Controlling blood sugar in diabetes: How low

should you go?

Published: January, 2011

Diabetes is an ancient disease, but the first effective drug therapy was not available until 1922,
when insulin revolutionized the management of the disorder. Insulin is administered by injection,
but treatment took another great leap forward in 1956, when the first oral diabetic drug was
introduced. Since then, dozens of new medications have been developed, but scientists are still
learning how best to use them. And new studies are prompting doctors to re-examine a
fundamental therapeutic question: what level of blood sugar is best?

Normal metabolism
To understand diabetes, you should first understand how your body handles glucose, the sugar
that fuels your metabolism. After you eat, your digestive tract breaks down carbohydrates into
simple sugars that are small enough to be absorbed into your bloodstream. Glucose is far and
away the most important of these sugars, and it's an indispensable source of energy for your
body's cells. But to provide that energy, it must travel from your blood into your cells.

Insulin is the hormone that unlocks the door to your cells. When your blood glucose levels rise
after a meal, the beta cells of your pancreas spring into action, pouring insulin into your blood. If
you produce enough insulin and your cells respond normally, your blood sugar level drops as
glucose enters the cells, where it is burned for energy or stored for future use in your liver as
glycogen. Insulin also helps your body turn amino acids into proteins and fatty acids into body
fat. The net effect is to allow your body to turn food into energy and to store excess energy to
keep your engine running if fuel becomes scarce in the future.

A diabetes primer
Diabetes is a single name for a group of disorders. All forms of the disease develop when the
pancreas is unable to supply enough insulin to meet the body's needs. In some cases, the problem
is a low supply, in others, the body resists the insulin it has, and in still others, it's both a low
supply and insulin resistance.

Type 1 diabetes usually begins abruptly before the age of 20, often with a critical rise in blood
sugar levels. The disease is caused by a combination of genetic abnormalities and environmental
triggers that cause the body's immune system to attack the pancreas, destroying its ability to
produce insulin. Since insulin is required for glucose to enter cells, blood sugar levels rise
sharply. Type 1 diabetes is the most severe form of the disease, but it accounts for only about 5%
of cases in the United States. Lifelong insulin therapy is mandatory.
Type 2 diabetes was once called adult-onset diabetes because it usually begins gradually in
adulthood. But with the alarming rise in childhood obesity, the disease is increasingly common
in children and adolescents. In most cases, the main problem is insulin resistance. The pancreas
produces reasonable amounts of the hormone, but the body's tissues don't respond properly, so
blood sugar levels are abnormally high. Oral medications can help many patients compensate for
insulin resistance. But over time, the ability of the overtaxed pancreas to secrete insulin may run
down, creating the need for insulin therapy.

Mild elevations of blood sugar don't produce any symptoms, which is why about a fourth of all
diabetics don't know they have the disease. When sugar levels get higher, they may produce
fatigue, blurred vision, excess urination, and excessive thirst. Increased hunger is another
symptom, but weight loss may develop despite a hearty appetite. This happens because while the
blood has too much sugar, the cells don't get enough. Diabetes is starvation in the midst of
plenty.

Extremely high blood sugar readings can lead to dehydration, widespread metabolic
abnormalities, coma, and death, conditions called diabetic ketoacidosis and hyperosmolar non-
ketotic coma. Insulin therapy has made these uncommon, but diabetics are still at risk for many
complications of the disease. In broad terms, these problems can be divided into two groups:

 Microvascular complications involve small blood vessels in the kidneys, eyes, and
nerves. These abnormalities explain why diabetes is a leading cause of kidney failure,
blindness, and nerve damage.
 Macrovascular complications involve larger blood vessels in the heart, brain, and legs.
These abnormalities explain why diabetes is a major cause of heart attack, stroke, and leg
amputations.

Many diabetics suffer from both microvascular and macrovascular complications. A particular
worry for men who have diabetes is erectile dysfunction, which often develops from the
combination of nerve and blood vessel damage.

The widespread organ damage produced by diabetes accounts for its dubious distinction as the
seventh leading cause of death in the United States. And the disease also causes long-term
distress and disability.

Do you have diabetes?

The American Diabetes Association (ADA) recommends testing for diabetes every three years
for people ages 45 and older. Individuals with risk factors such as being overweight, having a
diabetic parent or sibling, or having high blood pressure or high cholesterol levels should begin
testing earlier and should have repeat tests as often as yearly. Although several diagnostic tests
are available, two are most useful.

