🫀 Cardiovascular and Renal Pharmacotherapy

1. A 54-year-old man with uncomplicated stage 1 hypertension has no other cardiovascular risk factors. Which class is NOT considered a first-line option for him in Canadian practice?

1. A thiazide-like diuretic such as indapamide, taken once daily in the morning
2. An alpha-1 adrenergic blocker such as doxazosin titrated slowly at bedtime
3. An angiotensin converting enzyme inhibitor titrated to the usual maintenance dose
4. A long-acting dihydropyridine calcium channel blocker such as amlodipine

Alpha-1 blockers are reserved for a compelling indication such as symptomatic benign prostatic hyperplasia because they performed poorly as monotherapy for cardiovascular outcomes. Thiazide-like diuretics, ACE inhibitors and long-acting dihydropyridines are all recognised first-line choices for uncomplicated hypertension. Source: Hypertension Canada guidelines.

2. A patient started on ramipril two weeks ago returns with a persistent dry cough that disturbs her sleep. What is the most appropriate recommendation to the prescriber?

1. Switch to an angiotensin receptor blocker, which does not raise bradykinin levels
2. Reduce the ramipril dose by half, since the cough is dose-dependent and settles
3. Add a low-dose antitussive at bedtime and continue ramipril, since the cough settles with time
4. Stop all renin-angiotensin blockade permanently because of the risk of angioedema

ACE inhibitor cough is mediated by accumulation of bradykinin and substance P; it is not dose-related and does not respond reliably to antitussives. Switching to an ARB resolves it in most patients, whereas permanent avoidance of the whole renin-angiotensin system is reserved for angioedema, not cough. Source: Health Canada product monograph for ramipril.

3. Which pair of laboratory values should be rechecked one to two weeks after starting or increasing an ACE inhibitor?

1. Serum sodium and fasting glucose, because the class commonly causes hyponatraemia and dysglycaemia
2. Serum creatinine and serum potassium, to detect functional decline and hyperkalaemia
3. Alanine aminotransferase and bilirubin, to detect drug-induced hepatic injury
4. Complete blood count and ferritin, to detect suppression of erythropoiesis

Renin-angiotensin blockade lowers efferent arteriolar tone and reduces potassium excretion, so creatinine and potassium are the parameters that change first and matter most. Liver enzymes, glucose and haematology are not routine monitoring for this class. Source: Hypertension Canada guidelines and Health Canada product monographs.

4. A woman taking candesartan tells you she has just had a positive pregnancy test. What is the correct action?

1. Continue candesartan until the first prenatal visit, then reassess the indication
2. Contact the prescriber urgently, as this class is contraindicated in pregnancy
3. Halve the dose immediately and monitor blood pressure weekly during pregnancy
4. Substitute an ACE inhibitor, which carries no fetal risk in the first trimester

Angiotensin receptor blockers and ACE inhibitors both cause fetal renal injury, oligohydramnios and skull hypoplasia, and both are contraindicated in pregnancy at any stage. The exposure must be discussed with the prescriber immediately so that an agent compatible with pregnancy can replace it. Source: Health Canada product monograph for candesartan.

5. A patient on perindopril and spironolactone is prescribed trimethoprim-sulfamethoxazole for a urinary infection. What is the principal risk of this combination?

1. Hypertensive crisis, because sulfamethoxazole antagonises ACE inhibition directly
2. Profound hypoglycaemia, because sulfonamides displace insulin from binding sites
3. Acute rhabdomyolysis, because trimethoprim inhibits skeletal muscle metabolism
4. Severe hyperkalaemia, because all three agents reduce renal potassium excretion

Trimethoprim blocks the epithelial sodium channel in the distal nephron in a manner similar to amiloride, adding to the potassium-sparing effects of an ACE inhibitor and a mineralocorticoid receptor antagonist. Serious hyperkalaemia and arrhythmia have been reported, so an alternative antibiotic or close potassium monitoring is required. Source: Health Canada product monograph for trimethoprim-sulfamethoxazole.

6. Which beta-blockers have evidence of mortality benefit in heart failure with reduced ejection fraction and are therefore preferred?

