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In early September, researchers concluded a landmark, 20-year study on type 2 diabetes. The $38.6 million study, known as the United Kingdom Prospective Diabetes Study (UKPDS), examined the effects of various therapies on patients with type 2 diabetes. The study is considered the first of its kind in relation to examining diet, oral drug and insulin therapies for patients with type 2 diabetes.
The findings of the research indicate that intensive glucose control resulted in a 25 percent reduction in the risk of microvascular complications, as well as a 12 percent reduction in all diabetes-related complications such as eye disease, kidney failure and nerve damage. It was also discovered that systolic blood pressure brought below 150 mm and diastolic pressures brought below 85 mm resulted in a 24 percent reduction in diabetes-related complications as well as a 37 percent reduction in microvascular complications. Furthermore, the study established an ideal HbA1c for type 2 individuals at 7.1%, and emphasized that each percentage point reduction in HbA1c leads to a 35 percent reduction in diabetes-related complications.
The results appeared in five papers published in the September 12 issues of the British Medical Journal and The Lancet, and were presented at the European Association for the Study of Diabetes Control meeting in Barcelona.
"We now know that if we aim for lower to normal blood glucose concentration, and near-to-normal blood pressure, then it is possible to reduce the risk of complications, and maintain the health of the patient," said Robert Turner, MD, in a recent interview with Reuters Health. "It's not that we need a new treatment. We can use the present treatments that are available more intensively."
Dr. Turner headed the 20-year multicenter study, which began in 1977 and was conducted on 5,102 patients between the ages of 25 and 65 who had been newly diagnosed with type 2 diabetes.
The Purpose of a 20-Year Study
The UKPDS was conducted because researchers wanted to know more about the best ways to treat people with type 2 diabetes, and develop precautions against serious complications that could arise as a result of the malady. Recently, most doctors, educators and patients did not know of the benefits or ramifications associated with intensive diabetes management for people with type 2 diabetes. While the Diabetes Control and Complications Trial (DCCT) demonstrated that tight glucose control by people with type 1 diabetes was essential in avoiding complications, it still left people with type 2 diabetes wondering if such stringent glycemia management guidelines pertained to them as well.
"Finally, we have a definitive, 20-year study which proves that people with type 2 diabetes can reduce their risk of eye, kidney and nerve disease, as well as other diabetes-related complications, by simply lowering their HbA1c by 0.9 percent," stated Wendell Cheatham, MD and medical director for Novo Nordisk Pharmaceuticals.
The UKPDS had five specific arms that it wanted to address. The main arm of the study was designed to evaluate the effect of blood glucose management on diabetes-related endpoints or complications. Other arms of the study were designed to determine:
When patients were first admitted to the study, they were placed into a conventional diet therapy, and were observed for three months. After three months, the researchers evaluated their blood glucose levels. Patients who displayed marked effects of hyperglycemia were then randomized to an intensive treatment of drugs and insulin.
People who took oral medications took one of three types:
Throughout the flow of the study, 30 percent of the nonoverweight patients were assigned to intensive treatment with insulin, 40 percent were assigned to intensive treatment with sulphonylureas and 30 percent remained on a conventional diet therapy. Additionally, 24 percent of the overweight patients were assigned insulin; 32 percent were assigned sulphonylureas; 32 percent were assigned intensive treatment with metformin and 24 percent remained on a conventional diet therapy.
The results of the study's main arm proved what the Diabetes Control and Complications Trial (DCCT) confirmed for patients with type 1 diabetes, which is that lower blood glucose in patients with type 2 diabetes is essential.
The UKPDS demonstrated conclusive evidence that intensive control of blood glucose in type 2 diabetes significantly reduces the chance of blindness by 25 percent, and kidney disease by 25 percent. The study also links improved glucose control with a delay in the development of heart failure by 16 percent. Furthermore, lowering blood glucose in conjunction with medical therapy makes a significant difference in people's health.
Another finding associated with the study were the results of the HbA1c, and its effect on retinopathy, nephropathy and neuropathy. According to the UKPDS , it is proven that every percentage point reduction in HbA1c (i.e., from 8.1 % to 7.1 %) equals a 35 percent decrease in chances of damage to the eyes, kidneys and nerves. Additionally, every percentage point reduction in HbA1c also equaled a 25 percent reduction in diabetes-related deaths.
The UKPDS also pointed out that if people with type 2 diabetes lower their blood pressure to a mean of 144/82 mmHG, they will reduce the likelihood of heart failure by 56 percent, stroke by 44 percent and diabetes-related deaths by 32 percent. The study revealed that no blood pressure medication was proven more effective than others.
Gordon Weir, MD, a senior physician at the Joslin Diabetes Center, was particularly delighted at these findings.
