Departments | Articles | Patient Information

Editorals

New Diabetes Guidelines A Closer Look at the Evidence

STEVEN H. WOOLF, M.D., M.P.H.
STEPHEN F. ROTHEMICH, M.D.
Medical College of Virginia at Virginia Commonwealth University,
Richmond, Virginia

In this issue of American Family Physician, Mayfield¹ summarizes recent recommendations of the American Diabetes Association (ADA), which broaden the diagnostic criteria for diabetes mellitus and advocate routine screening. Under the new guidelines,² the threshold fasting plasma glucose level for the diagnosis of diabetes has been lowered from 140 mg per dL (7.8 mmol per L) to 126 mg per dL (7.0 mmol per L). Screening is recommended every three years, beginning at age 45 (or earlier in high-risk groups).

See Article in this issue.

These recommendations have broad implications. Lowering the diagnostic threshold shifts the definition of diabetes into the central bulge of the bell curve where the glucose level of most Americans falls. Among U.S. adults 40 to 74 years of age who have not been diagnosed with diabetes, 1.9 million have fasting plasma glucose levels of 126 to 140 mg per dL (7.0 to 7.8 mmol per L), which is almost as many as the 2.2 million who have levels over 140 mg per dL (7.8 mmol per L). Under the new guidelines, at least 1 million Americans (and possibly more) with fasting plasma glucose levels of 126 to 140 mg per dL (7.0 to 7.8 mmol per L), who previously would have been told that they had normal (or impaired) glucose tolerance, will now be informed that they harbor a disease.³ This more aggressive policy has strong support among those committed to detecting diabetes earlier and in larger numbers. The new threshold will certainly do this, but clinicians should look closely at the evidence and consider the potential harms before changing their approach to patients.

The evidence used for the new diagnostic criteria is from epidemiologic studies cited by Mayfield¹ that show a progressive increase in the risk of complications beginning with fasting plasma glucose levels as low as 110 to 120 mg per dL (6.1 to 6.7 mmol per L). There are three problems with basing the new policy on these data. First, other studies show no increase in risk at these low levels.⁴ Second, even if risk is increased, the new policy argues that having a risk factor (a mildly elevated fasting plasma glucose level) is tantamount to having a disease. There is wide overlap between healthy persons and persons with diabetes in the fasting plasma glucose range of 126 to 140 mg per dL (7.0 to 7.8 mmol per L). Each year only 1 to 5 percent of persons with impaired glucose tolerance develop manifestations of diabetes.⁵ After 10 years, most do not have diabetes or have normal results on retesting.⁵ Even among Native Americans, a population at high-risk for diabetes, the 10-year incidence of renal failure occurring in those with a fasting plasma glucose level of less than 140 mg per dL (7.8 mmol per L) is only 8.4 cases per 1,000 person-years.⁶ Labeling persons with a fasting plasma glucose level of 126 to 140 mg per dL (7.0 to 7.8 mmol per L) as having diabetes, when most will not develop meaningful disease, is akin to labeling persons with elevated cholesterol levels as having heart disease.

Third, and most important, there is no prospective evidence that correcting these mild elevations improves health. The evidence that does exist is for persons with higher glucose levels. In the Diabetes Control and Complications Trial (DCCT),⁷ the landmark study showing that glycemic control prevents microvascular complications, patients began treatment with a mean blood glucose level of 234 mg per dL (13.0 mmol per L) and lowered it to a mean of 155 mg per dL (8.6 mmol per L). Whether normalizing fasting plasma glucose levels in the range of 126 to 140 mg per dL (7.0 to 7.8 mmol per L) has a meaningful impact on patient outcomes is unknown.

Even for persons with higher glucose levels, the magnitude of benefit from glycemic control is uncertain. Although the DCCT⁷ demonstrated an impressive 44 to 76 percent reduction in the risk of microvascular complications in patients with type 1 diabetes mellitus, 95 percent of patients have type 2 diabetes mellitus. Because patients with type 2 diabetes are older and more likely to die of macrovascular complications and because microvascular complications only manifest after years of disease, patients with type 2 diabetes are less likely to live long enough to enjoy the microvascular benefits of glycemic control.

