New AACE Guidelines for Prediabetes Management

The management of prediabetes involves intensive lifestyle management and setting treatment goals of blood pressure and lipid level control matching those for diabetes, according to a consensus statement released July 23 by the American Association of Clinical Endocrinologists (AACE). Subsequent publication of the final document in Endocrine Practice is planned for later this year.

"As individuals and as a society, we need to address those forces which are creating the epidemic of obesity, diabetes, and prediabetes," Yehuda Handlesman MD, FACP, FACE, treasurer of AACE and medical director of the Metabolic Institute of America, said in a news release. "We understand the difficulties in implementing solutions, but as an association of endocrinologists we are committed to supporting community and national efforts in every way we can."

The new guidelines are the first comprehensive treatment regimen for patients with prediabetes recommended by a consensus of experts in diabetes and metabolic disorders. The consensus statement offers specific guidelines regarding lifestyle modification as well as pharmaceutical intervention where appropriate.

US prevalence of prediabetes, defined by elevated fasting glucose levels or impaired glucose tolerance, is greater than 56 million. However, an even greater number of individuals with prediabetes have not yet been diagnosed.

Because prediabetes increases the risk for cardiovascular disease as well as for the development of type 2 diabetes, these guidelines extend the overall effort to recognize and treat type 2 diabetes sooner and more intensively.

Because no pharmacologic therapies are currently approved by the US Food and Drug Administration (FDA) to prevent the development of diabetes in patients with prediabetes, the expert panel recommends a 2-fold approach to treating prediabetes.

The first goal is aggressive lifestyle management to prevent the progression to type 2 diabetes, following guidelines established by the Diabetes Prevention Program of the US government.

"Although lifestyle can clearly modify the progression of patients towards overt diabetes, it may not be sufficient," said Alan J. Garber, MD, PhD, FACE, professor of medicine, Baylor College of Medicine in Houston, Texas, and chairman of the Consensus Conference. "Medications may well be required, particularly in high risk groups."

The second goal is to avoid cardiovascular complications, with use of pharmacotherapy for those patients whose prediabetes is refractory to lifestyle modifications. In addition to medications for glycemic control, this strategy involves use of medications for hypertension and hypercholesterolemia when appropriate. High-risk individuals with levels of blood glucose approaching those seen in diabetes, hypertension, or hyperlipidemia should consider closer clinician monitoring of their risk factors.

"The data show that there is a spectrum of severity, with the most severely affected approaching the risks of people with diagnosed type 2 diabetes," said Daniel Einhorn, MD, FACP, FACE, vice president of AACE and medical director of the Scripps Whittier Institute for Diabetes in La Jolla, California. "In these highest risk individuals, who represent a minority, pharmacologic strategies may be appropriate if intensive lifestyle therapies fail. Regardless, all individuals at risk for diabetes should be aware of the level of their risk factors and be prepared to take action."

Specific questions and pertinent comments addressed in the Consensus Statement are as follows:

1. What is the spectrum between normal glucose tolerance, prediabetes, and diabetes, and what criteria should be used to diagnose each of these?

Normal glucose levels are defined as a fasting blood glucose level of less than 100 mg/dL and a postchallenge level of less than 140 mg/dL. Those considered diagnostic for diabetes are a fasting blood glucose level of 126 mg/dL or more and a postchallenge level of 200 mg/dL or more; the spectrum in between is poorly defined. In some individuals, these intermediate levels of glucose (fasting glucose level of 100 - 125 mg/dL; 2-hour levels of 140 - 199 mg/dL) may be a harbinger of overt type 2 diabetes, cardiovascular disease, and microvascular complications.

2. What clinical risks ensue if prediabetes is not treated?

In the large DECODE Study, risks for all-cause mortality increased linearly as the 2-hour blood glucose level increased from 95 to 200 mg/dL. In the Diabetes Prevention Program, approximately 8% of patients with impaired glucose tolerance had diabetic retinopathy as did nearly 13% of those whose condition progressed to diabetes. The STOP NIDDM trial showed an increase in hypertension (> 140/90 mm Hg) in the placebo-treated patients with impaired glucose tolerance during a 3-year period, with an increase in clinical cardiovascular disease (CVD) events by approximately 5% during 4 years. The Honolulu Heart Study showed that postchallenge hyperglycemia was associated with an increase in sudden death during a 23-year follow-up.

3. What goals and treatment modalities should the management of prediabetes target?

Intensive lifestyle management is preferred because it is safe and effective in improving glycemia and reducing cardiovascular risk factors. Treatment goals for blood pressure and lipid control should match those for diabetes. Individuals with prediabetes should reduce weight by 5% to 10% and maintain it long term, using strategies such as patient self-monitoring, realistic and stepwise goal setting, stimulus control, cognitive strategies, social support, and appropriate reinforcement.

Regular, moderate-intensity physical activity is recommended for 30 to 60 minutes daily, at least 5 days weekly. Diet should be low in total fat, saturated fat, and trans-fatty acids and should include adequate dietary fiber. Lower sodium intake and avoidance of excess alcohol are recommended for blood pressure control.

Because the FDA has not yet approved any drugs to prevent diabetes, any decision to start pharmacotherapy for prediabetes must consider available evidence and a risk-benefit analysis. For persons with prediabetes at particularly high risk, pharmacologic glycemic treatment may be considered in addition to lifestyle strategies. Metformin and acarbose are safe and have strong evidence for a reduction in the development of diabetes from prediabetes. Thiazolidinediones also reduce the risk for progression from prediabetes to diabetes, but there are safety concerns including congestive heart failure or fractures.

