Experts Recommend Two-Pronged Approach to Treating Prediabetes

“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 costs.

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 lifestyle changes.

“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 patient’s HbA1c has risen from 6% to 6.4%, do you wait until it reaches 6.5%?

“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 diabetes.

“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 antagonists.

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,” Buse said.

“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 you’re 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 metformin’s 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 said.

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 don’t 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 patient’s 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 doesn’t 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,” Matfin said.

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 child’s 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.