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Antidiabetic Drugs - Complete Teaching Guide

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OVERVIEW & CLASSIFICATION

1. Insulin & its preparations
2. Oral/injectable agents for Type 2 DM:
   • Sulfonylureas (1st and 2nd generation)
   • Meglitinides
   • Biguanides (Metformin)
   • Thiazolidinediones (TZDs)
   • Alpha-glucosidase inhibitors
   • GLP-1 receptor agonists
   • DPP-4 inhibitors
   • SGLT-2 inhibitors
   • Amylin analogs (Pramlintide)
   • Miscellaneous (Bromocriptine, Colesevelam)
3. Dual GIP/GLP-1 agonists (Tirzepatide)

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PART I: THE ENDOCRINE PANCREAS

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PART II: INSULIN

Chemistry & Biosynthesis

• Insulin is a 51 amino acid polypeptide (MW ~5808) made of 2 chains: A (21 aa) and B (30 aa) connected by two disulfide bridges.
• Synthesized as preproinsulin → proinsulin → insulin + C-peptide (by endopeptidases in secretory granules).
• Human insulin is produced by recombinant DNA technology using E. coli or Saccharomyces cerevisiae.

Insulin Secretion

• Basal secretion: ~1 unit/hour continuously.
• Stimulated secretion (by glucose, amino acids, GLP-1, GIP, vagal stimulation, sulfonylureas) occurs in two phases:
  • Phase 1: Rapid spike (within 2 min) - release of preformed insulin.
  • Phase 2: Sustained plateau (20-30 min) - newly synthesized insulin.
• Mechanism: Glucose uptake via GLUT-2 → ATP generation → ATP-sensitive K⁺ channel closes → membrane depolarization → Ca²⁺ influx → insulin exocytosis.

Pharmacokinetics

• Half-life in plasma: ~5-6 minutes.
• Degraded mainly in liver (40-50% in first pass) and kidney.
• Measurement: C-peptide levels reflect endogenous insulin secretion (not destroyed in first pass like insulin).

Insulin Receptor & Mechanism of Action

• The insulin receptor is a transmembrane glycoprotein composed of two α (extracellular) and two β (intracellular) subunits linked by disulfide bonds.
• The β subunit has intrinsic tyrosine kinase activity.
• Insulin binding → autophosphorylation of β subunit → phosphorylation of insulin receptor substrates (IRS-1, IRS-2) → downstream effects via PI-3 kinase and MAPK pathways.

Effects of Insulin

Insulin Preparations - By Duration

• Lispro: Pro-Lys reversed to Lys-Pro at B28-B29 positions.
• Aspart: Pro replaced by Asp at B28.
• Glulisine: Asn replaced by Lys at B3; Lys replaced by Glu at B29.
• Glargine: Asn→Gly at A21; two Arg added at B30 C-terminus → forms microprecipitate at SC injection site (acidic pH 4) → slow absorption.
• Detemir: Fatty acid (C14 myristic acid) attached to B29 Lys → binds albumin → prolonged action.
• Degludec: Multi-hexamer depot formation → extremely prolonged action (>42h), less hypoglycemia.

Adverse Effects of Insulin

1. Hypoglycemia - most common, most dangerous. Mild: tremor, palpitations, hunger. Severe: confusion, seizures, coma.
2. Allergic reactions - rare with modern human/analog insulins. IgE-mediated.
3. Insulin resistance - due to IgG antibodies (rarely significant).
4. Lipodystrophy - lipoatrophy (rare now with modern insulins); lipohypertrophy (from repeated injection at same site).
5. Hypokalemia - insulin drives K⁺ into cells.
6. Weight gain.

