Smithkline Beecham launched its new diabetes drug rosiglitazone (Avandia) this week. The drug is said to target the two fundamental causes of type 2 diabetes: insulin resistance and beta-cell dysfunction. It improves glucose control and SB is hoping that this means it will slow disease progression and reduce the risk of long-term diabetic complications.
Rosiglitazone is a thiazolidinedione (glitazone) drug. It is licensed for use in combination therapy with other oral hypoglycaemic agents in defined circumstances (see Panel, right). SB says that clinical trials have shown that, in combination with conventional hypoglycaemic drugs, rosiglitazone provides an additional 1 to 1.2 per cent reduction in glycosylated haemoglobin (HbA1c), and that this is achieved without exacerbating the hypoglycaemia associated with sulphonylurea monotherapy or the gastrointestinal disturbances associated with metformin monotherapy.
The new drug will be an alternative to insulin therapy in certain patients in whom conventional therapy is insufficient. At present, some 20 to 30 per cent of type 2 patients eventually use insulin.
At the launch of rosiglitazone on July 24, Professor Tony Barnett (professor of medicine, University of Birmingham) said that no other drug was able both to reduce insulin resistance (ie, increase insulin sensitivity) and to preserve beta-cell function. He explained that rosiglitazone acted by binding to peroxisome proliferator-activated receptor gamma (PPARg) nuclear receptor, leading to activation of genes involved in glucose and fat metabolism.

Licensed indications

Rosiglitazone is licensed for use in two groups of patients. It can be used with metformin in obese patients with insufficient glycaemic control despite maximal tolerated dose of metformin, and with a sulphonylurea in patients who cannot take metformin and have insufficient glycaemic control despite maximal tolerated dose of sulphonylurea.
SB is hoping to get a licence for use of rosiglitazone as monotherapy. Dr Alastair Benbow (medical director, SB) said that the European licensing authority had been "conservative" in its approval of the drug. "We think we have good data on monotherapy," he said.

The improved glycaemic control seen with a combination of rosiglitazone with metformin or a sulphonylurea was sustained for up to two years in clinical trials. "Rosiglitazone has the potential to delay disease progression and to alter disease outcomes, with a reduction in vascular disease," said Professor Barnett.
In terms of effects on lipids, after 18 months' treatment there was a decrease in total cholesterol:HDL cholesterol ratio. Longer-term data were obviously needed, but this lipid profile indicated protection against cardiovascular disease.
Professor Barnett added that the drug could lead to a weight increase of around 3kg. But it was also associated with a redistribution of body fat from central stores (associated with insulin resistance) to subcutaneous tissues. "It is redistributed from bad sites to good sites," he said.
Dr Peter Tasker (chairman of the primary care branch of Diabetes UK) said that the benefits of good control of type 2 diabetes had been shown in the UK Prospective Diabetes Study (UKPDS) in which a 0.9 per cent reduction in glycosylated haemoglobin had been shown to equate to a 25 per cent reduction in microvascular complications. He said that good glycaemic control (HbA1c less than or equal to 7 per cent) might initially be easy to achieve but, as a patient's disease progressed, control became more difficult. In UKPDS, after three years, 50 per cent of patients required combination therapy to maintain glycaemic control. Dr Tasker said that, at present, many patients with type 2 diabetes were uncontrolled.

Rosiglitazone and the liver

Rosiglitazone is in the same class as Glaxo Wellcome's troglitazone, a drug that was marketed for only a few months in 1997 before being withdrawn because of hepatic toxicity. SB says that there is no evidence of hepatic toxicity with rosiglitazone, although monitoring of liver function during treatment is recommended.
The company's summary of product characteristics notes that isolated cases of elevated liver enzymes and hepatocellular dysfunction have occurred in postmarketing experience. "Although in very rare cases fatal outcome has been reported, causal relationship has not been established," it says.
Speaking at the launch of the drug, Professor Tony Barnett (professor of medicine, University of Birmingham) said that the toxicity seen with troglitazone was "almost certainly" an idiosyncratic reaction related to its chemical structure. He said that in rosiglitazone clinical trials there had been no difference in liver enzyme abnormalities compared with placebo.