Fasting blood sugar (FBS). It's the simplest, most widely used test, requiring only a single
blood sample that is obtained after at least eight hours without caloric intake (see chart).
Diagnosis FBS HbA1C
Normal below 100 mg/dL below 5.7%
Pre-diabetes 100–125 mg/dL 5.7%–6.4%
Diabetes 126 mg/dL and above 6.5% and above

Glycosylated hemoglobin (HbA1C). This test measures the percent of your red blood cells'
oxygen-carrying hemoglobin molecules that have glucose attached to them. A normal value is
below 5.7%, meaning that around 5% of hemoglobin molecules have glucose attached to them.
At higher levels, glycosylation impairs function. Unlike the FBS, this test does not require
fasting or any other dietary changes. Another advantage of this newer test is that it reflects a
person's average blood sugar level over the preceding two to three months, while a blood sugar
test provides more of a minute-to-minute snapshot.

Beginning in 2010, the ADA gave these tests equal status for the diagnosis of diabetes.

Blood sugar control: Tightening up

Everyone likes to be normal. Quite aside from this natural human impulse, there were good
reasons for scientists to assume that lowering blood sugar levels to nearly normal would reduce
the risk of complications and extend the lives of patients with diabetes.

Several observations lent weight to this strategy of so-called tight blood sugar control, or
intensive therapy. First, scientists believe that high blood sugar levels actually damage blood
vessels over time, both directly and indirectly. When levels are high, glucose will stick to
proteins, cell structures, blood fats, and platelets. Like the hemoglobin in red blood cells, the
target molecules become glycosylated, which impairs their function. Proteins stick together and
the membranes around small arteries thicken, so less oxygen reaches the tissues and waste
products build up. The result is organ damage, which progresses slowly and steadily if blood
sugar levels stay high.

Second, studies from the 1970s onward suggest that even within the "normal" range, higher
blood sugar and HbA1C levels predict a higher risk of cardiovascular disease. Third, a study of
4,662 men found that blood sugar levels were directly linked to the death rate, both in men with
and without diabetes; in all, a 1% percent rise in HbA1C was linked to a worrisome 28% rise in
the death rate.

Biologic theory and observational studies gave rise to the very reasonable assumption that lower
blood sugar levels would translate to better health for diabetics. The next step was to test that
belief with clinical trials, which are much more definitive than observational studies. Indeed, two
important trials from the 1990s provided additional support for the strategy of tight blood sugar
control:

 The Diabetes Control and Complications Trial studied 1,441 patients with type 1
diabetes. As compared with standard blood sugar control, tight control helped slow the
progression of microvascular complications involving kidney, eye, and nerve damage.
 And a subsequent report covering 17 years of follow-up also linked tight control with a
substantial reduction in macrovascular complications, including heart attack, stroke, and
death from cardiovascular disease.
 The United Kingdom Prospective Diabetes Study compared intensive blood sugar control
with standard control in 3,867 patients with type 2 diabetes. Intensive treatment
significantly decreased the risk of microvascular complications, adding weight to the
argument that lower blood sugar levels are better. At the same time, though, intensive
control failed to provide significant protection against macrovascular complications, the
leading cause of death in diabetics.

Based on all these considerations, the strategy of tight blood sugar control was widely
recommended for both type 1 and type 2 diabetes. But that was not the end of the story; instead,
scientists launched additional studies.

Recent results
Three randomized trials published in The New England Journal of Medicine between 2008 and
2009 compared tight blood sugar control with standard control in patients with type 2 diabetes,
and two studies published in The Lancet in 2010 added additional information. Here's what they
found:

 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study compared

intensive blood sugar control with standard therapy in 10,251 patients who had type 2
diabetes and cardiovascular disease or major cardiac risk factors. The study was halted
ahead of schedule after 3.5 years because of an increased death rate in the patients
receiving intensive treatment.
 The Action in Diabetes and Vascular Disease trial included 11,140 patients with diabetes
and vascular disease or at least one vascular risk factor, such as hypertension. After five
years, tight glucose control provided protection against microvascular complications
(primarily kidney disease) but not against macrovascular complications such as heart
attack and stroke. Mortality was similar in patients receiving intensive and standard
therapy.
 The Veterans Affairs Diabetes Trial randomly assigned 1,791 military veterans with type
2 diabetes to either tight or standard blood sugar control. After 5.6 years, the two groups
displayed similar rates of microvascular and macrovascular complications and mortality.
 The United Kingdom's General Practice Research Database collected comprehensive
information on about 47,970 patients with type 2 diabetes. Scientists used these data to
evaluate the relationship between blood sugar control and survival in diabetics. As
compared with patients who enjoyed moderate blood sugar control (corresponding to
median HbA1C levels of about 7.5%), those with both better control (median HbA1C
about 6.4%) and worse control (median HbA1C as high as about 10.5%) experienced
more cardiac problems and higher death rates.
 In a 2010 follow-up study, the ACCORD study reported in 2010 that intensive therapy
provided very little protection against the microvascular complications of Type 2 diabetes
— and these small gains were overshadowed by the cardiovascular risks of tight control.
Dissecting disappointment
Patients with diabetes and the doctors who care for them may be surprised and disappointed that
tight blood sugar control has failed to live up to its promise. But they should not conclude that
control is unimportant. In fact, a closer look at the data can lead to new and better goals for
managing diabetes. Here are some considerations:

 The evidence at hand still supports tight control for patients with type 1 diabetes; in this
population, lowering blood sugar to near-normal levels reduces the risk of both
microvascular and macrovascular complications.
 Tight control is associated with an increased risk of hypoglycemia (abnormally low blood
sugar), which can be very dangerous. Tight control is also difficult to achieve, often
requiring multiple medications that may have adverse effects of their own, including
weight gain. Even a moderate relaxation of blood sugar goals can make life easier for
type 2 diabetics while also reducing the cost and complexity of their medical care.
 Not all patients with type 2 diabetes respond to tight blood sugar control the same way.
When researchers analyzed subgroups of patients, they found that those with newly
diagnosed diabetes enjoy cardiovascular benefit from tight control, while those with
longstanding diabetes and established heart disease do not. It may be that tight control
can protect healthy blood vessels from damaging glycosylation, but once damage has
occurred, it's too late for tight control to help.

The sweet spot

Research has modified some long-held assumptions about the treatment of diabetes, and new
studies are likely to further refine our standards and goals. Still, some principles seem clear:

1. Diet, exercise, and weight control should be the cornerstone of management for all diabetics.
In fact, a healthful lifestyle can prevent many, if not most, cases of type 2 diabetes, and it can
lower blood sugar levels and improve the outcome for all patients with the disease.

2. Good blood sugar control is important for all diabetics. Tight control reduces the risk of
microvascular complications (kidney disease, nerve damage, and eye disease) in type 1 diabetes.
It also helps protect type 1 patients from macrovascular complications (heart attack, stroke, and
cardiovascular death); it may have similar benefits for patients with newly diagnosed type 2
diabetes and healthy blood vessels, but is unlikely to help patients with longstanding type 2
diabetes and cardiovascular disease.

Patients who can achieve near-normal blood sugar levels with lifestyle therapy and simple drug
programs should do so. Current ADA guidelines call for achieving HbA1C levels of less than
7.0%; this corresponds to an average blood sugar level below 154 milligrams per deciliter
(mg/dL). The ADA also recommends striving for fasting blood sugar levels below 131 mg/dL
and peak post-meal levels below 180 mg/dL.
3. Patients who take insulin and others who aim for tight blood sugar control should monitor
their own blood sugar levels. They should also learn to recognize symptoms of hypoglycemia,
including anxiety, racing heart, sweating, tremors, and confusion, and they should know how to
raise excessively low sugar levels and how to get help in emergencies.

While the ADA guidelines remain important, many experts believe that one size does not fit all,
that blood sugar goals should be adjusted according to the needs of individual patients. In
general, an HbA1C target of 7.0% to 7.5%, which corresponds to an average blood sugar level of
about 150 to 170 mg/dL, seems reasonable for many patients with type 2 diabetes. Medical
therapy should be intensified when HbA1C levels exceed 8%, which corresponds to an average
blood sugar level of about 180 mg/dL.

4. Because diabetes is a major cause of cardiovascular disease and premature death, patients
should carefully control other risk factors. Current guidelines set targets for diabetics below
targets for otherwise healthy individuals; these include blood pressure readings below 130/80
millimeters of mercury (mm Hg) and LDL cholesterol levels below 100 mg/dL. Interestingly,
however, reports from the ACCORD investigators suggest that even lower targets for blood
pressure do not provide additional benefits for patients with type 2 diabetes.

5. Because special medications can slow the progression of diabetic kidney disease, patients
should have regular urine tests for microalbuminuria; blood tests of kidney function may also
help. Regular screening for eye disease (diabetic retinopathy) will also lead to helpful preventive
treatment. Foot care is important, too.

Diabetes is a chronic condition, and it is a serious illness. Lifelong attention to lifestyle,

medication, and monitoring is the key to a good outcome. It's a challenge for patients, their
families, and their doctors — but new emphasis on flexibility and moderation promises to make
life easier and better. How sweet it is.