The impressive relative reductions in microvascular complications translate into more modest reductions in absolute risk. For example, given the incidence of renal disease,⁸ the 44 percent relative reduction in albuminuria reported by the DCCT⁷ means that 1,695 patient-years of intensive treatment are required to prevent one case of chronic renal failure. Moreover, the proven benefits of glycemic control are for intermediate end points (e.g., albuminuria), not clinical outcomes. The 76 percent reduction in retinopathy reported by the DCCT is for a three-step change on a retinopathy scale, not for improved vision. For every patient in whom an intermediate outcome is prevented, a larger number must be treated to prevent symptomatic disease.

Finally, the degree of glycemic control that yielded the clinical trial results may be difficult to replicate in normal practice. The DCCT⁷ results were achieved when 44 percent of subjects were able to lower their glycohemoglobin level below 6.1 percent. In actual practice, 60 percent of patients with type 2 diabetes have glycohemoglobin levels of 8 percent or more after two years of insulin therapy.⁹

The benefits of an earlier diagnosis must also be weighed against potential harms. Having a diagnosis of diabetes introduces labeling effects (e.g., worry, decreased job and insurance eligibility) and starts patients on a taxing regimen of glucose monitoring, physician appointments, lipid screening, urinalyses, and foot and eye examinations. These visits cause inconvenience, work/school absences and out-of-pocket expenses. The diagnosis also labels patients as high risk, routing them into testing protocols if they develop symptoms such as chest pain. Although the first-line treatment for patients with mild fasting blood glucose elevations should be diet and exercise, some physicians may be tempted to prescribe glucose-lowering drugs if levels remain elevated, exposing patients to potential side effects (e.g., hypoglycemia). Given current uncertainties about the health benefits of detecting or correcting a fasting plasma glucose level of 126 to 140 mg per dL (7.0 to 7.8 mmol per L), these patients may be subjected to harm for no appreciable gain.

Finally, physicians should think twice about the ADA recommendation to routinely screen for diabetes. Most evidence-based groups (U.S. Preventive Services Task Force, American Academy of Family Physicians, American College of Physicians, Canadian Task Force on the Periodic Health Examination) do not recommend such screening. The ADA rationale that hyperglycemic persons are at increased risk of future complications is not particularly persuasive. Increased risk does not prove that screened persons benefit from early detection or that benefits outweigh harms. Similarly, the ADA arguments for starting screening at age 45 (because incidence increases at this age) and for recommending a three-year interval (because complications rarely develop sooner) do not prove whether these parameters improve outcomes. Such evidence is necessary before advocating the testing of 80 million Americans and, as the guidelines do, redefining medical, insurance and legal views on what constitutes appropriate care.

Dr. Woolf is a professor in the Department of Family Practice at the Medical College of Virginia at Virginia Commonwealth University, Richmond, Va. He chairs the Diabetes Policy Team of the American Academy of Family Physicians and is a member of the U.S. Preventive Services Task Force. Dr. Rothemich is associate professor in the Department of Family Practice at the Medical College of Virginia at Virginia Commonwealth University.