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PART III: ORAL ANTIDIABETIC DRUGS (TYPE 2 DM)

Classification of Type 2 Antidiabetic Drugs

1. Stimulate insulin secretion - Sulfonylureas, Meglitinides
2. Reduce hepatic glucose output / increase peripheral sensitivity - Biguanides, TZDs
3. Slow glucose absorption - Alpha-glucosidase inhibitors
4. Mimic/prolong incretin effect - GLP-1 agonists, DPP-4 inhibitors
5. Inhibit renal glucose reabsorption - SGLT-2 inhibitors
6. Other mechanisms - Pramlintide, Bromocriptine, Colesevelam

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1. SULFONYLUREAS

• Bind to the 140-kDa sulfonylurea receptor (SUR1) on pancreatic beta cells.
• This receptor is associated with an ATP-sensitive K⁺ (KATP) channel.
• Binding → K⁺ channel closes → membrane depolarization → Ca²⁺ influx → insulin release.
• Require functioning beta cells to work.

• Well absorbed orally. Highly protein-bound (albumin). Metabolized in liver; excreted in urine/bile.
• Chlorpropamide has the longest half-life (~35 h) and active metabolites - greatest risk of prolonged hypoglycemia.
• Glimepiride is preferred in renal impairment (hepatic elimination).

• Hypoglycemia (most important) - especially with chlorpropamide, glyburide.
• Weight gain.
• Disulfiram-like reaction - with chlorpropamide + alcohol.
• Hyponatremia/SIADH - chlorpropamide potentiates ADH.
• Skin rash, GI disturbances.

• Hypoglycemia potentiated by: salicylates, sulfonamides, fibrates, fluconazole, MAOIs.
• Effect reduced by: thiazide diuretics, corticosteroids, rifampicin.

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2. MEGLITINIDES (Non-Sulfonylurea Insulin Secretagogues)

• Repaglinide (benzoic acid derivative), Nateglinide (D-phenylalanine derivative).
• Mechanism: Same as sulfonylureas - bind SUR1/KATP channel but at a different binding site.
• Key feature: Very rapid onset, short duration → taken just before meals.
• Repaglinide: onset in 30 min, duration 4-6 h; safer in renal impairment.
• Nateglinide: weakest HbA1c lowering, primarily controls postprandial glucose.
• ADRs: Hypoglycemia (less than SUs), weight gain.

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3. BIGUANIDES - METFORMIN

• Primary effect: Inhibits hepatic gluconeogenesis (reduces hepatic glucose output by ~30%).
• Works via activation of AMP-activated protein kinase (AMPK) → inhibits mitochondrial respiratory chain complex I → reduces ATP/ADP ratio → activates AMPK.
• Also increases peripheral glucose uptake (sensitizes muscle to insulin via GLUT-4 upregulation).
• Does NOT stimulate insulin secretion → no hypoglycemia as monotherapy.

• Not metabolized, excreted unchanged in urine.
• Half-life: ~2-4 hours; needs twice-daily dosing (or extended-release once daily).

• No hypoglycemia as monotherapy.
• Weight neutral or causes modest weight loss.
• Reduces cardiovascular events (UKPDS data).
• Drug of choice for Type 2 DM (first-line per all guidelines).
• Cheap and effective.

• GI side effects (nausea, diarrhea, metallic taste) - most common; reduced by taking with food and gradual dose titration.
• Lactic acidosis - rare but potentially fatal. Risk increased in renal failure, liver disease, hypoxic states, alcoholism.
• Vitamin B12 deficiency - long-term use impairs ileal B12 absorption.
• Metallic taste.

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4. THIAZOLIDINEDIONES (TZDs / Glitazones)

• Bind and activate Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ) - a nuclear receptor.
• PPAR-γ activation → altered gene transcription → increases insulin sensitivity in adipose, muscle, liver.
• Promotes adipocyte differentiation, redistribution of fat from visceral to subcutaneous depots.
• Do NOT stimulate insulin secretion → no hypoglycemia as monotherapy.

