J.M., a 48-year-old Hispanic man, was seen in the primary care clinic for routine follow-up of hypertension, for which he had been treated for the past 8 years. His only medication was lisinopril, 20 mg/day. Home blood pressure monitoring averaged 128/82 mmHg. He had a family history for hypertension, type 2 diabetes, and coronary artery disease. J.M. reported a 20-lb weight gain over the past year, along with a sedentary lifestyle with no regular exercise routine. Other medical history was negative, including symptoms of fatigue, polyuria, or polydipsia. He denied past or current tobacco use.
J.M. presented with a waist size of 42 inches, BMI of 34 kg/m2, and blood pressure of 125/80 mmHg. A subsequent lipoprotein profile demonstrated the common pattern associated with pre-diabetes, including a low HDL cholesterol (30 mg/dl) and a high triglyceride level (185 mg/dl). The LDL was mildly elevated (132 mg/dl), and total cholesterol was 199 mg/dl. His fasting glucose was 111 mg/dl, with a repeat value of 115 mg/dl one week later.
Does this patient have pre-diabetes?
When should patients be screened for pre-diabetes?
How should pre-diabetes be treated in primary care settings?
Type 2 diabetes is a significant cause of death, disability, and health care burden in the United States, affecting an estimated 16 million Americans. A prodromal phase of this disease, in which patients manifest impaired glucose metabolism, has recently been identified as “pre-diabetes” by the U.S. Secretary of Health and Human Services.1 Pre-diabetes is also a major health care burden estimated to affect at least an additional 16 million Americans,2 and possibly as many as 43 million with the new criteria for impaired fasting glucose (IFG) being reduced to 100 mg/dl.3 Pre-diabetes is highly associated with concomitant cardiovascular risk factors and has been found to confer an increased risk of cardiovascular complications including myocardial infarction, stroke, and death.1
Pre-diabetes is clinically defined by either an IFG between 100 and 125 mg/dl or by a 2-hour oral glucose tolerance test (OGTT) result of 140–199 mg/dl, indicating impaired glucose tolerance (IGT), or both4 (Table 1). The normal fasting glucose level was recently adjusted downward from 110 to 100 mg/dl, after analysis by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.5 (This report is reprinted in full in this issue starting on p. 71.) The committee recognized that IGT was more common in most populations by the older criteria. Lowering the impaired fasting level to 100 mg/dl should make the predictive value of future diabetes more concordant, regardless of whether IFG or IGT is used.
With the favorable results of the Diabetes Prevention Program for Type 2 Diabetes (DPP) published in 2002,6 a recent position statement of the American Diabetes Association proposes screening recommendations for pre-diabetes to be done as part of a health care visit and suggests screening in individuals age ≥ 45 years, especially those who are overweight (BMI ≥ 25 kg/m2)1 (Table 2). Screening should also be considered in individuals who are < 45 years old and overweight in the presence of other risk factors, such as a first-degree relative with diabetes, history of gestational diabetes, high-risk ethnicity, hypertension, or dyslipidemia. Asian Americans may be screened at a lower BMI (≥ 23 kg/m2).
Based on these screening recommendations, J.M. was a candidate for screening with age, ethnicity, BMI, dyslipidemia, family history, sedentary lifestyle, and hypertension as prevailing risk factors. His low HDL, high triglyceride level, waist circumference, and hypertension made him a likely candidate for the diagnosis of pre-diabetes. These four risk factors, along with impairment of glucose tolerance, were established as clinical markers for insulin resistance by the National Cholesterol Education Program, Adult Treatment Panel III, and are used to confirm a diagnosis of the metabolic syndrome7 (Table 3).
J.M.’s fasting glucose results of 111 and 115 mg/dl confirmed the diagnosis of pre-diabetes. To exclude a diagnosis of diabetes, a 2-hour OGTT was ordered. Its result of 173 mg/dl indicated that J.M. had IGT in addition to IFG. A recent analysis of glucose progression over several decades in the Baltimore Longitudinal Study of Aging suggests that IFG and IGT may represent different phenotypes in the natural history of progression to type 2 diabetes.8 This suggestion, however, was based on the older definition of IFG.
