Reducing hemoglobin (Hb) A1c levels as soon as possible after the diagnosis of type 2 diabetes results in a reduction in the diabetes-related complications, including myocardial infarction (MI) and all-cause mortality. This early reduction in the HbA1c level explains the so-called legacy effect found in the UKPDS (United Kingdom Prospective Diabetes Study), stated Marcus Lind, MD, of the Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, who presented an analysis in a late-breaking abstract session at the 2012 ADA meeting.
The legacy effect refers to the significantly lower risk for diabetes-related complications found in patients randomized to intensive glycemic control compared with patients randomized to conventional glucose control, although the HbA1c levels were virtually the same in both groups during the 10-year observational follow-up of the original UKPDS. The legacy effect, which is the continuing benefit of early improvements in glucose control, is similar to the “metabolic memory” described in type 1 diabetes, said Dr Lind.
This persistence in effect was seen for MI and for all-cause mortality. MI was reduced by 16% with intensive HbA1c control versus conventional control at the end of the original study. At 10 years of follow-up, a 15% risk reduction was found with intensive control.
All-cause mortality was reduced by 6% with intensive versus conventional control at the end of the original study, and the rate increased to a 13% risk reduction with intensive control at 10 years (P = .006), with similar glycemic control in both groups.
Benefits of Legacy Effects Revealed
In the present analysis, the investigators examined data from 3849 patients assigned to intensive or conventional glycemic control in the UKPDS, using statistical models to determine the degree to which “historical” HbA1c values contribute to later reductions in the risks for MI and for all-cause mortality, and to elucidate the time-dependent impact of an earlier reduction in HbA1c values on a year-by-year outcome.
As the researchers learned from a model to determine the year-by-year benefit of the legacy effect, the benefit of a 1% reduction in HbA1c will increase over time. For all-cause mortality, the hazard ratio was 1 for years 0 to 10, but the risk reduction increased to 21% at year 15 and to 24.7% at year 20.
Furthermore, the earlier the HbA1c level is lowered, the greater the benefit. If the HbA1c level is lowered from the time of diagnosis of type 2 diabetes, there is a 15% risk reduction in all-cause mortality at year 15. This is cut nearly in half (7.1%) if HbA1c is not lowered until 10 years after the disease is diagnosed. Therefore, there is a 3-fold greater risk reduction in all-cause mortality because of the legacy effect of early HbA1c reduction.
An increased risk reduction in all-cause mortality, to 24.7%, is seen after 20 years if HbA1c level is lowered from the time of diagnosis versus a 14.1% reduction if HbA1c level is not lowered until 10 years after the diagnosis.
A similar pattern is seen in patients with MI. At year 15, there is a 21.6% risk reduction in MI if HbA1c is lowered 1% starting from the time of diagnosis, but the risk reduction was only 13.5% if lowering HbA1c was delayed until 10 years after diagnosis. At year 20, the risk reductions for the earlier and the delayed HbA1c lowering were 27.8% and 23.9%, respectively.
Using a fitted model, the benefit of early reduction of HbA1c and the legacy effect were illustrated by the example of a 50-year-old man with an 8% HbA1c at the time his type 2 diabetes was diagnosed. An immediate 1% HbA1c reduction will give him a 19% risk reduction in all-cause mortality when he is aged 60 to 70 years, whereas a delayed 1% HbA1c reduction will give him only a 6.6% risk reduction. An early HbA1c reduction provides a 3-fold greater effect on mortality.
“Achieving and maintaining optimal glycemic control is essential to minimize the long-term risk of diabetic complications,” said Dr Lind. Waiting to reduce glycemia will not recapture the full benefits of immediate intervention. These models confirm that an earlier reduction in HbA1c levels continues to contribute to reducing the risk of diabetic complications.