1. Bisoprolol, carvedilol and metoprolol succinate, the agents studied in outcome trials
2. Atenolol, propranolol and labetalol, because of their long clinical track record
3. Sotalol, acebutolol and pindolol, because intrinsic sympathomimetic activity protects the failing heart
4. Nebivolol, timolol and nadolol, because of their effect on nitric oxide release

Only bisoprolol, carvedilol and long-acting metoprolol succinate have demonstrated reduced mortality in randomised trials of heart failure with reduced ejection fraction, and a class effect cannot be assumed. Agents with intrinsic sympathomimetic activity are specifically avoided. Source: Canadian Cardiovascular Society heart failure guidelines.

7. A patient is being switched from enalapril to sacubitril/valsartan. What washout interval is required, and why?

1. No washout is needed if the first sacubitril dose is reduced by half for one week
2. At least 12 hours, because the two products compete for the same intestinal absorption pathway
3. At least seven days, because sacubitril requires complete renal clearance of enalapril
4. At least 36 hours, because overlapping neprilysin and ACE inhibition risks angioedema

Neprilysin and angiotensin converting enzyme both degrade bradykinin, so simultaneous inhibition markedly increases the risk of angioedema; a minimum 36-hour interval between the last ACE inhibitor dose and the first sacubitril dose is mandatory. No washout is required when switching from an ARB. Source: Health Canada product monograph for sacubitril/valsartan.

8. A patient starting spironolactone for heart failure asks what he should watch for. Which counselling point is most important?

1. Take the dose at bedtime because the diuretic effect peaks during the night
2. Avoid potassium-containing salt substitutes and report muscle weakness or palpitations
3. Expect the urine to turn dark orange, which is harmless and resolves in a week
4. Increase dietary potassium deliberately, because the drug promotes urinary potassium loss like a thiazide

Mineralocorticoid receptor antagonists retain potassium, so salt substitutes based on potassium chloride and potassium supplements can precipitate dangerous hyperkalaemia, which may present as weakness or arrhythmia. The drug does not discolour urine and deliberately increasing potassium intake is the opposite of correct advice. Source: Canadian Cardiovascular Society heart failure guidelines.

9. Which additional benefit explains why SGLT2 inhibitors are now used in heart failure with reduced ejection fraction even without diabetes?

1. They raise ejection fraction directly by increasing the calcium sensitivity of the failing myocardium
2. They reduce hospitalisation for heart failure and cardiovascular death independently of glucose
3. They replace loop diuretics entirely by producing an equivalent natriuretic effect
4. They correct the anaemia of chronic heart failure by stimulating erythropoietin only

Outcome trials showed a reduction in the composite of heart failure hospitalisation and cardiovascular death in patients with and without type 2 diabetes, which is why the class became a pillar of therapy rather than a glucose-lowering add-on. They do not replace loop diuretics and their effect is not explained by inotropy. Source: Canadian Cardiovascular Society heart failure guidelines.

10. Which self-monitoring instruction is most useful for a patient with chronic heart failure taking furosemide?

1. Count your pulse for a full minute after each dose of the diuretic and write it down
2. Measure your blood pressure lying and then standing each morning before breakfast and record it
3. Weigh yourself daily at the same time and report a rapid gain of two kilograms
4. Record your fluid intake in millilitres and keep it above three litres each day

Daily weight is the earliest and most reliable marker of fluid retention, and a sudden gain prompts contact with the care team before decompensation occurs. Blood pressure and pulse are useful but less sensitive, and a high fluid target contradicts the management of congestion. Source: Canadian Cardiovascular Society heart failure guidelines.

11. For which patient with atrial fibrillation is warfarin, rather than a direct oral anticoagulant, the required anticoagulant?

1. A patient aged 82 years with an estimated creatinine clearance of 40 mL per minute
2. A patient with a mechanical mitral valve prosthesis and normal renal function
3. A patient with a body weight of 120 kilograms and controlled hypertension
4. A patient with previous gastrointestinal bleeding now fully healed on endoscopy

Direct oral anticoagulants are contraindicated with mechanical heart valves and with moderate to severe mitral stenosis, where warfarin with an INR target set by the valve remains the standard. Advanced age, moderate renal impairment and high body weight are dose or agent selection issues, not absolute reasons to use warfarin. Source: Canadian Cardiovascular Society atrial fibrillation guidelines.

12. An 81-year-old woman weighing 58 kg has a serum creatinine of 140 micromol per litre and is starting apixaban for atrial fibrillation. What dose is appropriate?

