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CLINICAL CASES 5 FOR THE USMLE

DANIL HAMMOUDI.MD

SINOE MEDICAL ASSOCIATION

 

 

THESE INTERESTING DIFFERENT CASES ARE TAKEN FROM DIFFERENT MEDICAL JOURNAL AS AT MESDCAPE.COM SURGERY

IF YOU HAVE CASES LIKE THIS OR LINKS LET ME KNOW.

CASE 1

 

A 27-year-old woman with a 3-year history of intermittent right upper quadrant pain presented for evaluation. She has been in good health except for these attacks, which are worse after meals, can last up to 2 hours, and are not associated with any nausea, vomiting, or fever.

The attacks were occurring about 5 times per year until 6 months prior to presentation, at which time they began to occur monthly. However, during the last month, the patient has had 3 attacks of worsening severity. She has experienced no change in bowel habits and no signs of bleeding, jaundice, or pancreatitis.

Physical examination was performed when the patient was pain-free. Vital signs were normal and there was no jaundice. Results of abdominal examination were unremarkable, with no evidence of mass, tenderness, or organomegaly.

Routine laboratory studies, including complete blood count and liver chemistries, were all within normal range. Serum amylase and lipase levels were also normal.

An ultrasound of the right upper quadrant was performed because of the clinical suspicion of gallstones and biliary colic. Results of this imaging study showed no stones, but did demonstrate a poorly defined cystic structure or dilated bile duct. CT scan was recommended.

A CT scan of the abdomen was obtained and several cuts are shown in Figure 1. An abnormal cystic structure can be seen in the region of the common bile duct and hilum of the liver.

another series of cuts on CT scan. These cuts show that the cystic structure extends down toward the head of the pancreas.

Endoscopic retrograde cholangiopancreatography (ERCP) was performed. Injection of the common bile duct produced the cholangiogram shown in Figure 3. A guidewire was placed in the distal common bile duct and Figure 4 shows that the cystic structure (which communicates freely with the bile duct) is displacing and deforming the distal common bile duct.

Diagnostic Questions

  1. What is the cystic structure demonstrated on CT scan and ERCP?
  2. What are the typical and unusual features of the diagnosis in this case?
  3. What additional diagnostic studies are indicated?
  4. How can this patient be managed?

Answers and Discussion

1. What is the cystic structure demonstrated on CT scan and ERCP?

This patient has a cystic dilation of the bile duct without definite evidence of mechanical obstruction. The most likely diagnosis is choledochal cyst (congenital cystic dilatation of the common bile duct). This nonhereditary condition is characterized by a congenital predisposition to dilation of part of the intra- and/or extrahepatic bile ducts. There is no known etiology.

It has been speculated that in this clinical setting, there is abnormal reflux of pancreatic enzymes into the biliary tree. The pancreatic enzymes may then progressively weaken the bile duct walls.[1] The current classification of choledochal cysts is based on the different morphologies and distributions shown in Figure 5.[2] Our patient has a diffuse fusiform dilation of the extrahepatic bile duct. This corresponds to the type I shown in the Figure.

 

2. What are the typical and unusual features of the diagnosis in this case?

The typical features of choledochal cyst, as illustrated by this case, include: presentation in a young woman, association with intermittent abdominal pain, and normal liver chemistries. The unusual features of choledochal cyst, as demonstrated by this case, include the rarity of this diagnosis in adults in the United States.

Although rarely diagnosed in this country, choledochal cysts occur more frequently in Japan. They present more often in women and are typically diagnosed in infancy or childhood. It is estimated that only 20% to 30% of choledochal cysts are diagnosed in adults.[3] Chijiiwa and coworkers[2] reviewed and evaluated long-term follow-up results of 46 patients treated for choledochal cysts during the years 1965 and 1990 at Kyushu University in Japan. The mean ages for these patients at the time of initial operation were 22 years for females (range: 2 months-69 years) and 45 years for males (range: 5-71 years). Of the 46 patients with choledochal cysts, 41 (89%) were female and 5 (11%) were male. The most common symptom was abdominal pain and only 7 patients (15%) presented with the triad of abdominal pain, jaundice, and abdominal mass. The clinical signs and symptoms of a choledochal cyst are usually intermittent and may be quite nonspecific. Intermittent jaundice is the most common symptom in the infant, and abdominal pain the most common symptom in older children and adults.

No single laboratory test result is consistently abnormal in patients with choledochal cysts. An increased total bilirubin level is seen more commonly in children. In fact, hepatic aminotransferases, serum bilirubin, white blood cell count, and serum amylases were normal in more than 50% of patients at the time of diagnosis.[4] The diagnosis of choledochal cyst depends therefore on a high index of suspicion in patients who have recurrent right upper quadrant abdominal pain, with or without jaundice and/or a palpable mass or pancreatitis.

3. What additional diagnostic studies are indicated?

Abdominal ultrasound and CT scan, when reviewed by experienced observers, are valuable in raising suspicion for choledochal cyst. Additionally, ERCP is a definitive method for diagnosing choledochal cyst because it provides visualization to define the type of biliary cyst. In the absence of any unrelated findings such as mass, lymphadenopathy, or filling defects, no other diagnostic test is needed.

4. How can this patient be managed?

The treatment for choledochal cyst is surgery. This patient has symptoms that must be eliminated, and moreover, most choledochal cysts carry the risk of cholangiocarcinoma. The reason for the malignant degeneration of the hepatobiliary tree in this setting is not known, but it is believed to be related to chronic inflammation resulting from biliary stasis and reflux. The older the patient is at diagnosis, the greater the risk of malignancy.[4]

In patients who have choledochal cysts at 10 years of age or younger, the risk of developing cholangiocarcinoma is approximately 1%. This risk increases to 15% for patients older than 20 years of age.[5]

 

Clinical Course and Outcome

This patient underwent surgery and a typical type I choledochal cyst was found. The cyst can be visualized between the metal probes

The cyst was excised, the gallbladder removed, and a Roux-en-Y choledochojejunostomy performed. The patient did well.

 

This patient's presenting symptoms suggested biliary colic from gallstones. However, ultrasound examination showed no stones, and suggested the possibility of pancreatic cyst or pseudocyst. ERCP provided definitive diagnosis and allowed a confident decision to be made regarding therapy.

The treatment of choledochal cyst has changed over the last 20 years, and attempts at medical therapy are usually associated with mortality.[5] The causes of death have been biliary cirrhosis, liver abscesses, spontaneous rupture of the cyst, pancreatitis, gastrointestinal hemorrhage, portal vein thrombosis, and cancer arising in the cyst. Total excision of choledochal cyst Types I and II (along with cholecystectomy) is now standard of care.[6] Excision is the treatment of choice because it is associated with fewer postoperative strictures and cholangitis than attempts at repair, drainage, or bypass.[2,4] In addition, the possibility of carcinoma developing in the cyst or gallbladder is significantly reduced. Excision of the cyst with Roux-en-Y reconstruction of the biliary tree is the preferred treatment in most patients. Type IV cysts warrant a total excision of the extrahepatic biliary component.

However, management of the intrahepatic portion of type IV cysts is more controversial. This group of patients is more likely to have intrahepatic stones and problems with recurrent cholangitis. Intrahepatic cholangiocarcinoma is also a possibility. This patient population therefore must be closely followed for additional complications. If associated intrahepatic dilatation is confined to the left hepatic lobe, lobectomy is the recommended approach

 

 


 

 

CASE 2

 

A 63-year-old man with a mild, transient dysphagia underwent esophagogastroduodenoscopy. He had a previous history of stable idiopathic thrombocytopenic purpura that required no treatment, and his platelet counts have been fluctuating in the range of 94-105 x 109 cells/L during the last year.

At endoscopy a bluish protrusion covered by intact mucosa was seen in the middle esophagus

What is your diagnosis?

Diagnosis

This patient was diagnosed with hemangioma of the esophagus. The lesion was considered an incidental finding and no treatment was advised.

Discussion

Hemangiomas of the esophagus are vascular tumors, usually of congenital origin, that are mostly asymptomatic. They are an uncommon finding at endoscopy and very rarely present as a cause of bleeding or dysphagia.

The characteristic endoscopic appearance of these lesions makes the visual diagnosis quite easy. Biopsy sampling, however, can cause profuse bleeding.

The differential diagnosis should include other submucosal tumors, hematomas, and varices.

Generally no treatment is required for these lesions. In rare cases of large tumors causing dysphagia or bleeding, treatment is recommended. Surgical excision has been considered the standard therapy. Recently endoscopic sclerotherapy or endoscopic resection (especially of pedunculated lesions) has been reported to be successful


 

 

A 43-year-old woman with a 7-month history of intermittent abdominal pain and a 20-pound weight loss presented for evaluation. She denied a history of fever, chills, and jaundice.