• Fluid retention / edema (due to renal sodium retention, PPAR-γ in collecting duct).
• Weight gain (adipogenesis).
• Heart failure exacerbation - contraindicated in NYHA class III-IV HF.
• Fractures - increased risk, especially in women (decreased osteoblast differentiation).
• Rosiglitazone: associated with increased myocardial infarction risk → heavily restricted.
• Pioglitazone: possible increased risk of bladder cancer (long-term use); benefit on NAFLD and NASH.
• Macular edema (rare).
• Slow onset of action (4-8 weeks for full effect).

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5. ALPHA-GLUCOSIDASE INHIBITORS

• Competitively inhibit intestinal alpha-glucosidases (maltase, sucrase, glucoamylase) and pancreatic alpha-amylase (acarbose only).
• Delay digestion and absorption of complex carbohydrates and disaccharides.
• Reduce postprandial hyperglycemia.

• Acarbose: minimal systemic absorption; acts locally in GI tract.
• Miglitol: completely absorbed but no systemic effects on glucose.

• Flatulence, bloating, diarrhea, abdominal cramps - very common (fermentation of undigested carbohydrates by colonic bacteria). Main reason for discontinuation.
• Hepatotoxicity - rare with acarbose at high doses.
• No hypoglycemia as monotherapy.
• If hypoglycemia occurs with combination therapy - must treat with glucose (not sucrose), since sucrose absorption is blocked.

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6. GLP-1 RECEPTOR AGONISTS (Incretin Mimetics)

• GLP-1 (glucagon-like peptide-1) is secreted by L-cells of the intestine in response to meals.
• GLP-1 receptor agonists mimic its actions:
  1. Glucose-dependent insulin secretion (insulin released only when glucose is elevated - low hypoglycemia risk).
  2. Suppress glucagon secretion.
  3. Slow gastric emptying → reduces postprandial glucose rise.
  4. Reduce appetite and food intake (central action) → significant weight loss.
  5. Cardioprotective effects (reduce MACE, hospitalization for HF).

• Short-acting (exenatide BID, lixisenatide OD): mainly reduce postprandial glucose via gastric emptying delay.
• Long-acting (liraglutide OD, dulaglutide weekly, semaglutide SC weekly): reduce both fasting and postprandial glucose.
• Oral semaglutide (Rybelsus): available but bioavailability only 0.4-1%; must be taken fasting.
• Tirzepatide (GIP + GLP-1 dual agonist): HbA1c reduction 1.9-2.6%; weight loss 6.2-12.9 kg.

• GI side effects - nausea (11-40%), vomiting, diarrhea (most common, especially at start).
• Pancreatitis risk (counsel patients about severe abdominal pain).
• Medullary thyroid carcinoma risk in rodents; contraindicated in personal/family history of MEN-2 or medullary thyroid cancer.
• Acute kidney injury (exenatide - volume depletion).
• Injection site reactions.

• Liraglutide, semaglutide, dulaglutide: reduce cardiovascular mortality and MACE in patients with T2DM + established CVD.
• Approved for HFREF (liraglutide, semaglutide).

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7. DPP-4 INHIBITORS (Gliptins)

• DPP-4 (dipeptidyl peptidase-4) normally degrades GLP-1 and GIP within 2 minutes of release.
• DPP-4 inhibitors block this enzyme → prolonged action of endogenous GLP-1 and GIP → enhanced glucose-dependent insulin secretion.
• More modest effect than GLP-1 receptor agonists (no weight loss, smaller HbA1c reduction).

• Sitagliptin: oral 100 mg OD; bioavailability >85%; half-life ~12 h; renally excreted (reduce dose if eGFR <45).
• Linagliptin: primarily biliary/fecal excretion → no dose adjustment in renal impairment (useful in CKD).
• Saxagliptin: renal excretion; dose reduction needed in CKD.

• Generally well-tolerated.
• Nasopharyngitis (upper respiratory infections).
• Urinary tract infections.
• Pancreatitis (rare, controversial).
• Joint pain (arthralgia, rare but severe cases).
• Saxagliptin & Alogliptin: associated with increased heart failure hospitalizations in clinical trials (SAVOR-TIMI, EXAMINE trials).
• No hypoglycemia as monotherapy.
• Weight neutral.

