Lipid Luminations: Medications that Reduce Inflammation Also May Reduce Cardiovascular Disease

Along with lipid accumulation, inflammation plays a key role in the development of atherosclerosis.(1) Perhaps 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) inhibitors (statins) are effective in the prevention of atherosclerotic cardiovascular disease (ASCVD) because they significantly decrease low-density lipoprotein (LDL) particles and inflammation. In the cholesterol synthetic pathway, statins block the formation of mevalonate through the inhibition of HMG CoA reductase. However, there are multiple downstream products before the formation of cholesterol, and some of those — such as farnesyl pyrophosphate (FPP) and geranylgernayl pyrophosphate (GGPP) — may play essential roles in immune cell activation, cytokine production and other aspects of inflammation.(2) Therefore, by decreasing mevalonate, downstream products such as FPP and GGPP are decreased and their inflammatory potential reduced. Given that reducing inflammation may reduce ASCVD, let us review medications known to reduce inflammation and their potential effects in reducing ASCVD.

NSAIDs/COX-2 Inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are widely used in the treatment of inflammatory diseases such as rheumatoid arthritis and psoriasis among others. However, they have been associated with increased risks for ASCVD, possibly because of their effects on increasing blood pressure or decreasing renal function.(3) A recent meta-analysis demonstrated that increased risk was greatest during short-term use (8-30 days) and with a higher daily dose.(3) Therefore, NSAIDs and COX-2 inhibitors do not have a role in reducing ASCVD.

Aspirin

Aspirin irreversibly binds to cyclooxygenase-1, which reduces the formation of thromboxane A2, leading to decreased platelet aggregation and decreased ASCVD events.(4) In secondary prevention, low-dose aspirin (50-325 mg/d) is associated with a 21% decrease in nonfatal myocardial infarction (MI), nonfatal stroke and cardiovascular death. There is an increased risk of bleeding, but aspirin for secondary prevention is recommended for all patients.(5) However, the risks and benefits are not as universal in primary prevention. The United States Preventive Services Task Force reviewed the use of aspirin in primary prevention of cardiovascular disease and recommends use only in patients from 50 to 69 years of age with a 10-year risk ≥10% who do not have an increased risk for bleeding and are willing to take aspirin for at least 10 years.(6) Aspirin is a mainstay of ASCVD prevention and should be used in all patients in secondary prevention and in the appropriate patients for primary prevention.

Canakinumab

Canakinumab is a fully human monoclonal antibody that binds to human interleukin-1β (IL-1β) and prevents it from interacting with the interleukin-1 receptor, which leads to anti-inflammatory effects. (7) It is approved for the treatment of rare disorders, but a recent prospective, randomized trial — Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) — assessed its effects in reducing ASCVD.(8) The CANTOS study demonstrated in patients with a history of MI and a high-sensitivity C-reactive protein (hs-CRP) >2.0 mg/L that canakinumab had no effect on lipid levels, significantly reduced inflammatory biomarkers (hs-CRP by approximately 40% and IL-6 by approximately 35%), and significantly reduced the primary endpoint (nonfatal MI, nonfatal stroke or cardiovascular death) by 15% (p=0.021, 95% CI 0.74-0.98) for the 150 mg dose given subcutaneously every three months. However, there was an increased risk of death from infection or sepsis in the canakinumab arm versus placebo (0.31 events vs 0.18, p=0.02).(8) Also the price of one dose is estimated to be around $16,000, which may be cost-prohibitive.(9)

Methotrexate

Methotrexate inhibits dihydrofolate reductase, which interferes with DNA synthesis and cellular replication and, in turn, leads to a decrease in inflammation. It is approved for the treatment of some forms of cancer, rheumatoid arthritis and psoriasis.(10) Methotrexate use is associated with decreased amounts of IL-1β and IL-6.(11) A six-year study of 1,240 patients with rheumatoid arthritis taking a mean dose of 13 mg/ week of methotrexate demonstrated a 70% reduction in cardiovascular disease mortality.(12) A subsequent metaanalysis demonstrated a 21% lower risk for cardiovascular disease with an average methotrexate dose between 13-15 mg/week.(13) A large, prospective, randomized trial comparing methotrexate 15-20 mg/week versus placebo in patients with previous MI or multivessel coronary disease and either type 2 diabetes or metabolic syndrome has been completed to determine the effects on a primary endpoint of nonfatal MI, nonfatal stroke, cardiovascular death, and hospitalization for unstable angina leading to urgent revascularization.(14). In this trial, methotrexate did not reduce IL-1β, IL-6, or hs-CRP versus placebo and did not significantly reduce the primary endpoint (hazard ratio 0.96, CI 0.79-1.16, p=0.67). Methotrexate was associated with an increased risk of infection (p=0.02), leukopenia (p<0.001), gastrointestinal disorders (p=0.006), mouth sores (p=0.001), and elevated liver function tests (p=0.03).(14) Methotrexate did not demonstrate a benefit in ASCVD in this trial, however it may be due to the lower baseline hs-CRP levels of the participants (1.6 mg/L vs 4.2 mg/L in CANTOS).(14) Perhaps, a future study enrolling patients with more elevated levels of inflammation may produce different results.

Other Agents

Colchicine inhibits microtubule formation and may interfere with inflammasome, leading to decreased production of interleukin-1 beta (IL-1β).(15) A recent meta-analysis found that colchicine can reduce composite cardiovascular outcomes by 60%.(16) There are prospective trials under way to further evaluate this concept. Allopurinol inhibits xanthine oxidase, which will decrease the production of urate crystals. A study of allopurinol in chronic kidney disease demonstrated a lower risk of cardiovascular events in allopurinol versus the control group (HR 0.43; p=0.02; 95% CI 0.21-0.88).(17) This benefit may be because of a decrease in hs-CRP.(18) Further prospective, randomized controlled trials need to be conducted to validate this effect.

In summary, not all medications used to treat inflammation are beneficial to reduce ASCVD morbidity and mortality. Aspirin and canakinumab are the only entities proven effective through randomized, controlled clinical trials. Aspirin already is widely recommended, and it remains to be seen if canakinumab will be widely used for ASCVD. Some therapies, like NSAIDs and COX-2 inhibitors, have been proven to be harmful and should not be used. Lastly, there are older anti-inflammatory agents that are in various stages of large prospective clinical trials. It remains to be seen if they will be effective. If so, they may provide us with cost-effective alternatives to reduce inflammation toward the greater goal of reducing ASCVD.

Disclosure statement: Dr. Gupta has received honoraria from Amgen.