The patient had no significant past medical history. Physical examination was unremarkable, except for right upper quadrant tenderness without rebound. Laboratory analysis revealed a normal white blood cell count, normal metabolite levels, normal amylase and lipase levels, and a normal liver chemistry profile. Specifically, the patient demonstrated a serum alkaline phosphatase level of 52 U/L, an alanine aminotransferase level of 23 U/L, aspartate aminotransferase level of 17 U/L, and a total bilirubin of 0.7 mg/dL.

The patient's evaluation included magnetic resonance cholangiopancreatography (MRCP; see Figure 1) and endoscopic retrograde cholangiopancreatography

Coronal MRCP image reveals calculi (short arrows) in the dilated extrahepatic bile duct (long arrow). Dilated intrahepatic bile ducts (curved arrow) are also demonstrated. The pancreatic duct (arrowhead) in the pancreatic head, the duodenal bulb (D), and liver (L) are noted.

 

Coronal MRCP image obtained anterior to Figure 1A shows crowded, dilated ducts (long arrows) in the left hepatic lobe. The left hepatic ducts contain small calculi (short arrows). The gallbladder (GB) and liver (L) are noted.

 

A transverse T1-weighted, enhanced MR image of the liver demonstrates crowded, dilated ducts (long arrows) in the atrophic left hepatic lobe (short arrows). A lesser degree of dilatation involves the right hepatic ducts (curved arrow).

 

 

An ERCP image confirms the calculi (short arrows) in the dilated extrahepatic bile duct and the calculi (long arrows) in the left hepatic ducts

 

A:

Caroli's disease

B:

Primary sclerosing cholangitis

C:

Mirizzi's syndrome

D:

Recurrent pyogenic cholangitis

E:

Type 1 choledochal cyst

Recurrent pyogenic cholangitis (RPC)

Answer and Discussion

Recurrent pyogenic cholangitis typically occurs in individuals native to southeast Asia. This patient had lived in Asia prior to moving to the United States (this history was not revealed in the initial presentation in order to make the diagnosis more challenging).

RPC is characterized by: intrahepatic and extrahepatic biliary ductal dilatation that typically occurs proximal and distal to intraductal stones; castlike as well as rounded intraductal stones; biliary strictures; and atrophy that primarily involves the entire left hepatic lobe or the lateral segment of the left hepatic lobe.[1-3]

Caroli's disease -- also known as communicating cavernous ectasia -- is a congenital disease characterized by saccular dilatation of the intrahepatic ducts.[4] Clinical features include cholestasis, stone formation, cholangitis, liver abscesses, and portal hypertension. Although patients with Caroli's disease and RPC may demonstrate similar clinical and imaging features (such as recurrent cholangitis, intraductal stones, and liver abscesses), the appearance and location of the ductal abnormalities allow for distinction between the 2 diseases. Specifically, in Caroli's disease, the ductal dilatation is saccular and is confined to the intrahepatic ducts,[4] whereas in RPC the ductal dilatation is usually diffuse (due to loss of ductal elasticity) and involves both the intrahepatic and extrahepatic ducts in most cases.[1,2]

Primary sclerosing cholangitis (PSC) is an idiopathic fibrotic disease of the biliary tract. Although both PSC and RPC are associated with ductal dilatation, strictures, and biliary calculi, the degree of ductal dilatation in PSC is usually minor as a result of fibrosis, as opposed to the prominent ductal dilatation associated with RPC. Biliary calculi occur in approximately 8% of patients with PSC[5] vs only 74% to 98% of those with RPC.[1-3]

Mirizzi's syndrome occurs secondary to an impacted stone in the cystic duct that results in inflammation and narrowing of the adjacent bile duct.[6] Although patients with Mirizzi's syndrome may present with cholangitis and demonstrate biliary dilatation and calculi, the calculi in this syndrome originate in the gallbladder (in contrast to those associated with RPC, which develop in the bile ducts). Imaging findings allow for the distinction between Mirizzi's syndrome and RPC. The radiologic findings of Mirizzi's syndrome include a cystic duct stone located at the junction of the cystic duct and the extrahepatic bile duct seen in association with biliary dilatation and acute cholecystitis.[7]

Type 1 choledochal or bile duct cyst is a congenital anomaly that is characterized by fusiform dilatation of the extrahepatic bile duct and usually associated with an anomalous pancreaticobiliary ductal union.[8] In contrast to RPC, in this entity, the ductal dilatation is confined to the extrahepatic bile duct. Although stones may form within choledochal cysts, the stones are not castlike and are fewer in number and size than those that occur in patients with RPC.

 

Therapeutic Interventions and Clinical Outcome

The patient underwent ERCP to remove the ductal calculi. ERCP (see Figure 2) revealed multiple intraductal calculi as well as intrahepatic and extrahepatic biliary ductal dilatation. Performance of a sphincterotomy and balloon extraction resulted in removal of multiple pigmented stones from the extrahepatic and intrahepatic ducts. At completion of the procedure, multiple stones remained in the ducts. A 10-French, 15-cm biliary stent was left in place. One month later, the patient underwent a second ERCP during which balloon extraction of multiple ductal stones was performed. At the completion of this second ERCP, a 10-French, 15-cm biliary stent was left in place.

Because the patient continued to experience abdominal pain during the subsequent 4 months, she was referred for surgery. Intraoperative findings confirmed that the disease primarily involved the left hepatic lobe, which showed evidence of marked atrophy. Therefore, a left hepatic lobectomy was performed The surgical specimen (see Figure 3) was remarkable for atrophy predominating in the lateral segment. Dilated ducts that contained multiple, hard, black stones were identified. Multiple stones in the extrahepatic duct and a few stones in the right hepatic duct were extracted. After removal of all stones, completion choledochoscopy revealed minimal, residual ductal dilatation without strictures. A cholecystectomy was also performed. Pathologic evaluation confirmed RPC involving the liver and bile ducts. The resected gallbladder showed evidence of chronic cholecystitis, but no stones.

The cut surface of the resected left hepatic lobe is shown along with pigmented sludge and stones (arrows) removed from the left hepatic ducts

The patient's postoperative course was uneventful and she has remained asymptomatic for 2 years following left hepatectomy

Conclusion

RPC is a progressive cholangiopathy of uncertain etiology that demonstrates characteristic imaging features and that often requires a multidisciplinary approach to management. Although RPC occurs most commonly in southeast Asia, the recognition of this disease and its imaging features is important because this entity is occurring with increasing frequency in the United States.


CASE 3

 

Jane, a 46-year-old single white woman, is in your office today because she has been experiencing fatigue and lack of energy. Jane tells you she has felt this way for the past few years and the problem has not improved or become worse recently. She also comments that her job as an executive secretary is stressful.

Jane’s medical history reveals that she smoked a pack of cigarettes a day from the time she was in college until about three weeks ago. With the exception of her smoking and an aunt who had a heart attack at age 47, Jane’s medical history is unremarkable. Her only physical activity is the “running around” she does at work. Currently she is not taking any medications.

You realize that this patient’s fatigue and lack of energy could be attributed to a number of diverse causes, including the following:

All of these possible causes should be considered and either substantiated or rejected. You decide to include a lipid analysis and a fasting blood glucose test in Jane’s workup.

What are the criteria for complete lipoprotein analysis?

Criteria for Complete Lipoprotein Analysis*

HDL cholesterol less than 35 mg/dL or

Total cholesterol 200-239 mg/dL + HDL cholesterol less than 35 mg/dL (or two or more other risk factors) or

Total cholesterol greater than or equal to 240 mg/dL

LDL = low-density lipoprotien; HDL = high-density lipoprotien.
*Complete lipoprotein analysis comprises measurements of total and HDL cholesterol, triglycerides, and calculated LDL cholesterol (For triglyceride levels less than 400 mg/dL: LDL cholesterol=Total cholesterol-HDL cholesterol-[Triglycerides/5]). Patients with desirable total cholesterol (less than 200 mg/dL) and an HDL cholesterol level greater than or equal to 35 mg/dL should be given information on diet and risk reduction and retested in five years.

Source: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445.

 

 

Physical examination reveals that Jane is an overweight, premenopausal woman in no acute distress. Jane’s height is 5’3” and her weight is 149 lb (67.5 kg). Her blood pressure is 138/88 mm Hg in each arm after a five-minute rest, with no significant difference between lying and standing readings. (Click here for information on classification of blood pressure.) Her heart has a regular sinus rhythm, and her lungs are clear. There is no organomegaly, nor significant pretibial edema.

An electrocardiogram (ECG) reveals no acute changes or criteria that suggest the presence of heart disease or previous myocardial infarction (MI). However, Jane has an ST-segment depression of almost 1 mm and minor T-wave abnormalities, indicating reason to look further.

 

Classification of Blood Pressure*

Category

Systolic
(mm Hg)

 

Diastolic
(mm Hg)

Optimal

Less than 120

and

Less than 80

Normal

Less than 130

and

Less than 85

High-normal

130-139

or

85-89

Stage 1 hypertension

140-159

or

90-99

Stage 2 hypertension

160-179

or

100-109

Stage 3 hypertension

Greater than or equal to 180

or

Greater than or equal to 110

* When systolic and diastolic blood pressures fall into different categories, the higher category should be used for classification.