1. Apixaban 5 mg twice daily, because only three criteria together justify a reduction
2. Apixaban 10 mg once daily, because once-daily dosing improves adherence in the elderly
3. Apixaban 2.5 mg twice daily, because at least two reduction criteria are present
4. Apixaban 5 mg once daily, because renal impairment halves the total daily exposure

The reduced dose applies when at least two of the following are present: age 80 years or more, body weight 60 kilograms or less, and serum creatinine 133 micromol per litre or more. This patient meets all three, so 2.5 mg twice daily is correct; apixaban is never given once daily for this indication. Source: Health Canada product monograph for apixaban.

13. Which administration instruction is specific to rivaroxaban when used at the treatment dose for atrial fibrillation?

1. Separate it from all antacids and multivitamin products by a minimum of four hours
2. Take it on an empty stomach at least one hour before any food or beverage of any kind
3. Take it with the evening meal, because food substantially increases absorption
4. Dissolve the tablet in water before swallowing to improve dispersion in the gut

The bioavailability of the higher rivaroxaban strengths is markedly increased by food, so the dose must be taken with a meal to achieve reliable anticoagulation. There is no requirement for an empty stomach, no need for a four-hour antacid gap, and routine dissolution is only used for patients unable to swallow. Source: Health Canada product monograph for rivaroxaban.

14. Which direct oral anticoagulant is the most dependent on renal elimination and therefore the least suitable when creatinine clearance falls markedly?

1. Dabigatran, of which the large majority of absorbed drug is cleared by the kidney
2. Apixaban, which relies on renal clearance for very nearly all of its total elimination
3. Edoxaban, which is eliminated almost entirely by biliary excretion of metabolites
4. Rivaroxaban, which undergoes no renal handling of either parent drug or metabolite

Dabigatran is the most renally cleared agent of the class, so declining clearance produces a disproportionate rise in exposure and bleeding risk. Apixaban is the least renally dependent, and both edoxaban and rivaroxaban have substantial non-renal elimination as well. Source: Health Canada product monographs for the direct oral anticoagulants.

15. What is the correct advice about dietary vitamin K for a patient established on warfarin?

1. Keep your intake of vitamin K rich foods consistent from week to week
2. Avoid all green leafy vegetables completely for as long as warfarin is continued
3. Eat a large serving of spinach on the day before each INR measurement
4. Take a daily vitamin K supplement to stabilise the INR within its target range

Warfarin is dosed against the patient's habitual vitamin K intake, so consistency, not avoidance, keeps the INR stable; sudden changes in either direction destabilise control. Complete avoidance removes a valuable food group and deliberate loading before a test distorts the result. Source: CPhA Therapeutic Choices, anticoagulation chapter.

16. Which mechanism best explains why fluconazole markedly increases the INR in a patient stabilised on warfarin?

1. It slows gastric emptying, so a larger fraction of each warfarin dose is absorbed
2. It displaces warfarin from albumin, permanently doubling the free drug concentration in plasma
3. It induces vitamin K epoxide reductase, increasing the sensitivity of the target enzyme
4. It inhibits CYP2C9, reducing the metabolism of the more potent S-warfarin enantiomer

S-warfarin is three to five times more potent than the R enantiomer and is metabolised principally by CYP2C9, so inhibition of that isoenzyme by azoles produces a large and clinically important rise in INR. Protein displacement alone is transient, and azoles do not induce the target reductase or meaningfully alter gastric emptying. Source: Health Canada product monograph for warfarin sodium.

17. A patient on warfarin for a mechanical mitral valve asks what INR range applies to him. What is the usual target?

1. An INR of 2.5 to 3.5, because a mitral prosthesis carries a higher thrombotic risk
2. An INR of 2.0 to 3.0, the same range used for atrial fibrillation and venous thrombosis
3. An INR of 1.5 to 2.0, because valve thrombosis is rare with modern prostheses
4. An INR of 3.5 to 4.5, because a prosthesis in the mitral position requires maximal anticoagulation

A mechanical prosthesis in the mitral position is more thrombogenic than one in the aortic position and is therefore anticoagulated to a higher range, commonly 2.5 to 3.5. The 2.0 to 3.0 range applies to atrial fibrillation and venous thromboembolism, and ranges above 3.5 add bleeding without benefit. Source: CPhA Therapeutic Choices, anticoagulation chapter.

