“The Itch that Rashes” - CRP and Inflammation
Case Presentation:
54 year old hispanic female with a history of overweight (BMI of 29 kg/m2), prediabetes (AIC 6.2%), moderate hypertriglyceridemia (triglycerides of 219 mg/dL) and transaminitis (elevated liver enzymes - with AST and ALT in the 50’s on multiple blood draws).
At the advice of a friend, she had a hsCRP (high sensitivity c-reactive protein, which is a marker of inflammation) drawn and a CAC (coronary artery calcium) CT scan score done. Both were abnormal. CRP (we don’t need to always call it “hs” CRP - they are the same) was elevated at 5.0 mg/L. The CAC score was 45.
Her friend referred her to a Podcast about insulin and inflammation.
Since then she has cut back on carbs, opened a gym membership and started walking with her friend, in an effort to control her insulin and lose weight. However, she desperately wants to know what interventions she should take to better target inflammation.
She has added turmeric to her supplements as well as a proprietary blend from a supplement company that purports it reduces inflammation and promotes heart health.
She is not interested in statins because of the fear it will promote diabetes and make her liver enzymes worse. She states her LDL-C of 89 mg/dL is ok and believes that the primary focus needs to be on reducing inflammation and raising her low HDL-C.
And besides, her neighbor, who is a cardiologist, told her that her calcium score of 45 was low and she didn’t need to start any cholesterol meds or aspirin just yet. “Just keep an eye on it.”
Flying Under the Radar
This is an extremely high risk patient, who just doesn’t know it. She’s not alone - most clinicians, including her neighbor cardiologist, miss it too. There are many “clues” indicating residual risk in this case presentation but we will hit on just a few of them here.
Many practitioners of prevention clinics know these patients well - they are constantly on the search for some enigmatic cure for “inflammation”, often in denial of their true disease and at the expense of proven therapies to treat it. Social media and Podcast “experts” can sometimes fuel these misconceptions (either intentionally or inadvertently).
Whatever the barriers, these patients invariably either refuse, delay or tiptoe around appropriate and state of the art treatment for their atherosclerotic and cardiometabolic disease.
Tragically, these patients represent a large cohort of “residual risk” due to a disproportionate and poorly understood belief that their anti-inflammatory methods are somehow curing their atherosclerotic disease risk.
At 54, this young woman already has evidence of inflamed plaquing by virtue of early development of coronary calcification, a rather late stage finding in plaque development and the telltale sign that atherosclerosis exists and it's been inflamed. This has been occurring over decades, due to LDL particles depositing cholesterol into the lining of the blood vessel wall, which then becomes oxidized by our immune cells (monocytes).
While her calcium score of 45 is classified as “mild” by total score, this qualitative assessment speaks only to her 10 year risk. But according to the CAC Score Reference Values | MESA,
a score of 45 in an hispanic female places her at the 94th percentile rank (> 90th in all races), meaning, if I took 100 hispanic women aged 54 off the streets and put them in the CT scanner, she would be leading the pack in all but 6 of them. Considering that heart disease is still the #1 cause of death in women, that’s not a race you want to be winning.
Anything CAC score at the 75th percentile rank or higher is considered high “lifetime” risk by The National Lipid Association scientific statement on coronary artery calcium scoring to guide preventive strategies for ASCVD risk reduction.
Blowing it off and failing to take action now, is a dangerous and potentially deadly missed opportunity.
The best way to stop the inflammation is to stop the bombardment of the arterial wall with LDL particles trafficking cholesterol.
The best way to do that is to use extremely aggressive lipid lowering therapies which will achieve at least 50% lowering of LDL-C (ApoB or nonHDL-C would be preferred in her case - see “atherogenic triad” discussion for why) for life.
While diet and exercise are helpful in terms of reducing total cardiovascular mortality and morbidity, they have a very modest impact on atherogenic lipoproteins (LDL particles predominantly). Drugs, often in combination, are required.
But wait, what about the hsCRP being high?! Ah yes, the debate over hsCRP has been going on for decades. It’s highly debatable whether CRP is causal to atherosclerosis. It has been shown to be more associated with “adiposopathy” - pissed off fat and likely adds fuel to the fire already ignited by those atherogenic lipoproteins.
Reducing visceral fat (belly fat) through appropriate diet (Mediterranean) and exercise (cardio and resistance training) will indeed go a long way towards treating CRP (if due to pissed off fat), but it won’t, by itself, cure atherosclerosis.
