Heart In Diabetes 2019:

Blocking Cytokine Pathway Promises Best Intervention for Diabetes, CVD

with Michael H. Davidson, MD

At the opening session at the Heart in Diabetes 2019 conference, Michael H. Davidson, MD, FACC, FNLA, director of the Lipid Clinic at the University of Chicago Pritzker School of Medicine in Illinois, addressed the emerging role of inflammatory influences in type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD), and the need to consider the clinical implications in these patients.1

“In 2016, we gained insights coming out of the placebo controlled JUPITOR trial, 2 regarding the novel targets involved in atheroprotection as reflected in a risk ratio for high sensitivity C-reactive protein (hs-CRP) of 1.27 for IL-1.

Reducing systemic inflammation is the key to reversing diabetes, heart disease

Block Inflammatory to Treat Diabetes, Heart Disease

For patients taking a statin, Ridker et al reported an observed reduction in ASCVD events of 44% against the placebo (P < 0.0001),2 and more recently, findings from the FOURIER study,3 looking at the response proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibition with evolocumab added to background statin therapy versus placebo, achieved a 60% reduction in low lipoprotein cholesterol over a mean 2.2 year follow-up.

With regard to anti-inflammatory benefit, given prior findings from both genetic and imaging data,4,5 achieving a 35-40% reduction in hs-CRP and Il-6 despite no change in LDL-cholesterol has fostered a strong held belief that these agents are effective in reducing MACE and mortality as a result of reduced systemic inflammation,1 said Dr. Davidson.

More recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS),6 looking at interleukin (IL)-1ß inhibition with regard to primary cardiovascular endpoints (3-point MACE) followed more than 10,000 individuals across 10 countries who were randomized to canakinumab (50 mg, 150 mg, 300 mg) or placebo.

Dr. Davidson said, “While we now know the results to be remarkably favorable, the expectation at the outset of this study was very low, as indicated by a financial analyst’s statement made at the JP Morgan Healthcare Conference in May 2017:  

‘Our analysis suggests that the CANTOS trial is very unlikely to work. The inflammation hypothesis has repeatedly been contradicted by both genetic and imaging data. Even in trials showing a benefit on CV risk correlating with hsCRP, we believe the CV benefit is actually driven by a reduction in LDL-cholesterol. We believe that LDL reduction alone is critical to modifying CV risk and that a reduction in inflammation is a result of the effect of LDL lowering on atherosclerotic plaque, rather than being a driver of CV reduction itself.’”

“The findings from CANTOS were significant,6 such that when IL-1ß was inhibited, there was a suppression of IL-1ß, IL-6, and hs-CRP, which in turn produced a 15-17% reduction in MACE, a 31% reduction in all-cause and cardiovascular-specific mortality, following robust inhibition of inflammation,” he said.

In another CANTOS cohort—patients with had chronic kidney disease (CKD)— who represented a critical unmet need for clinical intervention also experienced inhibition of the inflammatory response as indicated by the achievement of hs-CRP levels of less than 2 mg/L.7

While there was a profound reduction in LDL-c with PCSK inhibition, there was no reduction in LDL- c with IL-1b, said Dr. Davidson: “Yet, the magnitude of independent risks associated with inflammation was at least as large if not greater than those of hypertension and hyperlipidemia.”

In contrast with CANTOS, a parallel study—the randomized, double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial (CIRT)— in which 4.786 patients received low-dose (15-20 mg/weekly) methotrexate proved disappointing. The National Heart, Lung, and Blood Institute stopped the study early due to sufficiently accrued data (albeit no safety concerns) since there was no significant positive impact on inflammatory markers, MACE, or other parameters; the researchers viewed the results as neutral, suggesting the benefit of understanding the limits of treating to this inflammation pathway.

How Might Inflammatory Risk be Achieved?

In preparing the Clinician’s Guide to Reduce Atherothrombotic Risk,9 cumulative data from four key trials: PROVE-IT, IMPROVE-IT, SPIRE 1 and 2, were analyzed to reflect residual inflammatory risk.10-12 The goal was to identify the right treatment target (ie, NLRP2, IL-1 or IL 6) and most efficacious anti-inflammatory agents for patients with diabetes and ASCVD; the greatest heart failure risk reduction was achieved in patients with lower hsCRP.13 

“We want to be sure there is a sound understanding that inflammation is known to be associated with a high cardiovascular risk, and to tease out whether it is a marker for risk or is it causal for cardiovascular disease? as there’s been an ongoing debate about this issue for years- going back more than 100 years actually,” said Dr. Davidson.

“We now have a lot of evidence that it is causal, supported by evidence from three main buckets of evidence: genomic data and animal data from preclinical models showing that when IL-6 is blocked, you do in fact get reduced inflammation,” he told EndocrineWeb. “But the most powerful information comes from the CANTOS trial demonstrating IL-6 inhibition with canakinumab. Since IL-6ß is upstream from IL-6 the result is a reduction in inflammation by 50%. Furthermore, this trial data demonstrated that when IL-6 is reduced in the liver, it is a clear marker of lower CRP.”

“This finding is what has changed the paradigm from one in which inflammation is considered just a marker to a causal factor” through the cytokine pathway, said Dr. Davidson.

“As such, when you lower CRP below the median, the result is a substantial 35% relative risk reduction,” he said. So the bottom line for clinicians is that while we were focusing specifically on the cytokine pathway to IL-1, the focus is needed to be on IL-6 to CRP. That appears to be the pathway that is linked most strongly to support the role of inflammation as contributory. By blocking this inflammatory pathway, we can, in fact, reduce cardiovascular events.”

“Since heart failure and CVD are highly inflammatory-driven, we need now to identify treatments that target IL1b, IL6, NRLP inhibitors,” Dr. Davidson said.

Action Needed to Reduce Inflammation in Patients with CKD

From the mounting evidence, we’ve also learned that individuals with chronic kidney disease who have an elevated CRP have a much higher cardiovascular risk. In these patients, the question for clinicians is: what to do for these patients?

Taking action is very important since better risk factor management including diabetes control and lipid therapy, does make a difference; and better hypertension control will make a difference, too,” Dr. Davidson told EndocrineWeb.

“So what do we do about it? We need to step up our risk factor analysis. If a patient is on dialysis and they have stage 3-5 kidney disease but are not at stage 5D, statins are helpful,” he said.

“The issue for patients with more severe disease is that the higher a patient is on the CDK spectrum, the less effective standard risk factor monitoring programs are, and the more inflammation is likely to be present, so we still need to find a way to reduce this heightened inflammation in the most severe cases of CDK,” he said.

In the meantime, “the one message you will want to share with patients today is that inflammation is driven by obesity and poor lifestyle behaviors, so it is necessary to minimize other risk factors in conjunction with guiding your patients to reduce their weight, adopt an anti-inflammatory diet, and get daily exercise—all of which have been proven to reduce systemic inflammation,”1  said Dr. Davidson.

For example, there is substantial support for the Mediterranean diet as an effective in reducing inflammation—as a heart-healthy, anti-diabetes lifestyle approach. Really, any low-calorie diet that fosters weight loss have been effective in reducing the inflammatory markers in the blood and promoting overall health,he said.

Dr. Davidson shared one possible financial conflict: Corvidia Therapeutics. 

Next Summary:
Choosing Treatments: Optimizing Care in Patients with Diabetes and CVD
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