This year’s European Association for the Study of Diabetes meeting took place in Rome, Italy. Rhonda Siddall reports on the highlights of the meeting, which included interesting results in diabetic retinopathy and a 10-year follow-up to UKPDS.
DIRECT results suggest increased regression of retinopathy in type 2 diabetes
Three studies of the effect of candesartan on diabetic retinopathy produced mixed results in the first large-scale programme assessing the effect of an angiotensin receptor blocker on the incidence and progression of eye complications in patients with diabetes.
The primary end points in the three DIabetic REtinopathy Candesartan Trials (DIRECT) were just missed. But investigators and independent clinicians argued the data were strong enough to influence clinical practice in secondary care although were insufficient to support a licence change.
Professor Anthony Barnett, Professor of Medicine, Consultant Physician and Clinical Director of Diabetes and Endocrinology at the University of Birmingham and Heart of England NHS Foundation Trust, said: “Though the trials did not reach their primary end points, the results suggest overall reduction in the risk of retinopathy in type 1 diabetes and increased chance of regression in type 2 diabetes”.
The three DIRECT trials: DIRECT-Prevent 1, DIRECT-Protect 1 and DIRECT-Protect 2 were later published in The Lancet (Lancet 2008;372:1394-1402). Results showed that treatment with candesartan reduced the risk of progression of retinopathy by 13% over placebo in normotensive or treated hypertensive, normoalbuminuric type 2 diabetes patients with retinopathy (p=0.2). Candesartan also increased the probability of regression of retinopathy by 34% compared to placebo (p=0.009, pre-defined secondary end point). In type 1 normotensive, normoalbuminuric diabetes patients without retinopathy at baseline, candesartan reduced incidence of retinopathy by 18% as measured by a two-step change on the Early Treatment of Diabetic Retinopathy Scale (p=0.0501) and a 35% reduction for a three-step ETDRS change (post-hoc analysis, p=0.003).
Professor Barnett said: “As a practising clinician, these data would persuade me to advise candesartan as a treatment for hypertension in patients with type 2 diabetes and established retinopathy and candesartan in type 1 diabetes patients at high risk of developing retinopathy because of poor control in spite of full support.”
Dr Paul Dodson, Associate Professor and Head of the Heart of England Diabetic Retinopathy Screening Centre of Excellence, said: “A potential medical option is welcome because tight control of blood glucose does not prevent all retinopathy progression and the use of laser photocoagulation of retinopathy is limited to when the disease is more advanced.”
West London GP Dr Sarah Jarvis said: “Candesartan is extremely well tolerated and safe, and while the primary end points were just missed, I consider the risk benefit profile to be positive for patients with diabetes, especially given the morbidity related to diabetic retinopathy and our limited options for primary prevention.”
UKPDS: 10-year results
Ten-year post-trial monitoring from publication of the landmark UKPDS (United Kingdom Prospective Diabetes Study) study presented at the meeting showed that while benefits of early intensive glucose lowering are sustained, blood-pressure lowering benefits are not.
The continuing benefits of intensive glucose lowering were seen in reduced risk of myocardial infarction (MI) and all-cause mortality as well as on major diabetes end points. UKPDS investigators described this as a “legacy effect”.
The original UKPDS study showed a non-significant reduction in MI and no improvement in all-cause mortality with intensive glucose lowering using a sulphonylurea or insulin, whereas metformin treatment in obese patients was associated with a significant reduction in MI risk and death (39% and 36% reductions, respectively).
Ten years on, significant risk reductions for MI (15%) and death (13%) were reported for the sulphonylurea/insulin group, while significant risk reductions persisted for any diabetes-related end point (21%), MI (33%) and death from any cause (27%) in the metformin group.
Tighter control of blood pressure, however, produced no lasting improvements in microvascular disease, MI, all-cause mortality or any diabetes-related end point. Differences in microvascular disease reported at the end of the original trial had disappeared over the next 10 years.
UKPDS investigators speculated that the difference between the blood pressure and the blood glucose findings suggested different pathophysiological mechanisms.
The effects of lowering blood pressure and intensive glucose control are additive in reducing the risk of cardiovascular mortality and all-cause mortality in type 2 diabetes patients, a new analysis of results from the ADVANCE trial showed.
An analysis of the blood pressure and intensive glucose control results already published in the Lancet and the New England Journal of Medicine showed that the benefits of the two strategies appeared to act independently. ADVANCE investigator Dr Bruce Neal, Senior Director at the George Institute for International Health in Australia, said: “This new data provides important confirmation that combination therapy is beneficial.”
The new data showed that the relative risk reduction for the combined intensive treatments both for all cause-mortality and for cardiovascular mortality were significantly reduced with combined treatment beyond that of either treatment independently.
Conflict of interest
Rhonda Siddall received sponsorship from Takeda to attend the EASD meeting.