Bottom Line:
An informed clinician (and CardioAdvocate reader) doesn’t need hsCRP to assess risk in the vast majority of cases.
CRP can be used to draw attention to what may be missed, but in many ways it represents a lazy way of doing it. But hey, if that’s what it takes in today’s busy clinics, so be it.
CardioAdvocate Checklist:
Do I need CRP?
Depends on context
Pro: It can be a useful easy biomarker for obtaining information about risk that’s not easily gleaned from the chart or patient encounter
Con: it can be misleading, confusing and steer a patient away from the actual disease at hand (i.e. atherosclerosis)
Much of the information obtained from CRP can be obtained through other biomarkers and history and physical exam findings (Exercise, diet, family and smoking history, history of rheumatologic inflammatory diseases, age, BMI, abdominal waist circumference, lipid panel, A1C, liver enzymes, renal function, to name a few).
Studies have shown that CRP offers no additional benefits beyond traditional risk factors and adds little to reclasifying individual risk into lower or higher risk categories, which is called net reclassification index (NRI).
Analysis from the MESA trial showed that the association of hsCRP and atherosclerosis was largely accounted for by obesity (High-Sensitivity C-Reactive Protein and Cardiovascular Disease: A Resolute Belief or an Elusive Link? | JACC).
Meaning, if you account for obesity (visceral fat, in particular), CRP doesn’t tell you much more.
What was your hsCRP?
< 1 mg/L: lower risk
1-3 mg/L: average risk
> 3 mg/L: higher cardiovascular risk
>10 mg/L: consider some other acute infection or active inflammatory disease/condition (psoriatic arthritis, rheumatoid arthritis, lupus)
Was it repeated?
CRP is an “acute phase reactant”, meaning it can be temporarily elevated due to many other acute infections or inflammation (cold, flu, vaccination, pericarditis, gout, ran a marathon)
Repeat it in 2-3 weeks if initially elevated
Did you rule out other causes?
As mentioned above, “pissed off fat” or “visceral adiposopathy” is one of the most likely cause of mildly elevated CRP
Visceral obesity/overweight
Fatty liver disease (usually with mildly elevated liver enzymes)
Diabetes
Prediabetes
Metabolic syndrome: At least 3 of 5 of the following:
High triglycerides (> 150 mg/dL)
Low HDL-C (< 40 mg/dL in men, < 50 mg/dL in females)
Insulin resistance/dysglycemia (diabetes, prediabetes)
Hypertension
Increased abdominal waste circumference (overweight/obesity)
Rheumotologic inflammatory conditions
Psoriatic arthritis
Rheumatoid arthritis
Lupus
Atherosclerosis may not be a prerequisite for an elevated CRP
It’s not clear that the presence of plaque inflammation causes an elevated CRP and vice versa
A CAC score of 0 does not indicate 0 risk
Don’t ignore other risk factors, including an elevated CRP
Elevated CRP may be more of an indicator of other troublesome cardiometabolic diseases brewing, that individually or in combination significantly increase ASCVD risk.
Elevated CRP may be an early warning sign - presenting much earlier than atherosclerosis manifests and perhaps before obvious cardiometabolic risk factors are detected by clinicians and standard testing.
Deep Dive
Countless research hours and a lot of money has been spent on repeated attempts and failures in the search for an anti-inflammatory pathway, subsequent target of therapy and a magic bulllet to combat residual risk in atherosclerosis that is directly attributable to the inflammatory cascade through its mediators, such as IL-1 (interleukin 1), IL-6 and TNF-alpha (Tumor Necrosis Factor alpha) and others.
The supplement industry has benefitted nicely from the quantity of promising targets and pathways, coupled with the lack of proven therapies and the uncertainty surrounding causality, by promoting various compounds that purport to impact favorably upon elements of inflammation. “Anti-inflammatory” claims are often misleading and/or completely false, with ingredients concealed in a “proprietary blend”.
When they do describe the pathways they sound well researched and just “scientificky” enough to get you to purchase them. If you beat your provider up enough they will often just shrug their shoulders. So far as well can tell, these products mostly offer expensive urine.
In legitimate scientific circles, the “Pro” and “Con” debates wage on. At national prevention meetings, debates between “celebrity” thought leaders and researchers on this topic are some of the most well attended sessions, with a packed house, passionate discussion and plenty of opportunities for filling bingo cards.
What’s the Debate?
The questions thrown up for debate (with the noted pitfalls in asking such questions) are something like these :
“In the absence of elevated atherogenic lipoproteins, can activation of the inflammatory cascade, by itself, be enough to cause atherosclerosis?”
