In addition to the intense pain and inflammation posed by arthritis flares, patients with gout also carry a higher risk for experiencing adverse cardiovascular events such as myocardial infarctions (MI,“heart attack”) or stroke. This heightened risk is related, at least in part, to the higher frequency of cardiovascular disease risk factors observed among this patient population. Among gout sufferers receiving care in the U.S. Veterans Affairs healthcare system, for example, approximately 3 in 4 have high blood pressure, 1 in 3 have diabetes, and 2 of 3 are overweight or obese.
Recent advances in our understanding of atherosclerotic cardiovascular disease have suggested a key role for inflammation in its development. Specifically, research has identified the NLRP3 inflammasome, a large complex of multiple intracellular proteins, as a central mediator of cardiovascular inflammation. With its activation, the inflammasome leads to the production of pro-inflammatory cytokines including both interleukin (IL-1) and IL-18, which act as downstream effectors on inflammatory cells. Of note, the same protein assembly has long been implicated in mediating the intense inflammation characteristic of gout flares.
These common biologic pathways suggest that inflammasome targeting may provide an opportunity to simultaneously reduce disease burden posed not only by gout but also by heart disease. Although its mechanism of action has long been incompletely understood, colchicine has been used in the treatment and prevention of gout flares for centuries. Increasingly, the benefit from colchicine in gout is felt to relate to its inhibition of inflammasome assembly in the cell, which ultimately prevents the generation of pro-inflammatory signals such as IL-1 and IL-18.
With observations that the same inflammasome biology may be central to heart disease, it is perhaps not surprising that this agent has recently been ‘repurposed’ in cardiology studies.
In the randomized, double-blind LoDoCo2 trial (Nidorf SM et al. N Engl J Med, 2020), more than 5,000 patients with known cardiovascular disease were randomized to receive either low dose daily colchicine (0.5 mg daily by mouth) or a matched placebo. Over a more than 2-year follow-up period, participants receiving colchicine were more than 30% less likely to experience a composite of cardiovascular death, myocardial infarction, ischemic stroke or ischemia-driven coronary revascularization. Already formally approved in the treatment of gout, in June of 2023 the U.S. Food and Drug Administration (FDA) gave its formal approval to colchicine (LodocoTM) 0.5 mg tablets for reducing the risk of adverse cardiovascular events. Recognizing that the landmark study conducted by Nidorf and colleagues did not include patients with gout, the “dual” benefit that might be gained with colchicine by simultaneously reducing flare burden and lowering heart disease risk in patients with gout remains to be defined.
These recent findings with colchicine parallel previous studies targeting IL-1, a downstream product of inflammasome activation that promotes inflammation characteristic of both gout flares and atherosclerotic heart disease. The efficacy of biologic agents targeting IL-1 (e.g., anakinra, canakinumab) in reducing the signs and symptoms of gout flares is well documented. In 2017, Ridker and colleagues (Ridker PM et al. N Engl J Med, 2017) published results from the pivotal CANTOS Trial. In this large double-blind, randomized controlled trial of canakinumab that involved more than 10,000 participants (without gout), subcutaneous injections (50 to 300 mg administered every 3 months) led to reductions in the risk of composite cardiovascular event among individuals with established heart disease over a median follow-up of 3.7 years. Although not formally approved in the management of heart disease, canakinumab (Ilaris®) injections have recently gained FDA approval for gout flare treatment. Though approved in the European Union, alternative biologics targeting IL-1 have yet to garner FDA approval in gout.
Our ever-improving understanding of the common biology leading to gout inflammation and heart disease holds promise for future advances. Targeting the inflammasome through the repurposing of colchicine and IL-1 inhibitors adds to other similar approaches that could conspire to reduce cardiovascular disease burden in this high-risk gout population (e.g., the use of SGLT2 inhibitors to treat diabetes or the use of losartan to treat high blood pressure, both of which yield serum urate lowering). Ultimately, these advances are poised to translate into newer and better treatment options for patients, leading to meaningful improvements in long-term outcomes among gout sufferers.
To learn more about the differing methods to treating gout flares, refer to our ‘Gout Treatment Options and Pain Relief,’ within our website for medical professionals.
