Factors Affecting Benefit/Harm Of Intensive Glucose Control In Type 2 Diabetes Reported
Main Category: Diabetes
Article Date: 10 Jun 2009 - 3:00 PDT
Factors affecting whether intensive glucose control is likely to reduce or increase the risk of cardiovascular events, including death, based on evidence in the VA Diabetes Trial, were reported in a symposium here today at the American Diabetes Association's 69th Scientific Sessions.
"We found that initiation of intensive control in the first 15 years after a diagnosis of type 2 diabetes reduced the risk of cardiovascular events, including mortality, but initiation 16 to 20 years after diagnosis yielded no such benefit," said William C. Duckworth, MD, Director of Diabetes Research, Carl T. Hayden VA Medical Center in Phoenix, Professor of Clinical Medicine, University of Arizona, and Co-Chair of the VA Diabetes Trial (VADT), in a recent interview.
"Further, initiation of intensive control 20 or more years after diagnosis increased the risk of cardiovascular events in the population studied in this trial," said Duckworth. These duration effects were not affected by age, despite the fact that age itself is an independent risk for CV events.
In contrast to the VADT report last year showing that intensive control did not have a statistically significant effect on reducing cardiovascular (CV) events, the subanalyses presented here clearly showed which patients benefited from intensive glucose control and which patients did not.
The effect of duration impact was complex. According to the research, the risk of having a primary CV event (i.e., heart attack or stroke) among people who had diabetes for 10 to 15 years was reduced 40% if they were on intensive glucose control. At the other end of the spectrum, if diabetes had been present for more than 21 years, the risk of primary CV events in patients on intensive control more than doubled.
"Unless other factors are present that would contraindicate intensive treatment, such as hypoglycemia, intensive control is appropriate in the first 15 years after diagnosis," said Duckworth. "However, intensive treatment should not be initiated if the individual has already had diabetes for 20 years." He said it is unknown whether a person who has already been on intensive treatment for many years can safely continue it beyond the 20-year mark.
Other major risk factors potentially precipitating a primary CV event or total mortality were hypoglycemia, a previous CV event, older age and impaired kidney function.
Duckworth and a colleague described in detail two factors -- HDL levels and hypoglycemia levels -- that could decrease or increase, respectively, the risk of CV events in people with type 2 diabetes, as well as pointed out areas where questions remain.
"The main factor decreasing mortality risk in the study was the individual's level of HDL -- the good cholesterol fraction," explained Duckworth. "There was an 80% decrease in risk of CV events, including mortality, for every 10 mg increase in HDL above each individual's baseline, a 50% decrease in risk of a first primary CV event for every 10 mg increase in HDL, and a 55% decrease in risk of all-cause mortality for every 10 mg increase in HDL." He said this is comparable to what has been seen in epidemiologic studies of people without diabetes. HDL levels can be raised through regular exercise and with certain medications.
Hypoglycemia as a Major Risk
Another factor found to increase the risks of intensive treatment was severe hypoglycemia (seriously low blood glucose levels).
"In the VADT, those who had episodes of severe hypoglycemia were much more likely to have severe adverse effects up to and including death," said Duckworth. "In both groups combined, those who had had hypoglycemia severe enough to cause changes in consciousness had an 88% increase in primary CV events and a three-fold increase in CV death."
According to Stephen N. Davis, MD, Chief, Division of Diabetes, Endocrinology and Metabolism, Mark Collie Professor, Medicine and Molecular Physiology and Biophysics, Vanderbilt University, "It is important to note that this association between severe hypoglycemia and heart attacks and mortality occurred in both the intensive and the standard groups, in contrast to prior perceptions that such hypoglycemia was just a problem with people on intensive control." Davis is an investigator and executive committee member with the VADT.
In addition, Davis pointed out that because type 2 diabetes is not a homogeneous condition, there may well be certain subgroups of patients who are particularly vulnerable to the effects of severe hypoglycemia. "Certain clinical predictors of such vulnerability could be duration of disease, prior CV disease, age, or renal dysfunction," explained Davis. "This means that clinicians must adjust A1C goals to the individual patient, seeking the best possible control while avoiding hypoglycemia, and patients must be cautioned to report all episodes of hypoglycemia to their physician."
Type 2 Diabetes
Nearly 24 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputation. It is a leading cause of death by disease in the United States. Type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes and involves insulin resistance -- the body's inability to properly use its own insulin. Type 2 occurs mainly in adults who are overweight and age 40 and older. More than 65% of people with diabetes die from heart disease or stroke. With diabetes, heart attacks occur earlier in life and often result in death.
The VA Diabetes Trial of Glycemic Control and Complications in Diabetes Mellitus Type 2, also known as the VA Diabetes Trial, enrolled 1,791 U.S. veterans at 20 Veterans' Affairs Medical Centers around the country. Among the participants: 97% were men; 16% were African-Americans; 16% were Hispanic whites; 62% were non-Hispanic whites; and 5% other races. The average age at study entry was 60 years.
Of the 40% who had prior CVD events, those events were mostly heart attacks and strokes, bypass surgery of the carotid or coronary artery or legs, and lesser conditions such as angina, or transient ischemic attacks. In addition to the 40.4% with prior CV events at the outset, 80% had hypertension, over 50% had lipid abnormalities, and the vast majority were obese.
The VADT specifically included only patients who had already failed what is called "simple therapy," i.e. they had unacceptable A1Cs on maximal doses of at least one oral antidiabetes drug and/or insulin, meaning they averaged 9.5% when a normal A1C is 6%. During the trial, most people received two to three oral agents plus insulin. By the end of the first year and thereafter throughout the trial, 90% in the intensive group were on insulin, whereas only 74% in the standard group were taking insulin throughout the trial after the first year. Ninety-four percent of all participants were taking oral antidiabetes drugs throughout the trial, albeit more so in the intensive group than the standard group. Everyone in both groups was also treated with maximum lipid, blood pressure, diet and lifestyle control, which included education and counseling on exercise, diet and smoking.
By the time the trial closed at the end of May 2008, it had been ongoing for 7.5 years, but the average follow-up time for individual participants had been 6.25 years.
The American Diabetes Association