Well, what defines “elevated” atherogenic lipoproteins?
Even normal levels (as defined by population normalcy curves) of LDL-C are plenty capable of causing atherosclerosis
“Can treatment of inflammation by only targeting the inflammatory cascade (IL-1 etc) cure or effectively treat the disease of atherosclerosis, apart from lipid lowering therapies?”
Well, what do you mean? Everyone with atherosclerosis ought to be on at least “usual care” treatment (treatment of the current time) which, in the presence of ahterosclerosis means “secondary prevention.”
Secondary prevention already involves very strict targets of therapy, which usually necessitates intense lipid lowering therapy to acheive very low levels of LDL-C.
What does CRP actually represent?
Vascular inflammation?
From what? Plaque in the artery wall?
How do you explain mildly elevated CRPs (apart from an obvious inflammatory condition) in the absence of any identifiable atherosclerosis (no evidence of plaque formation on imaging studies, for example)?
What about other sources?
Visceral adiposopathy - “sick (pissed off) fat”
Fatty liver disease
Insulin resistance/dysglycemia - diabetes, prediabetes
Dylipidemia - abundance of remnant lipoproteins (triglyceridees)
Rheumatologic inflammatory conditions - well known to accelerate atherosclerosis
Psoriatic arthritis
Rheumatoid arthritis
Systemic Lupus Erythematosus (SLE)
Does inflammation beget inflammation?
Once the inflammatory cascade gets triggered, does it propogate itself despite turning off the spicket that got it started in the first place (i.e.LDL particles)?
If triggered by atherosclerosis, do some folks have such an overwhelming burden of plaque that no matter how low we drive LDL particles, the inflammation persists?
Or is it that we just haven’t yet driven LDL particles low enough in them?
To date there have been no trials evaluating anti-inflammatory agents in high risk patient populations (secondary prevention) with ultra low levels of LDL-C (20-40 mg/dL) or ApoB (30-50 mg/dL)
What’s the Data?
Jupiter Trial:
The Jupiter Trial, published in 2008, was championed by Dr. Paul Ridker from Harvard’s Brigham and Women’s Hospital, who is the leading expert in CRP and in the field of inflammation in atherosclerosis. In fact, Dr. Ridker is coinventor for the CRP patent held by Brigham and Women’s Hospital and licensed to AstraZeneca and Siemens. AstraZeneca developed and sold Crestor, now generic, under the name rosuvastatin.
It was one of the first major RCT’s (Randomized Controlled Trials) to study the effect of lowering CRP with Crestor (rosuvastatin) in those supposedly “without hyperlipidemia” but with mildly elevated hsCRP (high levels.
It enrolled nearly 18,000 “apparently healthy men and women” with LDL-C < 130 mg/dL and hsCRP levels 2.0 mg/L or higher to rosuvastatin 20 mg daily or placebo “and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.”
Since statins were known to reduce both cholesterol and CRP (C-Reactive Protein Levels and Outcomes after Statin Therapy | New England Journal of Medicine) it was felt, during that era, that statins had so-called “pleiotropic effects”, meaning that they had other favorable cardiovascular benefits beyond their ability to lower cholesterol. This was all the rage back then.
“Pleiotropic effects” was a catch phrase throughout the 2000’s whenever anyone talked about statins or whenever they compared statins to other lipid lowering therapies. Given this observation it seemed like a perfect primary prevention study to evaluate a therapy which targets CRP and therefore reduces inflammation in those felt to be otherwise metabolically healthy, with perceived “normal” LDL cholesterol levels, but with something else causing inflammation (not the lipids).
Obviously the rosuvastatin would also impact the LDL-C and there would be an expected benefit, but if it also lowered CRP, then perhaps there would be an even greater benefit to those that had both biomarkers lowered, compared with those who only had their LDL-C lowered.
Indeed, rosuvastatin lowered LDL-C by 50% and CRP by 37%. There was no heterogeneity seen between subgroups (no major differences in benefit between those participants with significant differences in baseline characteristics) - they all benefitted.
No Control Group
A major criticism of the Jupiter trial, however is that, well, everyone benefitted - regardless of additional risk factors (wait, what risk factors? I thought they were all healthy) identified, and there was no control group of low LDL-C and low CRP for comparison. Meaning, there is no way to tell if there was truly a benefit to treating elevated CRP or simply treating cholesterol in individuals with their baseline risk.
