The fall-out from the furore over the cardiovascular safety of Avandia could mean delayed approvals for new antidiabetic drugs in future, increased requirements for safety data, and a lasting legacy of excessive caution among prescribers, experts suggested yesterday.
Professor John Wilding, consultant physician specialising in metabolic diseases and Dr Andrew Krenz, consultant diabetologists and endocrinologist at Southampton University, told journalists on a conference call that the safety and tolerability of new agents such as the upcoming class of dipeptidyl peptidase-4 (DPP-4) inhibitors would be at the forefront of clinicans’ minds in future when considering whether or not to prescribe them.
This was despite the cardiovascular risk associated with Avandia (rosiglitazone) amounting to an increased event rate of only 0.6% and of dubious clinical significance. Nevertheless, doctors will want more information on DPP-4 inhibitors now, they suggested. “‘I’m not entirely sure their mechanism of action of action has been fully elucidated,” said Professor Wilding. “There are theoretical concerns because of the ubiquitous nature of DPP-4 and of other substrates that these drugs may impact – some of which may be gut hormones we don’t even know about yet.”
However, so far, the data with Merck & Co’s Januvia (sitagliptin) and Novartis’ Galvus (vildagliptin) and their effects on other cardiovascular risk factors are reassuring and there is no signal of potential cardiovascular problems that might emerge, they said. “Au contraire, they are more likely to be cardioprotective,” claimed Dr Krenz. GLP-1 receptors expressed in the myocardium and endothelium show GLP-1 stimulation confers protection against infarcts in rat models. Drugs that enhance GLP-1 should therefore confer an advantage.
On cardiovascular risk factor profiles of the class, he added: “Unlike rosiglitazone, both Galvus and Januvia produce slight improvements in lipid profiles with all subfractions moving in the right direction.” Three abstracts at the American Diabetes Association meeting in Chicago this week also highlighted a significant blood-pressure lowering effect of Galvus, particularly evident among patients who were hypertensive at baseline, although this observation has not been reported for Januvia or other DPP-4 inhibitors in development.
“An unexpected finding for Galvus reported at ADA was its ability to significantly delay gastric emptying with a single 100mg dose in comparison to placebo,” said Dr Krenz. Delayed gastric emptying and consequent prolonged feelings of satiety are attributes of the GLP-1 agonists such as Lilly’s Byetta (exenatide) which claim to help patients lose excess weight, itself a cardiovascular risk factor, and thereby improve glycaemic control.
“Sitagliptin is probably the cleanest, most selective, of the DPP-4s developed,” he added “although all have high selectivity for DPP-4. Data regarding glucose-lowering extend to two years for Galvus and one year for Januvia and show efficacy is sustained.”
Januvia sales are said to have risen by around 30% since the Avandia story broke, according to US reports, reflecting clinicians’ confidence in the safety of DPP4 inhibitors. However, the FDA’s delayed approval of Galvus for further safety studies was understandable, given the concern from the glitazones, said Prof Wilding, who added that Europe will decide on approval of Galvus later this year.
“The claims for DPP-4s have resonances with those of the thiazolidinediones in their early days” said Dr Krenz. “Seven or eight years ago, we were hearing the same promise of beta cell preservation for rosiglitazone. Doctors will be keeping rosiglitazone in mind as the DPP 4 story unfolds.” By Olwen Glynn Owen