Table 2.
Management considerations for cardiovascular and metabolic complications in Cushing syndrome
| Complication | Agent | Considerations | Drug-drug interactionsa |
|---|---|---|---|
| DM | Metformin | First-line agent in all patients unless contraindicated | Levoketoconazole increases levels of metformin [27] |
| Beneficial in insulin resistant states [47, 49, 50, 55] | - Monitor | ||
| SGLT-2 inhibitors | Demonstrated CV benefit for DM2 patients with atherosclerotic CV disease or kidney disease [44, 47, 49, 50, 55] | ||
| Risk of genitourinary infections might be higher in CS | |||
| Risk of fractures | |||
| GLP-1 agonist | Demonstrated CV benefit for DM2 patients with atherosclerotic CV disease | ||
| May be beneficial in CS given impaired insulin secretion/incretin effect induced by glucocorticoids [48, 49, 55] | |||
| DPP4 inhibitors | May be beneficial in CS given impaired insulin secretion/incretin effect induced by glucocorticoids [48, 49, 55] | Ketoconazole may increase levels of saxagliptin [54] | |
| - Monitor | |||
| Sulfonylureas | May be less effective in CS | Mifepristone may increase levels of sulfonylureas [53] - Monitor |
|
| Thiazolinediones | Cause fluid retention and contraindicated in heart failure | Ketoconazole increases levels of pioglitazone [54] | |
| Side effects may outweigh insulin-sensitizing benefit | - Monitor | ||
| Insulin | Use for severe hyperglycemia and when rapid reduction of blood glucose is necessary | ||
| -Monitor hypertension | Mineralocorticoid | Block effects of cortisol and cortisol/aldosterone precursors at MR receptor | Ketoconazole increases levels of eplerenone [54] |
| Receptor blockers | Effective for hypokalemia, edema, and hypertension in CS and during treatment with mifepristone, metyrapone, and osilodrostat | - Contraindicated | |
| Additional cardiovascular benefits [44, 47] | Mifepristone increases levels of eplerenone [52] | ||
| - Avoid | |||
| ACE inhibitors/ARBs | Target activated RAAS system in CS | Ketoconazole increases levels of losartan [54] | |
| Reduce risk of CV events in patients with DM and atherosclerotic disease [44] | - Monitor | ||
| Potential benefit for hypokalemia | Mifepristone increases levels of losartan [52] | ||
| Thiazide diuretics | Reduce risk of CV events in patients with DM [44] | - Monitor | |
| May worsen hypokalemia | |||
| Loop diuretics | Beneficial in edematous states May worsen hypokalemia |
||
| Dihydropyridine calcium channel blockers | Reduce risk of CV events in patients with DM | Ketoconazole increases levels of nifedipine [28] | |
|
- Consider therapy modification |
|||
| Mifepristone may increase levels of carvedilol [52] | |||
| - Monitor | |||
| Ketoconazole increases levels of amlodipine [28] | |||
| β-Blockers | May be used for patients with previous MI, active angina, or heart failure | Osilodrostat may increase levels of carvedilol and propranolol [39] | |
| Hyperlipidemia | Statins | First-line in all patients with DM and atherosclerotic disease | Ketoconazole and levoketoconazole increase levels of simvastatin and lovastatin [27, 54] |
| For patients with DM but without established atherosclerotic disease, use based on ADA guidelines [44] | - Contraindicated | ||
| Ketoconazole and Levoketoconazole increase levels of atorvastatin [27, 28] | |||
| - Monitor | |||
| Mifepristone increases levels of simvastatin and lovastatin [53] | |||
| - Contraindicated | |||
| Osilodrostat increases level of simvastatin [51] | |||
| - Monitor | |||
| Mifepristone increases level of atorvastatin [52] | |||
| - Monitor | |||
| Ezetimibe | Add-on therapy to maximally tolerated statin in patients with very high CV risk [44] | ||
| PCSK9 inhibitors | Add-on therapy to maximally tolerated statin in patients with very high CV risk [44] | ||
| Antithrombotic therapy | Aspirin (or clopidogrel if allergy to aspirin) | Secondary prevention in patients with DM and atherosclerotic CV disease [44] Primary prevention in patients with DM who are at increased CV risk (after risk-and-benefit discussion) [44] |
Ketoconazole decreases effects of clopidogrel [54]; consider alternative |
| Hypokalemia | Potassium replacement | Oral in most cases, intravenous in severe cases | |
| Mineralocorticoid | Block effects of cortisol and cortisol/aldosterone precursors at MR receptor | Ketoconazole increases levels of eplerenone [54] | |
| Receptor blockers | Effective for hypokalemia in CS and during treatment with mifepristone, metyrapone, and osilodrostat | - Contraindicated | |
| Mifepristone increases levels of eplerenone [52] | |||
| - Avoid | |||
| ACE inhibitors/ARBS | Potential benefit for hypokalemia | Ketoconazole increases level of losartan [54] | |
| - Monitor | |||
| Mifepristone increases levels of losartan [52] | |||
| - Monitor | |||
| Screening for CV disease | Multidisciplinary evaluation in conjunction with PCP, cardiology and preoperative medicine | ||
| History, symptoms (eg, dyspnea, chest pain, edema), physical exam | |||
| Resting EKG preoperatively; additional CV testing and imaging may be needed based on clinical evaluation | |||
| CV risk assessment using established tools (eg, revised cardiac risk index, American College of Surgeons surgical risk calculator) prior to surgery | |||
| Referral to cardiology for established CV disease and/or if CV disease is highly suspected |
Abbreviations: ACE, angiotensin-converting enzyme; ADA, American Diabetes Association; ARB, angiotensin II receptor blocker; CS, Cushing syndrome; CV, cardiovascular; DM, diabetes mellitus; DM2, type 2 diabetes mellitus; EKG, electrocardiogram; GLP-1, glucagon-like peptide 1; MI, myocardial infarction; MR, mineralocorticoid receptor; PCP, primary care provider; RAAS, renin-angiotensin-aldosterone system; SGLT-2, sodium-glucose cotransporter 2.
a Summary of major drug-drug interactions.