Leqvio and Bupropion Interaction: What Patients and Clinicians Need to Know

Does Inclisiran Interact with Bupropion?

Inclisiran (Leqvio) does not interact with bupropion through a shared metabolic pathway. Inclisiran is a small interfering RNA (siRNA) molecule that targets PCSK9 mRNA in hepatocytes. It is not a substrate, inhibitor, or inducer of any cytochrome P450 enzyme, P-glycoprotein (P-gp), or organic anion transporter [1]. Bupropion inhibits CYP2D6 and is itself metabolized by CYP2B6. Because these two molecules do not share a common enzymatic route, co-administration does not alter the plasma exposure of either drug.

The relevant clinical question shifts, then, from "does inclisiran interact with bupropion" to "does bupropion change the risk profile of other drugs this patient takes alongside inclisiran."

How Inclisiran Is Cleared

Inclisiran reaches the liver via GalNAc-conjugate-mediated uptake through the asialoglycoprotein receptor (ASGPR) on hepatocytes [2]. Once inside the cell, it is incorporated into the RNA-induced silencing complex (RISC) and degrades PCSK9 mRNA. Systemic plasma half-life is approximately 9 hours, but the intracellular duration of action extends 6 months, which explains the twice-yearly dosing schedule [1].

Excretion is predominantly renal, accounting for roughly 16% of the administered dose. The remainder is degraded intracellularly by endogenous nucleases. No hepatic oxidative metabolism occurs, making CYP inhibitors and inducers irrelevant to inclisiran pharmacokinetics [1].

How Bupropion Is Metabolized

Bupropion is oxidized primarily by CYP2B6 to its main active metabolite, hydroxybupropion [3]. Hydroxybupropion reaches plasma concentrations three to five times higher than the parent compound and contributes substantially to both therapeutic effect and seizure risk [3].

Bupropion and hydroxybupropion are potent inhibitors of CYP2D6. This inhibition is clinically significant when patients are co-prescribed CYP2D6-sensitive substrates such as metoprolol, codeine, tamoxifen, tricyclic antidepressants, or certain antipsychotics [4]. A patient taking inclisiran for ASCVD who is also prescribed metoprolol (a very common combination) should have metoprolol's dose reviewed when bupropion is started, because bupropion can raise metoprolol exposure by two- to five-fold [4].

Pharmacodynamic Considerations: Seizure Risk

Bupropion lowers the seizure threshold in a dose-dependent manner [5]. The incidence of seizures with bupropion immediate-release at doses up to 450 mg/day is approximately 0.4%, rising sharply above that dose [5]. Sustained-release (SR) and extended-release (XL) formulations carry a lower seizure incidence of approximately 0.1% at recommended doses because peak plasma concentrations are attenuated [5].

Inclisiran itself has no known central nervous system activity and does not lower the seizure threshold. There is no pharmacodynamic seizure interaction between the two drugs.

When Seizure Risk Becomes Relevant

Clinicians should still map the patient's full medication list before co-prescribing. Patients with ASCVD (the indication for inclisiran) frequently take multiple drugs. If bupropion is added to a regimen that already includes tramadol, theophylline, systemic corticosteroids, or antipsychotics, seizure risk compounds. Inclisiran does not contribute to that risk, but the cardiovascular-focused prescriber should flag it.

The FDA label for bupropion (Wellbutrin XL) states: "The risk of seizure is dose-related. The dose should not exceed 450 mg/day. Abrupt discontinuation of alcohol or sedatives in patients currently using these substances may also increase seizure risk" [5].

Electrocardiographic and Cardiac Effects

Bupropion can cause mild increases in heart rate and blood pressure at standard doses [6]. In patients with established ASCVD (the population most likely to receive inclisiran), blood pressure elevation warrants attention. ORION-10 (N=1,561), a placebo-controlled phase 3 trial in patients with ASCVD, showed inclisiran produced a 52.3% time-averaged reduction in LDL-C at 17 months with no clinically meaningful change in heart rate or blood pressure [7]. Adding bupropion does not alter inclisiran's cardiovascular pharmacology, but the prescriber should reassess blood pressure targets when bupropion is started.

Inclisiran Efficacy Data: Context for the Combination

Understanding what inclisiran contributes to the treatment picture helps contextualize why maintaining the dosing schedule matters regardless of other psychiatric or smoking-cessation pharmacotherapy.

