Renal Benefit of Intensive Glucose Control Challenged

Kate Johnson

December 09, 2011

December 9, 2011 (Dubai, United Arab Emirates) — A convoluted dissection of new data from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) trial by its principal investigator was slammed by the session's chairperson at the International Diabetes Federation (IDF) World Diabetes Congress 2011 here.

"I think you should stick to the rules," professor Hans-Henrik Parving, MD, told principal investigator John Chalmers, MD, PhD, senior director and head of the professorial unit at the George Institute and emeritus professor of medicine at the University of Sydney and Flinders University in Sydney, Australia.

Dr. Chalmers' suggestion that end-stage renal disease might be prevented with intensive glucose involved a "unique" dissection of renal endpoints that drew harsh criticism from Dr. Parving, who is professor and chief physician in the Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Denmark.

"What you're doing with the renal data is unique from the point of view in that we have never, ever done anything like that," Dr. Parving told Dr. Chalmers before he left the podium. "The endpoint regarded by the FDA [Food and Drug Administration] and EMA [European Medicines Agency] is 'end-stage renal failure including renal death' — they are not separated — never, ever. And sustained doubling of serum creatinine — not one doubling, but sustained for 1 month. That is the official renal endpoint in all trials published until today. So I am a little puzzled by the fact that you start to separate them."

The new data Dr. Chalmers presented from the ADVANCE trial showed the effects of intensive glucose control on hard renal endpoints: new-onset microalbuminuria, new-onset macroalbuminuria, end-stage kidney disease (ESKD), renal death, and a doubling of creatinine above 200 U/L.

The study's 11,140 participants were randomly assigned to a gliclazide modified release–based intensive glucose control regimen targeting a hemoglobin A1c value less than 6.5% (n = 5571) or to standard guidelines-based glucose control (n = 5569).

Over a mean of 5 years of follow-up, the researchers found a significant 9% reduction in new-onset microalbuminuria (P = .012) and a significant 30% reduction in new-onset macroalbuminuria (P = .0004) for patients in the intensive treatment group.

Reporting "very new data only published in abstract form so far," Dr. Chalmers said that ESKD, defined as the need for dialysis or renal transplant, was reduced by a "very substantial" 65% (P = .012) with intensive therapy.

For the endpoint of renal death there was a tendency to improvement with intensive therapy, but with a hazard ratio [HR] of 0.85 this was not significant, he reported.

A combination of the dialysis, transplantation, and renal death endpoints showed a 36% reduction in risk with intensive therapy, a nonsignificant, "borderline" result, he said.

"A bit of a surprise" in the data was in the endpoint of doubling of serum creatinine above 200 U/L, Dr. Chalmers noted.

"Rather than an improvement, it looks like there's a slight deterioration — a 15% worsening [HR, 1.15] in the intensive [therapy] group," he said. "But let's look at it more closely."

Of the 129 patients who showed a doubling of serum creatinine greater than 200 U/L, 45 patients had a transient doubling that returned to normal before the end of the study and 84 had a sustained doubling, he said.

"That's very different because transient hemodynamic events — being put on this or that hypertensive agent during the study, et cetera, has an effect. So if we look at those with sustained doubling above 200 U/L you see that rather than a deterioration of 15% there's a suggestion of an improvement of 17%, though it's nonsignificant."

"And if we look at all sustained doubling, that is whether above 200 U/L or not, you see there is a suggestion of an improvement of 20%."

Dr. Chalmers said the results "strengthen the renal benefits of intensive glucose lowering and suggest that ESKD may be prevented with this approach. But the numbers are small and we do need confirmation from a larger trial in a higher risk population with sufficient renal endpoints to permit definitive determination of the effects of intensive glucose lowering on discrete renal endpoints including ESKD and renal death."

Although acknowledging Dr. Parving's criticism, Dr. Chalmers said his dissection of the data reveals some valuable information. "When you look at end-stage renal disease without renal death, [the effect of intensive therapy] was significant, and when you look at renal death it was highly suggestive and so my conclusion is we need larger numbers and we need to confirm. It points to a very real need to examine and confirm in a larger study."

Reached for comment on the findings, Hertzel Gerstein, MD, a member of the scientific committee of the International Diabetes Federation, which hosted this conference, said the analysis "suggests that intensive glycemic control can reduce some serious renal outcomes in people with type 2 diabetes and other cardiovascular risk factors."

Dr. Gerstein, also one of the principal investigators of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, is professor of medicine and holds the Population Health Institute Chair in Diabetes Research at McMaster University in Hamilton, Ontario, Canada.

"Since the analytic approach that was used does not appear to have been specified prior to completion of the trial, these results should be viewed as hypothesis-generating rather than hypothesis-proving," Dr. Gerstein told Medscape Medical News. "A careful review of the analysis once published will certainly provide more information."

The ADVANCE trial was sponsored by Servier. Dr. Chalmers and coauthors have received honoraria from Servier for speaking at scientific meetings. Dr. Chalmers also has served on the Servier Advisory Board and received research grants from Servier, administered through the University of Sydney, for the ADVANCE trial. Dr. Parving has disclosed no relevant financial relationships.

International Diabetes Federation (IDF) World Diabetes Congress 2011. Abstract #O-295. Presented December 8, 2011.

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