REFERENCES

1. Mayfield J. New classification and diagnostic criteria for diabetes mellitus. Am Fam Physician 1998; 58:1355-70.
2. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.
3. Harris MI, Flegal KM, Eastman RC, Eberhardt MS, Cowie CC. Comparison of diabetes diagnostic categories in the U.S. population according to 1997 American Diabetes Association and 1980-85 World Health Organization diagnostic criteria. Diabetes Care 1997;20:1859-62.
4. Reichard P. Are there any glycemic thresholds for the serious microvascular diabetic complications? J Diab Comp 1995;9:25-30.
5. Harris MI. Classification, diagnostic criteria, and screening for diabetes. In: Harris MI, Cowie CC, Stern MP, et al., eds. Diabetes in America, 2d ed. NIH Publication No. 95-1468. Bethesda, Md.: National Institutes of Health, 1995:15-32.
6. Lee ET, Lee VS, Lu M, Lee JS, Russell D, Yeh J. Incidence of renal failure in NIDDM: the Oklahoma Indian Diabetes Study. Diabetes 1994;43:572-9.
7. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
8. Humphrey LL, Ballard DJ, Frohnert P, Chu CP, O'Fallon WM, Palumbo PJ. Chronic renal failure in non­insulin-dependent diabetes mellitus: a population-based study in Rochester, Minn. Ann Intern Med 1989;111:788-96.
9. Hayward RA, Manning WG, Kaplan SH, Wagner EH, Greenfield S. Starting insulin therapy in patients with type 2 diabetes: effectiveness, complications, and resource utilization. JAMA 1997; 278: 1663-9.

---

Simplifying the Diagnosis of Diabetes Mellitus

JAY S. SKYLER, M.D.
University of Miami School of Medicine,
Miami, Florida

In the United States today, diabetes mellitus is a public health nightmare. Consider the following:

• Of the estimated 15.6 million persons nationwide who have diabetes, a projected 5.4 million persons are unaware that they have the disease; individuals may remain undiagnosed for an average of five to 10 years.
• Diabetes has the highest direct costs for health care of any disease category: the National Institutes of Health estimated that the total cost was $91.1 billion in 1995, and diabetes is responsible for one in every seven health care dollars spent in the United States.
• Diabetic retinopathy is the number one cause of blindness in working-age adults in the United States, but an estimated 90 percent of vision loss associated with diabetes is preventable.
• Diabetic nephropathy is the number one cause of end-stage renal disease in the United States, but an estimated 90 percent of future cases of end-stage renal disease related to diabetes are preventable.
• Diabetes is the number one cause of nontraumatic amputations in the United States, but an estimated 85 percent of cases of limb loss associated with diabetes are preventable.
• Health risks in patients with diabetes can be dramatically reduced by careful glucose control, aiming for near-normal levels of hemoglobin A_1c (HbA_1c), but national surveys demonstrate that only 12 percent of patients achieve these near-normal levels and that the average HbA_1c level among diabetic patients is 9.1 percent (normal: 3.9 to 6.0 percent); even worse, the majority of patients do not have HbA_1c measurements performed at all.

See Article in this issue.

The benefits of glycemic control have been unambiguously demonstrated in both type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus, or IDDM) and type 2 diabetes mellitus (formerly known as non­insulin-dependent diabetes mellitus, or NIDDM).^1,2 Over the past several years, the introduction of newer pharmacologic agents has made disease management easier and permitted development of treatment algorithms that facilitate the attainment of the requisite control.³ However, to take advantage of such treatment, patients need to be diagnosed.

Unfortunately, as pointed out by Mayfield⁴ in this issue of American Family Physician, the previous diagnostic criteria were based mainly on the use of the oral glucose tolerance test, which was inconvenient enough that it had limited use in clinical practice. As a consequence, the default criterion for diagnosis became the fasting plasma glucose level alone, which was pegged at a plasma glucose level of 140 mg per dL (7.8 mmol per L). Two problems occurred with using this level as a cutoff point. First, it simply was too high, based on retinopathy risk (see Figure 1 in the Mayfield⁴ article). Second, this cutoff point did not correspond with the oral glucose tolerance test level recommended for a diagnosis of diabetes. The unfortunate consequence was that patients with severe enough disease to lead to complications remained undiagnosed.

