Joe Lapiana had an ominous family history: both his parents had Type 2 diabetes, and both died of heart disease - the most frequent cause of death in all forms of diabetes. Since his 20's, Mr. Lapiana has had hypertension, a danger signal for diabetes and for heart disease.
HANDLING WITH CARE With his diabetes finally diagnosed, Joe Lapiana, 60, of Westford, Mass., is taking steps to keep his disease under control.
But until he was 50, when he mentioned his unquenchable thirst - a symptom of diabetes - to a doctor, Mr. Lapiana had slipped under the medical radar. The doctor tested his blood sugar and found that his glucose was five times as high as the normal level.
For many years now, researchers have known that high blood sugar levels are somehow bad for the heart. A person with diabetes has a risk of dying of a heart attack or stroke two to four times as great as someone who has already survived a heart attack.
But with the findings of a recent study, published Dec. 22 in The New England Journal of Medicine, doctors now have solid evidence that aggressively lowering a person's blood sugar level can cut the risk of heart attack and stroke nearly in half, at least for Type 1 diabetes, which was formerly called juvenile onset diabetes.
Whether stringent glucose control also halves cardiovascular disease in Type 2 diabetes, previously called adult-onset diabetes, is the subject of a large trial sponsored by the National Institutes of Health.
That trial could have a large effect on public health, since almost 95 percent of the 20 million or so people in the United States with diabetes have Type 2.
But the other side of the story is that signs of cardiovascular disease may precede signs of Type 2 diabetes. By the time someone like Mr. Lapiana feels ill enough to mention the symptoms to a doctor, the heart may already have suffered damage. Sometimes it is an emergency room doctor who first discovers diabetes in a heart attack victim.
Cardiologists who are treating heart disease may not check a patient's blood sugar levels, while doctors who treat diabetes may not check for signs of atherosclerosis. Primary care doctors may not check either, as Mr. Lapiana's case shows.
Before the diabetes diagnosis, Mr. Lapiana, a retired high school teacher from Westford, Mass., recalls having only one cholesterol test. When he had the test this time, he had the dangerously high triglycerides and worrisomely low levels of H.D.L. cholesterol that characterize both diabetes and cardiovascular diseases.
Even normal levels of L.D.L., the so-called bad cholesterol, spell trouble for diabetes patients, possibly because their protein molecules are smaller, denser and more damaging to blood vessels.
That damage presages artery-clogging plaque and its offspring, heart attacks and strokes.
"I wish that when you see one part of the syndrome, you would go and look for others," said Dr. Daniel Einhorn, medical director of the Scripps Whittier Institute for Diabetes in San Diego, speaking of doctors.
"If you see high triglycerides, look at sugar levels, and maybe you'd catch prediabetes," he said. "Cardiovascular disease begins very early in the course of diabetes, probably before you notice sugars are high."
Recently, researchers have come to understand that it is no mere coincidence that diabetes and cardiovascular disease are closely linked. Type 2 diabetes and cardiovascular disease share deep molecular roots in the regulation of sugar and fat throughout the body, said Dr. Mitch Lazar, director of the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania.
That relationship makes intuitive sense, because diabetes involves the way food is metabolized, a process that involves cholesterols, which can cause blood vessels to clog.
Figuring out the actual mechanism, though, has required studying a small family of chemical receptors in the body called peroxisome proliferators-activated receptors, and known as P.P.A.R.'s. The receptors belong to an extended family of steroid hormone receptors that sit on a cell's nucleus and turn on genes that then initiate numerous changes inside and outside the cell.
Dr. Ronald M. Evans, a Howard Hughes Medical Institute investigator at the Salk Institute in San Diego, calls the receptors "master switches" that regulate fat cells, lipids, glucose and, indirectly, insulin.
It turns out that two long-prescribed classes of drugs flip one or the other of these master switches. Drugs like TriCor and Lopid, cholesterol-lowering drugs called fibrates that are used to treat atherosclerosis, act by regulating lipids. Thiazolidinediones, like Actos and Avandia, used to increase insulin sensitivity in diabetes, act by regulating glucose and insulin.
Evidence from laboratory and animal studies has shown that thiazolidinediones also promote cardiovascular health, according to Dr. Jorge Plutzky, director of vascular disease prevention at Brigham and Women's Hospital in Boston.
The drugs turn off genes involved in atherosclerosis and inflammation - another link between diabetes and heart disease - and turn on protective genes. Doctors also observed that Type 2 diabetes patients taking thiazolidinediones showed fewer signs of heart disease.
All this evidence had raised hopes that fibrate and thiazolidinedione drugs might decrease heart attacks in Type 2 diabetes patients. But recent studies that directly tested the cardiovascular benefit of the drugs have deflated those hopes.
In Britain, research known as the PROactive trial studying the thiazolidinedione Actos looked at so many factors in patients taking so many drugs that results were inconclusive.
Another study, called Field, of the fibrate TriCor found an increase in deaths from heart attacks, as did smaller studies of muraglitazar, the first of a new breed of drugs that combines the properties of a thiazolidinedione with a fibrate in a single molecule.
No one - patients, clinicians, researchers or the companies that have invested millions in research - knows what to make of these results. Ultimately, Dr. Plutzky said, they reflect the arduous process of translating scientific discoveries into clinical practice, and the profound complexity of diabetes and heart disease.
There is one positive side to the diabetes-heart disease connection. What benefits the heart - healthy diets, exercise and vigilant doctors - also appears to prevent or delay Type 2 diabetes. That possibility makes missed opportunities for early interventions all the more painful.
As Dr. Einhorn of Scripps Whittier put it, "We are catching all people late."
