The metabolic risk factors that together earn the title metabolic syndrome turn out to not only raise the risk for metabolic disorders, such as diabetes, but also increase the risk for traditional immunological disorders, such as rheumatoid arthritis (RA), gout, psoriasis and Crohn’s disease. These conditions all appear to be driven by inflammatory processes that are also associated with diabetes. Moreover, some of these immunological diseases appear to be at the end of molecular pathways that also lead to metabolic disorders. All of this prompts the question: Is it time to start treating diabetes with the same types of drugs that we use to treat immunological disorders?
Multiple antiinflammatory drugs are under development or are already approved for the treatment of many diabetes-associated immunological conditions. Is it possible to repurpose these drugs for the treatment of diabetes itself? Alternatively, if diabetes is reconceived as an inflammatory disease, will new drug targets be revealed?
Marc Y. Donath, MD, of University Hospital in Basel, Switzerland, believes so. He recently published a review article describing potential treatment strategies that target inflammation in patients with type 2 diabetes.1 In his article, he describes the rationale for an immunomodulatory approach to the treatment of type 2 diabetes. He also surveys the single molecule targets that have thus far been identified for drug discovery and describes what could be expected when they are prescribed to patients with diabetes. He goes on to paint a picture of a future with drugs that act on an underlying dysfunctional pathway, normalizing the immune response and improving a patient’s health without specifically targeting a disease.
Dr. Donath’s approach is not only academic, but also clinical. “Antiinflammatory drugs are not approved yet for the treatment of diabetes alone. However, if I have a reason to treat a patient for a concomitant condition with such a drug, as described above [RA and gout], I am already doing it with sometimes impressive improvement of both conditions,” wrote Dr. Donath in an e-mail to The Rheumatologist.
Dr. Donath is also contributing to the creation of this next wave of diabetes drugs. He is listed as the inventor on a patent (WO6709) filed in 2003 for the use of an interleukin 1 (IL-1) receptor antagonist for the treatment of, or prophylaxis against, type 2 diabetes.
Target Molecules
Most investigators agree that inflammation plays a role in the pathogenesis of type 2 diabetes. Numerous studies have demonstrated that increased inflammation is associated with increased insulin resistance. Moreover, several inflammatory targets have been identified that may affect metabolism. These targets include tumor necrosis factor (TNF) and IL-1β. Twenty years ago, investigators discovered that TNF plays a role in insulin resistance in rodents. The work in rodents was followed by a human clinical trial that demonstrated that sustained TNF inhibition in obese individuals without diabetes resulted in a statistically significant decrease in fasting glucose and an increase in adiponectin.
Numerous studies have also described the role of IL-1β in impaired insulin secretion and insulin resistance. These include eight independent clinical trials using three different IL-1 modulators that confirm the important role of IL-1β for glucose metabolism in patients with diabetes. For example, anakinra (an IL-1β antagonist) treatment of patients with prediabetes resulted in improved β-cell secretory function. Later studies demonstrated that anakinra influences insulin secretion and insulin resistance, thereby improving type 2 diabetes pathogenesis. Canikinumab (another IL-1β-specific antibody) was also able to slightly improve insulin secretion rate in a small study of individuals with impaired glucose tolerance or well-controlled type 2 diabetes. A third IL-1 modulator (IL-1β-specific antibody, LY2189102) was able to improve glycated hemoglobin levels, fasting and postprandial glycemia, and inflammatory biomarkers.
Effective Immunomodulatory Drugs
Salsalate inhibits the NF-κB pathway. It is the prodrug form of salicylic acid and is prescribed because it has fewer side effects than sodium salicylate. Seven individual clinical trials have demonstrated that salsalate improves both inflammatory and metabolic markers. Specifically, treatment with salsalate improved glycemia, reduced levels of C-reactive protein and increased adiponectin blood plasma levels in obese and nondiabetic adults as well as adults with diabetes. In some cases, the mechanism of action of an antiinflammatory drug has not yet been fully elucidated. This is the case for diacerein and AC-201. Both of these antiinflammatory drugs have proven effective in patients with type 2 diabetes.
Future of Antiinflammatory Drugs
The cost of treating patients with diabetes is rapidly becoming a global concern. By extension, the cost of any new drug will likely be scrutinized, particularly since type 2 diabetes is a slowly progressing chronic disease. Treatment of diabetes with antiinflammatory drugs also raises numerous questions revolving around the magnitude of effect, as well as long-term safety. In particular, there is concern about the long-term effects of immunomodulatory drugs with long half-lives.
Dr. Donath believes rheumatologists will have an important role in exploring the effect of immunomodulatory drugs on the treatment of type 2 diabetes. “A large number of patients treated by rheumatologists have diabetes alongside with their rheumatoid disease. Some antiinflammatory drugs may improve both conditions. For example, patients with RA and diabetes may benefit for both conditions from a TNF antagonist or patients with gout and diabetes may have optimal treatment with an IL-1 antagonist.”
Can Obesity Be Ignored?
Deborah Jane Wexler, MD, an endocrinologist at Massachusetts General Hospital in Boston, spoke with The Rheumatologist by phone about the review article and the alternative approach to treating diabetes it describes. While agreeing that an antiinflammatory approach to treating diabetes is attractive for many diabetes scientists, she points out, “the problem is that the search for the antiinflammatory silver bullet drug has not been successful.”
She then turned the conversation to the subject of obesity, explaining that obesity triggers the inflammatory response. “To my mind, the best treatment is to deal with the obesity,” she says. Consequently, she believes that targeting one inflammatory molecule will not be enough to overcome the detrimental effect of obesity.
That said, she acknowledges that rheumatologists should be aware of the risk that the antiinflammatory drugs they prescribe may have an effect on diabetes. Patients with diabetes may be more prone to hypoglycemia when on antiinflammatory drugs and may require a modification of the dosage of their diabetes medicine.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
