Clinical research to prevent or control type 2 diabetes has been sparked by the significant association between the sub-clinical inflammatory process and the onset of diabetes. The Cantos study’s secondary efficacy criterion was to analyze the influence of canakinumab on the development of diabetes and glycemic control.
Since the late 1980s, the incidence of type 2 diabetes has been steadily growing in all nations due to environmental and sociological changes that encourage physical inactivity and overeating. Obesity and type 2 diabetes are both characterized by sub-clinical chronic inflammation of varying severity, which is linked with an increase in inflammatory biomarkers derived mostly from adipose tissue.
The association of an inflammatory syndrome with diabetes has already been reported in the 19th century when Epstein demonstrated that the administration of high doses of salicylates could reduce glycosuria in type 2 diabetic patients, thus suggesting that an anti-inflammatory treatment may improve diabetes control. In the 1950’s, insulin-treated diabetic patients were given heavy dosages of salicylates for persistent arthritis.
A Source of Inflammatory Cytokines!
TNF-, interleukin 1, interleukin 6, interleukin 10, leptin, adiponectin, MCP (“monoyte chemoattractant protein”), resistin, angiotensinogen, and many other cytokines and other compounds involved in inflammation are produced by white adipose tissue, particularly abdominal adipose tissue. In diabetes, adipose tissue is also a target of the inflammatory process.
Adipose tissue growth in obesity is marked by an influx of macrophages and immune cells. These cells contribute to local inflammation as well as chemokine and adipokine release. The endocrine pancreas is also subjected to an inflammatory assault due to immune cell infiltration and the presence of cytokines such as interleukin 1, which are generated locally, but also by circulating adipokines from adipose tissue and maybe by the phenomena of glucolipotoxicity.
What Causes The Inflammatory Syndrome?
The relationship between persistent sub-clinical inflammation and diabetes can be traced back to a variety of causes. Obesity, together with inflammatory cell infiltration of adipose tissue and the synthesis of adipokines and chemokines is critical in the development of the inflammatory syndrome associated with diabetes. Excess adipokines released by adipose tissue attract inflammatory cells, hence perpetuating the inflammation.
A diet high in saturated fats, for example, can also induce inflammation by altering the microbiota by boosting the translocation of bacteria through the intestinal wall and an increase in the synthesis of lipopolysaccharides. Diabetes-related inflammation is also characterized by an increase in the number of white blood cells, C-reactive protein (CRP), and fibrinogen.
Furthermore, CRP is a risk factor for the development of diabetes in overweight or obese people. Inflammation therefore seems associated or involved in insulin resistance but also at the level of the β cell whose function is altered indirectly by the inflammatory process and directly by chemokines and adipokines.
Treatment of Inflammation and Diabetes
The tight relationship between the sub-clinical inflammatory process and the establishment of diabetes has sparked clinical research aimed at modifying inflammation in order to prevent or manage type 2 diabetes and its consequences. Non-pharmacological diabetes prevention strategies, such as weight loss, are associated with a decrease in inflammatory markers.
Furthermore, several therapies, such as insulin and glitazones can reduce inflammatory indicators irrespective of their effect on glycemic control. On the other hand, statins, which lower inflammatory biomarkers, but raise the risk of diabetes can be cited. Other than salicylates at very high dosages, no anti-inflammatory drug has showed a significant and repeatable benefit in recent years.
Indeed, anti-TNF, anti-interleukin 6, and anti-interleukin 1 receptor antibodies have resulted in a modest or no reduction in glycosylated hemoglobin in relatively short-term trials of less than a year.
The Cantos Study
Canakinumab, a human monoclonal antibody against interleukin 1 that is now licensed for the treatment of juvenile idiopathic arthritis was tested for its effectiveness in cardiovascular prophylaxis in the Cantos research. Numerous pre-clinical investigations have shown that atherosclerosis is an inflammatory disease, and that the degree of inflammation as measured by an increase in CRP, can predict the likelihood of cardiovascular events.
Interleukin 1 is a key cytokine in the inflammatory response because it promotes interleukin 6 signaling. Canakinumab has previously been proven to have anti-inflammatory benefits by lowering interleukin 6 and CRP without affecting LDL cholesterol.
The Cantos research is therefore a randomized, double-blind, placebo-controlled trial including 10,061 individuals with a myocardial infarction and a CRP of more than 2 mg/l; four groups were created, each receiving either a placebo or 50, 150, or 300 mg of canakinumab. Non-fatal myocardial infarction, non-fatal cerebrovascular accident (CVA), and cardiovascular death were the key effectiveness determinants.
The median follow-up period was 3.7 years, and CRP may be lowered by 26% with 50 mg, 37% with 150 mg, and 41% with 300 mg of canakinumab. The major determinant was decreased from 4.5 occurrences per 100 patients per year in the placebo group to 4.1 events in the 50 mg group, 3.86 events in the 150 mg group, and 3.9 events in the 300 mg group.
Only in the 150 mg/day group did the decrease become significant. Total mortality and cardiovascular mortality were unaffected. Nonetheless, death from severe infection or septic shock rose, but cancer mortality decreased. This trial indicated that an anti-inflammatory medication might lower the risk of myocardial infarction, primarily among patients on secondary prevention who were previously taking a statin with modest effectiveness.
Cantos Study and Diabetes
A pilot research conducted as part of the Cantos project showed in 2012 that despite a reduction in inflammation as measured by CRP and interleukin 6 levels, canakinumab at dosages ranging from 5 to 150 mg/month had no effect on glycosylated hemoglobin levels in diabetic individuals after 4 months. Similarly, there was no effect on blood sugar levels, insulin levels, or insulin resistance.
The Cantos study’s secondary efficacy criterion was to analyze the influence of canakinumab on the development of diabetes and glycemic control. 4,057 (40.3 percent) of the 10,061 individuals had diabetes, while 4,960 (49.3 percent) had pre-diabetes. Higher CRP levels were related with an increased risk of acquiring diabetes among individuals without diabetes after a median follow-up of 3.7 years.
While canakinumab was able to reduce inflammation as measured by CRP and interleukin 6 levels it did not reduce the incidence of new episodes of diabetes or improve glycemic control as measured by the HbA1c test, except temporarily between 1 and 6 months with a 0.1 to 0.3 percent improvement.
However, the cardiovascular protective effect of canakinumab in diabetic individuals has been seen, as it has in non-diabetic patients.