American Diabetes Association Conference Highlights: Today's A1C Levels Have Consequences for Tomorrow

Experts discuss the legacy effect, or lack of it, found in studies of diabetes prevention and control

With John M. Lachin ScD, Rury R. Holman FRCP, William C. Knowler MD, DrPH, and Neda Laiteerapong MD, FACP

Early interventions in type 2 diabetes affect health outcomes for decades.

Your patient's A1c value today has consequences for outcomes tomorrow, agreed a panel of experts at a two-hour symposium at the ADA Conference. In a session titled "The 'Legacy Effect' in Diabetes: Are There Long-Term Benefits of Short-Term Tight Glycemic Management?" experts who spoke elaborated on why the answer to that question is often yes.

Here, some highlights from talks by four experts:

Metabolic Memory, DCCT, and EDIC

Leading off the symposium was John Lachin, ScD, research professor of biostatistics and bioinformatics and of statistics at George Washington University. "The basic idea, he says, is if you have two patients, one with an average A1c of 9% and the other an A1c of 7%, and after 10 years they both have an A1c of 8% for the rest of their lives, the one who had that initial lower A1c is going to continue to have a lower long term risk than the one who did not." That concept is born out in the studies he cited.

Whenever the level of glucose control can be improved, it should be, and the expectation should be long-term benefits. Patience by the provider is key, too, he says. While it may take 5 to 10 years to see the effects, think about long-term benefit of improving therapy now, he advices.

As evidence, he pointed to the Diabetes Control and Complications Trial (DCCT), which ran from 1983 to 1993 and the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, from 1994 to present. Those with type 1 diabetes assigned to intensive therapy initially had about the same risk of progression of diabetes complications as the one in the  conventional therapy group, but had markedly reduced risk of complications over time.

The primary outcome was retinopathy progression.  Over the first four years, there was no benefit. But the next four years showed a 76% reduction in risk during DCCT in those with intense therapy. The difference in A1C explains the reductions in risk, Dr. Lachin said. "These studies show that the dominant determinant of risk of complications is the lifetime exposure to hyperglycemia."

''A period of intensive therapy has long lasting benefits, even if followed by a period of elevated levels of glycemia," he said. Early implementation of intensive therapy is key, Dr. Lachin said, over the long term, and explains the reduction in risk.

That, in turn, suggests the validity of the concept known as metabolic memory, that hyperglycemia leads to physiologic changes that ultimately determine risk of complications.  As evidence, Dr. Lachin pointed to the more than four-year lag before treatment effects emerged.

Advanced glycation end products or AGEs, which have a long half life, may explain the mechanism, he said.

Dr. Lachin told Endocrine Web: "During the DCCT, even though the intensive group lowered their mean HbA1c from 9% to 7%, while the conventional group remained at 9%, there was no difference in risk over the first 4-5 years of treatment, the risks beyond 5 years in the conventional group then increasing exponentially. So the implementation of intensive therapy in subjects with a mean of 7 years duration of diabetes did not immediately or completely erase the risks of progression of complications."

However, after the close of the DCCT, during the EDIC follow-up study, the HbA1c levels in the former intensively and conventionally treated groups merged to about 8%, and remained virtually equivalent thereafter. Nevertheless, the former intensive group participants had a prolonged reduction in the risk of further progression, what we have termed metabolic memory, that has persisted for 10 or more years of follow-up. Thereafter, while the daily risk is the same in the two groups, the cumulative incidence of outcomes continues to separate with time because this calculation perpetuates past differences in risk into the future, reflecting the full public health impact, called the legacy effect.

What's important, Dr. Lachin said, is that further models ''showed that the risk of complications depends not only on the mean HbA1c but also the pattern of A1c values over time, such that a patient with 10 years of an HbA1c of 9% followed by 10 years at 7% has a 50% higher risk of a cardiovascular outcome than a patient with respective values of 7% followed by 9%."

Legacy Effect and Type 2 Diabetes

The legacy effect in type 2 diabetes was the focus of the next talk, by Rury R. Holman, FRCP, FMedSci, emeritus professor of diabetic medicine, University of Oxford, London.

