New questions about diabetes management
How far is it from type 1 to type 2?
By William A. Check, PhD
The Diabetes Control and Complications Trial (DCCT) answered one critical long-debated question: Would controlling blood glucose levels reduce the risk for complications in persons with type 1, or insulin-dependent, diabetes mellitus (IDDM)? The answer is largely yes. But DCCT's results raised a whole new batch of questions about the management of type 2, or non-insulin-dependent, diabetes mellitus (NIDDM):
- Will controlling blood glucose levels also decrease the risk for complications in type 2 patients?
- Can diet and exercise alone lower blood glucose levels adequately in type 2 patients?
- What is the best way to use oral drugs and/or insulin therapies in type 2 patients?
Just a few months ago, Frank Vinicor, FACP, MPH, led a media briefing on new study results that showed that certain inferences regarding treatments for type 1 disease can be extrapolated to type 2 diabetes. Dr. Vinicor is president of the American Diabetes Association (ADA) and director of the CDC's division of diabetes.
It seems reasonable to extrapolate the DCCT results to management of type 2 patients because the nature of complications in the two forms of diabetes are similar, even though the underlying cause of the hyperglycemia is different. For example, about 30% of type 1 patients end up with diabetic nephropathy compared with about 15% to 25% of type 2 patients. Kidney specimens from type 1 and type 2 patients with nephropathy cannot be differentiated under the microscope. Background retinopathy occurs in almost all type 1 patients and in 40% to 50% of type 2 patients. (The difference is probably due to the earlier onset and greater severity of IDDM.) Diabetic neuropathy also occurs in both populations but is more prevalent and severe in type 1 patients.
Among diabetologists, there is a cautious consensus that the benefits from intensive therapy seen in type 1 patients can probably be extrapolated to type 2 patients. Philip Raskin, FACP, CDE, professor of medicine at the University of Texas Southwestern Medical Center in Dallas, expresses a typical view: "Data from DCCT shows the clear-cut effect of intensive therapy on the complications of diabetes."
"There is no question now that if you keep the blood glucose level as close to normal as possible, you slow the onset and progression of complications. And I think the conclusions about insulin-dependent diabetics are extrapolatable to all diabetics, though there is no direct proof."
One area where benefits are less defined is in cardiovascular disease (CVD) which has a substantially higher incidence in diabetic patients than in the general population (see "The latest on managing cardiovascular disease in type 2 diabetics," p. 13). The DCCT showed a 44% decrease in the risk for peripheral vascular disease or heart attack with intensive treatment. This decrease was not significant, possibly because too few events occurred. Even so, Dr. Raskin calls the decrease "pretty amazing" because trial subjects were under age 40 and had no other risk factors for CVD.
According to O. Thomas Feagin, FACP, associate program director for the internal medicine residency program at Methodist Hospitals of Memphis, "Since the DCCT trial seemed to confirm the glycemic hypothesis--that the complications of diabetes are related to blood sugar levels--one would be extremely attracted to the theory that the conclusions can be extrapolated to type 2s, as well." However, Dr. Feagin adds, "we don't know for sure."
Controlling blood glucose levels
The DCCT showed a 61% risk reduction for developing diabetic neuropathy with intensive therapy, notes Eva Feldman, MD, PhD, of the department of neurology at the University of Michigan Medical Center. She believes that the principles of the DCCT can be extrapolated to type 2 patients despite no direct evidence. Dr. Feldman and her colleagues have shown that the higher the hemoglobin A1c level, the higher the risk for diabetic neuropathy. Although they have not yet shown that controlling blood glucose levels in type 2 patients can stabilize or reverse the disease, she believes it is a logical conclusion because the pathogenesis of diabetic neuropathy is the same in type 1 and type 2 diabetics.