"Most of us had assumed that controlling blood sugars was just as beneficial to type 2s as it is to type 1s" stated Weir. "It was a little troublesome that there was never a good study to prove it."
Dr. Cheatham of Novo Nordisk echoes Weir's sentiment.
"After the DCCT, we ran into problems with naysayers indicating that individuals with type 2 diabetes could not be compared to individuals with type 1 diabetes," stated Cheatham.
Dr. Steven Woolf of the Medical College of Virginia remains one of those naysayers despite the UKPDS results. Recently, at the 50th Scientific Assembly of the American Academy of Family Physicians conference in San Francisco, Woolf opted to rebut the results of the UKPDS, saying that many of the studies supporting tight glycemic control focus on reductions in the "relative" risk and not the "absolute risk" of diabetes-related endpoints among its patients.
"A 25 percent relative reduction in risk for retinopathy noted in the UKPDS study translates to a much smaller absolute risk to the individual patient," stated Woolf.
Woolf also pointed out that factors such as age at the onset of type 2 diabetes and the presence of existing diseases should also be considered in the patient's decision to aggressively treat type 2 diabetes.
Drug and Insulin Therapy
Another arm of the study which dealt with the advantages of diet and drug therapy could not find any evidence of cardiovascular problems as a result of taking either sulphonylureas, metformin or insulin. The doctors in the study went on to say that drugs such as sulphonylureas, metformin, acarbose and insulin only have effective qualities.
"This test gives new credibility to the use of sulphonylureas," stated Weir. " It proves that if there is any risk associated with the use of sulphonylureas, it is very, very low."
In the June '98 issue of Diabetologia, researchers from the University of Dusseldorf argued whether sulphonylureas posed an increased cardiovascular risk for individuals with type 2 diabetes. The research team cited evidence that sulphonylureas damage artery walls and cause an accumulation of plaque that clogs the vessels.
"The data from the UKPDS have not lead to any changes in our position," stated Michael Berger, MD, and one of the lead researchers at the University of Dusseldorf. "Recent findings in animals and humans have provided a pathophysiological plausibility to our hypothesis. "
Berger and his research team cited evidence from a study that compared the use of sulphonylureas to insulin treatment. In this study, the insulin group had lower mortality rates than the sulphonylurea group.
In a letter to the editor in the June '98 issue of Diabetologia, P. Fasching, MD, of the Department of Internal Medicine in Vienna, Austria, dismissed the claims made by the Dusseldorf researchers as being "mere speculation."
Insulin therapy, on the other hand, was given a new credibility for type 2 diabetes as a result of the UKPDS. For blood glucose control, insulin was considered the most effective drug therapy.
"A lot of people assumed that insulin helped accelerate atherosclerosis (irregular distribution of lipids in the bloodstream), and was therefore considered dangerous for type 2 treatment," said Weir. "The findings of this study are very welcome because it really indicates that treating type 2 diabetes with insulin is not only safe, but beneficial as well."
The study affirmed that metformin (which goes by the brand name Glucophage) was considered the first choice of therapy for overweight patients with type 2 diabetes. Metformin therapy was instrumental in reducing all diabetes-related complications by 32 percent, and all diabetes-related deaths by 42 percent in overweight patients who had been taking it from the outset of their diagnosis.
Acarbose (also known as Precose) arrived on the market during the study, and was introduced for three years of the trial. Patients experienced a significant reduction in HbA1c after using acarbose. Physicians like Weir suggest that if a type 2 individual wishes to treat the condition with oral agents, he or she should take acarbose in combination with sulphonylureas.
"Acarbose should be taken before every meal, and sulphonylureas should only be taken once a day," stated Weir.
What About Eating Right and Staying Healthy?
Several people felt that diet therapy seemed to be overshadowed by drug therapy in the UKPDS.
"Although patients benefited from the drug treatments administered through the UKPDS, there was a still a substantial weight gain in most of the treatment groups," stated Richard Krawiec, MD, director of corporate communications for Amylin Pharmaceuticals. Krawiec contends that 80 percent of all patients with type 2 diabetes are overweight, and even obese.
Kris Berg, professor and director of the physiological lab at the University of Nebraska-Omaha, still feels that diet and exercise are the most important therapies.
"There is ample data to demonstrate that physical activity can prevent type 2 diabetes, or at least keep people with type 2 diabetes from taking oral agents," stated Berg. "Most Americans are underexercised, and the reason they have type 2 diabetes in the first place is because they have too much body fat, and their insulin sensitivity drops."
Berg contends that if people with type 2 diabetes start taking insulin and certain oral agents to control their diabetes, they might have a corresponding weight gain.
"They're still going to need more physical activity to combat that weight gain," stated Berg.
Berg emphasizes that people with type 2 diabetes who have physical disabilities can still exercise. He recommends non-weight-bearing exercises such as swimming or cycling. For those who are confined to a wheelchair, he recommends arm pedaling and other aerobic exercises that can be performed from a sitting position.