The goal blood pressure for a diabetic patient is at or below 130/85 mm Hg.

Adapted 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;157:2413-2446.

 

 

Electrocardiographic Data

Sinus tachycardia (ST) segment

Almost 1 mm ST-segment depression

T wave

Minimal flattening in aVL

Atrioventricular (AV) conduction

Normal

Intraventricular (IV) conduction

Normal

 

You ask Jane to schedule a follow-up appointment in three to six weeks. You advise her to take the following steps between now and her next visit to reduce her weight and increase her level of physical activity:

LABORATORY RESULTS

When you review Jane’s test results, you notice that she has a slightly elevated glucose level, a low high-density lipoprotein (HDL) cholesterol level, and borderline to high total cholesterol level, low-density lipoprotein (LDL) cholesterol level and triglycerides levels.

Laboratory Values

Blood sugar

126 mg per dL (6.99 mmol per L)

Hematocrit

40%

Total cholesterol

229 mg per dL (5.92 mmol per L)

LDL cholesterol

151 mg per dL (3.90 mmol per L)

HDL cholesterol

34 mg per dL (0.87 mmol per L)

Triglycerides

220 mg per dL (2.48 mmol per L)

 

ADA Fasting Blood Glucose Guidelines

Blood glucose level (mg/dL)

Prognosis

Less than 110

Diabetes unlikely

110-125

Impaired glucose tolerance; potential for diabetes

Greater than or equal to 126 (on 2 tests)

Probable diabetes

ADA = American Diabetes Association.

Source: Impaired glucose tolerance. In: Diabetes A to Z: what you need to know about diabetes, simply put. 3rd ed. Alexandria, Va.: American Diabetes Association, 1997:94-96; and Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999;100:1134-1146.

NCEP Classification of Total Cholesterol Levels

Classification

Serum total cholesterol level (mg/dL)

Desirable

Less than 200

Borderline-high

200-239

High

Greater than or equal to 240

NCEP = National Cholesterol Education Program.

Source: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445.

 

NCEP Classification of LDL Cholesterol Levels

Classification

LDL cholesterol level (mg/dL)

Desirable

Less than 130

Borderline-high

130-159

High

Greater than or equal to 160

NCEP = National Cholesterol Education Program; LDL= low-density lipoprotein.

Source: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445.

NCEP Classification of HDL Cholesterol Levels*

Classification

HDL cholesterol level (mg/dL)

Risk factor

Less than 35

Negative risk factor

Greater than or equal to 60

NCEP = National Cholesterol Education Program; HDL = high-density lipoprotein.

*HDL cholesterol and CHD risk are inversely related. A low HDL level (less than 35 mg per dL) is a significant and modifiable risk factor for CHD, independent of LDL and other risk factors. At the same time, a high level of HDL (greater than or equal to 60 mg per dL) appears to protect against CHD and is therefore considered a “negative” risk factor.

Source: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445.

NCEP Classification of Triglyceride Levels*

Classification

Triglyceride level (mg/dL)

Normal

Less than 200

Borderline-high

200-400

High

Greater than 400-1000

Very high

Greater than 1000

NCEP = National Cholesterol Education Program.

*Increasing evidence suggests that isolated high triglycerides can increase the risk for CHD, but high triglycerides have a definite impact on CHD risk when linked to low HDL levels and to certain types of LDL (such as small, dense). High triglycerides often occur along with obesity, diabetes and excessive consumption of alcohol.

Source: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445.

The blood test results show that Jane’s fatigue is not caused by anemia. You also rule out chronic fatigue syndrome because she is performing her daily activities at an extremely high level of functioning. Since Jane still has regular menstrual cycles, it is clear that menopause has not begun. However, fatigue can be a symptom of perimenopause, as well as menopause, so you cannot entirely rule that out as a contributing factor. According to the American Diabetes Association’s (ADA) guidelines, Jane’s blood sugar level indicates either impaired glucose tolerance or probable diabetes, so you decide to schedule a follow-up fasting blood glucose test. It is possible that mild chronic depression is contributing to the patient’s fatigue. You consider giving her one of several clinician-administered rating scales at her next visit.

EVALUATION OF CHD RISK FACTORS

An evaluation of Jane's CHD risk factors produces the following findings:

Major CHD Risk Factors

Risk factor

Patient’s status

Obesity

Moderately overweight (~10 lb [4.5 kg])

Physical inactivity

At risk

Family history of premature CHD (first-degree relative)

Aunt (second-degree relative) with premature CHD

Age: men 45 years or older; women 55 years or older, postmenopausal

47 years, premenopausal

Cigarette smoking

Smoker for ~20 years, stopped 3 weeks ago

Diabetes mellitus

Blood sugar 126 mg per dL (6.99 mmol per L), indicating either impaired glucose tolerance or diabetes mellitus

Hypertension: greater than or equal to 140/90 mm Hg

138/88 mm Hg, high-normal, but close to threshold for stage 1 hypertension

Total cholesterol: greater than or equal to 240 mg per dL (6.21 mmol per L), high risk

229 mg per dL (5.92 mmol per L), borderline-high

LDL cholesterol: greater than or equal to 160 mg per dL (4.14 mmol per L), high risk

151 mg per dL (3.90 mmol per L), borderline-high

HDL cholesterol: less than 35 mg per dL (0.91 mmol per L), risk factor

34 mg per dL (0.87 mmol per L), at risk

Triglycerides: greater than or equal to 400 mg per dL (4.52 mmol per L), high risk

220 mg per dL (2.48 mmol per L), borderline-high

Sources: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445; and Impaired glucose tolerance. In: Diabetes A to Z: what you need to know about diabetes, simply put. 3rd ed. Alexandria, Va.: American Diabetes Association, 1997:94-96.

OBESITY

Obesity, a modifiable CHD risk factor, is measured by body mass index (BMI=kg/m2). A BMI of 25 to 29.9 is considered overweight, while 30 or above is considered obese. A study conducted from 1991-1998 by the Centers for Disease Control and Prevention showed that almost one in five American adults is obese.(9) Obesity is a risk factor primarily because of the other risk factors for CHD, such as diabetes mellitus, hypertension and lipid disorders, that it imposes.(1)

PHYSICAL INACTIVITY

Physical inactivity is a modifiable CHD risk factor. Studies have shown that regular physical activity, even moderate activity such as brisk walking three times a week for 30 minutes each time, offers protection against heart disease.(1)

FAMILY HISTORY OF PREMATURE CHD

Family history of premature CHD, a nonmodifiable risk factor, consists of definite MI or sudden death from an unidentified cause before age 55 in a person’s biological father or another male first-degree relative, or before age 65 in a person’s biological mother or another female first-degree relative. In epidemiological studies, a family history of premature CHD has emerged as an independent CHD risk factor. A person with a family history of CHD and an elevated LDL cholesterol level may have an inherited lipoprotein disorder.(1) The physician can gain useful information about genetic lipid disorders by considering second-degree relatives as well.(1)

AGE

Age, specifically 45 years or older for men and 55 years and older for women (or women in premature menopause without estrogen replacement therapy), is a nonmodifiable CHD risk factor. A person's risk for CHD increases with advancing age; however, CHD events are relatively rare until men reach their 40s and women their 50s.(1) Estrogen may help protect women from heart disease, causing women's risk for CHD to lag about 10 years behind men's risk.

CIGARETTE SMOKING

Cigarette smoking is a modifiable CHD risk factor. Even within the first year after a person stops smoking, his or her risk for CHD is significantly reduced. Smoking cessation is also important as a means to reduce one’s risk for stroke and prevent cancer and chronic lung disease.(1)

DIABETES MELLITUS

Diabetes mellitus, a modifiable CHD risk factor, increases the risk for CHD approximately threefold in men and may increase the risk even more in women. This risk is independent of other CHD risk factors

HYPERTENSION

Although treatment of hypertension, a modifiable CHD risk factor, may significantly reduce a person’s risk for CHD, it does not appear to eliminate the risk. High cholesterol and high blood pressure frequently coexist, and people who have one of these conditions have a higher-than-expected prevalence of the other

CASE DISCUSSION

Jane represents a “cardiac enigma.” When presented with such a patient, the physician may have the following questions:

Models are available to assist physicians in estimated CAD risk. One such prediction model uses age, total cholesterol or low-density cholesterol, high-density cholesterol, blood pressure, diabetes and smoking to assess and assign risk estimates. This simple model may be used in the office; PDFs of the score sheet for women and the score sheet for men can be downloaded. Detailed information on this model is available on the American Heart Association Web site.

