Is diltiazem safe for patients with chronic kidney disease, including those with an estimated glomerular filtration rate less than 30 mL/min/1.73 m² or on dialysis, and are any dose adjustments or monitoring required?

Diltiazem Safety in Chronic Kidney Disease

Diltiazem is safe and does not require dose adjustment in patients with chronic kidney disease, including those with eGFR <30 mL/min/1.73 m² or on dialysis, because it is extensively metabolized by the liver rather than excreted by the kidneys. 1, 2

Pharmacokinetic Profile in Severe Renal Impairment

• Diltiazem maintains a normal pharmacokinetic profile (peak plasma concentration, half-life, and urinary excretion) even in patients with severe renal failure (GFR 0.03–0.87 mL/s/1.73 m²), because it undergoes hepatic metabolism rather than renal elimination. 2
• The main metabolite, desacetyldiltiazem, is also metabolized rather than renally excreted, eliminating concerns about toxic accumulation in kidney disease. 2
• The FDA label confirms that diltiazem is extensively metabolized by the liver and excreted by both kidneys and bile, but emphasizes monitoring hepatic function rather than mandating renal dose adjustments. 1

Dosing in Dialysis Patients

• Sustained-release diltiazem 240 mg/day (120 mg twice daily) is the optimal dose for hemodialysis patients with coronary artery disease, providing superior efficacy in reducing both symptomatic and silent myocardial ischemia compared to lower doses. 3, 4
• Lower doses (120–180 mg/day) reduce symptomatic ischemic episodes but fail to adequately control silent ischemia, which is prevalent in dialysis patients. 3, 4
• The sustained-release formulation (120 mg twice daily) offers better tolerability during hemodialysis sessions compared to immediate-release formulations (60 mg four times daily), despite equivalent efficacy. 3, 4

Monitoring Requirements

• Monitor hepatic function at regular intervals during prolonged diltiazem therapy, as the drug is extensively metabolized by the liver; renal function monitoring is recommended but does not necessitate dose adjustment. 1
• Check blood pressure, heart rate, and ECG periodically, particularly in dialysis patients who may experience hemodynamic changes during treatment. 3
• No specific frequency of monitoring is mandated for renal function, but the FDA label recommends general laboratory surveillance of both renal and hepatic parameters. 1

Potential Renal Benefits

• In hypertensive patients with baseline eGFR ≤80 mL/min/1.73 m², diltiazem therapy improved glomerular filtration rate by 48% and effective renal plasma flow by 36%, likely through attenuation of intrarenal angiotensin II or norepinephrine effects. 5
• Diltiazem reduces renal vascular resistance while maintaining glomerular filtration rate and renal plasma flow in most hypertensive patients, suggesting a renoprotective hemodynamic profile. 5

Critical Drug Interactions in CKD

• Concomitant use of diltiazem with direct oral anticoagulants (DOACs) increases bleeding risk in patients with atrial fibrillation, regardless of kidney function (adjusted HR 1.56 for any bleeding, 1.84 for major bleeding), because diltiazem is a moderate CYP3A4/P-glycoprotein inhibitor. 6
• The increased bleeding risk with diltiazem plus DOACs is consistent in both CKD (eGFR <60 mL/min/1.73 m²) and non-CKD subgroups, with no significant interaction by renal function. 6
• When diltiazem is prescribed to DOAC users, close monitoring for bleeding signs is mandatory, and the combination should be used only when benefit clearly outweighs risk. 6
• Diltiazem increases midazolam and triazolam exposure 3- to 4-fold and prolongs their half-lives 1.5- to 2.5-fold through CYP3A4 inhibition; this effect is amplified in patients with renal and/or hepatic impairment, requiring dose adjustment of these benzodiazepines. 1
• Concomitant beta-blockers or digitalis may produce additive effects on AV conduction; careful titration is warranted, particularly in patients with left ventricular dysfunction or conduction abnormalities. 1

Common Pitfalls to Avoid

• Do not reduce diltiazem doses solely because of low eGFR; underdosing is common in dialysis patients due to unfounded concerns about adverse effects, resulting in inadequate control of myocardial ischemia. 3, 4
• Do not use immediate-release diltiazem four times daily in dialysis patients when sustained-release formulations are available, as the latter provide equivalent efficacy with better tolerability during hemodialysis. 3, 4
• Do not overlook hepatic function monitoring; although renal impairment does not alter diltiazem pharmacokinetics, hepatic dysfunction can lead to drug accumulation and toxicity. 1
• Do not combine diltiazem with DOACs without implementing a bleeding surveillance plan, as the interaction is pharmacokinetic and independent of renal function. 6