18. A patient on warfarin has an INR of 6.2 with no bleeding. Which response is generally appropriate?

1. Continue the same dose, since the bleeding risk only becomes clinically important above an INR of 10
2. Give intravenous vitamin K 10 mg immediately to normalise the INR within an hour
3. Hold warfarin, recheck the INR, and consider low-dose oral vitamin K as directed
4. Administer fresh frozen plasma before any laboratory recheck is performed

With a supratherapeutic INR and no bleeding, withholding doses and rechecking is the foundation of management, with low-dose oral vitamin K considered according to the degree of elevation and the patient's risk. High-dose parenteral vitamin K and plasma are reserved for serious bleeding, and continuing unchanged ignores a real risk. Source: CPhA Therapeutic Choices, anticoagulation chapter.

19. Why can a proton pump inhibitor reduce the antiplatelet effect of clopidogrel in some patients?

1. Clopidogrel is a prodrug activated by CYP2C19, which certain proton pump inhibitors inhibit
2. Proton pump inhibitors raise gastric pH so clopidogrel is destroyed before absorption
3. Proton pump inhibitors bind clopidogrel within the gut lumen and form a complex that cannot be absorbed
4. Clopidogrel requires an acidic environment in the liver to reach its receptor target

Clopidogrel needs hepatic conversion by CYP2C19 to its active thiol metabolite, and inhibitors of that isoenzyme, most notably omeprazole and esomeprazole, reduce the formation of the active species. Pantoprazole has a weaker effect and is often preferred when acid suppression is needed. Source: Health Canada product monograph for clopidogrel.

20. A patient started on ticagrelor after a coronary stent reports mild breathlessness at rest that started a few days after beginning therapy. What is the most likely explanation?

1. Early stent thrombosis, requiring the patient to stop ticagrelor immediately
2. A recognised adverse effect of ticagrelor that is usually mild and often self-limiting
3. An allergic reaction to the tablet coating that mandates a switch to prasugrel
4. Fluid overload caused by the sodium content of the ticagrelor formulation, which requires a diuretic

Dyspnoea is a well described adverse effect of ticagrelor, thought to relate to adenosine, and it is typically mild, appears early and frequently resolves without stopping therapy, although new or severe breathlessness must be assessed. Stopping a P2Y12 inhibitor after stenting on this basis alone would expose the patient to stent thrombosis. Source: Health Canada product monograph for ticagrelor.

21. What maximum daily maintenance dose of acetylsalicylic acid is recommended with ticagrelor, and why?

1. Up to 325 mg daily, because a higher dose gives more complete platelet inhibition
2. Up to 100 mg daily, because higher doses reduce the benefit of ticagrelor
3. At least 650 mg daily, to compensate for the reversible binding of ticagrelor
4. No acetylsalicylic acid at all, because ticagrelor already blocks cyclooxygenase

Analysis of the pivotal trial showed reduced efficacy of ticagrelor when maintenance acetylsalicylic acid exceeded 100 mg daily, so the low dose is specified in the monograph. Ticagrelor blocks the P2Y12 receptor and does not inhibit cyclooxygenase, so acetylsalicylic acid remains part of dual therapy. Source: Health Canada product monograph for ticagrelor.

22. Which statement about grapefruit juice and statins is accurate?

1. It raises exposure to rosuvastatin and pravastatin, which are also CYP3A4 substrates
2. It raises exposure to simvastatin and lovastatin by inhibiting intestinal CYP3A4
3. It lowers the absorption of every statin by binding the drug in the intestinal lumen
4. It has no interaction with any statin because statins bypass first-pass metabolism

Furanocoumarins in grapefruit irreversibly inhibit intestinal CYP3A4, substantially increasing exposure to simvastatin and lovastatin and raising the risk of myopathy. Rosuvastatin and pravastatin are not meaningfully metabolised by CYP3A4 and are unaffected. Source: Health Canada product monographs for the statins.

23. A patient on atorvastatin reports diffuse muscle aching without weakness or dark urine. What is the most appropriate initial step?

1. Stop the statin permanently and record a statin allergy in the profile so it is never prescribed again
2. Assess the symptom pattern, review interacting drugs and measure creatine kinase if indicated
3. Double the dose, because muscle symptoms indicate inadequate hepatic uptake
4. Add coenzyme Q10 at high dose, which reliably abolishes statin muscle symptoms

Most muscle complaints on statins are not true myopathy, so a structured assessment, a search for interacting drugs and a creatine kinase measurement when symptoms are significant usually allow therapy to continue, often with a different statin or dose. Permanent labelling as an allergy is inaccurate, increasing the dose is unsafe, and coenzyme Q10 has not shown consistent benefit. Source: Canadian Cardiovascular Society dyslipidemia guidelines.

