Author + information
- Received February 14, 2018
- Revision received February 28, 2018
- Accepted March 1, 2018
- Published online March 12, 2018.
- Brendan M. Everett, MD, MPHa,b,∗ (, )@_brendan_,
- Marc Y. Donath, MDc,
- Aruna D. Pradhan, MD, MPHa,d,
- Tom Thuren, MDe,
- Prem Pais, MDf,
- Jose C. Nicolau, MDg,
- Robert J. Glynn, ScDa,
- Peter Libby, MDb and
- Paul M. Ridker, MD, MPHa,b
- aCardiovascular Disease Prevention
- bDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston
- cEndocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
- dDivision of Cardiovascular Medicine, Department of Medicine, VA Boston Medical Center, West Roxbury, Massachusetts
- eNovartis, East Hanover, and Basel, NJ, Switzerland
- fSt. John’s Research Institute, Bangalore, India
- gInstituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- ↵∗Address for Correspondence: Brendan M. Everett, MD, MPH Brigham and Women’s Hospital Divisions of Preventive and Cardiovascular Medicine 900 Commonwealth Ave Boston, MA 02215 Telephone: 857-307-1990 Fax: 857-307-1955 .
Background Subclinical inflammation mediated in part by interleukin-1 beta (IL-1β) participates in peripheral insulin resistance and impaired pancreatic insulin secretion.
Objectives We tested the hypothesis that canakinumab, an IL-1β inhibitor, reduces incident diabetes.
Methods The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) randomized 10,061 patients with prior MI and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L to placebo or canakinumab at doses of 50mg, 150mg, or 300mg subcutaneously once every three months. We tested the effects of canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. We also evaluated the effect of canakinumab on fasting plasma glucose and HbA1c in patients with and without established diabetes.
Results Of CANTOS participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person years, P = 0.003). Canakinumab 150mg as compared to placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (HR 0.85, 95% CI 0.70-1.03), pre-diabetes (0.86, 95% CI 0.70-1.06), and normoglycemia (HR 0.81, 95% CI 0.49-1.35). Despite large reductions in hsCRP and interleukin-6, canakinumab did not reduce the incidence of new onset diabetes, with rates per 100 person years in the placebo, 50mg, 150mg, and 300mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (Log-rank P=0.84). The hazard ratio comparing all canakinumab doses to placebo was HR 1.02 (95% CI 0.87-1.19, P=0.82). Canakinumab reduced HbA1c during the first 6-9 months of treatment but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed.
Conclusions While IL-1β inhibition with canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes.
Funding: Funded by Novartis, Basel, Switzerland
Disclosures: PMR, RJG, PP, and JCN received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial. PMR, BME, and PL have served as a consultants to Novartis and BME has grant support from Novartis for work unrelated to CANTOS. PMR is listed as a co-inventor 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. TT is an employee of, and holds stock in, Novartis Pharmaceuticals. All other authors declare no competing interests.
- Received February 14, 2018.
- Revision received February 28, 2018.
- Accepted March 1, 2018.