Although Jane has no CHD risk factors that traditionally would be classified as high risk, she has many borderline risk factors. According to the recommendations of the National Cholesterol Education Program (NCEP), her borderline-high total cholesterol (229 mg per dL [5.92 mmol per L]) and low HDL cholesterol (34 mg per dL [0.87 mmol per L]) levels indicate that dietary and risk factor counseling is warranted.(1) The HDL cholesterol level is particularly predictive of CHD in females, and Jane's HDL level may be decreased due to her long history of smoking. For individuals who have a borderline-high LDL cholesterol level (in Jane's case, 151 mg per dL [3.90 mmol per L]) with two or more other CHD risk factors (here, lack of physical activity and low HDL), the NCEP guidelines recommend initiating dietary therapy and a program of physical activity.

The following treatment goals for LDL cholesterol have been established by the NCEP:

Therefore, lowering Jane's LDL level to less than 130 mg per dL (3.36 mmol per L) is a reasonable goal.

HOW TO TREAT: NONPHARMACOLOGIC OPTIONS

Although Jane was unable to follow through on a brisk 15-minute daily walk, you encourage her to try a less strenuous exercise program. You suggest that she begin with a five-minute daily walk at a moderate pace. She decides to accomplish this by getting off the bus one stop before her regular stop each evening. On weekends, Jane plans to walk for 10 minutes each day. You advise Jane that she should aim to eventually work up to exercising for 30 to 60 minutes, four to six times per week. Exercise should help relieve her fatigue and stress, reduce her triglyceride, blood pressure and blood sugar levels, and increase her HDL cholesterol level

NONPHARMACOLOGIC OPTIONS cont'd

You also recommend that Jane adopt the step II diet to help lower her LDL level to the NCEP goal of less than 130 mg per dL (3.36 mmol per L). Step II further reduces intake of saturated fat to less than 7 percent of calories and reduces cholesterol to less than 200 mg per day.(1) In addition to lowering Jane’s LDL level, improvements in her diet should help lower her triglyceride, blood pressure and blood sugar levels, and raise her HDL cholesterol level.(1,2) Dietary therapy to reduce cholesterol levels should be followed for a minimum of three to six months. If dietary therapy and exercise are not producing the desired results after this time, the physician may consider instituting pharmacologic therapy

HOW AGGRESSIVELY TO TREAT

Although it is appropriate to initiate dietary therapy and physical activity as initial treatment for a patient like Jane, nonpharmacologic therapy alone may not control her many borderline CHD risk factors. For example, in some patients, dietary therapy is ineffective or reduces lipids by only 5 to 10 percent.(1) Additionally, it is doubtful that Jane will substantially increase her physical activity.

In light of Jane’s additional risk factors for CHD (a history of recent smoking, a positive family history, impaired glucose tolerance or diabetes, high-normal hypertension, and being moderately overweight), more aggressive treatment is warranted to lower her LDL cholesterol level. Therefore, rather than waiting three to six months to determine whether nonpharmacologic therapy is working, you decide to initiate drug therapy right away.

DRUG THERAPY

A patient like Jane, who has a borderline-high LDL level without CHD but with two or more CHD risk factors, meets the NCEP’s criteria for initiation of drug therapy. However, the NCEP guidelines also recommend delaying drug therapy in premenopausal women whose LDL is less than 160 mg per dL (4.14 mmol per L).(1) More recent data suggest that such an approach may be too conservative

DRUG THERAPY cont'd

The Healthy Women Study findings suggest that addressing a woman’s CHD risk factors, such as borderline-high LDL cholesterol, low HDL cholesterol and borderline-high triglyceride levels, before menopause can reduce the risk of major cardiovascular disease after menopause.(5)

The Air Force/Texas Coronary Atherosclerosis Prevention Study, looking at a much broader population, found that therapy with lovastatin (Mevacor) was beneficial in reducing the risk of a first CHD event in both men and women who had average total and LDL cholesterol levels and below average HDL cholesterol levels (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey III). On the basis of these findings, the investigators recommended that the NCEP guidelines for pharmacologic intervention be reassessed

PHARMACOLOGIC AGENTS

Four classes of pharmacologic agents are in general use for cholesterol-lowering therapy: bile acid sequestrants (resins), nicotinic acid (niacin), fibric acid derivatives (fibrates) and HMG-CoA reductase inhibitors (statins). The impact of each class on lipid parameters varies.

Which one of the following would you choose for initial monotherapy in this patient?

A bile acid sequestrant such as cholestyramine (LoCHOLEST, Prevalite, Questran), colestipol (Cholestid) or colesevelam (Welchol).

A nicotinic acid (Niacin, Niaspan, Niacor).

A fibrate such as fenofibrate (Tricor) or gemfibrozil (Lopid).

A statin such as atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol) or simvastatin (Zocor).

BILE ACID SEQUESTRANT

Bile acid sequestrants, such as cholestyramine (LoCHOLEST, Prevalite, Questran), colestipol (Cholestid) or colesevelam (Welchol), interrupt the enterohepatic circulation of bile acids by binding them in the intestine so that they are excreted in the feces rather than being reabsorbed and returning to the liver. The decrease in bile acids triggers an increased conversion of cholesterol into bile acids. As a result, bile acid sequestrants have a moderate impact on LDL cholesterol and a minor impact on HDL cholesterol levels. These agents are inconvenient to administer and frequently cause gastrointestinal (GI) symptoms such as constipation.(1) Agents in this class either have no impact on or increase a patient’s triglyceride levels. Therefore, since Jane needs to lower her triglyceride levels, a bile acid sequestrant would not be the best first choice for drug monotherapy.

PHARMACOLOGIC AGENTS

Four classes of pharmacologic agents are in general use for cholesterol-lowering therapy: bile acid sequestrants (resins), nicotinic acid (niacin), fibric acid derivatives (fibrates) and HMG-CoA reductase inhibitors (statins). The impact of each class on lipid parameters varies.

Which one of the following would you choose for initial monotherapy in this patient?

A bile acid sequestrant such as cholestyramine (LoCHOLEST, Prevalite, Questran), colestipol (Cholestid) or colesevelam (Welchol).

A nicotinic acid (Niacin, Niaspan, Niacor).

A fibrate such as fenofibrate (Tricor) or gemfibrozil (Lopid).

A statin such as atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol) or simvastatin (Zocor).

NCEP Guidelines for Initiation of Dietary Therapy

 

Initiation LDL Level

LDL Goal

No CHD and fewer than 2 risk factors

Greater than or equal to 160 mg/dL

Less than 160 mg/dL

No CHD and 2 or more risk factors

Greater than or equal to 130 mg/dL

Less than 130 mg/dL

With CHD

Greater than 100 mg/dL

Less than or equal to 100 mg/dL

NCEP = National Cholesterol Education Program; CHD = coronary heart disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein.

Source: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1329-1445.

 

 

CASE4

 

 

David is a 52-year-old obese man whom you have been seeing over the past two years to help him lose weight. He is in your office today for that reason. He is married, has two children and works as an accountant for a local tax firm. His past medical history is unremarkable except for obesity. He takes no medicines and has no allergies. He has no family history of diabetes or cardiovascular disease. He eats “whatever is on the table when I get home” and has no regular exercise routine. His current height is 5’8” (170 cm) and his current weight is 190 lb (85.5 kg). You calculate his body mass index (BMI) at 29. A BMI calculator is available on the "Partnership foWould you screen David for diabetes?

Yes

No

 

Your answer conforms to the current ADA screening recommendations for diabetes. Although David has none of the common symptoms of diabetes, such as polydipsia, polyuria or unexplained weight loss, his weight and age put him at increased risk for the disease. The ADA currently recommends screening patients who are at high risk for diabetes every three years.

Although the ADA would recommend screening in this case, it is important to recognize that controversy exists regarding the value of screening.(4-6) While there is clear evidence that many people with diabetes experience a period of impaired glucose tolerance during which they may not exhibit symptoms,(7) the benefits of identifying and treating these patients during this earlier time frame are unclear. In its 1995 review, the U.S. Preventive Services Task Force found insufficient evidence for or against routine screening,(2) but this finding is currently under review.(8) After a review of the evidence and recommendations, the American Academy of Family Physicians has not issued a recommendation. Questions linger about the minor nature of risk reductions accomplished by early detection and the effectiveness of early treatment. Continued investigation of this important issue is warranted.

 

 

r Healthy Weight Management" web site.

 

SCREENING RESULTS

You elect to have David fast for eight hours so you can perform a fasting plasma glucose (FPG) test. The result is 158 mg per dL (8.8 mmol per L). When David returns to your office for a visit later in the week, you decide to perform a second fasting glucose test. The result is 190 mg per dL (10.6 mmol per L). He still reports no symptoms of diabetes, such as polydipsia, polyuria or unexplained weight loss.

Does David have diabetes?

Yes

No

 

DIAGNOSTIC CRITERIA

The correct answer is yes, according to current ADA criteria listed below. The diagnosis must be confirmed on a subsequent day by any one of the three criteria.