Lipid level goals should be the same for persons with prediabetes and those with established diabetes. Statins are recommended to achieve treatment goals of 100 mg/dL for low-density lipoprotein cholesterol levels, 130 mg/dL for nonhigh-density lipoprotein cholesterol levels, and 90 mg/dL for apolipoprotein B. Fibrates, bile acid sequestrants, ezetimibe, and other drugs may be useful adjunctive therapy in some patients. Niacin may improve lipid profile but has a potential for adverse glycemic effect.

Patients with prediabetes should have the same target blood pressure currently recommended for persons with diabetes (systolic < 130 mm Hg and diastolic 80 mm Hg). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are recommended as first-line agents and calcium channel blockers as second-line treatment. Because of adverse effects on glycemia, thiazides and/or β-blockers should be avoided if possible.

Aspirin is recommended for all persons with prediabetes who are not at increased risk for gastrointestinal tract, intracranial, or other bleeding.

4. How should prediabetes and its treatment be monitored?

Patients with prediabetes should have an annual glucose tolerance test and twice-yearly testing for microalbuminuria and fasting plasma glucose, hemoglobin A1C, and lipid levels. Patients at highest risk (> 1 of impaired glucose tolerance, impaired fasting glucose level, or metabolic syndrome) should be monitored more carefully.

5. How cost effective is treating prediabetes?

The costs of preventing diabetes can be balanced against cost savings realized from fewer patient-years of the disease, complications, and hospitalizations.

Clinical Context
Although the US prevalence of prediabetes, defined by elevated fasting glucose levels or impaired glucose tolerance, exceeds 56 million, an even larger number of individuals with prediabetes are still undiagnosed. Prediabetes increases the risk not only for the development of type 2 diabetes but also for cardiovascular disease. Some people with prediabetes already have microvascular changes such as retinopathy, amputations, or renal failure.

The AACE has convened a panel expert in management of diabetes and metabolic disorders to issue guidelines for comprehensive treatment of patients with prediabetes. These recommendations highlight a 2-fold approach to management, with lifestyle modifications for all patients as well as pharmaceutical intervention for patients at particularly high risk for the development of diabetes.

Study Highlights
Individuals with prediabetes have glucose levels lower than those with diabetes but higher than normal (fasting glucose level, 100 - 125 mg/dL; 2-hour levels, 140 - 199 mg/dL).
Prediabetes may be associated with, or may increase the risk for, cardiovascular disease and microvascular complications, and it may lead to the development of overt type 2 diabetes.
All patients with prediabetes should have intensive lifestyle management, which is safe and effective in improving glycemia and in decreasing cardiovascular risk.
Treatment goals for blood pressure and lipid control should match those for diabetes.
Individuals with prediabetes should lose 5% to 10% of body weight and maintain it long term.
Regular, moderate-intensity physical activity is recommended for 30 to 60 minutes daily at least 5 days weekly.
Diet should be low in total fat, saturated fat, and trans-fatty acids and should include adequate dietary fiber.
For blood pressure control, lower sodium intake and avoidance of excess alcohol are recommended.
No drugs are currently FDA approved for prediabetes, so decisions to start pharmacotherapy must be based on a risk-benefit analysis.
For persons with prediabetes at particularly high risk, pharmacologic glycemic treatment may be considered in addition to lifestyle changes.
Metformin and acarbose are safe and effective in helping prevent diabetes.
Although thiazolidinediones decrease the risk for progression from prediabetes to diabetes, safety concerns include congestive heart failure or fractures.
Lipid level goals for persons with prediabetes should be the same as for those with established diabetes.
Statins are recommended if needed to achieve treatment goals for low-density lipoprotein cholesterol levels (100 mg/dL), nonhigh-density lipoprotein cholesterol levels (130 mg/dL), and apolipoprotein B (90 mg/dL).
In some patients, fibrates, bile acid sequestrants, ezetimibe, and other drugs may be useful adjunctive therapy.
Niacin may improve lipid profile but has a potential for adverse glycemic effect.
Patients with prediabetes should have the same target blood pressure as do persons with diabetes (systolic < 130 mg Hg; diastolic 80 mm Hg).
Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are recommended as first-line agents and calcium channel blockers as second-line treatment of hypertension.
Thiazides and/or β-blockers should be used with caution because of adverse effects on glycemia.
All persons with prediabetes who are not at increased risk for gastrointestinal tract, intracranial, or other bleeding should take aspirin.
Monitoring for patients with prediabetes should include an annual glucose tolerance test and twice-yearly testing for microalbuminuria and fasting plasma glucose, hemoglobin A1C, and lipid levels.
Highest-risk patients should be monitored more often.
The costs of prediabetes management may be offset by cost savings from reduced patient-years of the disease, complications, and hospitalizations.

Pearls for Practice
All patients with prediabetes should have intensive lifestyle management, which is safe and effective in improving glycemia and in decreasing cardiovascular risk. Treatment goals for blood pressure and lipid level control should match those for diabetes. Target weight loss is 5% to 10% of body weight, which should be maintained long term, following a diet low in total fat, saturated fat, and trans-fatty acids and containing adequate dietary fiber.
No drugs are currently FDA approved for prediabetes, so decisions to start pharmacotherapy must consider specific patient risks and benefits. For persons with prediabetes at particularly high risk, pharmacologic glycemic treatment may be considered in addition to lifestyle changes, preferably with metformin and acarbose.