Practical Pearls: Top 10 Ways to Reduce Inflammation

Inflammation is a dynamic process with many interconnected signaling pathways involving multiple classes of cells by which the human body responds to pathogen exposure and/or tissue damage, playing a central role in all stages of atherosclerosis. (1) Cholesterol crystals directly activate nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and interleukin 1 beta (IL-1β) production. Therefore, cholesterol lowering, per se, has an anti-inflammatory effect.(2) The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has proven that blocking IL-1β signaling with canakinumab decreases cardiovascular (CV) events by ~15% without impacting lipid levels.(3) However, because of its very high cost, canakinumab is unlikely to be approved for CV risk reduction in the foreseeable future. The following are top 10 practical approaches to lower systemic inflammation — approaches that either reduce or may reduce CV risk. It needs to be kept in mind that, while those strategies are or may be beneficial, it is unclear how much of that benefit depends on the anti-inflammatory effect versus other mechanisms of action.

1. Diet — Western dietary pattern (high in red meat, full-fat dairy and refined carbohydrates) is pro-inflammatory, while healthy patterns such as low-fat, plant-based and Mediterranean diets are antiinflammatory. There is a proven CV benefit to following a Mediterranean diet, which is associated with highsensitivity C-reactive protein (hs-CRP) lowering in patients at risk for heart disease.(4,5) Moreover, weight loss associated with reduced energy intake leads to a reduction of inflammatory markers.(6)
2. Physical activity — Sedentary lifestyle is pro-inflammatory, while increased physical activity reduces inflammatory markers. Benefits of physical activity are at least partially caused by the release of several antiinflammatory cytokines from skeletal muscles. Moreover, even without weight loss, physical activity leads to a decrease in the size of visceral fat, which is a known producer of proinflammatory cytokines. Numerous studies have associated increased physical activity with longevity and decreased risk of cardiometabolic disorders.(6)
3. Probiotics — Emerging evidence links changes in gut microbiome with increased CV risk, possibly through the increased risk of obesity and systemic inflammation, raising the hypothesis that probiotics may decrease inflammation and thus, decrease CV risk.(7) Several probiotic strains, most notably L. reuteri NCIMB 30242, reduce hs-CRP and fibrinogen and directly lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels. (8) More trials are needed to fully determine anti-inflammatory effects of probiotics and their potential impact on CV outcomes Curcumin — Supplementation with this natural product derived from turmeric is associated with variably decreased levels of circulating hs-CRP and other inflammatory markers. This variability depends on the preparations used and the duration of supplementation. Its exact mechanism of action is unknown. More trials are needed to fully determine its anti-inflammatory effects and any potential impact on CV outcomes.(9)
4. Omega-3-polyunsaturated fatty acids (PUFAs) — While both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease triglycerides, DHA may increase LDL-C levels. However, they both decrease systemic inflammation. A recent meta-analysis of available trials suggests a modest 8% reduction in cardiac death associated with omega-3 supplementation.(10) In the Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT), administration of ~4 g daily of pure EPA over a median of 4.9 years to both primary and secondary prevention patients with LDL-C < 100 mg/dL and triglycerides 135 to 499 mg/dL lead to a 25% reduction in major adverse cardiovascular events.(11) Those beneficial effects can be at least partially accounted for by the anti-inflammatory effects of omega-3 PUFAs.
5. Statins — As demonstrated in Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), statins decrease CV events and allcause mortality, even in patients with low levels of LDL-C, when they have high levels of hs-CRP indicative of systemic inflammation.(12) On top of their well-known LDL-lowering effects, statins have demonstrated “pleiotropic effects” that include effects on multiple pathways associated with the lowering of inflammatory markers.(1,2)
6. Aspirin and other antiplatelet agents — While the benefits of aspirin mostly are attributed to the anti-platelet — and, thus, antithrombotic activity — the highest reduction in CV risk is achieved in patients with high hs-CRP levels, regardless of the degree of anti-platelet effects, indicating its potential value in patients with evidence of inflammation. (13) However, other nonsteroidal anti-inflammatory drugs (NSAIDs) increase cardiovascular risk despite efficiently decreasing inflammation. On the other hand, antiplatelet agents clopidogrel and prasugrel are able to lower hs-CRP and other inflammatory markers without affecting cyclooxygenase activity.(1,2)
7. Non-Statins — Effects of ezetimibe on inflammation, either alone or in combination with statins, are modest and likely directly stem from the degree of LDL-C lowering.(14) There also appears to be a beneficial effect of fibrates on inflammatory markers, especially in diabetic patients, possibly mediated downstream of peroxisome proliferator-activated receptor (PPAR).(15) Similarly, niacin appears to decrease hs-CRP levels in patients after a recent non-ST-elevation myocardial infarction (NSTEMI).(16) Surprisingly, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors do not lower hs-CRP levels based on metaanalysis of published trials.(17)
8. Angiotensin II receptor blockers (ARB) — Hypertension is a wellestablished CV risk factor. It can be treated by many agents, among them the renin–angiotensin–aldosterone axis blockade. While angiotensin-converting enzyme (ACE) inhibitors do not affect inflammation, despite their known CV benefits, ARBs appear to lower circulating inflammatory markers by blocking the angiotensin 1 receptor and, thus, may provide additional benefits.(18)

1. Metformin, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) — Type 2 diabetes is considered a coronary artery disease equivalent and is associated with inflammation. Emerging evidence indicates that the choice of antidiabetic agent matters, especially in patients at high CV risk. Among its many effects, metformin lowers hs-CRP and other inflammatory markers, having beneficial effects on the CV system.(19) GLP1-RAs and SGLT2i lower different inflammatory markers, which may, at least in part, account for their surprising CV benefits.(20)

Disclosure Statement: Dr. Wojcik has no financial disclosures to report.