VIENNA – Five years of intensive glycemic control in patients with type 2 diabetes safely halved long-term rate of end-stage renal disease, compared with placebo, in a multicenter study with about 8,000 patients, a finding that refutes prior suggestions that more intensive glycemic control can harm patients.
Intensive glucose control that produced an average hemoglobin A1c of 6.5% “is important for preventing serious renal complications and does not cause harm in patients with established type 2 diabetes,” Dr. Sophia Zoungas said at the annual meeting of the European Association for the Study of Diabetes.
Mitchel L. Zoler/Frontline Medical News
Dr. Sophia Zoungas
Following the report of results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial in 2008 (N. Engl. J. Med. 2008;358;2545-59), which showed increased mortality with intensive glycemic control, compared with standard treatment, many physicians became leery of treating patients to a HbA1c level below 7%. But 5-year follow-up results of patients originally enrolled in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560-72) has now shown that a prolonged period maintaining patients at a HbA1c of roughly 6.5% produced no excess rates of total mortality, major macrovascular events, or major clinical microvascular events when compared with patients on standard care with an average HbA1c of 7.2%, said Dr. Zoungas, an endocrinologist with the George Institute of the University of Sydney.
“Whether the excess mortality seen in ACCORD was a true effect or not, there has been concern [about tight glycemic control] that has translated into where HbA1c targets have been set,” Dr. Zoungas said in an interview. “We have been blinded by this signal of increased fatal myocardial infarctions [seen in ACCORD] that many have been a chance effect.”
She suggested that the safety that intense glycemic control showed during 10-year follow-up of patients in the ADVANCE posttrial Observational Study (ADVANCE ON) may be explained by the more gradual HbA1c reductions achieved in the ADVANCE patients, compared with patients in ACCORD. In ADVANCE, patients’ HbA1c levels came down to about 6.5% over the course of a year, compared with a 3-6 month period in ACCORD, Dr. Zoungas noted.
In addition to establishing safety, the new results reported by Dr. Zoungas showed a statistically significant, 46% reduction in the incidence of end-stage renal disease (defined as progression to dialysis or need for kidney transplant) during the entire, 10-year follow-up. Simultaneous with Dr. Zoungas’s report at the meeting the ADVANCE ON results were published online (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1407963]).
“This is the first time study results have shown that maintaining a HbA1cof less than 7% is associated with a long-term reduction in end-stage kidney disease,” she said. “End-stage kidney disease has been hard to study [as an endpoint] because the overall incidence is low, so patients need to be followed for a long time to see enough events.”
ADVANCE ON initially included 8,494 of the roughly 10,000 patients who completed the 5-year ADVANCE intervention trial at 215 centers in 20 countries. ADVANCE tested the impact of an antihypertensive intervention as well as the effect of intensified glycemic control in patients aged 55 years or older with type 2 diabetes and at least one other cardiovascular risk factor. At the time ADVANCE ended, average HbA1c levels were 7.2% in the control patients and 6.5% in those who had been on a more intensive hypoglycemic regimen. However, at the time patients began ADVANCE ON, their average HbA1c was 7.5%, regardless of which arm of ADVANCE they had been in, and the average level remained there through a median of 5 more years of follow-up. A total of 5,131 patients remained under study for the entire 10 years of follow-up. Analysis of the ADVANCE ON findings also showed a significant long-term effect from 5 years of added antihypertensive treatment, results reported in early September at the annual congress of the European Society of Cardiology.
ADVANCE ON received partial funding from Servier. Dr. Zoungas has received honoraria from Servier as well as from Merck, Bristol-Myers Squibb/AstraZeneca, Sanofi-Aventis, Novo Nordisk, and Amgen.
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