16th World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease :

Anti-Inflammatory Therapy for CVD, Diabetes Risk Reduction

With Brendan M. Everett, MD, MPH, and Sanjay Kaul, MD

Inflammation reduction is a catch-all term that applies to a wide range of chronic diseases and has been linked with vascular events for years, with anti-inflammatory actions promising beneficial health effects. However, any outcomes will depend upon many variables, and the agents employed to reduce inflammatory processes yield many different effects,1 as Brendan Everett, MD, MPH, explained at a well-attended session at the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease in Los Angeles, California.

During his presentation, Dr. Everett reviewed the epidemiologic associations between inflammation and atherosclerotic cardiovascular disease, heart failure, and diabetes, but the highlight was his overview of the effects that the available anti-inflammatory agents have on atherosclerotic cardiovascular disease (ASCVD) events as well as heart failure and complications of diabetes, citing results from two recent trials: CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study)2,3 and CIRT (Cardiovascular Inflammation Reduction Trial).4

There is great potential for interrupting the inflammatory process to change the course of key chronic diseases. "You can modulate this inflammatory cascade at different pathways in the process," he said.

Sanjay Kaul, MD, FACC, FAHA, a cardiologist and professor medicine at Cedars-Sinai Medical Center in Los Angeles, California, offered some caution regarding the findings from the CANTOS study in a presentation given during the same session.5

Inflammation Acts to Predict Disease Risk, Reverse Disease Course

For decades, experts have known that low-grade systemic inflammation occurs many years before the onset of vascular events, Dr. Everett said. Inflammation is also a strong, consistent predictor of cardiovascular risk. An analysis of 54 studies found that high sensitivity C-reactive protein (hs-CRP) concentrations and CV events were strongly linked.And, Dr. Everett indicated that the ''common soil'' hypothesis that inflammation is also linked with an increased risk of developing diabetes,6 has also long been discussed.

First, Dr. Everett tackled the CANTOS trial to address the efficacy of the study findings.2 The primary cardiovascular endpoints in this study were myocardial infarction (MI), stroke, and cardiovascular death (3-point MACE). The secondary endpoints were MACE plus unstable angina requiring urgent revascularization. And the prespecified secondary endpoint was new-onset diabetes among patients with protocol-defined prediabetes upon entry to the trial.

CANTOS randomized 10,061 patients from 39 countries and examined 1,490 primary events

The four groups included those randomized to receive one of three doses of the drug: 50 mg, 150 mg, 300 mg, or placebo. At baseline, patients across the groups were on average 61 years old with about one-quarter of the participants female, and about 40% of patients having a diagnosis of diabetes

After the five-year follow-up visit, researchers noted a 35-40% reduction in high sensitivity C reactive protein (hs-CRP) and interleukin-6 but no change in serum LDL-cholesterol. The HR was 0.85 for MACE (= 0.007) and 0.83 for MACE Plus (P = 0.0006). The researchers looked at whether some subgroups had smaller or larger benefits.

Individuals showing a greater hs-CRP reduction had a greater reduction in risk for MACE,2 Dr. Everett said. In fact, those who achieved a CRP level under 2 mg/L had a 25% reduced risk, and patients with a CRP at 2 mg/L or overachieved just a slight reduction in risk of 5%.

"We believe canakinumab has been demonstrated to reduce non-fatal MI, nonfatal stroke, and CV death based on results of the CANTOS trial," Dr. Everett said.

In addition, the drug appears ''effective in reducing atherosclerotic endpoints in patients with diabetes, prediabetes, and normal glycemic control but failed to prevent the progression of prediabetes to full diabetes,'' he said. That was true despite evidence that there was a small but insignificant reduction in hemoglobin A1c (HbA1c) in the initial months of the trial.2,3

The drug may also help heart failure patients, said Dr. Everett, but calls that data ''hypothesis generating.'' Due to time constraints, he did not elaborate on heart failure data but focused more intently on other aspects of CANTOS and CIRT.1

Too Good to Be True: Challenging the CANTOS  Findings

Dr. Kaul addressed the role of inflammation in cardiovascular disease, then turned his attention to the review of findings from the CANTOS trial.He focused on the question of whether the trial proved the inflammatory hypothesis of atherosclerosis.5

Among his most strident criticisms was the lack of a low or normal hs-CRP arm in CANTOS."Without this arm," he asked "can one be sure CANTOS unequivocally validates the inflammatory hypothesis? "

CANTOS, Dr. Kaul said, used an ''enriched'' population, with high-risk post-MI patients who had a residual inflammatory risk, with hs-CRP over 2 mg/L.3,4

Among his conclusions, ''the totality of evidence" from this research is not consistent with the inflammatory hypothesis., he said. He also noted prohibitive cost-effectiveness.5

Despite the study limitations, "Results from the CANTOS trial did move the needle forward for the inflammatory hypothesis, but not beyond a reasonable doubt."

Use of Methotrexate for Atherosclerotic Inflammatory Disease 

Dr. Everett also reviewed results of the Cardiovascular Inflammation Reduction Trial (CIRT), which focused on prescribing low-dose methotrexate (15 to 20 mg orally) once weekly with folic acid.4

In this study, for which Dr. Everett was the primary investigaor, 4,786 patients from 417 sites across the United States and Canadian with only 10 individuals lost to follow up. Patients were ages 65 or 66 years old with about 18% being female.4

All participants were diagnosed with type 2 diabetes or metabolic syndrome and had stable coronary artery disease and were taking statins, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACE/ARB), beta blockers and acetylsalicylic acid (ASA, aspirin). The researchers compared the anti-inflammatory effects of methotrexate plus folate to placebo and folate on outcomes of 3-way MACE, MACE plus, and cardiovascular mortality.4

The CIRT trial was halted early by the National Institutes of Health in response to sufficient data amassed by the investigators to answer the primary question with sufficient strength and having demonstrated a risk reduction CV benefit independent of any lipid-lowering effect. Earlier evidence has shown support for a reduction in vascular events among those with rheumatoid arthritis and psoriasis treated with this regimen.1

The results: "Methotrexate did not prevent recurrent CV events in this high-risk population," Dr. Everett said. The incidence rate per 100 person-years was 201 in the treated group and 207 in the placebo group.4

Treating systemic inflammation may reduce or reverse Diabetes symptoms.

Practical Applications to Achieve Anti-Inflammatory Risk Reduction 

In managing patients with regard to inflammation due to chronic disease, some of the key conclusions shared by Dr. Everett were as follows:1

  • Statins inhibit inflammation and lower LDL-C, but teasing out how much of their beneficial effects on ASCVD events is due to reduced inflammation versus LDL-reduction is not possible.
  • Canakinumab lowers ASCVD risk by about 15% by inhibition of IL-beta, while lowering hs-CRP by 40% with no change in LDL-C.
  • Low-dose methotrexate, as studied in CIRT, does not lower IL-6, hsCRP or IL-1 beta; it does not reduce ASCVD event risk.

How might clinicians anticipate the role of anti-inflammatory treatment advancing the care of patients in endocrine practices?

"At this point, I think the clinician needs to stay open-minded about the potential for future therapies to achieve inflammation reduction to prevent both atherosclerosis and hopefully heart failure when those studies and trials are done down the road," Dr. Everett told EndocrineWeb.

Financial disclosures:  Dr. Everett consults for Novartis, Roche Diagnostics, Abbott Diagnostic, and Amgen. Dr. Kaul is a consultant for Boehringer Ingelheim, Novo Nordisk, Johnson & Johnson, and Novartis and has stocks/equity in Johnson & Johnson.

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