The results of recent clinical trials to prevent or delay progression to type 2 diabetes demonstrate the benefit of identifying patients at risk and implementing early aggressive intervention. Although intensive lifestyle and selected pharmacological interventions have demonstrated effective outcomes in preventing or delaying progression to diabetes, many questions, including that of cost-effectiveness, persist in the translation of these interventions into primary care settings. Based on the DPP and the Finnish study,9 successful treatment of pre-diabetes requires thorough patient education, counseling, and support in lifestyle changes targeting a 5–7% reduction in total body weight and an exercise goal of 150 minutes/week. J.M. was provided with the necessary counseling for dietary intervention, and, following a pre-exercise treadmill stress test, a titrated exercise program was initiated.
Aggressive management of J.M.’s comorbidities may also help slow progression to diabetes. Studies of selected angiotensin-converting enzyme inhibitors (ramipril) and statins (pravastatin) have suggested that these drugs may delay the progression of pre-diabetes to diabetes.10,11 Results of studies such as the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) trial are needed to confirm these findings. J.M.’s blood pressure was well controlled with lisinopril, 20 mg/day. A statin was added to treat his dyslipidemia. Both of these interventions may help to delay the progression to diabetes. Aspirin therapy was initiated to reduce cardiovascular risk.
The use of the insulin sensitizers—metformin and the thiazolidinediones (TZDs)—has been shown to be beneficial in delaying the progression from pre-diabetes to diabetes.6,12 In the DPP, metformin, 850 mg twice daily, reduced the relative risk of progression to type 2 diabetes by 31%. Metformin may additionally improve outcomes by inducing weight loss. Although conducted in women with a history of gestational diabetes, the Troglitazone in the Prevention of Diabetes (TRIPOD) study demonstrated a 56% reduction in relative risk in progression of pre-diabetes to diabetes. Although treatment was discontinued because of the withdrawal of troglitazone from the U.S. market, persistent protective treatment effects were observed more than 8 months after discontinuation. Long-term clinical trial data are not yet available for the newer TZDs, but there is a reasonable expectation that the currently available medications in this drug class may provide similar benefits. Until further clinical trial data become available, clinician judgment–based individualized patient characteristics will determine the use of insulin sensitizers in pre-diabetes. However, lifestyle modifications are first-line treatment for pre-diabetes (Table 4).
J.M. met with a dietitian and a physical therapist for initial instruction. Brisk walking was the starting baseline exercise for 30 minutes each day, 5 days per week, with the use of a pedometer to measure distances. Calorie counting and knowledge of healthy choices from the food pyramid were discussed, but the intensive case management approach, as used in the DPP, was not possible because of insurance reimbursement issues and a lack of availability of individual case managers.
After a 6-month trial of diet and exercise, J.M. was only able to exercise for 20 minutes or less each week, had gained 7 lb, and had an increase in fasting glucose to 117 mg/dl. Although not approved by the Food and Drug Administration for this indication or recommended by the American Diabetes Association, metformin remains an alternative.
Pre-diabetes is diagnosed by a fasting glucose between 100 and 125 mg/dl (IFG) or a 2-hour OGTT result between 140 and 199 mg/dl (IGT), or both, confirmed.
The onset of type 2 diabetes can be prevented or delayed.
Screening for pre-diabetes should be considered for patients at age 45 years, especially for overweight or obese patients, and earlier for patients with a BMI of 25 kg/m2 or more with additional risk factors such as hypertension or dyslipidemia.
A dyslipidemic pattern of low HDL cholesterol and high triglycerides, in addition to hypertension and large waist size, are clinical markers for insulin resistance and impaired glucose metabolism.
Aggressive management of concomitant comorbidities, such as hypertension and dyslipidemia, may delay progression of pre-diabetes to diabetes.
Aggressive lifestyle modification has delayed the progression of diabetes by about 60%, while medications such as metformin have reduced progression by about 30%.
Efforts should be made to secure insurance reimbursement for intensive lifestyle modification, including classes and case managers such as those used in the DPP.
Richard J. Schrot, MD, CDE, is an associate professor, Frances M. Sahebzamani, PhD, ARNP, is an assistant professor, and H. James Brownlee, Jr., MD, is a professor and chairman in the Department of Family Medicine at the University of South Florida (USF) School of Medicine in Tampa, Fla. Dr. Schrot is a member of the research working group, and Dr. Sahebzamani and Dr. Brownlee are co-directors of the USF Pre-Diabetes Treatment and Research Center. Dr. Schrot has been director of the Ambulatory Care Diabetes Clinic at the James A. Haley VA Hospital in Tampa, Fla.