Treatment and Management of Non-infectious Diseases

Activity 1 — Match Treatments to Mechanisms

1. Atorvastatin: Category: pharmacological. Disease: CVD / atherosclerosis. Mechanism: Atorvastatin competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway for cholesterol synthesis in hepatocytes. Reduced intracellular cholesterol causes liver cells to upregulate LDL receptor expression on their surface, increasing clearance of circulating LDL-cholesterol from the bloodstream. Lower serum LDL reduces the lipid substrate available for atherosclerotic plaque formation in arterial walls, slowing disease progression and reducing the risk of myocardial infarction and stroke.

2. Structured dietary and exercise program for T2D: Category: lifestyle management. Why it is treatment not just prevention: the patient already has a T2D diagnosis; the program directly targets the pathophysiological mechanisms of the existing disease (insulin resistance, hyperglycaemia) rather than preventing future onset. Exercise mechanism: aerobic exercise activates AMPK in muscle cells, triggering translocation of GLUT4 glucose transporter vesicles to the cell membrane independently of insulin receptor signalling. This allows muscle cells to take up blood glucose during exercise without requiring insulin, directly lowering blood glucose. Resistance training increases muscle mass, expanding the body's capacity to act as a glucose sink. Weight reduction reduces visceral adipose tissue, which produces adipokines (TNF-alpha, IL-6) and free fatty acids that impair insulin receptor signalling — reducing visceral fat decreases this inhibitory signal and improves insulin sensitivity.

3. Imatinib for CML: Category: pharmacological — targeted therapy. Why more appropriate than chemotherapy: BCR-ABL tyrosine kinase is produced only by CML cancer cells carrying the Philadelphia chromosome translocation. Normal cells do not express BCR-ABL. Imatinib binds specifically to the ATP-binding site of BCR-ABL, blocking its kinase activity and preventing it from phosphorylating downstream signalling proteins that drive CML cell proliferation. Because imatinib only acts on BCR-ABL — absent in normal cells — it does not cause the severe damage to bone marrow, gut epithelium, and hair follicles that conventional cytotoxic chemotherapy causes. 10-year survival in CML exceeds 80% with imatinib compared with much shorter survival with prior chemotherapy regimens.

4. CABG + post-surgical statin/lifestyle management: Category: surgical. What CABG does: the surgeon grafts a blood vessel (typically saphenous vein from the leg, or internal mammary artery) from the aorta to a point on the coronary artery downstream of the blockage, creating a new conduit that allows oxygenated blood to bypass the stenosed section and reach the myocardium. This restores blood flow, relieves angina, and reduces myocardial infarction risk. Why statins + lifestyle still needed: CABG physically reroutes blood past the existing blockage but does not remove the atherosclerotic plaques or correct the underlying lipid metabolism abnormality. Without statins lowering LDL and lifestyle management reducing risk factors, atherosclerosis continues to develop in other coronary arteries and potentially in the graft vessel itself. Long-term outcomes post-CABG are substantially improved by ongoing statin therapy and cardiac rehabilitation.

Activity 2 — Evaluating Treatment Options

1. T2D patient (BMI 38, HbA1c 9.5% on metformin): Second medication (e.g. GLP-1 receptor agonist such as semaglutide): GLP-1 agonists stimulate insulin secretion in response to meals, suppress glucagon, slow gastric emptying, and promote satiety — leading to both blood glucose reduction and weight loss (typically 5–15%). They are highly effective at lowering HbA1c. Limitation: relatively expensive without full PBS subsidy; requires injection or oral administration. Bariatric surgery: the most effective long-term treatment for T2D remission in patients with BMI ≥35. Clinical trials show >50% T2D remission at 5 years following gastric sleeve or bypass surgery due to dramatic weight reduction (>15–20%), reduced visceral fat, and gut hormone changes that improve insulin sensitivity. Limitation: major surgical procedure with risk of anastomotic leak, nutritional deficiencies (requires lifelong vitamin supplementation), not suitable for patients with high surgical risk. Intensified lifestyle support: effective if sustained — weight loss of 15% can achieve remission. Limitation: difficult to achieve and maintain with HbA1c already at 9.5%, requiring intensive structured support (dietitian, diabetes educator, exercise physiologist) that may not be available. Conclusion: for a patient with BMI 38 and inadequately controlled T2D despite metformin, the evidence most strongly supports adding a GLP-1 agonist (combining glucose reduction with weight loss) and referring for bariatric surgery assessment — the combination addresses both pharmacological management and the root driver (obesity).

