9,800 mg → excrete 200 mg/day (matching absorption to maintain balance)

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3. The Three Regulatory Hormones

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A. Parathyroid Hormone (PTH)

• Secreted by chief cells of the 4 parathyroid glands
• Parathyroid cells express a Calcium-Sensing Receptor (CaSR) linked via Gq to phospholipase C
• When Ca²⁺ falls → less CaSR activation → less IP₃/Ca²⁺ signaling → PTH secretion increases (within seconds)
• When Ca²⁺ rises → CaSR activated → inhibits PTH

Note: The phosphaturic action of PTH is critical - without it, the phosphate released from bone would complex with ionized Ca²⁺ in ECF and blunt the rise in calcium.

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B. Vitamin D (1,25-Dihydroxycholecalciferol / Calcitriol)

Skin (UV light)
  Cholesterol → 7-dehydrocholesterol → Cholecalciferol (Vitamin D₃)
                                          ↓ (Liver)
                                   25-Hydroxycholecalciferol
                                          ↓ (Kidney - 1α-hydroxylase)
                                                  ↑ stimulated by PTH, low Ca²⁺, low PO₄
                              1,25-Dihydroxycholecalciferol (Calcitriol) ← ACTIVE FORM

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C. Calcitonin

• Secreted by parafollicular C cells of the thyroid gland
• Stimulus: hypercalcemia (high plasma Ca²⁺)
• Mechanism: binds Gs-coupled receptor on osteoclasts → ↑ cAMP → inhibits osteoclast activity

Calcitonin is physiologically less important in adults than PTH/Vitamin D, but it plays a significant role in calcium regulation in children during active bone growth.

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4. Effect of Acid-Base Disturbances on Ionized Ca²⁺

Clinically: Hyperventilation (acute respiratory alkalosis) causes tetany due to this mechanism even though total Ca²⁺ is normal.

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5. Integrated Regulatory Summary

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6. Summary Table of the Three Hormones

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