- Open Access
Mirroring the CANTOS revolution: is anti-inflammatory therapy for diabetes just around the corner?
Cardiovascular Diabetology volume 16, Article number: 91 (2017)
An awesome body of evidence supports inflammation as a pivotal player throughout all phases of diabetes and atherosclerosis development [1,2,3]. However, for the time being there was not any decisive substantiation that an anti-inflammatory treatment could be effective in the several clinical settings. For instance, in the SOLID-TIMI 52 trial the anti-inflammatory agent darapladib—a selective inhibitor of lipoprotein-associated phospholipase A2—failed to reduce the risk of recurrent coronary events . On this background, the first preliminary report of phase 3 CANTOS trial results seems to be an interesting and even revolutionary game changer .
In this trial the monoclonal antibody canakinumab given on top of standard care significantly reduced the risk of the composite of major adverse cardiovascular events (MACE) in patients with a prior myocardial infarction and inflammatory atherosclerosis (hsCRP level ≥2 mg/L). Canakinumab works by targeting interleukin-1beta (IL-1ß), a key cytokine in the inflammatory pathway of both atherosclerosis and type 2 diabetes mellitus (T2DM) [3, 6].
In this regard, one of the first pathophysiological mechanisms involved in the initiation of low-grade systemic inflammation in T2DM, obesity and the metabolic syndrome is the anatomic and functional modification of visceral adipose tissue. Following the imbalance between energy consumption and expenditure, the gene expression profile of numerous cells is altered , and several dysregulated pathways  cause adipocytes to accumulate large amounts of fatty acids in the cytoplasm, leading to an expansive process characterized by adipocyte hyperplasia and hypertrophy.
In response to changes taking place in the structural scaffold of visceral adipose tissue, some adipocytes located in areas distant from the blood vessels undergo hypoxia and subsequent necrosis, being then surrounded by phagocytic cells. These cells re-initiate the inflammatory process via increased pro-inflammatory cytokine expression oriented to the removal of the isolated cells [9, 10]. This route is even faster when high glucose conditions are present, in which the process may be hastened by several adipocytokines inducing insulin resistance, like leptin  and tumor necrosis factor alfa (TNF-α) .
Within the above mentioned biochemical framework leading in its first stage to obesity, there is an intimate and highly coordinated association between inflammatory and metabolic pathways, highlighting so the parallel between the roles of macrophages and adipocytes . Macrophages express most of the adipocyte protein products, such as fatty acid binding proteins (FABP) and peroxisome proliferator activated gamma (PPAR-γ), whereas adipocytes can express many pro-inflammatory proteins secreted mainly by macrophages, such as TNF-α and interleukin-6 (IL-6) . Reduction of PPAR-γ expression and generation of a pro-inflammatory environment in white adipose tissue contributes in turn to stress-induced glucose intolerance . Moreover, the functional ability of these two cell types further overlaps since macrophages can attract and store lipids to become atherosclerotic foam cells. In inflammatory conditions preadipocytes may have phagocytic and antimicrobial properties, with ability to differentiate into macrophages, suggesting a potential immunological role of preadipocytes [14, 16]. The interrelationship between adipocytes and macrophages is enhanced when there is an excess of adipose tissue, promoting thus insulin resistance  and eventually T2DM.
In patients with moderate or severe obesity and overt T2DM, the action of several pro-inflammatory adipocytokines like E-selectin and intercellular adhesion molecule-1 (ICAM-1)  closely correlates with the activation of the nuclear factor-kappa B (NFκB)  and IL-1β [20, 21], promoting endothelial dysfunction . While adipocytes also simultaneously secrete anti-inflammatory adipocytokines like adiponectin and omentin , this fact is usually unable to counterbalance the detrimental inflammatory effects of the pro-inflammatory ones. Finally, the overexpression of NF-κB in adipose tissue results in a high production of damaging cytokines with concomitant aggravation of T2DM  and further fostering of cardiovascular complications.
