Pharmacological Treatments for Controlling Blood Glucose in Diabetes Mellitus - Examination Notes

Learning outcomes

  • Know the various treatments for type II diabetes.
  • Understand the use of insulin in type I and II DM.
  • Discuss the mechanism of action of each agent.
  • Discuss their major adverse effects and adverse drug interactions.
  • Explain why agents used solely for managing blood glucose levels in type II DM are not used for type I DM.

Drug classes overview

  • Major drug classes covered for glycaemic control:
    • Sulfonylureas
    • Dipeptidyl peptidase-4 (DPP-4) inhibitors
    • Glucagon-like peptide-1 (GLP-1) analogues
    • Sodium-glucose cotransporter-2 (SGLT-2) inhibitors
    • Alpha-glucosidase inhibitors
    • Biguanides
    • Thiazolidinediones
    • Insulins
  • Additional notes:
    • Incretins (GLP-1 related) enhance pancreatic insulin release.
    • Insulin and non-insulin agents are used according to diabetes type, severity, and comorbidity.

Sulfonylureas

  • Agents: glibenclamide, gliclazide, glimepiride, glipizide
  • MOA: inhibit pancreatic K_ATP channels in β-cells → membrane depolarisation → Ca^{2+} influx → insulin exocytosis
    • Mechanism summary: block K_{ATP} channels → ↑ insulin release
    • Diagrammatically:
      ext{K}{ATP} ext{ channel inhibition} ightarrow riangle Vm
      ightarrow [Ca^{2+}]_i
      ightarrow ext{insulin release}
  • Pharmacodynamics/PK considerations:
    • Risk of hypoglycaemia associated with age, renal and liver disease; longer half-life → greater hypoglycaemia risk
    • Longer half-life vs shorter half-life impacts episode risk; commonly cited half-lives: approximately 12exth12 ext{ h} vs 3exth3 ext{ h} depending on agent
    • Weight gain commonly observed
  • Common adverse effects (>1%):
    • Hypoglycaemia (risk increased with age, renal/liver disease; longer half-life -> greater risk)
    • Weight gain
  • Common adverse effects (observation data):
    • "Gliclazide" and others have varying risk profiles; table indicates rh references: glibenclamide high risk, gliclazide intermediate, glimepiride high/intermediate, glipizide low/intermediate (12 h / 3 h references)
  • Rare adverse effects (<0.1%):
    • Blood disorders (thrombocytopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia)
    • Allergic reactions
    • Stevens–Johnson syndrome, exfoliative dermatitis, photosensitivity, hepatotoxicity
    • Note: onset can be around ~3 weeks after first dose; patient education essential
  • Drug interactions:
    • Amiodarone: CYP2C9 inhibition -> ↑ sulfonylurea concentration -> ↑ hypoglycaemia risk
    • Fluconazole: ↑ sulfonylurea concentration -> ↑ hypoglycaemia risk
    • Bosentan with glibenclamide: may ↓ efficacy; combination contraindicated
    • Rifampicin: long-term ↑ metabolism of glibenclamide -> ↓ efficacy; short course ↑ hypoglycaemia risk; with gliclazide: ↑ metabolism -> ↓ glucose-lowering effect
    • St John’s Wort: ↓ gliclazide concentration -> ↓ glucose-lowering effect
  • Additional notes:
    • Often considered second-line after metformin in many guidelines; require monitoring for hypoglycaemia and weight changes

DPP-4 inhibitors

  • Agents (examples): alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin (and combinations with metformin or other agents)
  • MOA: inhibit the enzyme DPP-4, which normally breaks down incretins (e.g., GLP-1)
    • Result: ↑ incretin half-life and availability
    • Effects on pancreas: ↑ insulin secretion from β-cells; ↓ glucagon from α-cells
    • GI effects: delay gastric emptying; ↓ GI peristalsis
  • Physiologic context: incretins normally reduce breakdown; by inhibiting DPP-4, incretin action is prolonged
  • Clinical implications: improve postprandial insulin response and glucagon suppression