24. Which agent works by inhibiting the intestinal sterol transporter NPC1L1 and is commonly added when a statin alone does not reach the target?

1. Niacin, which reduces hepatic release of very low density lipoprotein
2. Fenofibrate, which activates peroxisome proliferator-activated receptor alpha
3. Ezetimibe, which reduces absorption of dietary and biliary cholesterol
4. Cholestyramine, which binds bile acids within the intestinal lumen directly

Ezetimibe blocks the Niemann-Pick C1-like 1 sterol transporter at the brush border, reducing cholesterol absorption and lowering low density lipoprotein when added to a statin. Fibrates act mainly on triglycerides, niacin has a different hepatic mechanism, and bile acid sequestrants bind bile acids rather than blocking a transporter. Source: Health Canada product monograph for ezetimibe.

25. Why is a daily nitrate-free interval required for a patient using transdermal nitroglycerin?

1. To allow hepatic regeneration of the enzyme that activates the nitrate
2. To allow the skin to recover, because continuous wear of the patch causes a chemical burn at the site
3. To reduce the cost of therapy by extending the life of each patch
4. To prevent the development of tolerance, which blunts the antianginal effect

Continuous nitrate exposure produces tolerance within about 24 hours, so a nitrate-free period of roughly 8 to 12 hours each day preserves efficacy. Patch removal is not about skin injury, cost or hepatic enzyme recovery. Source: CPhA Therapeutic Choices, ischemic heart disease chapter.

26. A man using sublingual nitroglycerin asks whether he may take sildenafil for erectile dysfunction. What is the correct response?

1. The combination is contraindicated because it can cause profound hypotension
2. The combination is safe provided the two products are separated by at least two hours
3. The combination is safe provided the nitroglycerin dose is halved before the sildenafil
4. The combination is allowed only with tadalafil, which has no nitrate interaction

Phosphodiesterase-5 inhibitors and nitrates both increase cyclic guanosine monophosphate, and their combination can produce severe, refractory hypotension; the contraindication applies to the whole class including tadalafil. Time separation and dose reduction do not make the combination acceptable. Source: Health Canada product monograph for sildenafil.

27. What instruction should a patient receive about the use of sublingual nitroglycerin spray during an episode of chest pain?

1. Sit down, use one spray, and if pain persists after five minutes call emergency services
2. Take three sprays in immediate succession, then wait fifteen minutes before calling for help
3. Swallow the spray with a full glass of water so that it is absorbed faster from the stomach
4. Use the spray only after walking for ten minutes to confirm the pain is cardiac

Sitting reduces the risk of syncope from nitrate-induced hypotension, and current advice is to call emergency services if pain persists after the first dose rather than waiting through several doses. Swallowing destroys the sublingual route and deliberately provoking pain is unsafe. Source: Canadian Cardiovascular Society and Heart and Stroke public guidance.

28. Which combination of findings would most strongly suggest digoxin toxicity in an older patient?

1. Muscle cramps, dark urine, myalgia and a marked rise in creatine kinase
2. Dry cough, ankle oedema, flushing and a headache that worsens on standing
3. Photosensitive rash, tinnitus, metallic taste and a progressive rise in the serum creatinine value
4. Nausea, visual disturbance with yellow-green tinge, confusion and bradyarrhythmia

The classic toxic syndrome combines gastrointestinal upset, chromatopsia, central nervous system effects and conduction disturbance, and it is precipitated by hypokalaemia, renal decline and interacting drugs. The other clusters describe dihydropyridine adverse effects, sulfonamide or antibiotic reactions and statin myopathy. Source: Health Canada product monograph for digoxin.

29. Why does amiodarone increase serum digoxin concentration?

1. It inhibits P-glycoprotein, reducing renal tubular and intestinal efflux of digoxin
2. It inhibits CYP3A4, which is the principal route by which digoxin is cleared from the body
3. It displaces digoxin from cardiac binding sites, raising the measured plasma level
4. It increases gastric acid secretion, converting more digoxin to an absorbable form

Digoxin is a P-glycoprotein substrate that undergoes very little cytochrome metabolism, so amiodarone raises its concentration by transporter inhibition, and an empirical dose reduction with concentration monitoring is standard. The other mechanisms do not describe digoxin handling. Source: Health Canada product monographs for digoxin and amiodarone.

