ACCORDION CV Mortality Drops, Eye Benefits Remain in Follow-up

Miriam E Tucker

December 09, 2015

VANCOUVER, British Columbia — New results from long-term follow-up of participants from the ACCORD trial show that although the increased cardiovascular death rate is still significantly elevated in the group previously randomized to intensive glycemic control, the risk has diminished over time, while the increased all-cause mortality has disappeared.

New data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Follow-on Study (ACCORDION) also continue to show a retinopathy benefit from the average 3.7 years of intensive glucose-lowering in the original trial, while no effect is seen for the intervention on brain structure and function.

The ACCORDION findings for the glucose-lowering arm of the ACCORD trial were presented by three speakers on December 3 in a symposium here at the World Diabetes Congress 2015. Results from the ACCORDION blood-pressure–lowering arm were presented in November at the American Heart Association scientific meeting

In the original 77-site ACCORD trial, a total 10,251 patients with type 2 diabetes and other cardiovascular risk factors were randomized to intensive glucose lowering, targeting an HbA1c of less than 6.5% vs a standard-care group aiming for HbA1c levels 7% to 7.9%.

In 2008, the glucose-lowering arm of the trial was stopped early at a mean of 3.7 out of a planned 5.6 years, because of an unexpected 22% increase in cardiovascular and all-cause mortality in the intensively managed group. (The blood-pressure and lipid-lowering arms continued for the rest of the planned study period.)

"There is no clear explanation for the higher cardiovascular mortality, and this is not because we haven't looked. I can assure you that the ACCORD investigators have spent about 7 years pulling their hair out, trying to figure out if there is any biological explanation for the CV mortality signal," study principal investigator Hertzel C Gerstein, MD, professor of medicine and director of the division of endocrinology and metabolism, McMaster University, Hamilton, Ontario, said during his presentation.

In ACCORDION, the study patients — now with similar levels of glycemic control and managed by their personal physicians — were assessed seven times until October 2014, for a median 8.8 years of follow-up. A total 90% of the original ACCORD patients participated, including 98% of the 8777 with no primary outcomes, Dr Gerstein noted.

The new ACCORDION data suggest that the increased CV mortality among those previously in the intensively treated group is still statistically significant — an absolute increase of 0.13% per year or 1.3%/10 years — but far less so than before. And, at 9 years, there was a neutral effect for all-cause death, heart-failure hospitalization, and a predefined composite of CV death, nonfatal MI, and nonfatal stroke, he said.

Session moderator Irene Hramiak, MD, professor of medicine and division chair of diabetes and metabolism at the Schulich School of Medicine & Dentistry at Western University, London, Ontario, told Medscape Medical News, "We still don't know why there was increased mortality [in the original ACCORD trial], but it is reassuring that the intervention that was undertaken didn't continue to have effects long term. You sort of wonder whether it could have been a chance finding, which has been discussed in the literature."

She added, "I think the paradigm is early on, when you can easily treat people to [an HbA1c of] 6.5 to 7.0 with agents that don't cause hypoglycemia, there may be benefit….ACCORD was in people with established risk factors, older, and on insulin. There we see a waning benefit. I think where we intervene as clinicians may be the most important decision we make for each patient, and we don't treat all patients the same. These data suggest we shouldn't and we might have to individualize targets."

ACCORDION Shows Ongoing Retinopathy Benefit

Emily Y Chew, MD, deputy director of the division of epidemiology and clinical applications and the deputy clinical director at the National Eye Institute, National Institutes of Health, Bethesda, Maryland, presented the ACCORDION findings for retinopathy.

In the original ACCORD Eye Study, tight glycemic control and intensive control of dyslipidemia (using fenofibrate and simvastatin) slowed progression of retinopathy, defined as at least three levels of progression on the ETDRS scale assessed with fundus photography or the need for either photocoagulation or vitrectomy. Blood-pressure lowering had no such effect, however.