ORION Trial Program

The ORION program provided the key evidence base for inclisiran's approval. ORION-9 (N=482) enrolled patients with heterozygous familial hypercholesterolemia (HeFH); inclisiran 284 mg produced a 47.9% placebo-corrected reduction in LDL-C at Day 510 (P<0.0001) [8]. ORION-10 (N=1,561) enrolled patients with ASCVD and showed a 52.3% time-averaged LDL-C reduction [7]. ORION-11 (N=1,617) enrolled a mixed HeFH and high cardiovascular-risk population and demonstrated a 49.9% placebo-corrected LDL-C reduction at Day 510 (P<0.0001) [9].

Across all three trials, injection-site reactions were the most common adverse event (2.6% inclisiran vs. 1.8% placebo) [9]. No drug interaction signals were identified in any of the ORION trials for any co-administered medication.

VICTORION-2 PREVENT

The large cardiovascular outcomes trial VICTORION-2 PREVENT (NCT05030428), ongoing at the time of writing, is enrolling patients with established atherosclerotic cardiovascular disease to assess whether inclisiran reduces major adverse cardiovascular events (MACE) beyond LDL-C lowering [10]. Results from this trial will help determine whether inclisiran's biochemical effect translates directly to outcomes reduction in a real-world, polypharmacy population.

Bupropion in the Cardiovascular Patient: Clinical Context

Bupropion is prescribed to this patient population for two main reasons: smoking cessation and depression.

Smoking Cessation

Smoking is an independent ASCVD risk factor. The 2023 ACC/AHA guidelines on chronic coronary disease recommend smoking cessation counseling and pharmacotherapy as a Class I intervention [11]. Bupropion SR 150 mg twice daily is an FDA-approved pharmacotherapy for smoking cessation and remains a reasonable choice when varenicline is contraindicated or not tolerated [5].

Patients receiving inclisiran for ASCVD and bupropion for smoking cessation represent a clinically coherent combination. No dose adjustment of either drug is required based on their interaction profile.

Depression Screening in ASCVD

Depression affects 20 to 30% of patients after acute coronary syndrome [12]. The 2024 AHA Science Advisory on mental health and cardiovascular disease emphasizes that untreated depression worsens cardiovascular outcomes and that antidepressant treatment, including bupropion, should not be withheld out of unfounded cardiovascular concern [12]. Inclisiran's twice-yearly dosing schedule may actually support adherence in depressed patients who struggle with daily pill burdens.

CYP2D6 Inhibition by Bupropion: Downstream Impact on the Cardiology Medication List

This section is the most actionable for clinicians treating ASCVD patients.

When bupropion is added to an established cardiovascular regimen, CYP2D6 inhibition can alter the exposure of several co-medications. Inclisiran is unaffected. But the drugs listed below may need dose review.

Beta-Blockers

Metoprolol is extensively metabolized by CYP2D6. Adding bupropion can raise metoprolol plasma concentrations two- to five-fold, increasing the risk of bradycardia, hypotension, and fatigue [4]. Carvedilol is similarly affected. Atenolol, which is renally cleared, is unaffected by CYP2D6 inhibition and may be a preferable alternative in this setting [4].

Antiarrhythmics

Flecainide and propafenone are CYP2D6 substrates [4]. Adding bupropion to either agent can narrow the therapeutic window. An electrocardiogram within two to four weeks of starting bupropion is reasonable if the patient is on either antiarrhythmic.

Antiplatelet Agents

Clopidogrel bioactivation depends partly on CYP2B6 and CYP3A4, not CYP2D6, so bupropion's CYP2D6 inhibition does not substantially affect clopidogrel activation [4]. Prasugrel and ticagrelor are also unaffected by CYP2D6 status.

Opioids

Codeine requires CYP2D6-mediated conversion to morphine for analgesic effect. In patients receiving bupropion, this conversion is impaired, reducing codeine analgesia. Tramadol's conversion to the active O-desmethyltramadol metabolite is similarly reduced. Both effects compound with bupropion's independent seizure-lowering action if tramadol is used [4].

