The link between diabetes and heart disease is well-known -- diabetics are two to four times more likely to have cardiovascular disease than nondiabetics, and two-thirds will die of an early heart attack or stroke. But the link itself is poorly understood.
“A person with diabetes and no cardiovascular history has the same risk of having a heart attack as a person who has had a prior heart attack,” said Dr. Ruchi Mathur, an endocrinologist at Cedars-Sinai Medical Center in Los Angeles.
Now researchers are attempting to figure out both the precise connection and what it means for treatment.
“We need to understand why there is this risk because it has profound implications for therapy,” said Dr. Jorge Plutzky, director of the vascular disease prevention program at Brigham and Women’s Hospital in Boston. “You should conceivably treat every patient with diabetes as aggressively as a heart attack survivor.”
That means going beyond the traditional focus on dramatically lowering blood sugar levels. Patients should also minimize a cluster of other risk factors that are common to both diabetes and cardiovascular disease: obesity, hypertension, unhealthy cholesterol profiles and, recent research indicates, inflammation. It also means that doctors should screen patients with heart disease for diabetes, and visa versa.
By learning more about the mechanisms through which diabetes damages the heart, scientists may be able to interrupt or forestall the injury, extending patients’ life span and improving their quality of life along the way.
“People always think of diabetes as a sugar problem because it is diagnosed based on the amount of glucose in the blood,” said Dr. Richard Nesto, chairman of the cardiology department at the Lahey Clinic in Burlington, Mass. “However, we now recognize that there are many other factors in this metabolic disorder that increase the incidence of heart disease.”
Those other conditions may hold the key to the diabetes-heart connection, and many of them boil down to fat.
Factoring in fat
Fat is “packaged” differently in diabetes, researchers now realize, and can cause a low-grade inflammation in obese people that might contribute to both diabetes and heart disease.
Weight gain causes fatty acids to overflow into muscles and the liver, rather than stay in fat cells and cholesterol molecules where they are normally stowed, Plutzky says. In ways still not understood, scientists think that these fatty acids make muscle cells insulin-resistant, which makes them less able to absorb glucose, and that elevates blood sugar levels.
The fatty acids also cue the liver to make too much “bad” LDL cholesterol and too little “good” HDL cholesterol, said Dr. Daniel Rader, director of preventive cardiology at the University of Pennsylvania. HDL molecules normally remove cholesterol from the fatty plaques in the arteries that can rupture and cause heart attacks or strokes. The low HDL levels in diabetes allow these risky plaques to grow.
Also, LDL particles in most people are normally large and buoyant, but in diabetics, they are small, dense and harder to clear from the body. They become more easily embedded in the fatty arterial plaque, so even “normal” LDL levels can irritate the heart in diabetes.
For several decades, researchers have known that inflammation contributes to the formation of these fatty plaques, which contain immune cells called macrophages. Doctors routinely monitor the inflammatory molecule C-reactive protein (CRP), which is produced by macrophages, to measure heart disease risks.
Now researchers realize that fat tissue itself can become inflamed, and this could explain how obesity induces both diabetes and heart disease. In 2003, studies in both mice and people discovered that fat tissue harbors macrophages that increase in number with obesity.
“These macrophages spew out inflammatory molecules [including CRP] that circulate in the body and cripple the ability of insulin to work in other cells, leading to diabetes,” said Dr. Mitchell Lazar, director of the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania, who was not involved in the 2003 studies but now studies this inflammatory process.
Many researchers think these same inflammatory molecules could harm the arteries. They could also provide new diabetes diagnostic markers and new targets for diabetes drugs that also protect the heart.
“We don’t know how much inflammation’s role is in diabetes but we already have an intervention that can begin to ask that question,” said Steven Shoelson, section head of cellular and molecular physiology at Boston’s Joslin Diabetes Center.
The intervention to which he refers is salsalate, an inexpensive anti-inflammatory drug similar to aspirin that, unlike aspirin, does not promote bleeding. Salsalate is approved for use in rheumatoid arthritis and, Shoelson discovered, was used 140 years ago for diabetes. Salsalate is not the only intervention being tested -- statins are being studied as well -- but it appears to be one of the more innovatively simple and promising ones.
The NIH is now recruiting patients for two trials to gauge the effect of salsalate on diabetes and cardiovascular disease, TINSAL-T2D and TINSAL-CVD (Targeting Inflammation with Salsalate in Type 2 Diabetes/Cardiovascular Disease). Shoelson said an upcoming report on the first stage of the Phase III diabetes trial, which he heads, will show that salsalate significantly reduced blood sugar levels, but it will take years to see if it also decreases heart disease.
“We really need to figure out this link between diabetes and heart disease because we have more young people getting Type 2 diabetes every year and they will have heart attacks earlier in life,” Nesto said. “We need to know what we need to put in place for these young people to prevent this problem.”