For example, one instance of symptoms with casual plasma glucose >=200 mg per dL (11.1 mmol per L) warrants the diagnosis of diabetes if it is confirmed on a subsequent day by one of the following: 1) FPG >=126 mg per dL (7.0 mmol per L), 2) an OGTT with the two-hour postload value >=200 mg per dL (11.1 mmol per L) or 3) symptoms with a casual plasma glucose >=200 mg per dL (11.1 mmol per L). It is worth noting, however, that just as there is controversy about screening, there is some disagreement about these more inclusive diagnostic criteria.(9

CONTROVERSY ABOUT EARLIER DIAGNOSIS AND TREATMENT

Previous diagnostic criteria reflected a discordance between patients who were diagnosed on the basis of an OGTT and those diagnosed on the basis of FPG, with the former test being more sensitive. In other words, patients who had an FPG level of >=140 mg per dL (7.8 mmol per L) -- the previous ADA cutoff -- did not have a corresponding OGTT level that would indicate a diagnosis of diabetes (>=200 mg per dL [11.1 mmol per L]). Lowering the cutoff value for FPG to 126 mg per dL (7.0 mmol per L) makes this population more similar to those diagnosed via OGTT, but it also labels an additional 1 million patients as diabetics,(10) many of whom have normal hemoglobin A1c (HgbA1c) levels.(11)

While the ADA recommendations reflect the belief that earlier diagnosis and treatment will reduce rates of microvascular complications, many issues remain unresolved. Studies such as the United Kingdom Prospective Diabetes Study (UKPDS) have demonstrated small absolute (as opposed to relative) risk reductions in intermediate outcomes such as retinopathy or microalbuminuria when diabetes is diagnosed and treated early. Outcomes that are of greater concern to patients, such as blindness or renal failure, are more difficult to study. In addition, tight control may not be worthwhile in all patients. For example, elderly patients with cancer or heart disease may not live long enough to benefit from tight control

MAKING THE DIAGNOSIS

Review of David's medical history reveals no reason to suspect pancreatic disorders, infection, or drug-induced or genetic causes for his elevated glucose levels. Given his obesity, age and sedentary lifestyle, you feel confident that he has type 2 diabetes. The remainder of his history and physical examination reveals no evidence of end-organ damage. In-office laboratory tests reveal that his glycosylated hemoglobin is 9.1 percent (reference range: 4.0 to 6.0 percent), with normal electrolytes, liver function tests and complete blood count. His urinalysis (including microalbuminuria) and electrocardiogram are unremarkable.

You tell David the diagnosis. He is mildly shaken by the news but is anxious to proceed with treatment nonetheless. You briefly explain the diagnosis and treatment options to David and give him some patient education materials to take and read at home.

OTHER CAUSES OF HYPERGLYCEMIA

Clues in the history and physical examination that suggest less common causes of hyperglycemia might include diarrhea in the presence of pancreatic exocrine (in addition to endocrine) dysfunction, use of hyperglycemia-inducing drugs such as prednisone, or the presence of cushingoid facies as seen in hypercortisolic states or other system symptoms suggesting infection (e.g., fever, abdominal pain). See the etiologic classification of diabetes in the ADA's Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.[SEE BELOW THE DETAILS BIG BIG RED BOX]]

GLYCOSYLATED HEMOGLOBIN AND HEMOGLOBIN A1c

Although many physicians use the terms glycosylated (or glycated) hemoglobin and hemoglobin A1c (HbA1c) interchangeably, they are not equivalent in the strictest sense.

Glycosylated hemoglobin refers to the entire population of sugar-bound hemoglobin moieties, of which glucose-bound hemoglobin is a subset. The single largest contributor to the glycosylated hemoglobin population is hemoglobin A1c, so measurements of total glycosylated hemoglobin in a specimen are typically close to HbA1c measurements in the same specimen. Other moieties that can be measured (in research laboratories) include HbA1a, HbA1b, and innumerable other glycosylation products of glucose and other sugars.

It is important to remember that HbA1c levels can be influenced by the presence of abnormal hemoglobin such as sickle or fetal chains. The presence of these chains results in lower than anticipated HbA1c measurements compared with HbA1c measurements in similarly controlled patients without such chains.

The most important consideration when comparing results from glycosylated hemoglobin assays over time or from different laboratories is to determine which assay the lab is using so that you may compare like to like.

RECOMMENDED TREATMENT GOALS

On the basis of data from the Diabetes Control and Complication Trial (DCCT) and UKPDS, the ADA has established recommended treatment goals for HbA1c and blood glucose monitoring in adult patients with type 2 diabetes. Because reaching ideal blood glucose targets can increase a patient's risk of hypoglycemia, the ADA recommends that the physician evaluate the patient's risk for severe hypoglycemia, as well as his or her understanding of the treatment plan and capacity to carry it out properly. The physician should also consider other patient factors that might increase risk or decrease benefit of treatment. These factors may include very young or old age, advanced cardiovascular or cerebrovascular disease, end-stage renal disease (ESRD), or other comorbid conditions that would shorten the patient's life expectancy

 

 

ADA Guidelines for Glycemic Control in People with Diabetes*

 

Normal

Goal

Additional action suggested

Whole blood values

 

 

 

   

Average preprandial glucose (mg/dL)†

<100

80 to 120

<80 or >140

   

Average bedtime glucose (mg/dL)†

<110

100 to 140

<100 or >160

Plasma values

 

 

 

   

Average preprandial glucose (mg/dL)‡

<110

90 to 130

<90 or >150

   

Average bedtime glucose (mg/dL)‡

<120

110 to 150

<110 or >180

HbA1c (percent)

<6

<7

>8

*The values shown in this table are by necessity generalized to the entire population of individuals with diabetes. Patients with comorbid diseases, the very young and older adults, and others with unusual conditions or circumstances may warrant different treatment goals. These values are for nonpregnant adults. "Additional action suggested" depends on individual patient circumstances. Such actions may include enhanced diabetes self-management education, comanagement with a diabetes team, referral to an endocrinologist, change in pharmacologic therapy, initiation of or increase in self-monitoring of blood glucose (SMBG), or more frequent contact with the patient.
† Measurement of capillary blood glucose.
‡ Values calibrated to plasma glucose.

Reprinted with permission from the American Diabetes Association. Clinical practice recommendations 2001. Diabetes Care. 2001:24(suppl 1):S34.

TAILORING TREATMENT GOALS

You and David discuss and agree on the following overall goals for managing his diabetes:

Mindful of the ADA's recommendations, you and David decide he can best achieve his overall goals by trying to meet the following intermediate goals:

You instruct David on how to monitor his blood glucose level at home and initiate nonpharmacologic therapy. You arrange for David to meet with a registered dietitian for help making dietary changes. You suggest that David work up to exercising for at least 30 minutes, four to six times a week. Aerobic exercise would be best, but you encourage him to choose a form of exercise he enjoys and will maintain, and you instruct him to return in three months for a follow-up visit.

The following links to the ADA's web site provide detailed recommendations regarding dietary and exercise management of diabetes:

GRADED EXERCISE TESTING

A graded exercise test may be helpful when a patient is about to embark on a moderate- to high-intensity exercise program if the patient is at high risk for underlying cardiovascular disease based on the following criteria:

In some patients who exhibit nonspecific electrocardiogram (ECG) changes in response to exercise or who have nonspecific ST and T wave changes on the resting ECG, alternative tests such as radionuclide stress testing may be performed. In patients planning to participate in low-intensity forms of exercise (<60 percent of maximal heart rate) such as walking, the physician should use clinical judgment in deciding whether to recommend an exercise stress test

NONPHARMACOLOGIC THERAPY FAILS

Despite three months of nutrition and exercise therapy, David’s HbA1c remains at 9.0 percent and his fasting blood glucose levels remain in the high 100s. His weight is unchanged. You decide to add drug therapy to the treatment regimen.

Which one of the following would you choose for initial monotherapy in this patient?

A thiazolidinedione such as rosiglitazone (Avandia) or pioglitazone (Actos).

A sulfonylurea such as glipizide (Glucotrol) or glyburide (Micronase).

A biguanide such as metformin (Glucophage).

A meglitinide such as repaglinide (Prandin) or nateglinide (Starlix).

An alpha-glucosidase inhibitor such as acarbose (Precose) or miglitol (Glyset).

NPH insulin.

GLITAZONES

A glitazone, such as rosiglitazone (Avandia) or pioglitazone (Actos), is a reasonable choice for initial monotherapy in this patient. However, neither of these medications is commonly used as a first-line agent in the United States because of their cost and concerns about patient safety raised by troglitazone (Rezulin), which was recently removed from the U.S. market. Rosiglitazone and pioglitazone are as effective as troglitazone at lowering blood sugar, but do not appear to cause the liver toxicity seen with that agent.

In obese patients like David, the probable etiology of diabetes lies in diminished peripheral tissue sensitivity to insulin, which in turn results in hyperinsulinemia caused by the pancreas' attempts to compensate for hyperglycemia.(15) Therefore, it makes sense to choose a medication that improves peripheral insulin sensitivity (e.g., a biguanide, a glitazone).