These factors led the American Diabetes Association (ADA)⁵ and the World Health Organization (WHO)⁶ to commission expert committees to examine the available data and make recommendations that might allow persons with diabetes to be more easily diagnosed in clinical practice. The recommendations entail a major shift in the way diabetes is diagnosed. The expert committees performed analyses showing that lowering the fasting plasma glucose cutoff point to 126 mg per dL (7.0 mmol per L) or higher would result in two things. First, the change would acknowledge that the risk of retinopathy begins at a lower fasting plasma glucose level than is now used for diagnosis. Second, most persons with undiagnosed diabetes would be identified, without much risk of a false-positive diagnosis. Thus, 126 mg per dL (7.0 mmol per L) becomes a surrogate for an oral glucose tolerance test two-hour value of 200 mg per dL (11.1 mmol per L). This change in the cutoff point does not increase the number of persons with diabetes. Rather, it increases the number of persons with known diabetes. That is why it is a crucial public health measure.

The old criteria used a fasting plasma glucose level of 115 mg per dL (6.4 mmol per L) or lower for normal. In contrast, the new criteria use a fasting plasma glucose level of 110 mg per dL (6.1 mmol per L) or lower for normal. Persons who have fasting plasma glucose levels between 110 and 125 mg per dL (6.1 and 6.9 mmol per L), which are too high to be considered altogether normal, are now defined as having "impaired fasting glucose." This group of persons is considered to be at increased risk of diabetes, similar to those with impaired glucose tolerance, who have two-hour oral glucose tolerance test values of 140 to 199 mg per dL (7.8 to 11.0 mmol per L).

Measurement of HbA_1c is not currently recommended for the diagnosis of diabetes, although some studies have shown that the frequency distributions for HbA_1c have characteristics similar to those of the fasting plasma glucose test and the two-hour plasma glucose test. However, both HbA_1c and fasting plasma glucose (in type 2 diabetes) have become the measurements of choice in monitoring the treatment of diabetes, and decisions on when and how to implement therapy are often made on the basis of HbA_1c levels. The revised criteria are for diagnosis and are not treatment criteria or goals of therapy. No change was made in the ADA recommendations of a fasting plasma glucose level of 120 mg per dL (6.7 mmol per L) or lower and HbA_1c levels of 7.0 percent or lower as treatment goals.

Widespread adoption of the new criteria may have a large impact on the number of persons actually diagnosed with diabetes. Presently, about 30 to 40 percent of adults with diabetes in the United States are undiagnosed, but many might now be diagnosed if the simpler fasting plasma glucose test were always used. The use of the fasting plasma glucose test facilitates screening for type 2 diabetes.

Screening is important for a variety of reasons. Hyperglycemia is important in the pathogenesis of the specific complications of diabetes mellitus--microangiopathy (retinopathy and nephropathy) and neuropathy. Meticulous glycemic control slows the course of development of diabetic complications.^1,2 Prolongation of normoglycemia should reduce the risk of diabetic complications. Studies suggest that, in the earlier stages (impaired fasting glucose and impaired glucose tolerance), interventions such as diet and exercise may forestall the evolution of type 2 diabetes.⁷ Screening for type 2 diabetes is now easy because only a simple fasting plasma glucose test is required. The more cumbersome oral glucose tolerance test is no longer the primary screening tool. Screening and early diagnosis of type 2 diabetes should be highly cost effective. All adults over age 45 should be screened every three years. All individuals at higher risk (based on obesity, ethnicity, etc.) should be screened annually, starting at an earlier age.

Dr. Skyler is professor of medicine, pediatrics and psychology at the University of Miami (Florida) School of Medicine.

REFERENCES

1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.
2. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in type 2 diabetes (UKPDS 33). U.K. Prospective Diabetes Study Group. Lancet 1998;352:837-53.
3. Skyler JS. Targeted glycemic control in type 2 diabetes. J Florida Med Assoc 1998;85(2):7-15.
4. Mayfield J. New classification and diagnostic criteria for diabetes mellitus. Am Fam Physician 1998; 58:1355-70.
5. Report of the American Diabetes Association Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183-97.
6. Alberti KGMM, Zimmet PZ, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications, part 1. Diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation. Diabetic Med 1998;15:539-53.
7. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44.