Glucagon-Like Peptide-1 (GLP-1) analogues

  • Agents: dulaglutide, liraglutide, semaglutide
  • MOA: GLP-1 receptor agonists (GLP-1 receptor is a GPCR)
    • ↑ adenylyl cyclase activity → ↑ cAMP
    • Inhibits ATP-sensitive K^+ channels → enhances insulin release
    • Decreases glucagon release from α-cells
    • Delays gastric emptying → slower glucose absorption
    • Increases satiety
  • Pharmacokinetic note: these are synthetic analogues; longer half-life than native GLP-1 because they resist degradation by DPP-4
  • Adverse effects (common >1%):
    • Hypoglycaemia (mainly when used with sulfonylurea or insulin)
    • Slightly ↑ heart rate
    • Injection-site reactions
    • Anti-drug antibodies; GERD (GORD)
  • Infrequent (0.1–1%):
    • Cholelithiasis, cholecystitis (may require cholecystectomy)
  • Rare (<0.1%):
    • Pancreatitis; allergic reactions including anaphylaxis/angioedema; altered renal function
  • Key pharmacologic point: DPP-4 inhibitors are not effective at degrading GLP-1 analogues, leading to longer MOA for GLP-1 receptor agonists

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors

  • Agents: dapagliflozin, empagliflozin
  • MOA: inhibit SGLT-2 in the proximal tubule of the kidney; ↓ glucose reabsorption and thus ↑ urinary glucose excretion
    • Result: Promote elimination of glucose in urine
  • Renal physiology context:
    • 90% of glucose is reabsorbed via SGLT2 in the proximal tubule
    • Remaining ~10% via SGLT1 in later segments
    • Inhibition leads to decreased glucose reabsorption and increased glucosuria
  • Clinical implications (summary from slides):
    • Renal protection: slows progression of kidney disease by reducing glomerular hypertension, independent of glycaemic control
    • Lower risk of kidney failure and death in CKD populations
    • Possible heart failure benefits (mechanism not fully established)
  • Notes: mechanism summarized with renal tubule segments (proximal to distal) and glucose handling

Alpha-glucosidase inhibitors

  • Agent: acarbose
  • MOA: competitive inhibitor of α-glucosidase in the small intestine
    • Inhibits breakdown of oligosaccharides and disaccharides to monosaccharides
    • Delays absorption of glucose; reduces postprandial glucose, not basal glucose
  • Safety/efficacy:
    • Does not cause weight gain or hypoglycaemia when used alone
    • Hypoglycaemia can occur when combined with sulfonylureas or insulin
  • Adverse effects: high incidence of gastrointestinal side-effects (flatulence, bloating, diarrhoea)
  • Rare adverse effects (<0.1%): ileus, hepatotoxicity, skin reactions, anaemia, oedema

Biguanides

  • Drug: Metformin
  • MOA:
    • ↓ hepatic glucose production/output via inhibition of gluconeogenesis
    • ↑ peripheral glucose utilisation by increasing tissue insulin sensitivity (notably in the liver)
  • Does not promote insulin secretion
  • Adverse effects:
    • Common (>1%): nausea, vomiting, anorexia, diarrhoea, malabsorption of vitamin B12
    • Infrequent (0.1–1%): rash
    • Rare (<0.1%): lactic acidosis, acute hepatitis
  • Precautions: conditions that may alter renal function or increase tissue hypoxia/acidosis (e.g., dehydration, shock, sepsis, MI, severe heart failure, liver failure, pulmonary embolism, ketoacidosis) may increase lactic acidosis risk

Thiazolidinediones (PPAR-γ agonists)

  • Agent: Pioglitazone
  • MOA: agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ); upregulates genes involved in lipid and glucose metabolism
    • ↑ tissue insulin sensitivity in peripheral tissues
    • ↓ hepatic glucose output
  • Precautions and contraindications:
    • Ketoacidosis contraindicated; Type 1 diabetes contraindicated
    • Use with sulfonylurea or insulin may increase hypoglycaemia risk; insulin may increase heart failure risk
    • Acute illness requires monitoring; substitute insulin if control inadequate
    • Osteoporosis risk; potential bladder cancer risk; avoid in active bladder cancer history
    • Heart failure risk: may cause or worsen heart failure; contraindicated in NYHA class II–IV; caution in NYHA class I
    • Hepatic: avoid use if aminotransferase > 2.5× ULN
  • Adverse effects:
    • Common (>1%): peripheral oedema, weight gain, headache, dizziness, arthralgia, reduced haemoglobin/haematocrit, myalgia
    • Infrequent (0.1–1%): fractures (non-vertebral, more in women)
    • Rare (<0.1%): elevated liver enzymes/hepatocellular injury, heart failure, pulmonary oedema, macular oedema, elevated CK

