The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) study was presented at the American Diabetes Association (ADA) meeting in June 2012 and simultaneously published in the NEJM. It was a large trial (>12,500 participants), which sought to establish if early use of basal analogue insulin, titrated according to fasting blood glucose levels, would reduce cardiovascular events. ‘Early use’ was certainly the case since 12% of subjects had ‘pre-diabetes’ and 6% were newly diagnosed, meaning that 40% of participants were on no hypoglycaemic therapy at baseline. All were, however, at high cardiovascular risk (defined according to a previous event or presence of risk factors such as albuminuria or left ventricular hypertrophy). Trial subjects received glargine or no treatment in an open design but were also randomised to double blind therapy with omacor or placebo to assess the impact of omega 3 fatty acids in this scenario.
The outcome of the study was negative, in that neither glargine nor omacor reduced the rate of CV outcomes. There were, however, some positive messages. First, the trialists managed to retain a very high level of compliance with an injectable therapy, with more than 83% of subjects randomised to glargine remaining on therapy after 6 years. This is important in an era where all GLP-1 receptor agonist injectables are being subjected to placebo-controlled CV outcome studies. Second, the overall and individual cancer outcomes were identical for glargine versus standard therapy. Whilst the study was not powered to prove cancer safety, these data are reassuring and much more convincing than the pharmaco-epidemioligcal database trawling that led to the cancer scare in the first place.
Will the study alter practice? Almost certainly not. In the UK at least, early use of insulin is unusual and doesn’t fit with the cash limited QIPP algorithm for type 2 diabetes management. The suggestion that the study demonstrated a delay in new-onset of diabetes by early insulin use is also unlikely to cut ice, since the numbers needed to treat are large (15 to prevent one case) and hypoglycaemia, albeit uncommon, was increased by three-fold. Finally, the trial sponsors are unable to promote the results of ORIGIN since it was partly performed in an off-licence population (those who didn’t have diabetes).
Professor Steve Bain