30. Which electrolyte disturbance most increases the risk of digoxin toxicity at any given serum concentration?

1. Hypochloraemia, because chloride is required for renal secretion of digoxin
2. Hypernatraemia, because a high sodium load displaces digoxin from its plasma protein binding sites
3. Hypokalaemia, because potassium and digoxin compete at the sodium-potassium ATPase
4. Hyperphosphataemia, because phosphate binds digoxin in the intestinal lumen

Digoxin binds the sodium-potassium ATPase at a site that potassium also occupies, so a low potassium concentration increases binding and toxicity even when the measured digoxin level is within range. Diuretic-induced potassium loss is therefore a common precipitant. Source: Health Canada product monograph for digoxin.

31. Which adverse effect is most characteristic of high-dose intravenous furosemide given by rapid injection?

1. Pulmonary fibrosis presenting as a slowly progressive dry cough
2. Peripheral neuropathy presenting as glove and stocking numbness
3. Optic neuritis presenting as loss of red-green colour discrimination
4. Ototoxicity presenting as tinnitus or transient hearing loss

Loop diuretics are ototoxic, and the risk rises with high doses, rapid infusion rates, renal impairment and concurrent aminoglycosides, so slow administration is recommended. Neuropathy, optic neuritis and pulmonary fibrosis belong to other drug classes. Source: Health Canada product monograph for furosemide.

32. What is the best timing advice for a patient taking a once-daily dose of hydrochlorothiazide?

1. Alternate morning and evening dosing on successive days to reduce tolerance
2. Take it at bedtime so that the peak diuresis occurs while the patient is recumbent
3. Take it with the largest meal of the day to slow absorption and smooth the effect
4. Take it in the morning so that increased urination does not disturb sleep

Morning administration keeps the diuretic effect within waking hours and improves adherence by avoiding nocturia. Thiazide efficacy does not depend on recumbency, on meal size, or on alternating the time of day. Source: CPhA Therapeutic Choices, hypertension chapter.

33. Which metabolic effects are most typically associated with long-term thiazide therapy?

1. Hypocalcaemia, hyperchloraemia, a low uric acid and a rise in the serum bicarbonate
2. Hyperkalaemia, hypercalciuria, hypouricaemia and a marked fall in fasting blood glucose
3. Hypermagnesaemia, hyperphosphataemia, hypouricaemia and stable electrolytes overall
4. Hypokalaemia, hyponatraemia, hyperuricaemia and modest increases in blood glucose

Thiazides lower potassium and sodium, reduce urinary calcium excretion, raise uric acid by competing for tubular secretion, and can modestly worsen glycaemia and lipids. The alternative patterns describe potassium-sparing agents or do not correspond to thiazide pharmacology. Source: Health Canada product monograph for hydrochlorothiazide.

34. Which analgesic class should generally be avoided in a patient with advanced chronic kidney disease and why?

1. NSAIDs, because prostaglandin inhibition reduces renal perfusion and can precipitate injury
2. Acetaminophen, because its glucuronide metabolites accumulate in renal failure and injure the tubule
3. Topical capsaicin, because systemic absorption produces a dose-dependent fall in the filtration rate
4. Non-opioid antispasmodics, because they block tubular secretion of creatinine irreversibly

NSAIDs block the vasodilatory prostaglandins that maintain afferent arteriolar tone, so in a kidney already dependent on them they can precipitate acute injury, and they also raise potassium and blood pressure. Acetaminophen remains the preferred simple analgesic and topical capsaicin has negligible systemic exposure. Source: CPhA Therapeutic Choices, chronic kidney disease chapter.

35. Which combination is recommended for a patient with type 2 diabetes and albuminuric chronic kidney disease?

1. A renin-angiotensin blocker together with an SGLT2 inhibitor, titrated as tolerated
2. An ACE inhibitor together with an angiotensin receptor blocker, for maximal renin-angiotensin blockade
3. A loop diuretic together with a non-steroidal anti-inflammatory drug for control of the oedema
4. A calcium channel blocker together with an alpha blocker to protect the glomerulus

Renin-angiotensin blockade reduces intraglomerular pressure and albuminuria, and SGLT2 inhibition adds a further, largely independent slowing of kidney function decline. Combining an ACE inhibitor with an ARB increases harm without benefit, and the other pairings have no renoprotective evidence. Source: Diabetes Canada clinical practice guidelines.