2. Statins vs CABG for CVD: (a) Mechanism: statins inhibit HMG-CoA reductase → lower LDL → slow atherosclerotic plaque formation; CABG surgically creates a bypass route past blocked coronary arteries → restores myocardial blood flow. (b) Effectiveness by patient group: statins are effective for primary prevention (high-risk individuals without symptoms) and secondary prevention (post-MI) across all patient groups; CABG is most effective in severe multi-vessel coronary artery disease where pharmacological management alone is insufficient and blood flow to the myocardium is critically compromised. Large trials (FREEDOM, SYNTAXES) show CABG superior to stenting in complex multi-vessel disease. (c) Cost/accessibility: statins cost ~$5–40/month on PBS, are prescribed by GPs, and require no specialist access — highly accessible nationally including rural areas; CABG costs $30,000–$50,000 (Medicare-covered for eligible patients) but requires referral to a cardiothoracic surgeon, hospital admission, weeks of recovery, and is less accessible in rural and remote areas due to limited specialist presence. (d) Limitations: statins = must be taken indefinitely, myopathy in some patients, do not directly restore blood flow; CABG = surgical risk (mortality ~1–2% in elective cases), recovery time, graft failure over time, does not treat underlying disease. Conclusion: statins are the first-line and lifelong treatment for all CVD patients; CABG is reserved for severe multi-vessel disease unmanageable by medication. They are complementary — CABG patients require statins post-surgery.

Multiple Choice

1. C — Statins inhibit HMG-CoA reductase → reduced hepatic cholesterol synthesis → liver upregulates LDL receptors → increased LDL clearance from blood → slower plaque formation. Option A is wrong — statins do not dissolve existing plaques. Option B is wrong — statins have no role in insulin production. Option D is wrong — statins upregulate, not block, LDL receptors in the liver.

2. B — Imatinib specifically targets BCR-ABL tyrosine kinase, only present in CML cells, producing fewer off-target effects than chemotherapy. Option A is wrong — imatinib is not an immunotherapy. Option C is wrong — chemotherapy can be used for CML but imatinib is superior. Option D is wrong — imatinib is not gene therapy; it is a small-molecule kinase inhibitor.

3. A — CABG bypasses blockages but does not treat the underlying lipid metabolism disorder; statins and lifestyle management prevent progression in other arteries and the graft. Option B is wrong — CABG grafts are not limited to 6 months. Option C is wrong — statins do not dissolve plaques. Option D is wrong — statins are prescribed for ongoing CVD management, not infection prevention.

4. D — PBS listing reduces imatinib from ~$40,000/year to ~$40/month in Australia; without equivalent subsidies, the drug is unaffordable in many countries despite its high effectiveness. Option A is wrong — generic availability does not guarantee affordability in all countries. Option B is wrong — PBS increases Australian accessibility. Option C is wrong — biological effectiveness does not determine global availability.

5. B — Gene therapy remains experimental for most non-infectious diseases; statins and metformin have extensive evidence bases, proven long-term safety, and very high accessibility through PBS. Replacing them would require gene therapy to match on all these dimensions. Option A is wrong — gene therapy has not replaced these drugs in clinical practice. Option C is wrong — gene therapy has shown promise in some clinical trials. Option D is wrong — a 2–3 year timeline is not supported by current trial data.

Short Answer Model Answers

Q6 (4 marks): Enzyme activated: AMPK (AMP-activated protein kinase) in hepatocytes [0.5 mark]. Process 1: AMPK activation inhibits the expression of gluconeogenic enzymes (PEPCK, G6Pase) in the liver, reducing synthesis of glucose from non-carbohydrate precursors (amino acids, lactate, glycerol) — this lowers hepatic glucose output into the portal blood and reduces fasting blood glucose [1 mark]. Process 2: Metformin increases GLUT4 transporter vesicle translocation to the plasma membrane of muscle and adipose cells, improving glucose uptake from blood into peripheral tissues independently of insulin receptor signalling — effectively increasing insulin sensitivity without requiring more insulin [1 mark]. Why "improves insulin sensitivity" rather than "replaces insulin": metformin does not supply exogenous insulin, stimulate beta-cell insulin secretion, or mimic insulin at its receptor. It makes existing cells respond more effectively to the insulin already present — by improving the signalling and transporter mechanisms downstream of the insulin receptor. Insulin is still required for full glucose homeostasis; metformin reduces the amount needed by making peripheral tissues more responsive [1.5 marks — 4 marks total].

