November 12, 2011 (Philadelphia, Pennsylvania) — Intensive therapy for type 1 diabetes mellitus lowers the long-term risk for impaired glomerular filtration rate (GFR), a predictor of end-stage kidney disease and a risk factor for cardiovascular disease and death, Ian de Boer, MD, MS, assistant professor of medicine in the division of nephrology at the University of Washington in Seattle, told delegates in a late-breaker trials session here at Kidney Week 2011: American Society of Nephrology 44th Annual Meeting.
Compared with conventional therapy, intensive type 1 diabetes therapy halved the risk for impaired GFR over a median follow-up of 22 years. The study was published online today in the New England Journal of Medicine. Early intensive therapy appears to have a protective "memory effect" on the kidney.
The study consisted of an intervention trial, the Diabetes Control and Complications Trial (DCCT), and a follow-up observational trial, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. DCCT randomly assigned 1441 individuals with type 1 diabetes to intensive diabetes therapy (n = 711), with 3 or more insulin injections per day and a target of near-normal glucose concentrations, or to conventional diabetes therapy (n = 730) with 1 or 2 injections per day and a target of preventing hyperglycemic symptoms, for 6.5 years. Then 1375 of the participants were followed in the EDIC study; there were approximately equal numbers in the 2 groups.
"The DCCT/EDIC study had phenomenal retention throughout its course, with 85% of participants completing the EDIC year 16 visit, on average, 22 years after baseline," Dr. de Boer said at a news conference.
Throughout the course of the studies, the intensive and conventional treatment groups were well matched demographically. At the beginning of DCCT, people in both groups had an average age of 27 years (range, 13 to 39 years) and a diabetes duration of 6 years. At initiation, no subject was taking an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker, but by year 16 of EDIC, 53% to 57% of the 2 groups were taking these drugs. Blood pressures remained in the normal range throughout the course of both studies in both groups.
The studies incorporated annual measurements of serum creatinine levels. Over the course of the 2 studies, the investigators determined the long-term effects of intensive therapy on the risk for impairment of the GFR, which was defined as an incident estimated GFR of less than 60 mL/min per 1.73 m² at 2 consecutive study visits.
In DCCT, the primary prevention cohort (n = 711) had diabetes for 1 to 5 years, an albumin excretion rate below 40 mg/day, and no retinopathy; the secondary prevention cohort (n = 730) had diabetes for 1 to 15 years, an albumin excretion rate below 200 mg/day, and at least 1 retinal microaneurysm.
Intensive Therapy Cuts Adverse Outcomes in Half
During DCCT, mean glycated hemoglobin (hemoglobin A1c) in the intensive group was 7.3% and in the conventional group was 9.1%, Dr. de Boer reported. "In EDIC years 1 through 16, mean hemoglobin A1c was near 8% in each treatment group, and there was no clinically or statistically significant difference."
Over the 22 years of the 2 studies, 24 individuals in the intensive group developed impaired GFR, as did 46 in the conventional group, resulting in a risk reduction of 50% with intensive therapy (95% confidence interval,18 to 69; P = .006).
"It is important to notice the time of these events. Only 4 of 70 occurred during DCCT itself, and 66 of 70 occurred during EDIC study follow-up. You can see that almost all events occurred more than 10 years after randomization," Dr. de Boer said.
Furthermore, the cumulative incidence of impaired GFR was 5.5% with conventional therapy and 2.0% with intensive therapy, which is an absolute risk reduction of 3.3% and a number needed to treat of 29. Eight participants in the intensive group and 16 in the conventional group developed end-stage kidney disease.
Initially, the intensive group had greater reductions in GFR. In DCCT, intensive therapy was associated with a drop in the mean estimated GFR of 1.7 mL/min per 1.73 m², compared with conventional therapy. However, during EDIC, intensive therapy was associated with a slower rate of decline in the estimated GFR, and an increase in estimated GFR over conventional therapy of 2.5 mL/min per 1.73 m² (P < .001 for both).
The beneficial effect of intensive therapy on the risk for impaired GFR disappeared after adjustment for hemoglobin A1c levels and albumin excretion rates.
Dr. de Boer concluded that "intensive diabetes therapy applied early in the disease course has long-lasting kidney benefits. After combining these data with previous reports that DCCT intensive therapy reduces risks of retinopathy, neuropathy, albuminuria, and cardiovascular disease, these results support current recommendations to target hemoglobin A1c in the clinical care of people with type 1 diabetes." However, he explained that there is no evidence upon which to extrapolate the results from this study to people with type 2 diabetes.
Lawrence Agodoa, MD, director of the Office of Minority Health Research Coordination at the National Institute of Diabetes and Digestive and Kidney Diseases, and director of the chronic kidney disease and end stage renal disease programs at the National Institutes of Health in Bethesda, Maryland, told Medscape Medical News that the findings are very clinically relevant and will improve patient care.
He said the DCCT phase consisted of very intensive therapy for a relatively short time. "But when they finished, the patients did not go back to just the conventional [therapy], so there was some continuing of better-than-conventional management of these patients. The important thing is it's not as intense as during the therapy period, so what we're seeing is some kind of memory effect of the intensive therapy," he noted. "They actually are still benefiting from the short period of intensive therapy." He added that other studies have shown a similar effect, but DCCT is the first to show the effect for so long.
Dr. Agodoa said it is feasible for patients in the community to follow a program of intensive therapy involving 3 or more insulin shots a day. Patients know about the adverse and potentially serious outcomes of diabetes, and are motivated to try to prevent them. Also, better medications and longer-acting insulin formulations make adherence easier than when the earlier diabetes tight-control trials were done about 25 years ago.
The study showed that when the data were adjusted for hemoglobin A1c levels or the albumin excretion rate, the beneficial effect disappeared. Dr. Agodoa said that this fact shows that no matter how one lowers these parameters, the benefit becomes apparent. "If you lose weight and you exercise more and your glycemic control is better, that is good. However you get there is good," he said. "It's not saying that you have to have insulin shots 5 times, 6 times a day, but however you achieve normoglycemia, you benefit from it."
Besides US government grants and other support, the study received funding from Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Abbott, Animas, Aventis, Bayer, Becton Dickinson, Can Am, Eli Lilly, LifeScan, Medtronic, MiniMed, Omron, OmniPod, Roche, and sanofi-aventis provided free or discounted supplies or equipment. Dr. de Boer reports that his institution received grants from Abbott Laboratories. Dr. Agodoa is employed by NIDDK, which funded the study, but he was not the program director for the study and had no involvement with it.
N Engl J Med. Published online November 12, 2011. Abstract
Kidney Week 2011: American Society of Nephrology 44th Annual Meeting. Presented November 12, 2011.
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