Jun 23, 2013

New DCCT Data: HbA1c Matters Today, Tomorrow, and 20 Years On

CHICAGO — Dramatic reductions in diabetes complications achieved with intensive glycemic control in the landmark Diabetes Control and Complications Trial (DCCT) are still being seen — although to a somewhat lesser degree — nearly 2 decades after the study’s end.

After 18 years, the overall prevalence of diabetes complications is 50% lower among the type 1 diabetes patients in the DCCT who were randomly assigned to intensive glucose control compared with those who received conventional treatment, despite the fact that HbA1c levels are no longer different between the 2 study groups.

The findings were presented here at the American Diabetes Association (ADA) 2013 Scientific Sessions, in a special symposium commemorating the 30th anniversary of the launch of the National Institutes of Health–funded study that proved the benefit of intensive glucose control for patients with type 1 diabetes and established the practice as the standard of care (N Engl J Med. 1993;329:977-986).

DCCT/EDIC biostatistician John M. Lachin, ScD, professor of biostatistics and epidemiology, and statistics at the Biostatistics Center of George Washington University, Rockville, Maryland, told Medscape Medical News that even after so many years, “The message is exactly the same. The HbA1c matters today, tomorrow, and for many, many years to come. It matters.”

EDIC Investigates “Metabolic Memory”

The new data come from the DCCT’s long-term follow-up study Epidemiology of Diabetes Interventions and Complications (EDIC), which began in 1994, the year after DCCT ended. Glycemic control in the 2 groups became roughly the same soon after patients went back to their communities for care, so EDIC is measuring the ongoing impact of glycemic control in the initial study’s 10 years, a phenomenon investigators have dubbed “metabolic memory.”

Previously reported end points of retinopathy, nephropathy, neuropathy, and cardiovascular disease continue to be reduced among those originally in the intensive-treatment group, albeit to a lesser degree than in previous EDIC analyses in 2000 (N Engl J Med. 2000;342:381-389).

The investigators are also looking at mortality in EDIC, with results under embargo, as they are due to be published soon. However, Dr. Lachin did divulge that there is no increased mortality among the intensive-treatment group, a phenomenon that has been seen in some trials involving patients with type 2 diabetes.

EDIC coordinating center principal investigator, Rose Gubitosi-Klug, MD, assistant professor, pediatrics at Case Western Reserve University School of Medicine, Cleveland, Ohio, said: “In some ways, it’s surprising how it’s gone on this long. [The original DCCT investigators] expected the effect to wane after 10 or 12 years. But here we are at 18 years, and we still have significant risk reduction. Although it’s starting to decrease over time, there’s still a significant reduction. It’s fantastic.”

The lesson from all of it, said Dr. Gubitosi-Klug, is: “Start intensive diabetes management as soon as safely possible.”

Benefit of Intensive Therapy on Severe Eye Disease

The original DCCT, which involved 1441 patients with type 1 diabetes, demonstrated that intensive glycemic control — resulting in a mean HbA1c of about 7% — reduced the risk for retinopathy, nephropathy, and neuropathy by 76%, 50% and 60%, respectively, compared with the conventional-treatment group, whose HbA1c averaged about 9%.

After DCCT ended, patients who had been in the conventional-treatment group were instructed in intensive glycemic control. Their average HbA1c levels dropped to about 8%. At the same time, control worsened in the original intensive-control group to about 8%. That level has remained relatively unchanged during EDIC.

Lloyd P. Aiello, MD, PhD, head of the Joslin Diabetes Center, Section on Eye Research, Boston, Massachusetts, reported the new EDIC retinopathy findings. The difference in retinopathy rates between the previous intensive- and conventional-treatment groups was 70% at 4 years, 53% at 10 years, and 46% at 18 years. Rates of ocular surgery were also lower at 18 years in the prior intensive group, with differences of 48% in cataract extraction and 44% in vitrectomy or retinal detachment.

“Further EDIC follow-up has demonstrated a consistent beneficial effect on severe eye disease. Even though the risk reduction has decreased with time, the effect is still substantial after 18 years of EDIC follow-up,” said Dr. Aiello, who is also associate professor of ophthalmology at Harvard Medical School, Boston, Massachusetts.

A Generation of Improved Care

Among the most recent neuropathy findings, presented by Catherine L. Martin, MS, APRN, CDE, from the University of Michigan, Ann Arbor, were a 30% reduction in the development of confirmed clinical neuropathy and 31% reduction in confirmed autonomic neuropathy among the intensive-treatment group at year 14 of EDIC, both statistically significant.

Ian H. de Boer, MD, associate professor of medicine and adjunct professor of epidemiology from the University of Washington, Seattle, presented the 18-year update demonstrating continued effects of intensive glycemic control on kidney function.

For example, at 18 years there was a 39% reduction in risk for the development of microalbuminuria among the subjects who did not have it at the start of DCCT. At 8 years, that risk reduction had been 57%.

The comparable numbers for the development of macroalbuminuria were 61% at 18 years, compared with 84% at the 8-year analysis. A parallel reduction in hypertension is a likely mechanism, he said.

Previously, his group had shown a 50% risk reduction in the development of impaired glomerular filtration with intensive control.

At the beginning of Dr. deBoer’s presentation, he showed a photo of himself at age 10 in 1982, the year DCCT started.

“To me, the fact that the DCCT started when I was 10 years old and is still active today speaks to its durable influence and highlights that the DCCT/EDIC study continues to provide knowledge and the opportunity to improve the care of patients with type 1 diabetes, for more than a generation.”

Clinically Meaningful CVD Reductions Persist

However, at 9 years into EDIC, there was a 42% decrease in any cardiovascular event and a 57% reduced risk for nonfatal heart attack, stroke, or death from cardiovascular causes, as previously reported (N Engl J Med. 2005;353:2643-2653).

Extending those analyses through 2012, those same risk reductions are 33% and 35%, “both still statistically significant and of course clinically meaningful,” he observed.

Previously published EDIC analyses have shown benefits of intensive glycemic control in carotid intimal-medial thickness (Diabetes. 2011;60:607-613) and cardiac function, he added.

Dr. Gubitosi-Klug concluded the symposium by summarizing future directions, noting that all the currently monitored end points will continue to be followed, with cardiovascular end points expected to become more prevalent in the now middle-aged study population.

Additional new analyses are planned to look at hearing impairment, gastric emptying, and the impact of residual C-peptide excretion on HbA1c and the development of complications, she said.

Both the DCCT and the EDIC are funded by the US National Institutes of Health. Dr. Gubitosi-Klug, and Ms. Martin have reported no relevant financial relationships. Dr. Lachin is a board member of Boehringer Ingelheim, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, and Reata and is a consultant for Andromeda Biotech and Magellan Health Services.

American Diabetes Association (ADA) 2013 Scientific Sessions. DCCT/EDIC 30th Anniversary Symposium-Contributions and Progress, presented June 22, 2013.


— Miriam E. Tucker


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