To say this another way - so-called “normal cholesterol” can be dangerous enough to see a benefit to high intensity statin therapy (high intensity, by definition, means to lower cholesterol 50% from baseline) in those of a particular risk (you always need to start with baseline risk…we’re not putting statins in the water, ok?)
Let’s all say it again - “normal cholesterol is plenty” when it comes to the ability to form atherosclerosis.
“Apparently Healthy”
They took a lot of liberties with the term “apparently” in the “Methods” section of the study description.
An LDL-C of less than 130 mg/dL, by itself, does not make one “healthy.”
Jupiter participants:
50% had Framingham 10-year Risk Score > 10% (well above the threshold used now to treat with statin therapy)
41% had metabolic syndrome (see atherogenic triad article): at least 3 of the following
High triglycerides (> 150 mg/dL)
Low HDL-C (< 40 mg/dL in men, < 50 mg/dL in females)
Insulin resistance/dysglycemia (diabetes, prediabetes)
Hypertension
Increased abdominal waste circumference (overweight/obesity)
15% were active smokers
Median blood pressure was elevated, in the “prehypertensive” range
Median BMI was elevated (suggests overweight/obesity)
Bottom Line:
They “apparently” weren’t so healthy. Many of them already warranted treatment based on existing guidelines at that time - without the need to check hsCRP.
CANTOS Trial: canikinumab
Fortunately, the criticism of the Jupiter did not stop Dr. Paul Ridker from continuing his investigation on inflammatory targets.
Again, it’s quite possible that in some folks, the inflammatory cascade may yet offer valuable targets for reducing residual risk.
The CANTOS Trial, or "Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease" | New England Journal of Medicine, published in 2017 and sponsored by Novartis, was an RCT of canakinumab (ILARIS.com), a monoclonal antibody targeting interleukin-1β (IL-1).
IL-1 is a cytokine that drives the IL-6 pathway, which along with CRP have demonstrated an increase risk in cardiovascular events.
It enrolled 10,000 patients with prior myocardial infarction - secondary prevention, this time - but again with an elevated CRP of 2 mg/L or greater, to 3 doses (50 mg, 150 mg and 300 mg) of Canakinumab given every 3 months. The primary end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Canakinumab reduced CRP levels up to 41% in the highest dose. Importantly, it had no impact on cholesterol levels.
The 150 mg dose of canakinumab showed statistical significance in reducing cardiovascular events.
The Good News:
Targeting the innate immunity pathway lead to a reduction in cardiovascular events, by about 15%, without impacting lipids.
The Bad News:
“Canakinumab was associated with a higher incidence of fatal infection than was placebo.”
Bottome Line:
Canakinumab (ILARIS.com) obviously has a place for its FDA approved intended use - rare autoinflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS), but at the price of $73,000 annually and the risk of fatal infection, it just isn’t a sensible addition to the cardiovascular armamentarium.
Colchicine
What about existing cheaper (and safer) alternatives? Colchcine has shown the most promise in this regard with not 1, but 2 large scale RCT’s showing benefit (a colleague once told me: “show me 1 RCT and I’m interested…show me 2 and I’m in”).
Colchicine has been around forever (centuries - and fortunately generic, though we’ll get back to that) and is most commonly used for gout. It has shown promise in other inflammatory conditions, most notably for the treatment and prevention of recurrent pericarditis (A Randomized Trial of Colchicine for Acute Pericarditis | New England Journal of Medicine).
Colchicine binds to tubulin, a protein involved in the structure and movement of cells. It works as an anti-inflammatory by inhibiting the migration, adhesion and activation of inflammatory cells such as neutrophils and macrophages, to sites of inflammation in the cardiovascular system.
The COLCOT, or Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction | New England Journal of Medicine, pulished in 2019 was the first major RCT showing a reduction in cardiovascular events in those with recent myocardial infarction. It enrolled nearly 5,000 patients and randomized half to colchicine at 0.5mg once daily on top of standard care or placebo and followed them for nearly 2 years. Colchicine showed a 23% reduction in cardiovascular events.
This was followed by the LoDoCo2, or Colchicine in Patients with Chronic Coronary Disease | New England Journal of Medicine Trial which was published 1 year later, looking at those with chronic coronary artery disease (lower risk patients than those with recent myocardial infarction). It randomized just over 5,000 patients to colchicine 0.5 mg daily or placebo for just over 2 years. It showed a 31% reduction in cardiovascular events.
Exciting right?! Well, critic’s enthusiasm was tempered by the findings of a higher incidence of death from any cause and noncardiovascular death in the colchicine arm.
Not So Fast My Friends!