Likewise the pathways described for T2DM, it has been proposed that silent subacute inflammation is also operative in type 1 diabetes mellitus (T1DM) as a promoter of cardiovascular disease development . Recently, the possible role in atherosclerosis of new inflammatory biomarkers as YKL-40 has been investigated in patients with either type of diabetes [26,27,28]; the beneficial effects of many pharmacological and nutritional agents in diabetes, obesity and metabolic syndrome are suggestively connected to their anti-inflammatory properties in both experimental and clinical settings. Particularly, anti-inflammatory properties were demonstrated for unsaturated fatty acids [29, 30], acetylsalicylic acid , healthy diet [32, 33], sodium-glucose co-transporter 2 (SGLT2) inhibitors , glucagon-like peptide-1 (GLP-1) receptors agonists  and statins .
The CANTOS trial enrolled into the study more than 10,000 patients over the last 6 years. As previously stated, its phase 3 demonstrated that canakinumab significantly reduced the risk of MACE, a composite of cardiovascular death, and both non-fatal myocardial infarctions and strokes in patients with a prior heart attack and inflammatory atherosclerosis . Thus, the anti-inflammatory agents targeting the IL-1ß pathway appear to be currently the most promising for clinicians. Specifically, dipeptidyl peptidase-4 (DPP4) inhibitors (gliptins) have been found to reduce the inflammatory state and restrain the elevation of IL-1ß in animal studies [37, 38]. The CANTOS findings reinforce the concept that atherosclerosis is a systemic disease, and in light of its inflammatory nature, it basically requires systemic therapies that can no longer be restricted to the reversal of coronary and peripheral arteries stenoses .
Recently, our research group has shown in a prospective randomized study that the addition of the DPP4 inhibitor vildagliptin to metformin treatment in patients with T2DM led to a significant restrain of IL-1ß levels, accompanied also with a significant reduction of hsCRP and HbA1c . Therefore, seems that the entire field of inflammation and disease has reached a point where problem-oriented studies are needed to recognize specific targets for therapeutic interventions .
Since patients with diabetes are at a particularly high risk for cardiovascular events, the main question now is whether an appropriate anti-inflammatory strategy could be clinically effective for diabetic individuals as well. In this context, targeting inflammation to treat a given systemic disease is not nowadays “thinking outside the box”, but rather a mainstream working hypothesis. Namely, is anti-inflammatory therapy for diabetes just around the corner? Further large and well-controlled prospective clinical trials targeting inflammatory pathways for its treatment are warranted.
Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008;54:24–38.
Fisman EZ, Motro M, Tenenbaum A. Cardiovascular diabetology in the core of a novel interleukins classification: the bad, the good and the aloof. Cardiovasc Diabetol. 2003;2:11.
Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720–32.
O’Donoghue ML, Braunwald E, White HD, Lukas MA, Tarka E, Steg PG, Hochman JS, Bode C, Maggioni AP, Im K, Shannon JB, Davies RY, Murphy SA, Crugnale SE, Wiviott SD, Bonaca MP, Watson DF, Weaver WD, Serruys PW, Cannon CP, SOLID-TIMI 52 Investigators, Steen DL. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014;312:1006–15.
Novartis. Novartis phase III study shows ACZ885 (canakinumab) reduces cardiovascular risk in people who survived a heart attack (press release). 2017. https://www.novartis.com/news/-releases/novartis-phase-iii-study-shows-acz885-canakinumab-reduces-cardiovascmediaular-risk. Accessed 29 June 2017.
Liu Z, Zhao N, Zhu H, Zhu S, Pan S, Xu J, Zhang X, Zhang Y, Wang J. Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2. Cardiovasc Diabetol. 2015;14:125.
Moreno-Viedma V, Amor M, Sarabi A, Bilban M, Staffler G, Zeyda M, Stulnig TM. Common dysregulated pathways in obese adipose tissue and atherosclerosis. Cardiovasc Diabetol. 2016;15:120.
