Two famous studies showed that tight control of glucose did not cause a statistically significant reduction in heart attacks or early death. But roughly 20 years after the studies ended, tight control subjects are living longer and healthier than those who were in the comparison groups. What is going on?
This long-delayed benefit is called the “legacy effect.” It was found in follow-up of patients in the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS).
I learned about the legacy effect in a symposium at the American Diabetes Association’s 74th Scientific Sessions in San Francisco on June 13.
DCCT included more than 1400 people with Type 1 diabetes and lasted from 1983 to 1993. Half of the participants worked for “intensive therapy,” defined as an A1C “as close to normal as possible,” that “included three or more daily insulin injections or a continuous subcutaneous insulin infusion, guided by four or more glucose tests daily.” Many achieved an A1C of 7.0 or less.
The other half had one to two insulin injections a day. Their A1C levels averaged close to 9.0. The intensive therapy lasted an average of 6.5 years.
The participants in the study have since been followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which is still going on.
The intensive control group had immediate benefits. They had far less eye and kidney damage and less diabetic neuropathy (nerve damage that can cause sensations such as pain and numbness.) These are called “microvascular complications,” because the blood vessels in the eyes, kidneys, and nerves are small.
But they had no significant benefit in heart disease or stroke. These are called “macrovascular complications,” because the blood vessels in the heart and brain are large. The rates of heart attack, stroke, and death were the same in both groups at the study’s close in 1993. (According to researchers, at the time the study ended, it was still too soon to assess the impact on cardiovascular health.)
They’re not the same any more. According to the National Diabetes Information Clearinghouse:
More than 10 years after the DCCT ended, when both groups began receiving similar care (and had similar glucose levels), the benefits to the heart of the earlier treatment emerged. Moreover, the EDIC study found the benefits of tight glucose control on eye, kidney, and nerve problems persisted long after the DCCT ended. Researchers call the long-lasting benefit of tight control ‘metabolic memory.’
Same in Type 2
The UKPDS tried to do for Type 2 diabetes what DCCT had done for Type 1: show the effects of tight glucose control. UKPDS included about 5,000 recently diagnosed people with Type 2. Half were assigned to a tight control group, defined as a fasting blood sugar (FBS) below 108 mg/dl (6.0 mmol/ml). In practice, the tight control group had a median (midpoint) A1C of about 7.0.
Just as in DCCT, people receiving “intense control” had fewer eye, kidney, and nerve problems. But heart problems and strokes were no different for the two groups at the end of the study. After ten years, “no attempts were made to maintain previously assigned therapies,” and glucose levels in the two groups became similar. However, 15 years later, the tight control group has had far fewer cardiac events and a lower death rate.
What this means
What does the legacy effect mean for you? Mainly, that your heart, brain, and legs will benefit from gaining good glucose control as soon as you can. According to Colombian researchers, a few months of high glucose can deposit proteins called kinase C and nuclear factor κB in blood vessels. These proteins don’t easily go away and lead to more damage over the years.
So don’t wait. Complications can occur even before diabetes is diagnosed, because dangerously high levels can be balanced by low levels at other times. These variations can lead to an OK A1C level, even if you have elevated glucose levels much of the time.
There is a “lag time” between starting tight control and seeing advantages in your large blood vessels. Big arteries take time to clog up, and they take time to heal. Expect a 3–5 year wait before seeing cardiac benefits from tight control. Even after blood sugar levels become completely normal, it may take 5–10 years for your cardiac risk to return to those of a person without diabetes. But you should feel a lot better in the meantime. Your small vessels will be protected, and your big vessels will be healing.
Third, even if heart disease and stroke (macrovascular complications) are unchanged with better control, protecting the eyes and kidneys (microvascular complications) is well worth the effort. So is reducing neuropathy, which can involve sexual dysfunction.
Fourth, it’s important to know that the “tight control” in DCCT and UKPDS wasn’t that tight. It’s possible to do quite a bit better than an A1C of 7.0, as we’ve written about on this site here and here.
Finally, tight control in these studies came primarily from drugs, not from self-management or lifestyle changes. This is an important distinction and may account for why the benefits were not even greater.
More recent trials of tight control, such as ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease), and VADT (Veterans Affairs Diabetes Trial) showed no cardiac advantage for tight control. But this failure may have been due to the harmful effects of the drugs used, not to the lower blood sugar levels. Probably, as the ACCORD, ADVANCE, and VADT groups are followed for decades, legacy effects will emerge for them, too, especially if they are controlling their diabetes with lifestyle.
No legacy for blood pressure treatment
Interestingly, in all trials to date, there has been no legacy effect and no lag time for blood pressure control. You are safer while you are keeping your pressure down. But if your pressure goes back up, your risk immediately returns.
Learn more about the differences between microvascular and macrovascular complications in this article from the journal Clinical Diabetes.
I posted an inspirational true story on my blog Reasons to Live, called “All is Well.” It’s at www.reasons2live.net — you might like it.