Q7 (5 marks): (a) Mechanism: conventional chemotherapy (e.g. cisplatin) forms covalent crosslinks between DNA strands, preventing DNA polymerase from replicating the template and blocking cell division; taxanes stabilise microtubules, preventing spindle assembly and mitosis. These mechanisms affect all rapidly dividing cells. Imatinib binds to the ATP-binding site of BCR-ABL tyrosine kinase, competitively blocking ATP binding and preventing BCR-ABL from phosphorylating downstream proteins in the MAPK and PI3K growth-signalling pathways — CML cells cannot divide without this signal [1.5 marks]. (b) Specificity: chemotherapy has low specificity — any rapidly dividing cell is a target, regardless of whether it is cancerous. This means bone marrow progenitor cells, gut epithelial cells, and hair follicle cells are also damaged. Imatinib has high specificity — BCR-ABL is only expressed in CML cells carrying the Philadelphia chromosome translocation; normal cells lack this oncoprotein [1.5 marks]. (c) Side effects: chemotherapy causes immunosuppression (bone marrow suppression), mucositis, alopecia (hair loss), severe nausea and vomiting, and increased infection risk. Imatinib typically causes mild nausea, fluid retention, and fatigue; severe bone marrow suppression is rare because normal haematopoietic cells are not targeted [1 mark]. Why not suitable for all cancers: targeted therapy requires a specific identifiable molecular driver that can be pharmacologically inhibited and that is expressed in the patient's tumour. If a cancer lacks the relevant protein target (the tumour has no BCR-ABL, HER2 overexpression, or BRAF V600E mutation), the drug will have no molecular target and will be ineffective. Many cancers involve complex, heterogeneous mutation profiles without a single dominant targetable driver, making targeted therapy inappropriate for the majority of cancer types [1 mark — 5 marks total].

Q8 (6 marks): Introduction: The statement is incorrect — biological effectiveness is a necessary but insufficient criterion for determining the most appropriate treatment for an individual patient. Appropriateness requires consideration of effectiveness, cost, accessibility, side effects, and patient-specific factors [0.5 mark]. Example 1 — CVD (statins vs CABG): CABG is the most biologically effective intervention for severe multi-vessel coronary artery disease, restoring myocardial blood flow directly and superior to medication alone in major trials. However, for an 80-year-old patient with multiple comorbidities, the surgical risk of CABG (mortality ~1–2%, stroke, infection) outweighs its biological advantage — statins + lifestyle management are more appropriate despite being less immediately effective. For a rural patient, limited access to cardiothoracic surgical centres makes CABG less accessible even if clinically indicated. Cost is managed through Medicare in Australia, but rural access and surgical risk remain barriers [1.5 marks]. Example 2 — Type 2 diabetes (bariatric surgery vs metformin vs lifestyle): bariatric surgery produces the greatest long-term biological effect (>50% T2D remission in severe obesity); however, it involves major surgical risk, requires lifelong nutritional supplementation, and demands profound dietary compliance. For a patient with early-stage T2D (HbA1c 8.2%), the risk-benefit calculation favours lifestyle modification + metformin (PBS cost ~$6/month) — equally effective for this disease stage with far lower risk and cost. Metformin, despite being less dramatic than surgery, is the most appropriate first-line treatment because it is safe, cheap, accessible, and evidence-based for this patient profile [1.5 marks]. Effectiveness, cost, accessibility, patient factors: effectiveness alone does not determine appropriateness because a treatment that is highly effective but unavailable (geographic barrier), unaffordable (no PBS listing), or unsafe for a given patient (comorbidities, age) cannot be administered. A treatment that a patient can access, afford, and adhere to long-term will produce better real-world outcomes than a theoretically superior treatment they cannot receive or sustain [1.5 marks]. Conclusion: The most appropriate treatment is the most effective option that can be safely administered, accessed, and maintained by the specific patient — integrating biological effectiveness with cost, accessibility, surgical risk, and individual patient circumstances [1 mark — 6 marks total].