Diabetes Forecast

Early and Often

A glucose control and heart health update

By Erika Gebel, PhD , ,

If you have diabetes, you're at an increased risk for heart disease and stroke. This much is clear. So, what should you do about it? A number of major recent studies of type 2 diabetes have come at this problem from different angles, looking at how controlling blood pressure, blood cholesterol, and blood glucose can improve the outlook for your cardiovascular system (the heart and the vessels that move blood around the body). While the details of these studies are complex and not yet completely understood, two keys have emerged: It's important to keep blood glucose under control starting at day one of diagnosis, while at the same time managing risk factors like cholesterol and blood pressure. Here's why.

The Steno-2 Study

Research has already shown the cardiovascular benefits of keeping blood pressure and blood lipids—cholesterol and triglycerides—under control in people with diabetes. Three major clinical trials that culminated in 2008 were meant to add blood glucose to this list. But the studies—known by the acronyms ACCORD, ADVANCE, and VADT--failed to show a reduced cardiovascular risk in people with type 2 diabetes through intensive blood glucose control. More troubling still, researchers in one of these trials (ACCORD) abruptly stopped intensive glucose treatment because of an increased risk of death in that group. Participants in these studies had been diagnosed with type 2 a decade earlier, on average, and had known heart disease or multiple risk factors for cardiovascular disease.

These results shocked scientists, in part because some population studies (after-the-fact trend analyses) of people with type 2 diabetes and clinical trials in people with type 1 had previously shown that blood glucose vigilance translates into cardiovascular risk reductions. It had seemed only a matter of getting enough money, people, and time to do the necessary trials to finally prove this bygone conclusion.

But were these new studies in one sense missing the point? "All these trials are glucocentric. They're single-factor intervention trials," says Oluf Pedersen, MD, DMSci, professor at the Steno Diabetes Center in Copenhagen. Pedersen is the principal investigator in a study called Steno-2, which approaches the question in a different way. "We treated all known modifiable risk factors," says Pedersen. "Since type 2 diabetes is a multifactorial disorder, Steno-2 compared multifactorial interventions." Steno-2's goal was to see just how healthy it could make its participants by targeting all suspected contributors to cardiovascular disease at the same time.

Steno-2 participants randomly received either intensive or conventional treatment, but not just with respect to glucose. The trial was set up to look at the cumulative effects of several long-term intervention strategies targeting blood pressure, blood lipids, and blood glucose. Anti-platelet therapy with aspirin was also included in the intensive treatment regime. The researchers concluded that, after 8 years, intensive therapy patients had 50 percent lower rates of nephropathy, retinopathy, and cardiovascular disorders. Thirteen years after the original study, the patients who originally had been treated intensively showed a 50 percent lower rate of death from cardiovascular disease.

So, does this show that tight blood glucose control lowers risk of cardiovascular death? Maybe, maybe not: The study was not set up to tease out the specific effects of the treatment's individual components, so it is difficult to say what if any benefit blood glucose lowering itself had. But the salient point is that this "whole patient" strategy—intensively controlling all risk factors at once—worked, and worked extremely well, for high-risk type 2 diabetes patients.

The UKPDS Follow-Up

Another recent study did show what ACCORD, VADT, and ADVANCE had hoped—but failed—to demonstrate, that intensive glucose management does reduce cardiovascular risk in people with type 2 diabetes. In this new study, a follow-up to the landmark United Kingdom Prospective Diabetes Study (UKPDS), the cardiovascular benefits of glucose control showed up years later.

UKPDS, a groundbreaking clinical trial in people with newly diagnosed type 2 that ran from 1977 to 1997, first established the now well-known association between glucose control and the reduction of microvascular complications (eye disease, kidney disease, and the neuropathy that can lead to limb amputation) in people with type 2. As with ACCORD, VADT, and ADVANCE, UKPDS did not find any cardiovascular benefit with increased glucose control at the time of the study's completion. However, when researchers revisited UKPDS participants 10 years later, they found that those who had been selected to achieve tight blood glucose control during the trial had a lower risk of heart attack and death than those who, at the time of the trial, had less well-controlled blood glucose.

This finding was somewhat surprising because, within one year of UKPDS ending, differences in A1C—a measure of average blood glucose—disappeared between the intensive and conventional groups. One might have thought the health disparities would disappear as well. But as researchers found out, the health gap actually widened over time. They're calling this a "legacy effect" and are uncertain about its biological origins.

In UKPDS, intensive blood glucose control was achieved using sulfonylurea pills or insulin in normal-weight people and the drug metformin in overweight people. Compared to what researchers mean these days when they say "intensive," says Rury Holman, FRCP, chief investigator of the study, for UKPDS, "intensive … is not a good label." UKPDS aimed to treat patients using only a single medication—even if blood glucose became quite high—because, at the time, there was some suspicion that using multiple medications might be harmful. In the conventional therapy cohort they didn't use drugs at all; lifestyle alone was used to control blood glucose. "We could never do our study again, it would be unethical," says Holman, given what is now known about diabetes management. Ten years later, though, despite the UKPDS's conservative protocol, researchers found that greater blood glucose control fostered healthier hearts: The follow-up study reported that heart attack risk was reduced 15 percent in the sulfonylurea/insulin group and 33 percent in the metformin group, while overall risk of death was reduced 13 percent and 27 percent, respectively.

Though it appears the UKPDS follow-up found different results than any of the big three trials published last year, Holman says "there's no real dissension here." He explains that ACCORD, ADVANCE, and VADT were each leaning toward the same conclusion: that tight control boosts cardiovascular health. "The benefit is there, but it is modest," says Holman. And while ACCORD was prematurely ended due to an increased number of deaths in the intensive glucose therapy group, Holman believes that can be attributed to the nature of its subjects. He refers to ACCORD as a "rescue study," as participants already had advanced diabetes and, in many cases, a history of cardiovascular disease. "If you do intervene late [participants] will be rather frail and won't tolerate low blood glucoses," he says.

"The fundamental difference [in UKPDS] is, we started at the time of diagnosis," says Holman. "By and large the treatment population had no cardiovascular disease." And that may be the most important distinction. Holman recommends doctors "find and treat people early because we now know it gives extended benefits in the long term."

What Next?

In other words, preventing heart attacks and strokes means starting early and being thorough. Soon after a diabetes diagnosis, talk to your doctor about an appropriate blood glucose goal and then make a plan to get there. All of these studies have shown that with the right combination of lifestyle and medication, just about anyone can achieve healthy, well-controlled blood glucose levels. It's all a matter of working with your health care providers, figuring out what works best for you—and sticking to it.

But remember, it's not all about glucose. Find out your blood pressure as well as your LDL cholesterol, HDL cholesterol, and triglycerides. Then check them against the established ideal numbers for people with diabetes. Not there? Again, come up with a strategy with a doctor to bring your numbers in line. Research is showing that by getting on top of your blood glucose soon after diagnosis and then adding measures to control blood pressure and blood lipids, health is within your control after all.



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