Diabetes-Modifying Antirheumatic Drugs: The Roles of DMARDs as Glucose-Lowering Agents

Abstract

Systemic inflammation represents a shared pathophysiological mechanism which underlies the frequent clinical associations among chronic inflammatory rheumatic diseases (CIRDs), insulin resistance, type 2 diabetes (T2D), and chronic diabetes complications, including cardiovascular disease. Therefore, targeted anti-inflammatory therapies are attractive and highly desirable interventions to concomitantly reduce rheumatic disease activity and to improve glucose control in patients with CIRDs and comorbid T2D. Therapeutic approaches targeting inflammation may also play a role in the prevention of prediabetes and diabetes in patients with CIRDs, particularly in those with traditional risk factors and/or on high-dose corticosteroid therapy. Recently, several studies have shown that different disease-modifying antirheumatic drugs (DMARDs) used for the treatment of CIRDs exert antihyperglycemic properties by virtue of their anti-inflammatory, insulin-sensitizing, and/or insulinotropic effects. In this view, DMARDs are promising drug candidates that may potentially reduce rheumatic disease activity, ameliorate glucose control, and at the same time, prevent the development of diabetes-associated cardiovascular complications and metabolic dysfunctions. In light of their substantial antidiabetic actions, some DMARDs (such as hydroxychloroquine and anakinra) could be alternatively termed “diabetes-modifying antirheumatic drugs”, since they may be repurposed for co-treatment of rheumatic diseases and comorbid T2D. However, there is a need for future randomized controlled trials to confirm the beneficial metabolic and cardiovascular effects as well as the safety profile of distinct DMARDs in the long term. This narrative review aims to discuss the current knowledge about the mechanisms behind the antihyperglycemic properties exerted by a variety of DMARDs (including synthetic and biologic DMARDs) and the potential use of these agents as antidiabetic medications in clinical settings.

BNT162b2 mRNA COVID-19 Vaccine Does Not Impact the Honeymoon Phase in Type 1 Diabetes: A Case Report

“…The transient alteration in blood glucose levels may be more pronounced in individuals with existing impaired glucose control. Of note, the rise in circulating levels of pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6, IFN-γ) in response to different triggers (e.g., vaccine excipients, adenoviral vectors, or the vaccine-derived SARS-CoV-2 spike protein immunogen) may cause pancreatic beta-cell dysfunction/injury [ 43 , 44 ] and/or insulin resistance [ 45 , 46 , 47 ], resulting in an acute impairment of blood glucose levels [ 7 , 48 , 49 ].…”

Antidiabetic effect of disease-modifying antirheumatic drugs

“…There is a growing body of data indicating a key role for the inflammatory process in the pathogenesis of type 2 diabetes (T2D) and T2D-dependent organ complications [2]. Findings indicate that a low-grade inflammatory process persists in T2D patients, and is associated with elevated serum levels of acute-phase proteins (e.g.…”

“…visfatin, resistin) and reduced levels of anti-inflammatory adipocytokines that enhance insulin sensitivity (e.g. adiponectin, omentin) [2]. A state of pro--inflammatory responsiveness is observed even before the diagnosis of diabetes, during a period of persistent hyperglycaemia.…”

“…A state of pro--inflammatory responsiveness is observed even before the diagnosis of diabetes, during a period of persistent hyperglycaemia. Therefore, T2D is currently considered an inflammatory disease that is associated with ongoing chronic systemic inflammation and pancreatic islet inflammation, resulting in the development of insulin resistance and pancreatic islet b-cell dysfunction [2].…”

“…Insulin resistance, diabetes and other signs of the metabolic syndrome are more frequently observed in patients with chronic arthritis, compared to healthy control, which may be related to the persistence of chronic systemic inflammation and type of therapy used (e.g. glucocorticosteroids [GCs]) [2,3].…”