According to the most recent data compiled by the CDC, 57 million U.S.
adults have prediabetes, a figure that has reached pandemic levels.
In an ideal world, you want to diagnose high-risk people early in
order to prevent progression to full-blown diabetes and its associated
complications, Glenn Matfin, MD, clinical associate professor at
New York University and senior staff physician at the Joslin Diabetes Center,
told Endocrine Today.
Whether prediabetes progresses to diabetes depends on a number of
variable factors, including lifestyle changes, genetics and treatment
practices, which have some physicians supporting the use of medication and
others vehemently against it.
We draw lines in order to differentiate between normal glucose
tolerance, prediabetes and diabetes, but it is an interlinked, continuous
chain, Matfin said. The clock is ticking, and the health risks rise
significantly as prediabetes goes untreated.
To examine the current state of prediabetes treatment, Endocrine
Today spoke with a number of experts to best understand how lifestyle
and pharmacological approaches should be utilized to reverse glucose functions
to normal levels. The issue is also examined from a financial aspect, as the
ability to keep patients with prediabetes from turning into patients with
diabetes translates into hundreds of millions of dollars saved in health care
Ralph DeFronzo, MD, and diabetes experts discuss preferred
therapeutic approaches for people with prediabetes.
Photo courtesy of:
The University of Texas Health
Science Center at San Antonio
Perhaps due to its subtle set of symptoms, the identification and
diagnosis of patients with prediabetes has proved to be a challenge. Research
has shown that although 30% of the U.S. population had prediabetes in 2005 to
2006, only 7.3% were aware that they had it.
A consensus from diabetes and metabolic disorder experts at the American
College of Endocrinology and American Association of Clinical Endocrinologists
define prediabetes as impaired fasting glucose (100 mg/dL-125 mg/dL); impaired
glucose tolerance (2-hour postglucose load, 140 mg/dL-199 mg/dL); or both.
These intermediate levels of glucose constitute inherent disease risk, experts
said. AACE also identified metabolic syndrome as a prediabetes equivalent.
AACE guidelines recommend screening for prediabetes in individuals with
the following characteristics: family history of diabetes; cardiovascular
disease; overweight or obesity; a sedentary lifestyle; non-white ancestry;
previously identified IGT, IFG and/or metabolic syndrome; hypertension; high
triglycerides; low HDL; history of gestational diabetes; delivery of a baby
weighing more than 9 lb; polycystic ovary syndrome; antipsychotic therapy for
schizophrenia; and severe bipolar disease.
Selective screening for prediabetes in high-risk individuals and
subsequently enrolling them in Diabetes Prevention Program (DPP) lifestyle
intervention has been shown to have an adjusted cost-effectiveness ratio of
$9,511 per quality-adjusted life-year compared with no screening.
To me, you can easily sort out the people who you would like to
treat with screening, Ralph DeFronzo, MD, professor of medicine
and chief of the diabetes division, University of Texas Health Science Center
and the Audie L. Murphy Memorial VA Hospital, said in an interview.
Numerous studies, most notably the DPP, have lauded the benefits
resulting from a lifestyle modification of diet and exercise, finding that it
is the ideal first-line treatment to halt the progression of diabetes.
The ACE/AACE consensus statement recommends a two-pronged approach to
treating prediabetes: intensive lifestyle intervention, followed by the
prevention of CV complications using CV risk reduction medications for abnormal
blood pressure and cholesterol, independent of glucose control medications.
Guidelines from the American Diabetes Association (ADA) suggest that
patients who are diagnosed with prediabetes be referred to an effective ongoing
support program, with a weight loss goal of 5% to 10% of their current body
weight, as well as a call for an increase in physical activity of at least 150
minutes per week of a moderate activity such as walking. According to DPP
findings, patients who lose weight often regain normal glucose regulation.
Clinical data suggest that if a patient is able to adhere to it,
then lifestyle intervention has broader benefits than drug therapies, and
without the side effect profile, John B. Buse, MD, PhD, professor
of medicine and endocrinology chief at the University of North Carolina, Chapel
Hill, told Endocrine Today.
Although many physicians cite the patient compliance issues inherent in
lifestyle change, others reference the financial burden that the changes can
place on patients in the form of costly gym memberships, fitness
equipment, diet foods, and fresh fruits and vegetables. However, the long-term
cost-savings of a successful lifestyle modification program are significant.
The most expensive one-on-one DPP care was $1,000 per person,
annually, Robert E. Ratner, MD, senior scientist at MedStar Health
Research Institute, Hyattsville, Md., said in an interview. The reduction
of medical costs that resulted from this had offset the cost of the lifestyle
intervention within 3 years.
Sunder Mudaliar, MD, clinical professor of medicine, University
of California, San Diego, said there are difficulties in relying solely on
Clearly, a diet and exercise regimen is the first option for
anyone with prediabetes, and it seems to work in almost everyone who actually
follows it, he said. The problem is that we give people diet and
exercise recommendations and they come back in 3 or 6 months and nothing
happens. Making intensive lifestyle changes requires a lot of institutional
support and individual attention, and this often does not occur.
For some physicians, lifestyle change is just one aspect of prediabetes
treatment. At present, although not FDA approved, pharmacological intervention
is widely used in the United States as a prediabetes treatment; however, a
number of questions remain regarding which medications are most effective and
when, or if, they should even be initiated.
Obesity is driving this epidemic, DeFronzo said. The
fact is diet and exercise trials do not work on a long-term basis in the real
world, and people regain the weight. I believe that, particularly in high-risk
people, the treatment of choice, optimally with combination with diet and
exercise, should be pharmacologic therapy.
For other prediabetic patients, lifestyle changes, even when adhered to,
do not provide the results needed to avoid progression to diabetes.