Saul Genuth, FACP, chief of the division of endocrinology at the Mt. Sinai Medical Center in Cleveland, believes one can reasonably conclude that keeping blood glucose levels close to normal will lower the risks for diabetic retinopathy, neuropathy and nephropathy in type 2 patients. A trial comparable to the DCCT--the United Kingdom Prospective Diabetes Study--now in progress among 5,000 type 2 diabetic persons in the United Kingdom, is measuring the effects of diet, various oral drugs and insulin therapies. The major end point of this long-running study, which is projected to end in 1997, is change in the incidence of and mortality from CVD.
"We hope that the trial will tell us whether cardiovascular complications can be similarly benefited by keeping glucose levels close to normal, and whether it makes any difference how you lower glucose levels," Dr. Genuth says.
Diet and exercise therapy
How one lowers glucose levels--with diet and exercise, oral drugs, insulin, or a combination of these therapies--is a hotly debated issue. Dr. Feagin contends that diet and exercise are "extraordinarily important" and presents patients the results of trial outcomes in detail.
"I tell them it is important to control sugars and that number one is diet, number two is diet and number three is diet. Beyond that they have a choice between oral medications and insulin. That is a negotiation that one has to make with one's patients. Many people are deathly afraid of sticking themselves with a needle," says Dr. Feagin.
Dr. Feagin has found minimizing fat intake using diet and exercise helped him achieve his ideal body weight after a recent increase in his blood sugar. "It is not necessarily easy for people to do," he concedes. To keep blood sugar in a safe range he recommends most people add a twice-daily regimen with both long-acting and short-acting insulins.
Dr. Genuth, on the other hand, sees a limited role for diet and exercise. "I think that there is no one who would disagree that diet, weight reduction and exercise are the preferred means of treatment in persons with type 2 diabetes," he says. "But these steps do not usually lower blood glucose levels to near normal. About two-thirds of patients respond well at the outset, but then cannot stay with those regimens for many years."
"I don't think that should be called noncompliance," he adds. "And I don't think we should blame the patients or the doctors. I think it is a symptom of the disease diabetes that patients cannot modify their behavior forever so as to reset their body weights and caloric intakes to levels that normalize blood glucose."
Dr. Raskin of the University of Texas Southwestern Medical Center advocates initial control with diet, exercise and weight loss. "Diet and exercise is the most frustrating course to modify," he says. "But if you don't go into it with the attitude that it will be successful, you stand little chance of success."
He recommends working with patients rather than just giving them a list of instructions to follow. "In half the cases you're not talking to the person who buys and makes the food," he says.
Dr. Raskin has access to support staff to work with patients on behavioral changes. He acknowledges that financial constraints make this type of patient education difficult for office-based primary care practitioners. "I'm not sure if I had to charge the patient and pay a dietitian that I could afford it," he says. "Internists will probably need to do this (type of patient education) themselves."
Oral and insulin therapies
When a second step in treatment is needed, oral drugs, which include the sulfonylureas glyburide and glipizide and now metformin are prescribed. All three drugs have about equal effect when compared directly in patients with new-onset diabetes who have failed on diet treatment, Dr. Genuth says. If adequate control is not achieved or maintained with monotherapy, a sufonylurea and metform- in may be combined.
Finally, when oral drugs are no longer effective, even when combined, the patient must use insulin. "Of particular concern," Dr. Genuth says, "is whether insulin will be overall beneficial in type 2 diabetes." Insulin is the most effective agent for lowering blood glucose levels, but it has been implicated by some epidemiological studies and some in vitro studies to promote atherosclerosis. This finding could be of particular concern to obese type 2 diabetic persons who require large amounts of insulin to control their blood glucose levels.
Dr. Genuth believes that, if insulin is used, the goal should be to achieve near-normal glucose levels. "I don't think one should be using insulin in a token way," he says, "just to eliminate symptoms of thirst and frequent urination."
In addition to lowering blood glucose levels effectively, insulin promotes a favorable lipid profile. This is not selective to insulin, according to Alan Garber, ACP Member, PhD, of the Baylor College of Medicine. Metformin has independent lipid lowering action, he says. Serum triglyceride levels are decreased (some diabe-tologists think high triglycerides are a risk factor for CVD in type 2 diabetics), and in half of the patients, there is some decrease in high-density lipoprotein cholesterol levels.