Glitazones act primarily by increasing peripheral tissue sensitivity to insulin and, like metformin, they reduce hepatic glucose production. One added benefit of glitazones is that they commonly reduce serum triglyceride levels (by 20 to 25 percent with troglitazone) and increase HDL levels (6 to 8 percent with troglitazone).(18)

Although glitazones would be an acceptable choice, because of their cost and side effects metformin is a better first-line therapy.

What side effects may be associated with glitazones?

How do the oral antidiabetics compare?

SIDE EFFECTS OF GLITAZONES

The most common side effects of glitazones are headache, fatigue and edema. Liver toxicity, the reason for troglitazone’s removal from the market, has been seen with much rarer incidence with rosiglitazone or pioglitazone. Nevertheless, it is recommended that the physician check the patient's liver enzymes prior to initiating therapy with either of these agents and avoid glitazone therapy in patients with preexistent liver disease (alanine transaminase [ALT] >2.5 times normal). If therapy with a pioglitazone or rosiglitazone is initiated, the physician should monitor liver function tests every two months during the first year of therapy and periodically thereafter.

One other side effect of glitazones is worth mentioning. Because of their insulin-sensitizing effects, glitazones carry the theoretical risk of inducing ovulation in premenopausal women who are anovulatory due to an insulin resistant state (e.g., women with polycystic ovary syndrome).(19) The clinical significance of this side effect has yet to be determined.

Although glitazones have no potential to cause hypoglycemia when used as monotherapy, when used in combination with insulin or a sulfonylurea they potentiate the hypoglycemic effect of the other agent, and therefore increase the likelihood of hypoglycemia. Unlike metformin, glitazones are cleared by the liver and therefore are not contraindicated in patients with renal disease.

COMPARISON OF ORAL ANTIDIABETIC AGENTS

Medication Class

Sulfonylureas

Meglitinides

Thiazolidinediones

Biguanide*

Alpha-glucosidase inhibitors

Mechanism of action

Increase insulin secretion

Major effect on fasting glucose levels

·

Increase insulin secretion

·

Major effect on post-prandial glucose levels

·

Increase glucose uptake

·

Major effect on post-prandial glucose levels

·

Decrease hepatic glucose production

·

Increase peripheral glucose uptake

·

Major effect on fasting glucose levels

·

Inhibit intestinal glucose absorption

·

Major effect on post-prandial glucose levels

Starting dosage

"Treatment Options for Type 2 Diabetes" AFP monograph.

Repaglinide:

·

0.5 mg with meal

·

Increase by 0.5 mg increments on weekly basis

Nateglinide:

·

120 mg 1-30 minutes before meals three times a day

·

May use 60 mg 1-30 minutes before meals for patients near HgbA1c goal when therapy is initiated

Rosiglitazone:

·

4 mg once daily, or divided doses twice daily

·

Increase if patient does not respond adequately after 12 weeks of treatment

Pioglitazone:

·

15-30 mg once daily

·

Increase in increments if patient does not respond adequately after 12 weeks of treatment

·

500 mg twice daily, or 850 mg once daily

·

Increase by 500 mg every week up to 2500 mg per day, or 850 mg every other week up to 2550 mg per day

·

For Glucophage XR (sustained-release metformin):
start at 500 mg with the evening meal, and increase by 500 mg each week up to 2000 mg per day.

25 mg three times a day with the first bite of each main meal. To minimize GI side effects, start with 25 mg once per day with meal.

·

Increase at 4 to 8 week intervals by 25 mg increments with each meal

Maximum dosage

"Treatment Options for Type 2 Diabetes" AFP monograph.

Repaglinide:

·

4 mg with meals; may be dosed pre-prandially 2, 3 or 4 times a day (in response to meal pattern) up to 16 mg per day

Nateglinide:

·

120 mg three times a day

·

Skip dose of repaglinide or nateglinide when skipping meal

Rosiglitazone:

·

8 mg once daily, or divided doses twice daily

Pioglitazone:

·

45 mg once daily

·

850 mg three times a day

·

Sustained-release metformin: 2000 mg per day

Acarbose:

·

Patients <60 kg: 50 mg three times a day with meals

·

Patients >60 kg: 100 mg three times a day with meals

Miglitol:

·

100 mg three times a day with meals

Side effects

Hypoglycemia, weight gain, hyperinsulinemia

Hypoglycemia

Liver toxicity, edema, ovulation induction

GI upset, lactic acidosis

GI upset, diarrheal stools

Warnings/ monitoring

Hypoglycemia

Hypoglycemia

Hepatic toxicity (do not initiate therapy in patients with ALT >2.5 times normal)

Lactic acidosis or conditions predisposing to acidosis, such as congestive heart failure, liver disease, renal disease, gastroenteritis

Do not use in patients with elevated serum creatinine (>=1.5 in men; >=1.4 in women)

Use glucose for hypoglycemic episodes

Cost range (per month)

$1-$30

$50-$60

>$100

$40-$50

$40-$50

GI = gastrointestinal; ALT = alanine transaminase.

* Metformin is now available in combination with glyburide and a sulfonylurea (Glucovance).

Sulfonylurea Therapy for Type 2 Diabetes

Agent

Daily dosage range

Number of doses per day

First-generation agents

 

 

Tolbutamide (Orinase)

500-3,000 mg

2 or 3

Chlorpropamide (Diabinese)

100-500 mg

1

Tolazamide (Tolinase)

100-1,000 mg

1 or 2

Acetohexamide (Dymelor)

250-1,500 mg

1 or 2

Second-generation agents

 

 

Glyburide (Micronase)

1.25-20 mg

1 or 2

Glyburide, micronized (Glynase)

0.75-12 mg

1 or 2

Glipizide (Glucotrol)

2.5-40 mg

1 or 2

Glipizide, extended release (Glucotrol XL)

5-20 mg

1

Glimepiride (Amaryl)

1-8 mg

1

Adapted with permission from Ertel NH. Newer therapeutic agents for type 2 diabetes in Managing type 2 diabetes: New science and new strategies. Postgraduate Medicine Special Report, March 1998:25-32. © 2001 The McGraw-Hill Companies, Inc.

 

NONPHARMACOLOGIC THERAPY FAILS

Despite three months of nutrition and exercise therapy, David’s HbA1c remains at 9.0 percent and his fasting blood glucose levels remain in the high 100s. His weight is unchanged. You decide to add drug therapy to the treatment regimen.

Which one of the following would you choose for initial monotherapy in this patient?

A thiazolidinedione such as rosiglitazone (Avandia) or pioglitazone (Actos).

A sulfonylurea such as glipizide (Glucotrol) or glyburide (Micronase).

A biguanide such as metformin (Glucophage).

A meglitinide such as repaglinide (Prandin) or nateglinide (Starlix).

An alpha-glucosidase inhibitor such as acarbose (Precose) or miglitol (Glyset).

NPH insulin.

 

 

ADA's Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus

 

 

The current classification and diagnosis of diabetes used in the U.S. was developed by the National Diabetes Data Group (NDDG) and published in 1979 (1). The impetus for the classification and diagnosis scheme proposed then holds true today. That is,

the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1)

It is now considered to be particularly important to move away from a system that appears to base the classification of the disease, in large part, on the type of pharmacological treatment used in its management toward a system based on disease etiology where possible.

An international Expert Committee, working under the sponsorship of the American Diabetes Association, was established in May 1995 to review the scientific literature since 1979 and to decide if changes to the classification and diagnosis of diabetes were warranted. The Committee met on multiple occasions and widely circulated a draft report of their findings and preliminary recommendations to the international diabetes community. Based on the numerous comments and suggestions received, including the opportunity to review unpublished data in detail, the Committee discussed and revised numerous drafts of a manuscript that culminated in this published document.

This report is divided into four sections: definition and description of diabetes, classification of the disease, diagnostic criteria, and testing for diabetes. The aim of this document is to define and describe diabetes as we know it today, present a classification scheme that reflects its etiology and/or pathogenesis, provide guidelines for the diagnosis of the disease, develop recommendations for testing that can help reduce the morbidity and mortality associated with diabetes, and review the diagnosis of gestational diabetes.

DEFINITION AND DESCRIPTION OF DIABETES MELLITUS — Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the -cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia.

Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.

Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Glycation of tissue proteins and other macromolecules and excess production of polyol compounds from glucose are among the mechanisms thought to produce tissue damage from chronic hyperglycemia. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral vascular, and cerebrovascular disease. Hypertension, abnormalities of lipoprotein metabolism, and periodontal disease are often found in people with diabetes. The emotional and social impact of diabetes and the demands of therapy may cause significant psychosocial dysfunction in patients and their families.

The vast majority of cases of diabetes fall into two broad etiopathogenetic categories (discussed in greater detail below). In one category (type 1 diabetes), the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. In the other, much more prevalent category (type 2 diabetes), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In the latter category, a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected. During this asymptomatic period, it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load.