Health Care Advantages
Another important arm of the study dealt with health care advantages of therapies. It was suggested that one form of treatment will not always be the only form of treatment. As type 2 diabetes progresses, a change in therapy may be necessary to maintain proper control. The sulphonylureas, metformin and acarbose oral agents may become ineffective in time, which would then require the patient with type 2 diabetes to switch to insulin therapy. Cheatham suggests that in this event, the physicians should be careful, but not hesitant, to add subsequent forms of therapy in order to achieve the appropriate form of control.
"We have good evidence that putting individuals with type 2 diabetes on insulin therapy is important," stated Cheatham, whose company, Novo Nordisk, has 20 percent of all insulin sales in the United States.
Negative Side Effects
The arm of the study dealing with the deleterious side effects of therapies could not uncover many dangerous side effects. A small group of patients originally took sulphonylureas at their maximum dosage, and then had metformin added. As a result of this transition, there was actually an increase in the rate of diabetes-related deaths. Furthermore, many patients complained of acarbose's side effects, which included flatulence and diarrhea.
Insulin usage was associated with the most weight gain, as well as the highest number of hypoglycemic episodes.
Diabetes Community Pleased
Reaction to the UKPDS from the diabetes community has been very positive. In a press release, the American Diabetes Association (ADA) said that the UKPDS is "another landmark diabetes study proving the value of metabolic control." The press release went on to say that the UKPDS did not establish a direct effect of lowering blood glucose on cardiovascular complications, but it did answer a lot of questions about type 2 treatment.
"It [the UKPDS] did show that neither the use of insulin, sulphonylureas or metformin appear to increase the risk of cardiovascular events. We feel that health care practitioners should begin or continue to pursue the ADA's treatment goals for the lowering of blood glucose and blood pressure as close to normal as possible."
The Juvenile Diabetes Foundation International was just as pleased.
"The Juvenile Diabetes Foundation applauds the UKPDS as it highlights the need for tight blood sugar control in all patients with diabetes," says Kevan Herold, MD, scientific director of the JDF. "The UKPDS study has shown that near-normal control of glucose is the appropriate goal for diabetes treatment in order to prevent its chronic complications including eye, kidney, nerve and vascular disease."
Richard Kahn, chief scientific and medical officer for the American Diabetes Association emphasized that the UKPDS proved what the ADA believed years prior to the study.
"Decades prior to the DCCT, we believed that glycemic control was important to people with type 1 diabetes, " stated Kahn. "We felt the same way about people with type 2 diabetes, and now that UKPDS has proven that as well."
The First Study of its Kind for Type 2 Diabetes
Prior to the UKPDS, there had been three studies that attempted to test the benefits of blood glucose control for people with type 2 diabetes. The first study was known as the University Group Diabetes Study (UGDS) which was published in 1970. In that study, 1000 patients were assigned various therapies for about 5 1/2 years. At the time, HbA1c was not yet a resource in measuring the long-term cardiovascular benefits of proper blood glucose maintenance. The study is recognized in many circles as being a study that had problems in its design and outcome.
Another type 2 study that was conducted was the 1995 Kumamota Study, in which 110 Japanese subjects with lean physiques were subjected to multiple insulin injections. Subjects who maintained an overall HbA1c reading of 7.1% showed an overall reduction in microvascular complications. The results of the study supported the DCCT's findings on the importance of blood glucose control.
The other study was a pilot study that randomized 153 men to intensive or conventional therapy. This trial was incapable of proving any difference in cardiovascular health after several months.
"I feel that the UKPDS will finally put those studies to rest," said Kahn.
"I certainly feel that the UKPDS study, with a larger and more representative group of individuals with type 2 diabetes, should be looked at more carefully than the previous studies," stated Cheatham.
The Future if Type 2 Treatment
Several diabetes physicians and educators feel that with the results of the UKPDS, we are going to see a mixture of different types of treatments. Some physicians will try to encourage diet and exercise first, and if that fails, patients will have to move onto oral agents and insulin.
Kahn feels that it will be difficult to address the roll of glycemia in people with type 2 diabetes who have already had cardiovascular events.
"Since the UKPDS guidelines have been set, people with newly-developed type 2 diabetes will certainly benefit more than those who have had it for some time," stated Kahn.
Cheatham feels that effective treatment rests in the hands of patients, physicians and educators.
"We need to recognize that early diagnosis is important," stated Cheatham. "We need to recognize that monitoring is important, and that education is important. There needs to be aggressive blood glucose therapy in all patients with type 2 diabetes, while avoiding the pitfalls of hypoglycemia and other medical side-effects. When that can be accomplished, patients will achieve the appropriate form of control that they need."
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