Insulins

  • Types (as listed):
    • Ultra-short acting (very rapid): insulin aspart (Fiasp), insulin lispro (Humalog), insulin glulisine (Apidra), insulin aspart (Fast-acting)
    • Short-acting (regular): Neutral insulin (Actrapid, Humulin R)
    • Long-acting: Isophane insulin (Protophane, Humulin NPH)
    • Long-acting analogues: insulin detemir (Levemir), insulin glargine (Optisulin, Toujeo)
  • Indications: diabetes mellitus including type I, type II, and gestational diabetes
  • Pharmacology: binds to insulin receptors; promotes glucose uptake into liver, muscle, and adipose tissue
  • Notes on preparations: insulin mixtures combine short-acting and long-acting components to mimic endogenous secretion
  • Adverse effects: most frequent and serious is hypoglycaemia; warn patients about warning symptoms and dosing adjustments
  • Common warning symptoms of hypoglycaemia (ANS responses):
    • Hunger, profuse sweating, palpitations; tremor, anxiety, hypotension; vasoconstriction with pale/cool skin
    • Impaired cerebral function due to glucose as primary fuel: headache, faintness, confusion; slurred speech, visual disturbance; mood changes

Hypoglycaemia management

  • Threshold: blood glucose < 2.2extmmol/L2.2 ext{ mmol/L}
  • Common triggers: over-treatment, delayed/inadequate food intake, exercise, alcohol
  • Immediate steps if possible: measure blood glucose to differentiate from DKA
  • Rapid treatment options:
    • Oral glucose (e.g., glucose tabs, sweets, sweet drinks)
    • Intravenous dextrose with a preparation of 50 ext{%} ext{ w/v dextrose}
    • If severe or unconscious: intramuscular/subcutaneous/IV glucagon
  • Note: rapid treatment is mandatory; insulin therapy may be warranted if glucose remains low or symptoms persist

Glucagon

  • Uses: treat hypoglycaemia when the patient cannot take oral carbohydrates or is unconscious
  • Mechanism: raises blood glucose via several processes:
    • ↑ gluconeogenesis
    • ↑ glycogenolysis
    • ↑ lipolysis
    • ↑ proteolysis
    • ↓ GI motility
  • Context: glucagon is a fuel-mobilising hormone

Diabetic Ketoacidosis (DKA)

  • Definition: absolute or relative insulin deficiency state, life-threatening emergency; common in known or newly presenting type I diabetics
  • Pathophysiology: derangement of glucose and fat metabolism
    • Insulin deficiency leads to increased fat metabolism (lipolysis) and increased glucose production; decreased glucose uptake
    • Result: hyperglycaemia, ketonemia, metabolic acidosis, dehydration
    • Clinical cascade: hyperglycaemia → osmotic diuresis → dehydration; acidosis → hyperventilation → potential shock & coma
  • Clinical features: hyperglycaemia, ketonemia, acidosis, dehydration, hyperventilation, possible coma

Treatment of Diabetic Ketoacidosis (DKA)

  • Primary interventions:
    • Insulin replacement: soluble insulin given by intravenous infusion (pump)
    • Rehydration: normal saline; colloid in shock; may require hypotonic fluids
    • Potassium replacement: maintain serum K^+ within 3.5–5.5 mmol/L
    • Correction of acidosis: bicarbonate, phosphate, magnesium as indicated
  • Monitoring and goals: stabilize circulation, correct acidosis, replete electrolytes, and restore metabolic homeostasis

Mechanism of action and summary of drug classes (quick reference)

