Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

Abstract

Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states.

Conflict of interest statement

S.E. Shoelson is a shareholder in Catabasis Pharmaceuticals, which uses novel chemical approaches to target muscular dystrophy. He is also an inventor on the following patents: US Patent 6,468,755 (2002) and US Patent 6,630,312 (2003). A.B. Goldfine receives research support from the American Diabetes Association, the NIH, Cleveland Clinic (with support from Covidien and Ethicon), Xoma, and Diasome. She is a consultant for Kowa Pharmaceuticals, Baronova, the Translational Research Institute for Metabolism and Diabetes at Florida Hospital, and the National Institute of Diabetes and Digestive and Kidney Diseases. She is an inventor on the following patent: US Patent 8524661 (2016). In addition both S.E. Shoelson and A.B. Goldfine are inventors on US Patent 8445467.

Figures

Figure 1. Clinical trials to target inflammation in T2D and ASCVD.

Heightened inflammation that often accompanies obesity or excessive weight gain is a hypothesized mechanism for the associated increase in risk for T2D and ASCVD. Signaling pathways (e.g., NF-κB, inflammasome) and specific proinflammatory cytokines (e.g., TNF-α, IL-1β) have been both implicated in these pathologic processes and are potential targets for reversal and risk reduction. Salicylate and low-dose methotrexate (LDM) inhibit NF-κB as a downstream consequence of AMPK activation. IL-1β blockade mediated by IL-1Ra or specific antibodies inhibits IL-1β action and suppresses IL-1β production by dampening its self-induction; the same effect is potentially true for TNF-α blockade. Randomized, placebo controlled, double-masked clinical trials of salsalate (–, –132, 134, 137), LDM (8, 144), IL1Ra (–11, 178, 179, 181) anti–IL-1β (181, 184, 191, 192), and anti–TNF-α (12, 169) are being used to determine whether these antiinflammatory approaches affect disease risk in T2D and ASCVD. Reported randomized trials of 3 months duration or longer are referenced. CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcomes Study; CIRT, Cardiovascular Inflammation Reduction Trial; TINSAL T2D, Targeting Inflammation Using Salsalate for Type 2 Diabetes.

Figure 2. AMPK-regulated metabolism and inflammation.

AMPK activation via nutrient restriction or various drugs increases endogenous activators, leading to positive metabolic effects and inhibition of inflammation. AMPK activation promotes (green) nutrient uptake and energy storage while generally suppressing (red) cellular biosynthesis and growth. In cells mediating inflammatory responses, AMPK activation also suppresses NF-κB and synthesis of its targets (red). The antiinflammatory properties of salicylates and methotrexate are mediated, at least in part, through this pathway.