CLASSIFICATION OF DIABETES MELLITUS AND OTHER CATEGORIES OF GLUCOSE REGULATION — A major requirement for epidemiological and clinical research and for the clinical management of diabetes is an appropriate system of classification that provides a framework within which to identify and differentiate its various forms and stages. While there have been a number of sets of nomenclature and diagnostic criteria proposed for diabetes, no generally accepted systematic categorization existed until the NDDG classification system was published in 1979 (1). The World Health Organization (WHO) Expert Committee on Diabetes in 1980 and, later, the WHO Study Group on Diabetes Mellitus endorsed the substantive recommendations of the NDDG (2). These groups recognized two major forms of diabetes, which they termed insulin-dependent diabetes mellitus (IDDM, type 1 diabetes) and non–insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes), but their classification system went on to include evidence that diabetes mellitus was an etiologically and clinically heterogeneous group of disorders that share hyperglycemia in common. The overwhelming evidence in favor of this heterogeneity included the following:

  1. There are several distinct disorders, most of them rare, in which glucose intolerance is a feature.
  2. There are large differences in the prevalence of the major forms of diabetes among various racial or ethnic groups worldwide.
  3. Patients with glucose intolerance present with great phenotypic variation; take, for example, the differences between thin, ketosis-prone, insulin-dependent diabetes and obese, nonketotic, insulin-resistant diabetes.
  4. Evidence from genetic, immunological, and clinical studies shows that in western countries, the forms of diabetes that have their onset primarily in youth are distinct from those that have their onset mainly in adulthood.
  5. A type of non–insulin-requiring diabetes in young people, inherited in an autosomal dominant fashion, is clearly different from the classic acute-onset diabetes that typically occurs in children.
  6. In tropical countries, several clinical presentations occur, including diabetes associated with fibrocalcific pancreatitis.

These and other lines of evidence were used to divide diabetes mellitus into five distinct types (IDDM, NIDDM, gestational diabetes mellitus [GDM], malnutrition-related diabetes, and other types). The different clinical presentations and genetic and environmental etiologic factors of the five types permitted discrimination among them. All five types were characterized by either fasting hyperglycemia or elevated levels of plasma glucose during an oral glucose tolerance test (OGTT). In addition, the 1979 classification included the category of impaired glucose tolerance (IGT), in which plasma glucose levels during an OGTT were above normal but below those defined as diabetes.

The NDDG/WHO classification highlighted the heterogeneity of the diabetic syndrome. Such heterogeneity has had important implications not only for treatment of patients with diabetes but also for biomedical research. This previous classification indicated that the disorders grouped together under the term diabetes differ markedly in pathogenesis, natural history, response to therapy, and prevention. In addition, different genetic and environmental factors can result in forms of diabetes that appear phenotypically similar but may have different etiologies.

The classification published in 1979 was based on knowledge of diabetes at that time and represented some compromises among different points of view. It was based on a combination of clinical manifestations or treatment requirements (e.g., insulin-dependent, non–insulin-dependent) and pathogenesis (e.g., malnutrition-related, "other types," gestational). It was anticipated, however, that as knowledge of diabetes continued to develop, the classification would need revision. When the classification was prepared, a definitive etiology had not been established for any of the diabetes subclasses, except for some of the "other types." Few susceptibility genes for diabetes had been discovered, and an understanding of the immunological basis for most type 1 diabetes was just beginning.

The current Expert Committee has carefully considered the data and rationale for what was accepted in 1979, along with research findings of the last 18 years, and we are now proposing changes to the NDDG/WHO classification scheme (Table 1). The main features of these changes are as follows:

  1. The terms insulin-dependent diabetes mellitus and non–insulin-dependent diabetes mellitus and their acronyms, IDDM and NIDDM, are eliminated. These terms have been confusing and have frequently resulted in classifying the patient based on treatment rather than etiology.
  2. The terms type 1 and type 2 diabetes are retained, with arabic numerals being used rather than roman numerals. We recommend adoption of arabic numerals in part because the roman numeral II can easily be confused by the public as the number 11. The class, or form, named type 1 diabetes encompasses the vast majority of cases that are primarily due to pancreatic islet -cell destruction and that are prone to ketoacidosis. This form includes those cases currently ascribable to an autoimmune process and those for which an etiology is unknown. It does not include those forms of -cell destruction or failure for which non–autoimmune-specific causes can be assigned (e.g., cystic fibrosis). While most type 1 diabetes is characterized by the presence of islet cell, GAD, IA-2, IA-2 , or insulin autoantibodies that identify the autoimmune process that leads to -cell destruction, in some subjects, no evidence of autoimmunity is present; these cases are classified as type 1 idiopathic.
  3. The class, or form, named type 2 diabetes includes the most prevalent form of diabetes, which results from insulin resistance with an insulin secretory defect.
  4. A recent international meeting reviewed the evidence for and characteristics of malnutrition-related diabetes (3). While it appears that malnutrition may influence the expression of other types of diabetes, the evidence that diabetes can be directly caused by protein deficiency is not convincing. Therefore, the class termed malnutrition-related diabetes mellitus has been eliminated. Fibrocalculous pancreatopathy (formerly a subtype of malnutrition-related diabetes) has been reclassified as a disease of the exocrine pancreas.
  5. The stage termed impaired glucose tolerance (IGT) has been retained. The analogous intermediate stage of fasting glucose is named impaired fasting glucose (IFG).
  6. The class termed gestational diabetes mellitus (GDM) is retained as defined by the WHO and NDDG, respectively. Selective rather than universal screening for glucose intolerance in pregnancy is now recommended.
  7. The degree of hyperglycemia (if any) may change over time, depending on the extent of the underlying disease process (Fig. 1). A disease process may be present but may not have progressed far enough to cause hyperglycemia. The same disease process can cause IFG and/or IGT without fulfilling the criteria for the diagnosis of diabetes. In some individuals with diabetes, adequate glycemic control can be achieved with weight reduction, exercise, and/or oral glucose-lowering agents. These individuals therefore do not require insulin. Other individuals, who have some residual insulin secretion but require exogenous insulin for adequate glycemic control, can survive without it. Individuals with extensive -cell destruction and therefore no residual insulin secretion require insulin for survival. The severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself.
  8. Assigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individuals do not easily fit into a single class. For example, a person with GDM may continue to be hyperglycemic after delivery and may be determined to have, in fact, type 1 diabetes. Alternatively, a person who acquires diabetes because of large doses of exogenous steroids may become normoglycemic once the glucocorticoids are discontinued, but then may develop diabetes many years later after recurrent episodes of pancreatitis. Another example would be a person treated with thiazides who develops diabetes years later. Because thiazides in themselves seldom cause severe hyperglycemia, such individuals probably have type 2 diabetes that is exacerbated by the drug. Thus, for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively.

Figure 1—Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., "honeymoon" remission). **In rare instances, patients in these categories (e.g., Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival.

Type 1 diabetes ( -cell destruction, usually leading to absolute insulin deficiency)
Immune-mediated diabetes. This form of diabetes, previously encompassed by the terms insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes, results from a cellular-mediated autoimmune destruction of the -cells of the pancreas (4). Markers of the immune destruction of the -cell include islet cell autoantibodies (ICAs), autoantibodies to insulin (IAAs), autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2 (513). One and usually more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycemia is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and B genes, and it is influenced by the DRB genes (14,15). These HLA-DR/DQ alleles can be either predisposing or protective.

In this form of diabetes, the rate of -cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults [16]). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual -cell function sufficient to prevent ketoacidosis for many years. Many such individuals with this form of type 1 diabetes eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life.

Autoimmune destruction of -cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, and pernicious anemia.

Idiopathic diabetes. Some forms of type 1 diabetes have no known etiologies. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian origin. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for -cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go (17).

Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance)
This form of diabetes, previously referred to as non–insulin-dependent diabetes, type 2 diabetes, or adult-onset diabetes, is a term used for individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency (1821). At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. There are probably many different causes of this form of diabetes, and it is likely that the proportion of patients in this category will decrease in the future as identification of specific pathogenic processes and genetic defects permits better differentiation among them and a more definitive subclassification. Although the specific etiologies of this form of diabetes are not known, autoimmune destruction of -cells does not occur, and patients do not have any of the other causes of diabetes listed above or below.

Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance (22,23). Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region (24). Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen, it usually arises in association with the stress of another illness such as infection (2527). This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of diabetes (2830). Nevertheless, such patients are at increased risk of developing macrovascular and microvascular complications (3034). Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their -cell function been normal (35). Thus, insulin secretion is defective in these patients and insufficient to compensate for the insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal (3640). The risk of developing this form of diabetes increases with age, obesity, and lack of physical activity (29,41). It occurs more frequently in women with prior GDM and in individuals with hypertension or dyslipidemia, and its frequency varies in different racial/ethnic subgroups (29,30,41). It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes (42,43). However, the genetics of this form of diabetes are complex and not clearly defined.