  • Sulfonylureas: inhibit K_{ATP} channels in β-cells → insulin release
  • Biguanides (metformin): ↓ hepatic glucose production; ↑ peripheral insulin sensitivity; no insulin secretion
  • Thiazolidinediones (pioglitazone): PPAR-γ agonists → ↑ insulin sensitivity; ↓ hepatic glucose output
  • Alpha-glucosidase inhibitors (acarbose): delay carbohydrate digestion/absorption; reduce postprandial glucose
  • GLP-1 receptor analogues: GLP-1 mimetics → ↑ insulin, ↓ glucagon, delay gastric emptying, reduce appetite
  • DPP-4 inhibitors: inhibit GLP-1 breakdown → ↑ incretin effect; ↑ insulin, ↓ glucagon
  • SGLT-2 inhibitors: block renal glucose reabsorption → ↑ urinary glucose excretion; renal and CV/CKD benefits observed in guidelines
  • Insulins: replace or supplement endogenous insulin across type I and type II DM; various onset/duration profiles; mixtures mimic endogenous secretion

Important interfaces and physiological notes

  • Gut–liver–kidney axis in glucose homeostasis:
    • Small intestine: glucose absorption is transporter-mediated; SGLT transporters in kidney handle reabsorption
    • Gut incretins (GLP-1) enhance insulin release via pancreas and slow gastric emptying
    • Liver: gluconeogenesis and glycogenolysis influence hepatic glucose output; metformin reduces hepatic glucose production
  • GLUT transporters:
    • Glut-2: bidirectional transporter in liver and pancreas, insulin-independent initial glucose uptake
    • Glut-4: insulin-dependent glucose uptake in adipose tissue and muscle
  • MOA of insulin secretion and action:
    • Glucose metabolism leads to ↑ ATP in β-cells; closure of K_{ATP} channels → depolarisation → Ca^{2+} influx → insulin granule exocytosis
  • Graphical membrane and transporter references from slides: figures illustrating glucose handling at gut, liver, kidneys and transporters

Additional notes and context from references

  • Boxed/text references include Box 14.1 from Pharmacology for Pharmacy & the Health Sciences (Boarder et al.) and figures from Goodman and Gilman’s Pharmacology (12th edition, 2011) used to illustrate MOA and pathways
  • References section includes key texts such as Huether & McCance; Rang & Dale; Bryant et al.; Winstanley & Walley; Golan et al.; and Australian Medical Handbook (AMH) 2023

Learning outcomes (revisited)

  • You should be able to recall diabetes drug classes, their mechanisms, and their major adverse effects and interactions
  • Explain why type II DM agents are not used for type I DM without replacing insulin therapy
  • Understand how insulin therapy can be tailored for different diabetes types and clinical scenarios

References (from slide set)

  • Understanding Pathophysiology, Huether, McCance, Brasher and Rote, Elsevier, 6th edition, 2017, Chapter 19
  • Rang and Dale’s Pharmacology, Rang HP et al., multiple editions
  • Pharmacology for Health Professionals, Bryant et al., Mosby, various editions
  • Medical Pharmacology, Winstanley & Walley, Churchill Livingstone, 2nd edition, 2002
  • Principles of Pharmacology, Golan et al., Lippincott Williams & Wilkins, 2nd edition, 2005
  • Pharmacology for Pharmacy & the Health Sciences, Boarder et al., Oxford University Press, 1st ed., 2010
  • Australian Medical Handbook (AMH) 2023

Summary of key numerical and factual references

  • Hypoglycaemia risk by sulfonylurea: glibenclamide high; gliclazide intermediate; glimepiride high/intermediate; glipizide low/intermediate
  • Hypoglycaemia risk associated with drug half-lives: longer half-life increases risk (example values given: 12exth12 ext{ h} vs 3exth3 ext{ h})
  • Dosing/administration details include: dextrose concentration for IV glucose as 50 ext{%} ext{w/v}; glucagon dosing (standard emergency dose not explicitly listed in slides, but commonly 1 mg IM/IV in many guidelines)
  • DKA management emphasizes IV insulin replacement and aggressive fluid resuscitation with normal saline; electrolyte management targets potassium 3.5−5.5extmmol/L3.5-5.5 ext{ mmol/L}
  • Postprandial glucose reduction is a primary target for alpha-glucosidase inhibitors, not basal glucose