Author + information
- Brendan M. Everett, MD, MPH∗ ( and )
- Paul M Ridker, MD, MPH
- ↵∗Divisions of Cardiovascular and Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, Massachusetts 02215
Pareek and colleagues correctly note that we observed a significant dose-dependent reduction in hemoglobin A1c (HbA1c) in patients with pre-diabetes who were randomly allocated to receive canakinumab compared with placebo. The attenuation in this effect that we observed after the first 6 to 9 months was not due to a reduction in the anti-inflammatory efficacy of canakinumab (1). The effect of canakinumab on high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6 concentrations was consistent throughout the trial, and canakinumab is a fully human monoclonal antibody, with no evidence of anticanakinumab antibodies in CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) (2). We outlined a number of possible explanations in the Discussion of our paper (1) for the attenuation of the effect of canakinumab on HbA1c among those with baseline pre-diabetes in CANTOS, including the possibility that cytokines beyond IL-1 may drive the progression of type 2 diabetes. We agree with Pareek and colleagues that a less-targeted anti-inflammatory agent, such as methotrexate, which we are testing in the Cardiovascular Inflammation Reduction Trial (3), colchicine (4), or hydroxychloroquine, may lead to reductions in HbA1c that translate into lower rates of incident type 2 diabetes. However, we note that canakinumab had a significant effect on hsCRP, IL-6, and major adverse cardiovascular events while not altering low-density lipoprotein cholesterol (LDL-C). In contrast, Pareek and colleagues report that hydroxychloroquine, when given in combination with atorvastatin, had beneficial effects on LDL-C and HbA1c when compared to atorvastatin alone, but did not lead to any significant differences in hsCRP concentrations (5). These observations suggest that any observed effects of hydroxychloroquine on HbA1c or cardiovascular disease may be through alternative, non–IL-6 inflammatory pathways, or through reductions in atherogenic lipids such as LDL-C. In conclusion, we eagerly anticipate the results from these randomized, double-blind, placebo-controlled trials, as we suspect they will provide further insight into the role of inflammation reduction for the prevention and management of diabetes and cardiovascular disease.
Please note: Dr. Everett has served as a consultant to Novartis; and has received grant support from Novartis Pharmaceuticals for work unrelated to CANTOS. Dr. Ridker has served as a consultant to Novartis; has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial; and is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens.
- 2018 American College of Cardiology Foundation
- Everett B.M.,
- Donath M.Y.,
- Pradhan A.D.,
- et al.
- ↵ClinicalTrials.gov. Effects of colchicine in non-diabetic adults with metabolic syndrome. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02153983. Accessed July 3, 2018.
- Pareek A.,
- Chandurkar N.,
- Thulaseedharan N.K.,
- et al.