From the Division of Endocrinology and the Behavioral Medicine Research Center, Departments of Medicine, Pediatrics and Psychology, University of Miami School of Medicine, Miami, Fla.

---

Current Hypertension Control Is Just Not Good Enough

HARRIET P. DUSTAN, M.D.
University of Vermont College of Medicine,
Burlington, Vermont

See Article in this issue.

Dramatic decreases in hypertension-related mortality from strokes and heart attacks have occurred in the 25 years since the National High Blood Pressure Education Program (NHBPEP) began: a 59.0 percent reduction for stroke mortality and a 53.2 percent reduction for coronary heart disease (CHD) mortality. These decreases resulted from a concerted effort to encourage physicians to conduct blood pressure screening in their patients and treat hypertension and to inform the general population about the importance of knowing their own blood pressure values and seeking treatment for hypertension.

FIGURE 1 Incidence rates of reported hypertensive end-stage renal disease therapy, 1978-1995.

FIGURE 2 Prevalance of heart failure by age, 1976 to 1980 and 1988 to 1991.

Among educational methods used by NHBPEP are periodic guidelines from the Joint National Committee (JNC) on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The Sixth Report of the JNC (JNC-VI) has recently been published¹; it details some unsettling trends, as discussed in the article by Kaplan.² The first trend can be found in U.S. death rates for strokes and CHD from 1972 to 1994. The stroke curve is practically level, and the rate of decline of the age-adjusted mortality rates from CHD has slowed. Also, the incidence of end-stage renal disease related to hypertension continues to increase (Figure 1), as does the prevalence of CHD (Figure 2).

Finally, findings from the recent Third National Health and Nutrition Examination Survey (NHANES III, phase 2)¹ show that awareness, treatment rates and control of hypertension are lower than expected from previous trends (Table 1). In addition, recent reports show that blood pressure control had deteriorated in patients in a Minnesota survey³ and in a cohort of elderly persons in Iowa.⁴ These various trends, although unexplained, suggest that physicians should be more vigilant in controlling hypertension.

TABLE 1 Trends in the Awareness, Treatment and Control of High Blood Pressure in Adults, United States, 1976-1994 NHANES II (1976-1980)* NHANES III, phase 1 (1988-1991)* NHANES III, phase 2 (1991-1994)* Awareness 51 73 68 Treatment 31 55 53 Control† 10 29 27 NHANES=National Health and Nutrition Examination Survey. *--Data are percentage of adults aged 18 to 74 years with systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking antihypertensive medication. †--Systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg. Used with permission from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.

The goal for the treatment of hypertension is a blood pressure level of less than 140/90 mm Hg or as low as tolerated.¹ The latter goal is important for patients with renal disease and hypertension because a reduction in blood pressure to 130/85 mm Hg or lower (125/75 mm Hg) in those who also have proteinuria (defined as over 1 g per 24 hours) is recommended to slow the progressive decline in the glomerular filtration rate.⁵ That hypertension itself without preexisting renal disease is a risk factor for end-stage renal disease was found in the long-term follow-up of several thousand men who were screened for the Multiple Risk Factor Intervention Trial⁶; this was particularly true among African Americans.

FIGURE 3 Average systolic blood pressure and diastolic blood pressure during the Systolic Hypertension in the Elderly Program Follow-up.

Another group deserving heightened attention is elderly persons, because they have a higher incidence of hypertension. For example, NHANES III⁷ found that the prevalence of hypertension was 60 percent in non-Hispanic whites, 71 percent in African Americans and 61 percent in Mexican Americans 60 years of age or older. Not only is the prevalence of hypertension among elderly persons an important consideration, but the number of elderly persons with hypertension is also important. These numbers have increased greatly, and increases will continue. By 2030, the number of U.S. citizens 65 years of age or older is expected to be 70 million--up from 33 million in 1994.⁸ Thus, unless hypertension can be prevented, millions of additional people will need treatment for high blood pressure.