Obata Y, Maeda N, Yamada Y, Yamamoto K, Nakamura S, Yamaoka M, Tanaka Y, Masuda S, Nagao H, Fukuda S, Fujishima Y, Kita S, Nishizawa H, Funahashi T, Matsubara KI, Matsuzawa Y, Shimomura I. Impact of visceral fat on gene expression profile in peripheral blood cells in obese Japanese subjects. Cardiovasc Diabetol. 2016;15:159.
Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008;49:1562–8.
Yoshizaki T, Kusunoki C, Kondo M, Yasuda M, Kume S, Morino K, Sekine O, Ugi S, Uzu T, Nishio Y, Kashiwagi A, Maegawa H. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun. 2012;417:352–7.
Vavruch C, Länne T, Fredrikson M, Lindström T, Östgren CJ, Nystrom FH. Serum leptin levels are independently related to the incidence of ischemic heart disease in a prospective study of patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:62.
da Costa RM, Neves KB, Mestriner FL, Louzada-Junior P, Bruder-Nascimento T, Tostes RC. TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice. Cardiovasc Diabetol. 2016;15:119.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Investig. 2005;115:1111–9.
Charriere G, Cousin B, Arnaund E, André M, Bacou F, Pénicaud L, et al. Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem. 2003;278:9850–5.
Pereira VH, Marques F, Lages V, Pereira FG, Patchev A, Almeida OF, Almeida-Palha J, Sousa N, Cerqueira JJ. Glucose intolerance after chronic stress is related with downregulated PPAR-γ in adipose tissue. Cardiovasc Diabetol. 2016;15:114.
Garland SH. Short chain fatty acids may elicit an innate immune response from preadipocytes: a potential link between bacterial infection and inflammatory diseases. Med Hypotheses. 2011;76:881–3.
Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367–77.
Janowska J, Chudek J, Olszanecka-Glinianowicz M, Semik-Grabarczyk E, Zahorska-Markiewicz B. Interdependencies among selected pro-inflammatory markers of endothelial dysfunction, C-peptide, anti-inflammatory interleukin-10 and glucose metabolism disturbance in obese women. Int J Med Sci. 2016;13(7):490–9.
Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E740–7.
Bădulescu O, Bădescu C, Ciocoiu M, Bădescu M. Interleukin-1-beta and dyslipidemic syndrome as major risk factors for thrombotic complications in type 2 diabetes mellitus. Mediat Inflamm. 2013. doi:10.1155/2013/169420.
Peiró C, Romacho T, Azcutia V, Villalobos L, Fernández E, Bolaños JP, Moncada S, Sánchez-Ferrer CF. Inflammation, glucose, and vascular cell damage: the role of the pentose phosphate pathway. Cardiovasc Diabetol. 2016;15:82.
Odegaard AO, Jacobs DR Jr, Sanchez OA, Goff DC Jr, Reiner AP, Gross MD. Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes. Cardiovasc Diabetol. 2016;15:51.
Du Y, Ji Q, Cai L, Huang F, Lai Y, Liu Y, Yu J, Han B, Zhu E, Zhang J, Zhou Y, Wang Z, Zhao Y. Association between omentin-1 expression in human epicardial adipose tissue and coronary atherosclerosis. Cardiovasc Diabetol. 2016;15:90.
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al. Local and systemic insulin resistance resulting from hepatic activation of IKKβ and NF-κB. Nat Med. 2005;11:183–90.
Peeters SA, Engelen L, Buijs J, Chaturvedi N, Fuller JH, Schalkwijk CG, Stehouwer CD, EURODIAB Prospective Complications Study Group. Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: the EURODIAB Prospective Complications Study. Cardiovasc Diabetol. 2015;14:31.
Mathiasen AB, Harutyunyan MJ, Jørgensen E, Helqvist S, Ripa R, Gøtze JP, Johansen JS, Kastrup J. Plasma YKL-40 in relation to the degree of coronary artery disease in patients with stable ischemic heart disease. Scand J Clin Lab Investig. 2011;71:439–47.
