Can I Take Vitamin B12 with Leqvio (Inclisiran)?

How Inclisiran (Leqvio) Works

Inclisiran is a first-in-class small interfering RNA (siRNA) that reduces low-density lipoprotein cholesterol (LDL-C) by silencing the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) inside hepatocytes. After subcutaneous injection, the drug is taken up by liver cells via GalNAc-receptor-mediated endocytosis and loaded into the RNA-induced silencing complex (RISC), where it degrades PCSK9 messenger RNA before the protein can be translated 1.

Hepatocyte-Specific Uptake

The GalNAc (N-acetylgalactosamine) conjugate on inclisiran binds asialoglycoprotein receptors expressed almost exclusively on hepatocytes. This design confines the drug's activity to the liver, limiting off-target tissue exposure. Inclisiran does not circulate systemically for extended periods. Plasma concentrations peak within hours of injection, then decline rapidly as hepatocytes internalize the compound 2.

PCSK9 Suppression and LDL Reduction

In the ORION-10 trial (N=1,561), inclisiran 284 mg reduced LDL-C by 52.3% from baseline at day 510 compared with placebo 1. The parallel ORION-11 trial (N=1,617) showed a 49.9% LDL-C reduction over the same timeframe. These reductions remained consistent across dosing intervals, with injections given only twice yearly after an initial loading dose at month 3.

Metabolism and Elimination

Inclisiran is not metabolized by cytochrome P450 enzymes. It does not inhibit or induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 3. This is the single most relevant pharmacokinetic fact for supplement interactions: because inclisiran bypasses the CYP system entirely, the standard mechanisms by which drugs and supplements interfere with each other simply do not apply.

How Vitamin B12 Works in the Body

Vitamin B12 (cobalamin) is a water-soluble vitamin absorbed in the terminal ileum through a process requiring intrinsic factor, a glycoprotein secreted by gastric parietal cells. Once absorbed, B12 circulates bound to transcobalamin II and is delivered to tissues where it acts as a cofactor for two enzymatic reactions: the conversion of methylmalonyl-CoA to succinyl-CoA (via methylmalonyl-CoA mutase) and the remethylation of homocysteine to methionine (via methionine synthase) 4.

Absorption and Transport

Oral B12 supplements (cyanocobalamin, methylcobalamin, or hydroxocobalamin) are absorbed by two routes. The intrinsic-factor-dependent pathway saturates at roughly 1.5 to 2 mcg per meal. A passive diffusion pathway absorbs approximately 1% of the oral dose regardless of intrinsic factor availability, which is why high-dose oral supplements (1,000 to 2,000 mcg) can still correct deficiency even without adequate intrinsic factor 5.

Why B12 Deficiency Matters for Cardiovascular Patients

B12 deficiency raises homocysteine levels. Elevated homocysteine has been associated with increased cardiovascular risk in observational studies, though intervention trials such as HOPE-2 showed that lowering homocysteine with B-vitamin supplementation reduced stroke risk by 25% (HR 0.75, 95% CI 0.59 to 0.97) but did not significantly reduce overall cardiovascular events 6. For patients already on inclisiran for ASCVD, maintaining adequate B12 is reasonable but should not be expected to produce additive LDL-lowering effects.

Why No Interaction Exists Between Inclisiran and Vitamin B12

The absence of interaction between these two agents is explained by three independent lines of evidence: non-overlapping pharmacokinetics, non-overlapping pharmacodynamics, and the absence of any signal in clinical trial safety databases.

No Pharmacokinetic Overlap

Inclisiran enters hepatocytes through receptor-mediated endocytosis and is processed intracellularly by the RISC pathway. It is not a substrate, inhibitor, or inducer of any CYP enzyme, drug transporter (P-glycoprotein, OATP, OCT), or conjugation pathway 3. Vitamin B12 is absorbed in the ileum, transported by transcobalamin, and used intracellularly as a cofactor. These pathways do not intersect at any point.

No Pharmacodynamic Overlap

Inclisiran silences PCSK9 mRNA. Vitamin B12 participates in one-carbon metabolism and mitochondrial function. There is no shared receptor, enzyme, signaling cascade, or physiological endpoint where one agent could amplify or attenuate the effect of the other.

No Signal in Clinical Data

The ORION clinical trial program enrolled over 3,600 patients across ORION-9, -10, and -11 1. Multivitamin and individual supplement use was not restricted. The FDA prescribing information for Leqvio lists no supplement interactions, and the Natural Medicines Comprehensive Database does not flag a B12-inclisiran interaction. The absence of a signal across thousands of patient-years of exposure is strong negative evidence.

The Metformin Connection: When B12 Monitoring Becomes Critical

The reason this question arises frequently is not because of inclisiran itself but because many patients on inclisiran also take metformin. Metformin reduces B12 absorption by interfering with the calcium-dependent intrinsic factor-B12 complex in the ileum 7.

Prevalence of B12 Deficiency on Metformin

A cross-sectional analysis of NHANES data found that metformin users had significantly lower serum B12 concentrations than nonusers. In the Diabetes Prevention Program Outcomes Study (DPPOS), 4.3% of the metformin group developed biochemical B12 deficiency (serum B12 <203 pg/mL) compared with 2.3% of the placebo group after a mean of 5 years 8. The American Diabetes Association (ADA) 2024 Standards of Care recommend periodic B12 monitoring in patients on long-term metformin, particularly those with anemia or peripheral neuropathy 9.

