Which vitamin, when combined with HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, also known as statins, increases the risk of rhabdomyolysis?

Niacin Increases Rhabdomyolysis Risk When Combined with Statins

Niacin is the vitamin that increases the risk of rhabdomyolysis when combined with HMG-CoA reductase inhibitors (statins). 1

FDA-Approved Drug Label Warning

The FDA drug label for niacin explicitly states: "Caution should be used when prescribing niacin (≥1 gm/day) with statins as these drugs can increase risk of myopathy/rhabdomyolysis." 1 This warning appears prominently in the drug interactions section and is reinforced in the warnings and precautions section. 1

Clinical Guideline Evidence

Multiple diabetes and cardiovascular disease management guidelines consistently identify niacin as problematic when combined with statins:

• The 2003 HIV Medical Association guidelines note that "combining fibrate and statin increases the risk of rhabdomyolysis (use with caution and monitor for clinical evidence of myopathy)" and that "niacin may worsen insulin resistance." 2

• The 2012 American Diabetes Association guidelines acknowledge that "niacin is the most effective drug for raising HDL cholesterol" but warn that combination therapy with statin and niacin "is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis." 2

• The 2019-2025 American Diabetes Association Standards of Care consistently state: "Statin plus niacin combination therapy has not been shown to provide additional cardiovascular benefit above statin therapy alone, may increase the risk of stroke with additional side effects, and is generally not recommended." 2

Mechanism of Increased Risk

The pharmacodynamic interaction between niacin and statins creates additive myotoxicity. 3 Both agents independently affect muscle tissue, and when combined, the risk of muscle injury escalates from benign myalgias to potentially life-threatening rhabdomyolysis. 4, 3

Clinical Trial Evidence

The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides) randomized over 3,000 patients (approximately one-third with diabetes) to statin therapy plus extended-release niacin versus placebo. 2 The trial was halted early due to:

• Lack of efficacy on primary cardiovascular outcomes 2
• Possible increase in ischemic stroke in the combination therapy group 2

The HPS2-THRIVE trial enrolled 25,673 individuals with prior vascular disease randomized to receive extended-release niacin plus laropiprant versus placebo. 2 Results showed:

• No significant difference in coronary death, MI, stroke, or coronary revascularization (13.2% vs. 13.7%; rate ratio 0.96; P = 0.29) 2
• Increased incidence of new-onset diabetes (absolute excess 1.3 percentage points; P < 0.001) 2
• Increased serious adverse events affecting gastrointestinal, musculoskeletal, and skin systems 2

Why Not the Other Vitamins?

• Pyridoxine (Vitamin B6): No evidence links this vitamin to increased rhabdomyolysis risk with statins
• Riboflavin (Vitamin B2): No evidence links this vitamin to increased rhabdomyolysis risk with statins
• Thiamine (Vitamin B1): No evidence links this vitamin to increased rhabdomyolysis risk with statins

Clinical Implications

Do not combine niacin with statin therapy for the following reasons:

• No cardiovascular benefit demonstrated beyond statin monotherapy 2
• Increased risk of myopathy and rhabdomyolysis 1
• Possible increased stroke risk 2
• Worsening of glycemic control in diabetic patients 2
• Increased incidence of new-onset diabetes 2

If a patient requires additional lipid management beyond statin therapy, consider alternative agents such as ezetimibe, PCSK9 inhibitors, or bempedoic acid rather than niacin. 5