What are the recommendations for a patient with diabetes (diabetes mellitus) and hypertension being treated with pembrolizumab (pembrolizumab) and paclitaxel (paclitaxel)?

Management of Diabetes and Hypertension in Patients on Pembrolizumab and Paclitaxel

For a diabetic patient with hypertension receiving pembrolizumab and paclitaxel, initiate or optimize blood pressure control with an ACE inhibitor or ARB as first-line therapy, targeting <130/80 mmHg, while maintaining vigilant monitoring for pembrolizumab-induced diabetic ketoacidosis and hyperglycemia. 1

Blood Pressure Management

Target Blood Pressure

• Aim for blood pressure <130/80 mmHg if this can be safely achieved 1
• Blood pressure should be measured at every routine visit or at least every 6 months 1
• Confirm elevated readings on separate days before diagnosing hypertension 1

Pharmacological Treatment Strategy

For blood pressure 140/90 mmHg or higher:

• Start an ACE inhibitor or ARB immediately as first-line therapy, in addition to lifestyle modifications 1
• This recommendation is particularly strong given the cardiovascular and renal protective benefits in diabetic patients 1
• If one class is not tolerated, substitute with the other 1

For blood pressure 160/100 mmHg or higher:

• Initiate two antihypertensive drugs simultaneously or use a single-pill combination 1
• The second agent should be either a thiazide-like diuretic (chlorthalidone or indapamide preferred) or a dihydropyridine calcium channel blocker 1

For blood pressure 130-139/80-89 mmHg:

• Begin with lifestyle modifications for up to 3 months 1
• If targets are not achieved, add pharmacological therapy with an ACE inhibitor or ARB 1

Important Medication Considerations

• Never combine ACE inhibitors with ARBs - this combination increases adverse events without additional benefit 1
• Never combine ACE inhibitors or ARBs with direct renin inhibitors 1
• Multiple-drug therapy is typically required to achieve blood pressure targets in diabetic patients 1

Monitoring Requirements

• Monitor serum creatinine/eGFR and potassium levels within 3 months of starting ACE inhibitors, ARBs, or diuretics 1, 2
• If stable, continue monitoring every 6 months thereafter 1, 2
• This is critical given the risk of hyperkalemia, especially when combining these agents 1

Lifestyle Modifications

Implement the following non-pharmacological interventions concurrently: 1

• Reduce sodium intake to 1200-2300 mg/day 1, 2
• Engage in at least 150 minutes of moderate-intensity aerobic activity per week, distributed over at least 3 days with no more than 2 consecutive days without activity 1
• Achieve weight loss if overweight or obese 1
• Increase consumption of fresh fruits, vegetables, and low-fat dairy products 1, 2
• Limit alcohol to no more than 1 drink per day for women, 2 for men 1, 2

Critical Pembrolizumab-Specific Considerations

Immune-Related Diabetes Complications

Pembrolizumab can cause new-onset diabetes mellitus and diabetic ketoacidosis (DKA), even in patients with previously normal glucose levels. 3, 4

• Monitor for polyuria, polydipsia, and unexplained weight loss during pembrolizumab therapy 3, 4
• DKA can occur suddenly and present as severe metabolic acidosis with hyperglycemia 3, 4
• This is an immune-related adverse event that may require permanent insulin therapy 3, 4
• Diabetes autoantibodies are typically negative in immune checkpoint inhibitor-induced diabetes 4

Monitoring Strategy During Chemotherapy

• Check blood glucose levels regularly throughout pembrolizumab treatment 3, 4
• Maintain high clinical suspicion for DKA if the patient develops symptoms of hyperglycemia 3, 4
• Be aware that enfortumab vedotin (if used in combination regimens) can also cause hyperglycemia 5

Paclitaxel Premedication Considerations

Standard paclitaxel premedication includes dexamethasone 20 mg PO at 12 and 6 hours before infusion. 6

• In patients with advanced HIV disease receiving paclitaxel, reduce dexamethasone to 10 mg PO 6
• While the evidence provided focuses on HIV patients, clinicians should be aware that dexamethasone can significantly worsen glycemic control in diabetic patients
• Consider closer glucose monitoring on days when dexamethasone is administered

Resistant Hypertension Management

If blood pressure remains uncontrolled on three antihypertensive medications (including a diuretic):

• Consider adding a mineralocorticoid receptor antagonist 1
• This requires even more vigilant monitoring of potassium levels given the increased hyperkalemia risk when combined with ACE inhibitors or ARBs 1
• Refer to a hypertension specialist if targets still cannot be achieved 1

Common Pitfalls to Avoid

• Do not delay pharmacological therapy in patients with blood pressure ≥140/90 mmHg - prompt initiation is essential 1
• Do not overlook the possibility of immune checkpoint inhibitor-induced diabetes - this can occur even in patients with previously well-controlled diabetes 3, 4
• Do not use beta-blockers as first-line therapy in diabetic patients unless specifically indicated for other conditions, as they can mask hypoglycemia symptoms and worsen metabolic parameters 7, 8
• Do not use thiazide diuretics as monotherapy - while they reduce cardiovascular events, they should be added to ACE inhibitors/ARBs rather than used alone 1