Risk factors

Inflammation the next risk factor to be targeted in atherosclerosis

Inflammation is just as important a risk factor for atherosclerotic disease as dyslipidaemia and we will soon be using drug therapies targeted at ‘residual inflammatory risk’ in combination with lipid lowering therapies, according to an international cardiology speaker.

Delivering the keynote RT Hall lecture at the start of CSANZ 2020, Dr Paul Ridker of Brigham and Women’s Hospital, Boston, said trials with anti-inflammatory agents such as  canakinumab and colchicine had provided proof-in-principle that cardiovascular risk could be reduced substantially in the absence of lipid lowering.

There was now good evidence that reductions in inflammatory biomarkers such as C-reactive protein (CRP) correlated with cardiovascular risk reduction of the same magnitude seen with lipid lowering, and the next step will be to specifically target the upstream inflammatory cytokines such as interleukin-1β, he told the meeting.

Dr Ridker said it had been known since the 1940s that chronic inflammation played an important role in atherosclerosis, but it was only taken seriously after the serendipitous discovery that statin benefits were due as much to their anti-inflammatory effects as well as lipid lowering action.

This had led to renewed interest in the relationship between cardiovascular risk, chronic inflammation and the subsequent landmark findings from trials such as JUPITER that statin treatment in patients with relatively normal LDL but with an elevated CRP could reduce cardiovascular events.

More recently the CANTOS study, led by Dr Ridker, had shown that an anti-inflammatory drug targeting interleukin-1β could reduce recurrent cardiovascular events such as MI by 24% in people with chronic proinflammatory responses, defined by CRP levels.

However no benefit seen in a trial with another anti-inflammatory drug, methotrexate, which had no effect on IL-1β, IL-6, or CRP levels. Dr Ridker said this showed the importance of a targeted approach at upstream cytokines rather than broad spectrum anti-inflammatory effect.

With the abandonment of canakinumab for cardiovascular indications on commercial grounds, Dr Ridker told the meeting that the main hope now lay with the inexpensive anti-inflammatory agents colchicine. He praised the “excellent work “done by Australian researchers such as Dr Mark Nidorf in conducting trials of low-dose colchicine which had recently shown a 30% reduction in major cardiovascular events compared to placebo.

“The COLCOT and LoDoCo2 trails provide clinically important independent confirmation of the inflammation hypothesis with an apparently safe and much less expensive oral agent, colchicine,” he said.

There were other promising agents anti-inflammatory agents including a movie upstream to target he IL-1β producing NLRP3 inflammasome, he added.

Dr Ridker told the meeting that with two distinct methods of action, it was likely that lipid lowering agents and anti-inflammatory agents could be used in combination and would have synergistic effects against cardiovascular risk.

“Quality cardiovascular care requires us to recognise the distinction between ‘residual cholesterol risk and residual inflammatory risk” as these patient groups have different reasons for recurrent events,” he said.

“In the future it can be anticipated that all atherosclerosis patients will receive aggressive lipid lowering and inflammation inhibiting therapy in addition to behavioural and lifestyle interventions,” he concluded.

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