Medications for Type 2 (adult-onset) diabetes are very effective at controlling blood sugar levels. You'd think, then, that the drugs would also be very effective at controlling complications of the disease related to those spikes in blood sugar: cardiovascular disease, kidney failure, blindness, nerve damage and amputation of limbs. Surprisingly, though, that has not turned out to be the case for cardiovascular events such as heart attacks and strokes. One study, in fact, hints that too-tight control may even cause patients harm.
Because of these findings, some doctors are beginning to argue that more is not always better with glucose control, particularly when weighed against the downsides of intensive drug treatment, such as hypoglycemic episodes (potentially dangerous dips in blood sugar levels) and weight gain.
Here's a closer look at how treating diabetes with medications affects the risk of cardiovascular disease, one of the most difficult and common complications of diabetes.
Patients with Type 2 diabetes have rates of heart disease two to four times the normal rate, and some two-thirds of them die from a heart disease-related event. Researchers have studied how well the anti-diabetes drugs protect against this worst-case scenario.
The first real tipoff that the heart might not be protected by these medications came from a 10-year British study of 3,867 men and women with diabetes that was published in the Lancet in 1998. It compared treatment with oral medications (sulfonylurea or metformin) or insulin with a more conventional treatment for that time: dietary control supplemented with drugs if blood glucose climbed higher than 270 mg/dL.
The more intensive treatments helped patients keep their blood sugar in check and reduced the risk of side effects on the eyes, kidneys and nerves. Protection against heart disease, however, was not statistically significant.
These findings spurred more research, and in June 2008 results from two much larger U.S. studies were published in the New England Journal of Medicine.
One of them, which had been discontinued after three years because of safety concerns, treated 10,251 patients with diabetes in one of two ways. One group got standard treatment (with oral drugs such as metformin, glimepiride, thiazolidinedione and often insulin) to get blood glucose levels down to an average of 155 mg/dL to 180 mg/dL over a period of three months. The other got intensive treatment to achieve even lower blood glucose levels, below 125 mg/dL.
The trial was stopped when researchers found that there were more deaths from any cause and more cardiovascular-related deaths in the intensive treatment group than in the standard treatment group.
This discouraging result suggests that working harder to lower blood glucose in Type 2 diabetes not only doesn't reduce risk for heart disease, but may in fact bring harm.
The other study, of 11,140 diabetic men and women who were followed for five years, also tested intensive therapy against standard therapy and found neither benefit nor harm with regard to cardiovascular disease or death.
Parsing the risks and benefits in diabetes treatment is complicated by the fact that patients with diabetes receive a broad variety of drugs to help control blood sugar: In addition to metformin (Glucophage) and sulfonylureas, such as Diabinese and Glucotrol, there are the meglitinides, such as Prandin and Starlix, the thiazolidinediones, such as Avandia and Actos, alpha-glucosidase inhibitors such as Precose and Glyset, and the dipeptidyl peptidase-4 inhibitor Januvia (sitagliptin). The possibility remains that these drugs differ in how well they protect against long-term complications of the disease. But studies to test this have not been done.
"The majority of patients start with metformin," says Steven Chen, a USC pharmacist who runs a diabetes management program. Often, patients need a second drug to achieve glucose control; Chen says sulfonylureas typically come next. "Once you get to that point -- a maximum dose of metformin and sulfonylurea -- now you have this whole laundry list of drugs you can choose from. But what you don't have are clinical trials showing long-term safety and efficacy."
Dr. William Duckworth, who directs diabetes research at the Carl T. Hayden VA Medical Center in Phoenix, says that heart disease goes hand-in-hand with diabetes. He doesn't think that the drugs are raising the risk, as one of the two large studies found -- just that they're not very good at lowering it.
Duckworth was co-author of a study of diabetes treatment and cardiovascular disease in 1,791 veterans, which -- like the others -- showed no significant cardiovascular benefit. However, when he did a reanalysis of his data, he found a reduced risk of cardiovascular disease in more recently diagnosed patients who underwent intensive treatment. That leads him to believe that "glucose control is effective if you do it early in the disease," he says.
But this reanalysis (which was presented at a diabetes meeting in June) still needs confirmation, says Dr. Victor Montori, a physician-researcher at the Mayo Clinic in Rochester, Minn. For his part, he thinks that tight glucose control may be getting far too much emphasis in the management of diabetes.
In an April paper in the Annals of Internal Medicine, he pointed to the dearth of benefits of tight glucose control in studies and advocated "good enough" glucose control instead. What this means would depend on the individual patient, Montori says, but would include weighing the benefits of sugar control against some of the undesirable effects of diabetes medications. Many of the drugs cause patients to gain weight, and they can often trigger hypoglycemia, a dip in blood sugar (to less than 70 mg/dL) that's accompanied by shaking, dizziness and sudden sweating.
Montori notes that a good-enough blood sugar strategy would also ease the sheer time and energy it takes to manage diabetes. Treatment regimens -- with frequent doses of pills or insulin, blood-sugar monitoring and doctor visits -- are complicated and burdensome, particularly in patients who may be elderly and have other chronic conditions, such as high blood pressure and high cholesterol. One estimate of the time patients spend taking care of their condition, if they follow all the advice of their doctors, is 143 minutes per day. "That's as much as a part-time job," Montori says.