With a 60-year-old with a BMI of 30 who has made lifestyle changes
and either cannot lose weight or despite losing some weight their HbA1c starts
to rise, then it makes sense to initiate drug therapy, Ratner said.
If a patients HbA1c has risen from 6% to 6.4%, do you wait until it
If a patient is either unable to accomplish the lifestyle goals or
despite accomplishing the lifestyle goals has deterioration in glycemia, then
it is reasonable to add pharmacological therapy, he said.
According to DeFronzo, much of the resistance to treating prediabetes
with medication stems from people not understanding that prediabetes is
People do not often understand the pathophysiology; they do not
understand that prediabetes is associated with all of the same problems as
diabetes, including severe insulin resistance and loss of beta cell function.
If you blindfolded a physician and said, I have a patient who has lost
80% of beta cell function and he/she is maximally insulin resistant. Do I
treat? Most would say treat.
The ACE/AACE prediabetes consensus statement recommends that lipid and
BP goals be the same for those with prediabetes as those with full-blown
diabetes. The experts recommend statins to achieve lipid treatment goals of 100
mg/dL for LDL; 130 mg/dL for non-HDL; and 90 mg/dL for apolipoprotein B. Other
adjunctive therapies may be useful, such as fibrates, bile acid sequestrants
and ezetimibe. For BP, the goals should be less than 130 mm Hg systolic and
less than 80 mm Hg diastolic, using first-line angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers, or second-line calcium
After a patient has been verified as a candidate for pharmacological
treatment, the proper medication to prescribe must be addressed.
Metformin is currently the only medication recommended by the ADA for
the treatment of prediabetes. According to the ADA, it is typically prescribed
for patients who are at high risk for developing diabetes, including those who
have an HbA1c greater than 6%; hypertension; low HDL; elevated triglycerides;
family history of diabetes in a first-degree relative; are obese; and are
younger than 60 years.
If people fail at lifestyle modification therapy and their glucose
is progressing, I think that metformin is a reasonable second choice,
Mudaliar said there are numerous reasons for metformin use.
Metformin has been around for nearly 50 years, its side effect
profile is reasonably predictable, it can be used in a large majority of people
and it is extremely inexpensive, he said.
With the sheer number of potential patients, this familiarity is
essential, Matfin said: There is a lot of experience with it. So when
youre talking about a population this size of millions and millions and a
health care system that is straining, then metformin after diet and exercise
would be a good candidate.
However, despite metformins widespread use, the medication is not
for all patients.
An important caveat for metformin to point out is that its
efficacy to prevent diabetes in the DPP in a patient over the age of 60 with a
fasting glucose of 109 mg/dL or lower or a BMI under 30 was basically zero.
Metformin clearly is not for patients who fall in this category, Buse
Overall, metformin was shown to be moderately efficacious in
the DPP, DeFronzo said.
My problem with it is that it does not preserve beta cell
function, he said. I dont think it is the best drug from the
standpoint of pathophysiology in correcting the underlying disturbances.
Until the FDA approves any drug for prediabetes or IGT, physicians may
be nervous using a drug off-label, DeFronzo said.
According to AACE guidelines, any decision to implement pharmacologic
therapy for prediabetes, specifically in children and adolescents, is off-label
and requires careful judgment regarding the risks and benefits of each specific
agent in each individual patient.
Some physicians are not hesitant to prescribe pharmacotherapy, based on
the patients decision.
If a patient has an HbA1c of 6% and wants to take drugs, I have
absolutely no problem prescribing them, Buse said. The higher the
risk for developing diabetes, the more reasonable it is to treat the patient
with a drug.
But, if it is an 85-year-old with an HbA1c of 6%, then it
doesnt make a lot of sense to treat.
Because of the vast number of Americans with prediabetes and recent
reports of adverse events attached to diabetes medications, policymakers have
not changed existing policies.
If you are treating millions of people, costs aside, you have a
lot of serious complications that are going to occur, which I believe is one
reason that the FDA has not approved drugs specifically for prediabetes,
A number of programs are in development and have been implemented to
decrease the prevalence of prediabetes and stop the progression to diabetes.
The promotion of healthy lifestyles needs to begin at a young age
to start healthy habits early in life, Mudaliar said.
The U.S. Department of Agriculture (USDA) has proposed an investment of
$10 billion during the next 10 years to improve childhood nutrition programs.
It announced several improvements in school nutrition, including improved meal
quality; increased eligibility for free or reduced price meals; diversified
food service programs; school meal report cards for parents to help guide their
childs food choices; and a stronger farm-to-school link.
A major issue for both medication and lifestyle modification is
cost, particularly among the lower socioeconomic groups who have the highest
incidences of prediabetes and diabetes, DeFronzo said.
Neighborhood programs that encourage lifestyle change at an affordable
price, such as 16-week health and exercise programs sponsored by area YMCAs,
may play a role in improving adherence.
The key is to enroll people in programs that they are willing to
participate in, and where they will be seen frequently, Buse said.
It has zero efficacy to simply tell a patient to diet and exercise 5 days
a week and lose 30 pounds. The programs that work involve a variety of
lifestyle coaches who see patients frequently. by Katie
Kalvaitis and Stephanie Portnoy
Should the LDL target be
the same for prediabetes as overt diabetes?
For more information:
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- Geiss LS. Am J Prev Med. 2010;38:403-409.
- Hoerger TJ. Diabetes Care. 2007;30:2874-2879.
- Knowler WC. N Engl J Med. 2002;346:393-403.
- Matfin G. Ther Adv Endocrinol Metab. 2010;
- Perreault L. Diabetes Care. 2009;32:1583-1588.