Aguilera E, Serra-Planas E, Granada ML, Pellitero S, Reverter JL, Alonso N, Soldevila B, Mauricio D, Puig-Domingo M. Relationship of YKL-40 and adiponectin and subclinical atherosclerosis in asymptomatic patients with type 1 diabetes mellitus from a European Mediterranean population. Cardiovasc Diabetol. 2015;14:121.
Batinic K, Höbaus C, Grujicic M, Steffan A, Jelic F, Lorant D, Hörtenhuber T, Hoellerl F, Brix JM, Schernthaner G, Koppensteiner R, Schernthaner GH. YKL-40 is elevated in patients with peripheral arterial disease and diabetes or pre-diabetes. Atherosclerosis. 2012;222:557–63.
Sawada T, Tsubata H, Hashimoto N, Takabe M, Miyata T, Aoki K, Yamashita S, Oishi S, Osue T, Yokoi K, Tsukishiro Y, Onishi T, Shimane A, Taniguchi Y, Yasaka Y, Ohara T, Kawai H, Yokoyama M. Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial. Cardiovasc Diabetol. 2016;15:121.
Merone L, McDermott R. Nutritional anti-inflammatories in the treatment and prevention of type 2 diabetes mellitus and the metabolic syndrome. Diabetes Res Clin Pract. 2017;127:238–53.
Derosa G, Mugellini A, Pesce RM, D’Angelo A, Maffioli P. A study about the relevance of adding acetylsalicylic acid in primary prevention in subjects with type 2 diabetes mellitus: effects on some new emerging biomarkers of cardiovascular risk. Cardiovasc Diabetol. 2015;30(14):95.
Steckhan N, Hohmann CD, Kessler C, Dobos G, Michalsen A, Cramer H. Effects of different dietary approaches on inflammatory markers in patients with metabolic syndrome: a systematic review and meta-analysis. Nutrition. 2016;32:338–48.
Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48:677–85.
Kusaka H, Koibuchi N, Hasegawa Y, Ogawa H, Kim-Mitsuyama S. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol. 2016;15:157.
Rizzo M, Rizvi AA, Patti AM, Nikolic D, Giglio RV, Castellino G, Li Volti G, Caprio M, Montalto G, Provenzano V, Genovese S, Ceriello A. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovasc Diabetol. 2016;15:162.
Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18:1519–30.
Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol. 2015;14:129.
Dai Y, Dai D, Wang X, Ding Z, Mehta JL. DPP-4 inhibitors repress NLRP3 inflammasome and interleukin-1β via GLP-1 receptor in macrophages through protein kinase C pathway. Cardiovasc Drugs Ther. 2014;28:425–32.
Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, Bianchi R, Crisci M, D’Acierno L, Giordano R, Di Palma G, Conte M, Golino P, Russo MG, Calabrò R, Calabrò P. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep. 2014;16:435.
Younis A, Eskenazi D, Goldkorn R, Leor J, Naftali-Shani N, Fisman EZ, Tenenbaum A, Goldenberg I, Klempfner R. The addition of vildagliptin to metformin prevents the elevation of interleukin 1ß in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study. Cardiovasc Diabetol. 2017;16:69.
Hunter P. The inflammation theory of disease. EMBO Rep. 2012;13:968–70.
Both authors have equally contributed in the conception and drafting of the manuscript. Both authors read and approved the final manuscript.
The authors would like to thank the support of the Cardiovascular Diabetology Research Foundation (RA 58-040-684-1), Holon, Israel.
Both authors are the Editors-in-Chief of Cardiovascular Diabetology and declare that they have no competing interests.
Consent for publication
The authors agree to publish this article.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tenenbaum, A., Fisman, E.Z. Mirroring the CANTOS revolution: is anti-inflammatory therapy for diabetes just around the corner?. Cardiovasc Diabetol 16, 91 (2017). https://doi.org/10.1186/s12933-017-0573-z