Because many type 2 patients already have a complication when they are diagnosed, management of complications and predisposing conditions is essential. Treatment of hypertension is one important example. It is generally agreed that all drugs available for lowering blood pressure are effective. But some drugs should not be considered as first choices for type 2 patients. Thiazide diuretics, for example, are very effective and inexpensive, but tend to raise cholesterol and triglycerides. Some trials suggest they raise blood sugar. Some agents, particularly alpha-methyldopa, can uncover subclinical impotence or postural hypertension caused by autonomic diabetic neuropathy.
For diabetic persons, the best antihypertensives are angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers and alpha-1 antagonists such as doxazosin and prazosin, says Dr. Garber.
Dr. Garber advocates a stringent goal for lowering blood pressure in diabetic patients, even lower than the latest Joint National Committee on the Treatment of Hypertension (JNC-V) guidelines. A blood pressure goal suggested by the JNC is 130/85, or a mean arterial pressure (MAP) of 100 mm Hg (MAP = diastolic blood pressure + 1/3 [systolic blood pressure-diastolic blood pressure]. But Dr. Garber, chairman of a recent ADA nephropathy consensus conference, reviewed data suggesting going even lower, to a MAP of 93 (below 120/80), based on data from Carl E. Mogensen, MD, of Denmark.
Diabetic nephropathy is a major health problem in the United States, says Michael W. Steffes, MD, of the department of laboratory medicine and pathology at the University of Minnesota Medical School. Sixty percent of the cases are accounted for by type 2 disease. The incidence of nephropathy is actually higher among type 1 patients, but there are 10 times as many type 2 patients.
When treating microalbuminuria in routine practice, Dr. Steffes cautions, one must make sure that patients have the disease. "If microalbuminuria is positive, it is important to repeat the test," Dr. Steffes says. "It is not recommended to start treatment before getting a confirmatory test. The more careful you are in confirming any early indication of disease, the more likely you are to be successful in treatment."
Turning to neuropathy, Dr. Feldman of the University of Michigan Medical Center says that a sizable fraction--10% to 15%--of patients presenting with type 2 diabetes already have neuropathy. As the disease progresses, there is a marked increase in the incidence and prevalence of neurologic complications.
Chief among neurologic complications is neuropathy of the foot and lower limb, which manifests as foot pain, foot infection and non-healing foot ulcers. Such problems are the leading cause of non-traumatic amputation below the knee. Early intervention is key, Dr. Feldman maintains: "Very careful foot care coupled with glucose control can truly make a difference in the patient's quality of life."
Dr. Feldman recommends referring the patient to a podiatrist, who can measure the foot, determine special shoe needs and treat callus, as well as perform proper toenail trimming. "I routinely send all my patients who have neuropathy to a podiatrist," Dr. Feldman says. "Patients enjoy going to a podiatrist and routinely tell me how pleased they are with those visits."
She does not recommend routine referral to a neurologist. An internist or office nurse can screen for neuropathy using a neurological screening test that Dr. Feldman developed. It involves inspection of the feet for dry skin, ulceration, infection or callus formation, followed by tests for loss of vibratory sensation in the great toes and for decreased ankle jerks. If the patient has more than two of eight possible points, there is an 85% likelihood of diabetic neuropathy.
"A neurologist can play a useful role if there are any atypical features or pain is difficult to control," Dr. Feldman says. Atypical features include asymmetrical neuropathy, hands much more affected than feet or a motor weakness out of proportion to the sensory loss.
Until results become available from the United Kingdom trial among type 2 diabetics, physicians must make decisions based on clinical judgment. (Also ultimately helpful will be the results of a primary prevention trial in glucose intolerant subjects started by NIH.) For now, Dr. Raskin says, the most important new skill for primary care doctors to learn is not complex drug management, but an attitude that "blood glucose level is important, and you need to do whatever it takes within reason to keep the blood glucose level as close to normal as possible."
William A. Check is a freelance writer living in Wilmette, Ill., who writes on medical and scientific topics.
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