OncologyLow Blood Glucose Levels Do Not Explain Excess Deaths In Accord Trial - Converse Is True: Higher Death Risk With Higher A1C
Low blood glucose
levels do not explain the excess deaths seen in the intensive control
group of the Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial, according to a report presented here today at the
American Diabetes Association"s 69th Scientific Sessions.
"After the original ACCORD report showed an increased mortality risk
in the intensive strategy group aiming to lower A1C level under 6%,
concern arose that this approach might be dangerous," said Matthew C.
Riddle, MD, Professor of Medicine, Oregon Health Science University
and a member of the Glycemia Management Group of ACCORD, in a recent
interview. He was also a site principal investigator in the study.
While he confirmed the estimate reported last year of a 20% increased
risk of death associated with ACCORD"s intensive treatment strategy,
new analyses did not confirm the proposed theory that low A1C levels
might be the cause. A1C is a measure of blood glucose control over
the prior two to three months.
"An A1C below 7% alone does not appear to explain the excess deaths
in the ACCORD trial and is not necessarily a predictor of mortality
risk," said Riddle. "Further, the rate of one-year change in A1C
showed that a greater decline in A1C was associated with a lower risk
of death." Analyses to identify the cause of the increased
mortality, such as hypoglycemia (low blood glucose), weight gain, or
a particular drug or combination of drugs -- are continuing.
"However, we found a 20% higher risk of death for every 1% higher A1C
level above 6%, suggesting that lower blood glucose levels may be a
worthy target in some patients," said Riddle. That higher risk of
death remained even after statistical adjustment for age, duration of
diabetes, or prior cardiovascular events. This analysis is
consistent with analyses from other epidemiologic studies showing a
relationship between higher A1Cs and higher risk of death.
The goal was for the intensive group to reach an A1C level of less
than 6% and for the standard group goal to reach between 7 and 7.9%.
The Role of Hypoglycemia
A closer look at the role of hypoglycemia was presented by Denise
Bonds, MD, MPH, who was an investigator at ACCORD"s Coordinating
Center and who is now a medical officer for the trial at the National
Heart, Lung, and Blood Institute (NHLBI) at the National Institutes
of Health (NIH).
The study defined severe hypoglycemia as a blood glucose level of
less than 50 mg/dl or symptoms consistent with hypoglycemia and
recovery with glucagon or an oral carbohydrate. It was further
divided into those who required any assistance versus those who
required emergency medical assistance at home or in a hospital.
"Some predictors of hypoglycemia cannot be changed. For example, we
found that more frequently those who required medical assistance for
severe hypoglycemia were female or African-American, had a longer
duration of diabetes, or had entered the study already receiving
insulin," said Bonds. "However, more than half of severe hypoglycemic
events were preceded by a missed meal, delayed meal, or a meal with
fewer carbohydrates than normal -- information that individuals with
diabetes can use to modify their behavior and help in preventing and
reducing hypoglycemic events."
About one-third of severe hypoglycemic events resulted in confusion
or abnormal behavior for the individual, one-third resulted in loss of
consciousness, and one-third required hospitalization.
A total of 451 deaths occurred in the ACCORD standard and intensive
groups combined, and 7% of those individuals had at least one severe
hypoglycemic event requiring medical assistance.
"We found that severe hypoglycemia in both groups was associated with
a higher risk of death but, among those who had severe hypoglycemia in
the intensive arm, it was associated with a lower risk of death
compared to those who had severe hypoglycemia in the standard group,"
said Bonds.
The explanation for this is unclear, but it must be remembered that
patients in the intensive group were seen more frequently, had more
phone calls with health care providers, and more frequent but milder
hypoglycemic events. It is theorized that these patients learned how
to recognize and treat themselves at the first signs of hypoglycemia
or perhaps that the hypoglycemia that caused mortality was of a
different type.
The ACCORD group also adjudicated each death for the potential role
of hypoglycemia. Of the 451 deaths, they were only able to identify
one case where it was concluded that severe hypoglycemia definitely
played a role. However, there cannot be complete certainty because
glucose measures are not available near or at the times of deaths.
Continuous glucose monitoring was rarely done during the trial.
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 ACCORD Study
ACCORD enrolled 10,251 adults at 77 clinics in the U.S. and Canada.
The average age at study entry was 62 years. The 35% who had prior
CVD events (heart attacks and strokes) were the secondary prevention
group, while the balance who were at high risk for such events had
problems such as left ventricular hypertrophy, microalbuminuria, or
at least two of the following risk factors: high LDL (the "bad"
cholesterol), low HDL (the "good" cholesterol), high blood pressure,
an elevated BMI (an indicator of overweight or obesity), or were
smokers.
ACCORD was testing an intensive strategy of glycemic control versus a
standard strategy, so intensive group patients had more frequent
clinic visits and were required to do more frequent self-monitoring of
blood glucose because they modified certain medications themselves in
response to self-monitoring results. The same menu of medications
was available to physicians treating both groups, but patients in the
intensive group tended to be prescribed more of them, based on the
individual physician"s clinical judgment, to get to the target. A
broad comparison is that 52% of intensive patients vs. 16% of those
in the standard group were likely to be on insulin plus three oral
agents.
ACCORD"s comparison of two forms of glycemic therapy ended after 3.4
years of follow up due to the excess deaths in the intensive group,
and that experience forms the basis for all reports to date.
However, the trial has continued and, together with other studies for
blood pressure and lipid control, will end June 30th, with complete
analyses of all three studies expected in the next year.
ACCORD is primarily sponsored by NHLBI, with additional funding and
scientific expertise from the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK). Other components of the NIH --
the National Institute of Aging and National Eye Institute -- as well
as the Centers for Disease Control and Prevention, provide support
substudies.
Action to Control Cardiovascular Risk in Diabetes