The table below summarizes CYP2D6-substrate medications commonly used in ASCVD patients and their expected interaction with bupropion. Inclisiran is included for reference.

| Drug | CYP2D6 substrate? | Expected change with bupropion co-administration | |---|---|---| | Inclisiran (Leqvio) | No | No change | | Metoprolol | Yes (extensive) | AUC increases 2 to 5x; monitor heart rate | | Carvedilol | Yes | Exposure increases; titrate carefully | | Atenolol | No | No change | | Flecainide | Yes | Exposure increases; ECG monitoring advised | | Propafenone | Yes | Exposure increases; ECG monitoring advised | | Codeine | Yes (prodrug) | Reduced activation; analgesia decreases | | Tramadol | Yes (prodrug) | Reduced activation; seizure risk may increase | | Clopidogrel | No (CYP2B6/3A4) | No clinically significant change |

FDA Labeling Summary for Both Drugs

Inclisiran (Leqvio) FDA Label

The FDA approved inclisiran in December 2021 for adults with HeFH or established ASCVD who require additional lowering of LDL-C. The prescribing information contains no drug interaction warnings related to CYP enzymes, P-gp, or drug transporters, because inclisiran is not a substrate or modulator of any of these systems [1]. The label lists injection-site reactions and nasopharyngitis as the most frequently reported adverse events. No dose adjustments are specified for renal impairment above a GFR of 15 mL/min/1.73 m² or for hepatic impairment [1].

Bupropion (Wellbutrin XL, Zyban) FDA Label

The FDA-approved prescribing information for bupropion identifies CYP2D6 inhibition as a clinically relevant interaction mechanism affecting multiple drug classes [5]. The label specifies that bupropion and its metabolites inhibit CYP2D6 in vitro and in vivo. Maximum daily dose is 450 mg for the IR formulation and 300 mg for XL and SR formulations. The label warns against use in patients with a seizure disorder, eating disorder, or those undergoing abrupt withdrawal from alcohol or benzodiazepines [5].

Monitoring and Patient Counseling Protocol

Before Starting Bupropion in an Inclisiran Patient

Review the complete medication list for CYP2D6 substrates. Pay attention to beta-blockers, antiarrhythmics, and any opioid analgesics. Obtain a baseline blood pressure reading, because bupropion can raise systolic BP by 2 to 4 mmHg at standard doses [6]. Screen for prior seizure history, eating disorders, and current alcohol use.

After Starting Bupropion

Check blood pressure at the two-week and six-week visits. If the patient is on metoprolol or carvedilol, ask about symptoms of bradycardia or dizziness at the first follow-up. No change to inclisiran dosing schedule is needed; continue the every-six-month injection as planned [1].

Patient Counseling Points

Tell patients that Leqvio and bupropion do not directly interact. Explain that bupropion may affect how other heart medications work, so full medication disclosure is essential. Instruct patients to report seizures, syncope, or new neurological symptoms immediately. Remind patients that missing inclisiran injections allows LDL-C to rebound; the twice-yearly schedule should be protected even during psychiatric medication adjustments.

Special Populations

Renal Impairment

Inclisiran has been studied in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²). Exposure increased approximately 1.5-fold compared to normal renal function, but no dose adjustment is recommended [1]. Bupropion metabolite accumulation also increases in severe renal impairment, elevating seizure risk [5]. Patients with CKD stage 4 or 5 receiving both drugs need closer monitoring for bupropion toxicity.

Hepatic Impairment

Inclisiran pharmacokinetics are not meaningfully affected by hepatic impairment because uptake occurs via hepatocyte surface receptors and intracellular processing rather than oxidative metabolism [1]. Bupropion exposure increases substantially in moderate-to-severe hepatic impairment; the maximum dose should be reduced to 75 mg daily (IR) or 100 mg daily (SR) in Child-Pugh B or C [5].

Older Adults

Adults aged 65 and older account for a large share of the ASCVD population receiving inclisiran. Bupropion's seizure risk is heightened in this group due to age-related pharmacokinetic changes and polypharmacy. Starting at the lowest effective dose (150 mg XL) and titrating slowly is appropriate [5].

Summary of Interaction Severity Rating

Across standard drug interaction databases, the inclisiran-bupropion pair receives either a "no known interaction" or "minimal" rating. This reflects the fundamental difference in their metabolic pathways. The clinical burden of the combination comes from bupropion's effects on the broader medication list, not from any direct inclisiran-bupropion interplay.

Clinicians should treat this as a "B-level" interaction workup: no interaction between the named pair, but mandatory audit of all CYP2D6-sensitive co-medications before bupropion is started.