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8. SGLT-2 INHIBITORS (Gliflozins)

• Sodium-glucose co-transporter 2 (SGLT-2) is expressed in the proximal tubule of the kidney.
• It reabsorbs ~90% of filtered glucose.
• SGLT-2 inhibitors block this transporter → glucosuria (glucose excreted in urine) → lowered blood glucose.
• Also cause natriuresis (sodium excretion) → lower blood pressure.
• Insulin-independent mechanism.

• Empagliflozin (EMPA-REG OUTCOME): reduced cardiovascular death by 38%, HF hospitalization by 35%.
• Dapagliflozin (DAPA-HF): reduced HF hospitalization and CV death in HFREF regardless of diabetes status.
• Slow progression of chronic kidney disease (CKD).
• Approved for HFREF (empagliflozin, dapagliflozin) and HFpEF (empagliflozin).

• Genital mycotic infections (candidal infections) - most common; due to glucosuria creating a favorable environment.
• Urinary tract infections.
• Diabetic ketoacidosis (DKA) - even with near-normal blood glucose (euglycemic DKA); with Type 1 DM use.
• Fournier's gangrene (necrotizing fasciitis of perineum) - rare.
• Volume depletion/hypotension - especially in elderly.
• Lower limb amputations (canagliflozin - CANVAS trial).
• Fractures (canagliflozin).
• Reduced eGFR initially (not harmful but transient) - do not use if eGFR <45 mL/min.

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9. AMYLIN ANALOG - PRAMLINTIDE

• Synthetic analog of amylin (IAPP) secreted by beta cells alongside insulin.
• Mechanism: Slows gastric emptying, suppresses glucagon, reduces appetite.
• Used as an adjunct to insulin in both Type 1 and Type 2 DM.
• Given by subcutaneous injection before meals.
• ADRs: Nausea, vomiting, hypoglycemia (when combined with insulin - insulin dose must be reduced by 50%).

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10. BROMOCRIPTINE (Cycloset)

• Dopamine D2 receptor agonist. Taken in the morning.
• Mechanism in DM incompletely understood - thought to reduce hepatic glucose output via central dopaminergic pathways.
• Modest HbA1c reduction (~0.5-0.8%). Not widely used.

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11. COLESEVELAM (Bile Acid Sequestrant)

• A bile acid sequestrant also approved for glucose lowering.
• Mechanism in DM unclear - may reduce intestinal glucose absorption and increase GLP-1 secretion.
• Modest HbA1c reduction. Also lowers LDL cholesterol.
• ADRs: constipation, may reduce absorption of other drugs.

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PART IV: TREATMENT PRINCIPLES

Type 1 DM

• Requires insulin (complete beta-cell destruction).
• Regimen: Basal-bolus insulin - long-acting insulin (glargine/degludec) once daily + rapid-acting analog (lispro/aspart) before each meal.

Type 2 DM

• Step 1: Lifestyle modification + Metformin (first-line).
• Step 2: Add a second agent based on patient profile:
  • With CVD or HF risk: add GLP-1 agonist or SGLT-2 inhibitor.
  • With CKD: SGLT-2 inhibitor (if eGFR >45).
  • Need HbA1c lowering + weight loss: GLP-1 agonist.
  • Cost concern: Sulfonylurea or TZD.
• Step 3: Insulin when oral agents fail.

Hypoglycemic Emergency

• Mild: oral glucose (15-20g).
• Severe/unconscious: IV 50% dextrose (25 mL) or glucagon 1 mg IM/SC.

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QUICK MEMORY AIDS

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Note: The KD Tripathi textbook (Essentials of Medical Pharmacology) is not directly available in this library. The above teaching is drawn from Katzung's Basic & Clinical Pharmacology, 16th Edition, Chapter 41 which covers the same content with equivalent depth - Katzung, Ch. 41, pp. 1166-1200.