The odds ratios in ACCORD were 0.67 for glycemia, 0.60 for lipids, and 1.23 for blood pressure. The results were similar using photographic grading data only, with odds ratios of 0.61 (P = .001), 0.54 (P = .002), and 0.97 (P = .88), respectively.

Photographic grading data alone were used in ACCORDION, with follow-up at baseline and year 8. Data were available for 1268 of the original 2175 ACCORD Eye Study patients.

At 8 years, the effective of intensive glycemic control in the original ACCORD trial remained highly statistically significant, with an odds ratio of 0.42 compared with the standard-care group (P < .0001). There was still a difference between the two lipid arms, although no longer significant (odds ratio, 1.13; P = .60). (The statin was continued during ACCORDION, but not fenofibrate.) And as before, blood-pressure lowering did not have an effect (P = .59).

"Intensive [glycemic control] appears to demonstrate a 'legacy effect,' or 'metabolic memory,' similar to [that seen in] patients with type 1 diabetes," Dr Chew commented.

She also said, "Was the effect of fenofibrate seen in ACCORD a real beneficial effect? Further evaluation of fenofibrate for treatment of diabetic retinopathy is planned."

Dr Hramiak commented, "I think that the ACCORDION trial definitely shows the impact of glycemic as well as fibrate treatment as beneficial for retinopathy. There was no nephropathy data presented, but there might be in the future."

No Effect on Brain Structure, Function

Anne M Murray, MD, a geriatrician, internist, and epidemiologist specializing in dementia at Hennepin County Medical Center, Minneapolis, Minnesota, presented the findings for the Memory in Diabetes (MIND) results for ACCORDION.

The rationale for the trial includes the fact that diabetes is associated with increased risk of incident dementia of any type, with a relative risk of about 1.5 for all dementia and a 2.4-fold increased risk for vascular dementia, Dr Murray noted.

The original ACCORD MIND study involved a subset of 2977 ACCORD patients at 50 centers, of whom 614 underwent MRIs. No significant differences were found among the glucose-, lipid-, and blood-pressure–lowering arms in decline on the cognitive assessment called the Digit Symbol Substitution Test (DSST) or total brain volume on MRI.

For ACCORDION MIND, 1328 of the surviving ACCORD participants were reexamined at an average 47 months after the intensive glycemic intervention was stopped and 31 months after the close of the blood-pressure and lipid arms.

No significant differences were found among the original ACCORD treatment groups in the 80-month mean change from baseline in DSST scores or in total brain volume.

While the reasons for the lack of effect of the intervention on brain function aren't clear, possible reasons might include that the 10-year diabetes duration of the ACCORD study subjects at baseline was already too late for the interventions to have had an impact on vascular and neuronal function or that the age of the group — mean of 62.5 years at baseline — might have been too young to see cognitive-function declines, which typically occur after age 70, Dr Murray speculated.

Dr Hramiak commented, "In terms of the MIND study, there was no advantage. I think, as the speaker said, it may depend on when you intervene, and perhaps these people weren't at high risk for dementia because of their youth. But definitely, there was no impact of glycemia on the development of dementia."

Dr Gerstein receives grant/research support from Sanofi, Lilly, AstraZeneca, and Merck and consulting fees/honoraria from Sanofi, Lilly, AstraZeneca, Merck, Novo Nordisk, Abbot, Roche, Amgen, Boehringer Ingelheim, Kaneq Bioscience, and Berline Chemie. Dr Hramiak has been a board member for AstraZeneca/Bristol-Myers Squibb, Eli Lilly, Janssen-Ortho/Johnson & Johnson, Merck, Novo Nordisk, Pfizer, Sanofi, Abbott, Boehringer Ingelheim, GlaxoSmithKline, and Medtronic. She has also received payment for lectures from AstraZeneca/Bristol-Myers Squibb, Eli Lilly, Merck, and Novo Nordisk. Drs Chew and Murray have no relevant financial relationships.

World Diabetes Congress 2015. Presented December 3, 2015.

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