When All Three Are Used Together

A patient with type 2 diabetes, ASCVD, and an LDL-C above goal might be on metformin, inclisiran, and a B12 supplement simultaneously. In this scenario, the interaction concern is between metformin and B12, not between inclisiran and B12. Inclisiran does not worsen B12 absorption, alter B12 metabolism, or interfere with metformin's effect on B12 uptake.

Monitoring Recommendations

For patients on metformin and B12 supplements who are also receiving inclisiran, the following monitoring applies:

• Serum B12: check at baseline and annually while on metformin
• Methylmalonic acid (MMA): a more sensitive marker of tissue B12 deficiency; order if serum B12 is borderline (200 to 400 pg/mL)
• Complete blood count: macrocytic anemia (MCV >100 fL) may indicate functional B12 deficiency
• Homocysteine: elevated levels suggest inadequate B12 (or folate); may be relevant for ASCVD risk stratification

None of these markers are altered by inclisiran.

Dosing and Timing Considerations

Because no interaction exists, there is no need to separate the timing of vitamin B12 supplements from inclisiran injections.

Inclisiran Dosing Schedule

Inclisiran is administered as a 284 mg subcutaneous injection at month 0, month 3, and every 6 months thereafter. The injection is given by a healthcare provider. Patients do not self-inject.

B12 Supplement Dosing

Standard oral supplementation ranges from 500 to 2,000 mcg daily for maintenance and up to 2,000 mcg daily for correction of deficiency. Intramuscular B12 (1,000 mcg monthly) is used for patients with intrinsic factor deficiency or malabsorption 10.

Practical Guidance

Take your B12 supplement on your usual schedule regardless of when your inclisiran injection is given. No adjustment to either dose is necessary. If you are taking other medications that do interact with B12 absorption (proton pump inhibitors, H2 blockers, or metformin), discuss timing with your prescriber.

What About Other Supplements and Inclisiran?

The same pharmacokinetic logic that clears B12 applies broadly to most common supplements.

Low-Risk Supplements

Fish oil (omega-3 fatty acids), vitamin D, CoQ10, magnesium, and multivitamins have no known interaction with inclisiran. The siRNA mechanism is insulated from the metabolic pathways these supplements use.

Supplements That Warrant Caution

Red yeast rice contains monacolin K, which is chemically identical to lovastatin. If a patient is on inclisiran plus a statin, adding red yeast rice could produce additive statin exposure and increase the risk of myopathy. This is a statin-related concern, not an inclisiran-related one, but it matters for patients managing total cholesterol-lowering therapy.

General Rule

If a supplement does not affect hepatic PCSK9 expression, GalNAc receptor density, or RISC pathway function, it will not interact with inclisiran. No commercially available dietary supplement meets any of those criteria as of 2026.

Who Should Pay Attention to B12 Levels on Leqvio

Not every patient on inclisiran needs to worry about B12 status. The patients who should are those with independent risk factors for B12 deficiency.

High-Risk Groups

• Metformin users: as discussed, metformin impairs B12 absorption in a dose- and duration-dependent manner
• Patients over 65: gastric acid and intrinsic factor production decline with age, reducing B12 absorption. The Framingham Offspring Study found that 12% of adults over 65 had serum B12 below 258 pmol/L 11
• Patients on long-term proton pump inhibitors (PPIs): PPIs suppress gastric acid, which is needed to release protein-bound B12 from food. A nested case-control study (N=25,956 cases) found that PPI use for 2+ years was associated with a 65% increased risk of B12 deficiency (OR 1.65, 95% CI 1.58 to 1.73) 12
• Patients with prior gastric surgery: partial or total gastrectomy removes parietal cells that produce intrinsic factor
• Strict vegans: plant foods contain no bioavailable B12

When to Test

The Endocrine Society and ADA do not mandate universal B12 screening for all cardiovascular patients. Testing is appropriate when clinical suspicion arises (fatigue, paresthesias, macrocytosis) or when a patient belongs to a high-risk group.

Peripheral Neuropathy: Distinguishing B12 Deficiency from Statin Effects

Patients on inclisiran and a statin who develop new-onset tingling or numbness may wonder whether B12 deficiency or statin-associated peripheral neuropathy is the cause.

B12 Deficiency Neuropathy

B12-related neuropathy typically presents as symmetric distal paresthesias in a stocking-glove distribution, progressing to loss of vibration and proprioception. It results from demyelination in the posterior columns of the spinal cord and peripheral nerves. Serum B12 below 200 pg/mL with elevated MMA and homocysteine confirms the diagnosis 4.

Statin-Associated Neuropathy

A Danish population-based study (N=statins: 166,958; controls: 666,269) found a small but statistically significant increase in idiopathic peripheral neuropathy among statin users (RR 1.16, 95% CI 1.08 to 1.24), though the absolute risk was low 13. The mechanism is poorly understood and may relate to reduced coenzyme Q10 or altered nerve membrane cholesterol.

Diagnostic Approach

If neuropathy develops, check serum B12, MMA, and homocysteine before attributing symptoms to the statin. B12 deficiency is treatable and reversible if caught early. A trial of parenteral B12 with reassessment at 3 months is a reasonable first step before discontinuing any cholesterol-lowering therapy.

Clinical Bottom Line

Vitamin B12 and Leqvio (inclisiran) do not interact. No dose adjustment, timing separation, or additional monitoring is required solely because of their coadministration. If you take metformin, a PPI, or are over 65, check your B12 level annually regardless of whether you are on inclisiran. The 2024 ADA Standards of Care recommend periodic B12 assessment for patients on long-term metformin 9. Your prescriber can order a serum B12 and methylmalonic acid level at your next routine blood draw.