Ample evidence now shows that drug therapy for elderly patients with hypertension can reduce the incidence of stroke and heart attack. The NHBPEP recently reviewed data from seven trials⁹; in all, benefit was achieved with drug therapy for stroke, CHD and cardiac failure. Isolated systolic hypertension was the focus of the Systolic Hypertension in the Elderly Program (SHEP) Trial.¹⁰ This trial was randomized and placebo controlled, and enrolled 4,736 participants 60 years of age or older. The patients in the trial first received chlorthalidone, then received atenolol, if necessary. Average pretreatment blood pressure values in the drug- and placebo-treated groups were 171/77 mm Hg and 170/76 mm Hg, respectively. Blood pressure values in the subjects who received treatment averaged 142/68 mm Hg over five years, and blood pressure values in the placebo group averaged 155/74 mm Hg (Figure 3). Strikingly, the difference of 13.6 mm Hg resulted in a reduced stroke rate of 36 percent and a reduced myocardial infarction rate of 27 percent. If such benefits can be achieved with minor decreases in blood pressure, imagine what might be gained by a tolerated reduction to even lower levels.

It seems wise, therefore, that all physicians pay close attention to the blood pressure values that they achieve with treatment of their patients--be it with nonpharmacologic modalities or antihypertensive drugs--and aim for strictly normal levels if such are well tolerated.

Current hypertension control is just not good enough. We can do much better.

Dr. Dustan spent most of her professional career in hypertension research and care. For 26 years she was a staff member in the Research Division of the Cleveland Clinic. In 1977, she became director of the Cardiovascular Research and Training Center, University of Alabama School of Medicine, a position she held for 10 years. After three years as Veterans Administration Distinguished Physician, she retired to Vermont. She is now visiting professor of Pharmacology and Medicine at the University of Vermont College of Medicine, Burlington. Dr. Dustan has participated in the preparation of all six Joint National Committee Reports. She was chair of JNC III and an executive committee member of JNC VI.

REFERENCES

1. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.
2. Kaplan NM. Treatment of hypertension: insights from the JNC-VI report. Am Fam Physician 1998; 58:1323-30.
3. Meissner I, Whisnant JP, Sheps S, Schwartz G, O'Fallon WM, Coralt J, et al. Stroke prevention: assessment of risk in a community: the SPARC study, part 1: blood pressure trends, treatment and control (abstract). Ann Neurol 1997;42:433.
4. Glynn RJ, Brock DB, Harris T, Havlik RJ, Chrischilles EA, Ostfeld AM, et al. Use of antihypertensive drugs and trends in blood pressure in the elderly. Arch Intern Med 1995;155:1855-60.
5. Lazarus JM, Bourgoigne JJ, Buckalew VM, Greene T, Levey AS, Milas NC, et al. Achievement and safety of a low blood pressure goal in chronic renal disease: the Modification of Diet in Renal Disease Study Group. Hypertension 1997;29:641-50.
6. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J. End-stage renal disease in African-American and white men: 16-year MRFIT findings. JAMA 1887;227:1293-8.
7. National Center for Health Statistics. Health United States, 1996. Hyattsville, Public Health Service, 1997.
8. American Association of Retired Persons and the Administration on Aging. U.S. Department of Health and Human Resources. Profiles of older Americans, 1995.
9. National High Blood Pressure Education Program Working Group report on hypertension in the elderly. Hypertension 1994;23:275-85.
10. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-64.

Figure 1 is from the U.S. Renal Data System. USRDS 1997 annual report. Bethesda, Md.: U.S. Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, 1997. Figure 2 was used with permission from Levy D, Larson MG, Vasan RS, Kannel WB, Ho KKL. The progression from hypertension to congestive heart failure. JAMA 1996;275:1557-62. Figure 3 was used with permission from the Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-64.

Copyright © 1998 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.