Cytokine Blocker Eases Beta Cell Stress in Type 2 Diabetes

ZURICH, Switzerland, April 11 -- A rheumatoid arthritis agent delivered subcutaneously appears to be effective for type 2 diabetes, found investigators here.

In a placebo controlled trial of 70 patients, those given anakinra (Kineret), a recombinant human interleukin-1-receptor antagonist, had a mean hemoglobin A1c level at 13 weeks that was a almost a half percentage point lower than controls, the researchers reported in the April 12 issue of the New England Journal of Medicine.

Those given the drug also had improved insulin secretion and reduced inflammation markers, found Marc Y. Donath, M.D., of University Hospital Zurich, and colleagues.

"Our study suggests that antagonism of interleukin-1 has possible therapeutic potential in the treatment of type 2 diabetes," Dr. Donath's team wrote. "Further studies are needed to test higher doses of anakinra, to evaluate its long-term use, and to test interleukin-1 antagonists that have a prolonged half-life, with the aim of preventing beta cell destruction and promoting beta-cell regeneration in type 2 diabetes."

Because expression of the IL-1-receptor antagonist is decreased in beta cells from patients with type 2 diabetes, the researchers hypothesized that intervening in the islet balance between IL-1-receptor antagonist and IL-1?, a proinflammatory cytokine, might improve beta-cell function and glycemic control, according to the investigators.

In the double-blind, parallel-group trial, 34 patients were randomly assigned to 100 mg of anakinra once daily for 13 weeks while 36 patients were assigned to placebo. All patients continued their baseline antidiabetic therapy, dietary habits, and other lifestyle habits. Anakinra was FDA-approved in 2001 for rheumatoid arthritis.

At baseline and at 13 weeks, all patients had an oral glucose-tolerance test, followed by an IV bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study.

Patients were recruited from two centers in Denmark and Switzerland from January 2004 to March 2005.

At 13 weeks, the average absolute difference in HbA1c was a reduction of 0.33 percentage point in the anakinra group and an increase of 0.13 percentage point in the placebo group, yielding a between-group difference of 0.46 percentage point (95% CI, 0.01 to 0.90, P=0.03), the researchers reported.

Levels were also significantly lower in the anakinra group after four weeks with an absolute reduction of 0.36%, slightly better than the 0.33% at 13 weeks.

At 13 weeks, C-peptide secretion was enhanced (P = 0.05), and there were reductions in the ratio of proinsulin to insulin (P = 0.005) and in levels of IL-6 (P<0.001) and C-reactive protein (P = 0.002), the researchers reported.

Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and body-mass index were similar in the two study groups, the researchers said.

Symptomatic hypoglycemia was not reported by any patient, and there were no apparent drug-related serious adverse events.

This study showed that antagonism of interleukin-1 signaling with anakinra improved glycemic control, most likely through enhanced beta-cell secretory function. In fact, the investigators said, improved glycemia in the anakinra patients correlated with improved measures of beta-cell secretory capacity.

There were no alterations in insulin sensitivity on the basis of clamp studies, insulin sensitivity indexes, insulin-regulatory gene expression in skeletal muscle, or serum adipokine levels.

Finally, the researchers said, the BMIs of patients remained stable, thus excluding an anorexigenic effect of anakinra. However, they added, the possibility that higher doses of the drug might improve insulin sensitivity cannot be excluded.

Limitations of the study, they said, included its short duration and the lack of dose finding. Considering the short half-life of anakinra (six to eight hours), it is possible that a longer-lasting drug might improve the outcome.

In an accompanying perspective, Kristina I. Rother, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., wrote that it has become clear that the effectors of beta-cell failure are similar in both type 1 and type 2 diabetes. Thus, she said, alleviating beta-cell stress opens the door to therapeutic approaches that would probably be useful in all types of disease.

Anakinra is not alone in bridging the divide between disease mechanisms and appropriate treatments for the different types of diabetes, she said. There is growing interest in developing therapies that not only improve beta-cell function in the short term but also preserve beta-cell mass or promote beta-cell regeneration.

However, none of the currently available medications, including anakinra, is successful in long-term monotherapy, and none has effectively halted the continuous decline in beta-cell mass, she said.

She also pointed out a note of caution concerning potential long term benefits or lack of it, "Anakinra treatment led to a modest improvement in the control of glycemia, with a maximal effect at four weeks but with an upward trend in the glycated hemoglobin level at 13 weeks," she wrote.

"Although the findings regarding anakinra break new ground by demonstrating that inhibition of cytokine function can restore insulin secretion, the ultimate goal is the improvement of blood-glucose control without the need for triple- and quadruple-combination therapies, as well as the prevention of beta-cell death," Dr. Rother concluded.

Dr. Rother, the "Perspective" author, reported no financial conflict of interest.