During the UK Propsective Diabetes Study (UKPDS), in which Dr. Holman was the principal investigator, reducing glucose exposure (7% versus 7.9% over median 10.0 years) reduced the risk of any diabetes-related endpoint by 12% and microvascular disease by 25%, with a 16% trend to a reduced risk of myocardial infarction (P=0.052).  

From these studies, which Dr. Holman reviewed, he tells Endocrine Web that the most important takeaway for clinicians is this: "Identification of the glucose 'legacy effect' by the UKPDS shows unequivocally that to best minimize the lifetime risk of glycemic complications for people with type 2 diabetes, blood glucose control must be optimized from diagnosis (if not before) and maintained for as long as feasible.”

Probably most surprising, he said, is the finding that ''historical HbA1c values continue to contribute to the risk of diabetic complications for at least 20 years."

Lifestyle Interventions

In a third talk, the topic shifted to the effects of lifestyle intervention with reviews of research by William Knowler MD, DrPH, chief of the diabetes, epidemiology, and clinical research section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix.

Among the studies he discussed were the Diabetes Prevention Program, the DPP Outcomes Study, and the Look AHEAD trial. In the DPPOS, the researchers found that prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years and that the cumulative incidence of diabetes was lowest in the lifestyle group.

In Look AHEAD, no effect was found on cardiovascular outcomes, but other health benefits of lifestyle intervention were found, including reduced need for diabetes medicines. 

It's hard to determine effects of lifestyle, as there is a latency period, he said.   

Dr. Knowler tells Endocrine Web that he feels the best take-away from his presentation is that "There is great variation among clinical trials in the long-term (or “legacy”) effects of weight loss interventions. Some trials had intensive intervention periods of 3 to 6 years followed by many more years of observations to assess long-term health outcomes such as development of diabetes or diabetes complications. 

In some trials, the intensive intervention periods slowed the development of disease during the active intervention phase, after which progression continued at a similar rate to that in the comparison group, although resulting in a sustained delay in onset of the disease or complication because of the initial delay during the active intervention period."

Dr. Knowler added: "In others, the lifestyle intervention may have had a lasting effect on the rate that was sustained during inactive follow-up. In many trials, these 'legacy' effects are hard to understand because little or no information was reported on whether the lifestyle behavioral changes were maintained after the active intervention period. Maintaining lifestyle interventions long-term is necessary for understanding their long-term effects, and is probably necessary to maximize health benefits."

The information most surprising to him is that, "In the Look AHEAD clinical trial, the lifestyle intervention was very effective in reducing weight and cardiovascular disease risk factors, but it did not reduce the incidence of cardiovascular disease events. The potential beneficial effects of lifestyle intervention on cardiovascular disease events may have been reduced in the face of intensive management of risk factors by other means."

Lack of Legacy in Modern Studies

In a final talk, Neda Laiteerapong MD, associate professor of general internal medicine, University of Chicago, focused on the lack of a legacy effect in modern glucose-lowering trials. She discussed the results of  several trials, including the ACCORD and ADVANCE trials.

Among the possible reasons for a lack of legacy effect found in modern studies, she said, include differences in how cardiovascular risk is managed or that the legacy effects depends on vascular age. More follow-up time may be needed.  

The most important take-away? Dr. Laiteerapong tells Endocrine Web: "For patients with newly diagnosed T2D and an estimated life expectancy of 10 years or greater, intensive glycemic control (A1c<6.5%) as soon as possible, and preferably within the first year of diagnosis, will likely reduce their future risk of complications for the rest of their lives (i.e., put them on a path for much better health). For patients with T2D and high risk for, or pre-existing cardiovascular disease, the focus of control should be on immediate concerns such as blood pressure, cholesterol, and achieving an A1c of <8% or <8.5% (if they are elderly). There is no long-term benefit of glycemic control in these patients, so immediate issues are of greater importance."

"Most surprising," she said, ''is that the level of glycemic control for the first year after T2D diagnosis has effects on diabetic complications and death that persist for at least 10 years."

Drs. Lachin, Knowler and Laiteerapong have no disclosures. Dr. Holman is on advisory boards for Merck Sharpe & Dohme, Novartis and Novo Nordisk. He reports honoraria from Bayer, Intarcia, Merck Sharp & Dohme, Novatis, and Novo Nordisk.

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