Alongs comes the CLEAR-SYNERGY Trial, or Colchicine in Acute Myocardial Infarction | New England Journal of Medicine, published in 2024, which was an RCT of just over 7,000 patients and showed no benefit.
However, these patients were just a bit different. Very high risk patients, having suffered from an acute STEMI - the most feared of all heart attacks. Think large clot lodging in a major coronary artery and the entire cath lab racing in to the hospital in the middle of the night and the patient bypassing the ER and going straight to the lab to have an artery opened up as fast as humanly possible, where “time is myocardium.” High risk right? And you think a little colchicine is going to make a big difference? That’s asking a lot. Ok, so that was one criticism raised.
The other major criticism was that the conduct of the trial suffered during the COVID-19 pandemic and that more than a third of the trial participants were enrolled from “1 small eastern european country” (We have seen this movie before - famously, The TOPCAT trial of Spironolactone for Heart Failure with Preserved Ejection Fraction | New England Journal of Medicine was also hampered by suspected foul play by 2 Eastern European countries - Russia and Georgia - for either not enrolling patients with true heart failure and/or selling the drugs on the black market), raising suspicions about the quality of this trial.
Meta-analysis to the Rescue!
However, meta-analyses, which include 6 RCT’s show a 25% reduction in cardiovascular events without significant adverse events with minor gastrointestinal issues (diarrhea, loose stools).
In aggregate, the positive data with colchicine was enough to garner a Class IIa recommendation from the European Society of Cardiology (elevated from Class IIb) and a Class IIb recommendation from the American College of Cardiology. They emphasize that its role is favored in those with residual inflammatory risk, such as hsCRP > 2.0 mg/L. Others recommend using it in those with existing inflammatory conditions, such as psoriatic arthritis, rheumatoid arthritis or lupus. These conditions are well know to accelerate atherosclerosis.
In the US, since the typical formulation of colchicine is in 0.6 mg tablets, this paved the way for branded LODOCO to market it’s 0.5mg dose forumation for heart disease, but with a substantially higher price tag for many.
Does this matter? Well, 0.6 mg daily represents a 20% increase in dose and for those with even mild renal (kidney) impairment, this may cause steady-state blood levels of colchicine to rise above the safe upper limit for such patients. The 0.5 mg dose appears to be safer.
Bottom Line:
Not for everybody. Slow adoption from clinicians is likely due to the conflicting and less than robust data despite multiple RCT’s.
May be an option for those with residual inflammatory triggers such as psoriatic arthritis, rheumatoid arthritis and lupus.
In the absence of one of those obvious inflammatory conditions a mildly elevated CRP should prompt investigation and treatment into way more common cardiometabolic diseases associated with visceral adiposopathy (angry, pissed off fat) like diabetes, prediabetes, fatty liver disease, metabolic syndrome etc.
Other Trials:
Methotrexate
Failed to show a benefit in the CIRT trial, or Low-Dose Methotrexate for the Prevention of Atherosclerotic Events | New England Journal of Medicine, which was another Dr. Paul Ridker study, published in 2018.
This trial also enrolled nearly 5,000 patients with “prior myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome” to methotrexate at 15 to 20 mg weekly or placebo.
The thought behind this was that methotrexate had been around forever and was a cheap, effective and “widely used treatment for inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis.”
It didn’t work. It didn’t reduce cardiovascular events. But it also didn’t reduce IL-1, IL-6 or CRP either.
Bottom Line:
Firstly, just because something sounds good - and has proven effective in other inflammatory conditions, doesn’t mean it cures all forms of inflammation.
Secondly, just because signals of inflammation may be closely associated with atherosclerosis does not mean that targeting those signals and effectively lowering them will have a clinically meaningful impact on the disease apart from treating it’s root cause - atherogenic lipoproteins.
Lastly, to date no RCT of any anti-inflammatory agent has been conducted to study its independent effects on individuals treated to very low targets of LDL-C or ApoB - the kind of targets that lipid/prevention experts believe is necessary to control the disease, which is an LDL-C 20-40 mg/dL and ApoB 30-50 mg/dL.
It’s highly unlikely such a trial will ever be performed. It would be extraordinarily expensive and exceedingly challenging to enroll a large enough sample size and carry the trial out long enough to see a meaniful difference. Just look at the difficulties the clinical trialists are currently experiencing with studying lipoprotein (a) drugs. Such “event-driven” trials, on a background of increasingly more aggressive secondary prevention are simply too hard to pull off. But the silver lining is that we’re doing a damn good job with the existing therapies - we just need better adherence.