Other specific types of diabetes
Genetic defects of the -cell. Several forms of diabetes are associated with monogenetic defects in -cell function. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age (generally before age 25 years). They are referred to as maturity-onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action (4446). They are inherited in an autosomal dominant pattern. Abnormalities at three genetic loci on different chromosomes have been identified to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1 (47,48). A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule (49,50). Glucokinase converts glucose to glucose-6-phosphate, the metabolism of which, in turn, stimulates insulin secretion by the -cell. Thus, glucokinase serves as the "glucose sensor" for the -cell. Because of defects in the glucokinase gene, increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion. A third form is associated with a mutation in the HNF-4 gene on chromosome 20q (51,52). HNF-4 is a transcription factor involved in the regulation of the expression of HNF-1 . The specific genetic defects in a substantial number of other individuals who have a similar clinical presentation are currently unknown.

Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness (5355). The most common mutation occurs at position 3243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome); however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion (56).

Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families, and such traits are inherited in an autosomal dominant pattern (57,58). The resultant glucose intolerance is mild. Similarly, the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families and is associated with an autosomal inheritance and only mildly impaired or even normal glucose metabolism (5961).

Genetic defects in insulin action. There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes (62,63). Some individuals with these mutations may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries (64,65). In the past, this syndrome was termed type A insulin resistance (62). Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance (63). The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia.

Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipoatrophic diabetes. Therefore, it is assumed that the lesion(s) must reside in the postreceptor signal transduction pathways.

Diseases of the exocrine pancreas. Any process that diffusely injures the pancreas can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma (6668). With the exception of cancer, damage to the pancreas must be extensive for diabetes to occur. However, adenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes. This implies a mechanism other than simple reduction in -cell mass. If extensive enough, cystic fibrosis and hemochromatosis will also damage -cells and impair insulin secretion (69,70). Fibrocalculous pancreatopathy may be accompanied by abdominal pain radiating to the back and pancreatic calcifications on X ray (71). Pancreatic fibrosis and calcium stones in the exocrine ducts have been found at autopsy.

Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action. Excess amounts of these hormones (e.g., acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma) can cause diabetes (7275). This generally occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is removed.

Somatostatinoma- and aldosteronoma-induced hypokalemia can cause diabetes, at least in part, by inhibiting insulin secretion (75,76). Hyperglycemia generally resolves after successful removal of the tumor.

Drug- or chemical-induced diabetes. Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate diabetes in individuals with insulin resistance (77,78). In such cases, the classification is unclear because the sequence or relative importance of -cell dysfunction and insulin resistance is unknown. Certain toxins such as Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic -cells (7982). Such drug reactions fortunately are rare. There are also many drugs and hormones that can impair insulin action. Examples include nicotinic acid and glucocorticoids (77,78). Patients receiving -interferon have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin deficiency (83,84). The list shown in Table 1 is not all-inclusive, but reflects the more commonly recognized drug-, hormone-, or toxin-induced forms of diabetes.

Infections. Certain viruses have been associated with -cell destruction. Diabetes occurs in patients with congenital rubella (85), although most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of the disease (8688).

Uncommon forms of immune-mediated diabetes. In this category, there are two known conditions, and others are likely to occur. The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms (89). Patients usually have high titers of the GAD autoantibodies and approximately one-third will develop diabetes.

Anti–insulin receptor antibodies can cause diabetes by binding to the insulin receptor, thereby blocking the binding of insulin to its receptor in target tissues (63). However, in some cases, these antibodies can act as an insulin agonist after binding to the receptor and can thereby cause hypoglycemia. Anti–insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases (63). As in other states of extreme insulin resistance, patients with anti–insulin receptor antibodies often have acanthosis nigricans. In the past, this syndrome was termed type B insulin resistance.

Other genetic syndromes sometimes associated with diabetes. Many genetic syndromes are accompanied by an increased incidence of diabetes mellitus (90). These include the chromosomal abnormalities of Down's syndrome, Klinefelter's syndrome, and Turner's syndrome. Wolfram's syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes and the absence of -cells at autopsy (91). Additional manifestations include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Other syndromes are listed in Table 1.

Gestational diabetes mellitus (GDM)
GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition applies regardless of whether insulin or only diet modification is used for treatment or whether the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy (92). Six weeks or more after pregnancy ends, the woman should be reclassified, as described below (see diagnostic criteria for diabetes mellitus), into one of the following categories: 1) diabetes, 2) IFG, 3) IGT, or 4) normoglycemia. In the majority of cases of GDM, glucose regulation will return to normal after delivery.

GDM complicates ~4% of all pregnancies in the U.S., resulting in ~135,000 cases annually (93). The prevalence may range from 1 to 14% of pregnancies, depending on the population studied (93). GDM represents nearly 90% of all pregnancies complicated by diabetes (94). Clinical recognition of GDM is important because therapy, including medical nutrition therapy, insulin when necessary, and antepartum fetal surveillance, can reduce the well-described GDM-associated perinatal morbidity and mortality (95). Maternal complications related to GDM also include an increased rate of cesarean delivery and chronic hypertension (9597). Although many patients diagnosed with GDM will not develop diabetes later in life, others will be diagnosed many years postpartum as having type 1 diabetes, type 2 diabetes, IFG, or IGT (98103).

Deterioration of glucose tolerance occurs normally during pregnancy, particularly in the 3rd trimester. The criteria for abnormal glucose tolerance in pregnancy, which are widely used in the U.S., were proposed by O'Sullivan and Mahan (98) in 1964 and were based on data obtained from OGTTs performed on 752 pregnant women. Abnormal glucose tolerance was defined as two or more blood glucose values out of four that were greater than or equal to two standard deviations above the mean. These values were set based on the prediction of diabetes developing later in life.

In 1979, the NDDG revised the O'Sullivan and Mahan criteria, converting the whole blood values to plasma values (1). These criteria were adopted by the American Diabetes Association and the American College of Obstetricians and Gynecologists (ACOG) (104), but are at variance with WHO criteria.

Carpenter and Coustan (105) suggested that the NDDG conversion of the O'Sullivan and Mahan values from the original Somogyi-Nelson determinations may have resulted in values that are too high. They proposed cutoff values for plasma glucose that appear to represent more accurately the original O'Sullivan and Mahan determinations. In three studies, these criteria identified more patients with GDM whose infants had perinatal morbidity (106108). Additional studies have been completed to define abnormal 75-g OGTT values in different populations (109111). This method has provided values for plasma glucose concentrations that are similar to the Carpenter/Coustan extrapolations of the 100-g OGTT.

Recommendations from the American Diabetes Association's Fourth International Workshop-Conference on Gestational Diabetes Mellitus held in March 1997 support the use of the Carpenter/Coustan diagnostic criteria as well as the alternative use of a diagnostic 75-g 2-h OGTT (111a). These criteria are summarized below.

Testing for gestational diabetes. Previous recommendations have been that screening for GDM be performed in all pregnancies. However, there are certain factors that place women at lower risk for the development of glucose intolerance during pregnancy, and it is likely not cost-effective to screen such patients. This low-risk group comprises women who are <25 years of age and of normal body weight, have no family history (i.e., first-degree relative) of diabetes, have no history of abnormal glucose metabolism or poor obstetric outcome, and are not members of an ethnic/racial group with a high prevalence of diabetes (e.g., Hispanic American, Native American, Asian American, African-American, Pacific Islander) (112114). Pregnant women who fulfill all of these criteria need not be screened for GDM.

Risk assessment for GDM should be undertaken at the first prenatal visit. Women with clinical characteristics consistent with a high risk of GDM (marked obesity, personal history of GDM, glycosuria, or a strong family history of diabetes) should undergo glucose testing (see below) as soon as feasible. If they are found not to have GDM at that initial screening, they should be retested between 24 and 28 weeks of gestation. Women of average risk should have testing undertaken at 24–28 weeks of gestation.

A fasting plasma glucose level >126 mg/dl (7.0 mmol/l) or a casual plasma glucose >200 mg/dl (11.1 mmol/l) meets the threshold for the diagnosis of diabetes, if confirmed on a subsequent day, and precludes the need for any glucose challenge. In the absence of this degree of hyperglycemia, evaluation for GDM in women with average or high-risk characteristics should follow one of two approaches:

One-step approach: Perform a diagnostic OGTT without prior plasma or serum glucose screening. The one-step approach may be cost-effective in high-risk patients or populations (e.g., some Native-American groups).

Two-step approach: Perform an initial screening by measuring the plasma or serum glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test [GCT]) and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT. When the two-step approach is employed, a glucose threshold value >140 mg/dl (7.8 mmol/l) identifies approximately 80% of women with GDM, and the yield is further increased to 90% by using a cutoff of >130 mg/dl (7.2 mmol/l).

With either approach, the diagnosis of GDM is based on an OGTT. Diagnostic criteria for the 100-g OGTT are derived from the original work of O'Sullivan and Mahan, modified by Carpenter and Coustan, and are shown in the top of Table 2. Alternatively, the diagnosis can be made using a 75-g glucose load and the glucose threshold values listed for fasting, 1 h, and 2 h (Table 2, bottom); however, this test is not as well validated as the 100-g OGTT.

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)
The terms IGT and IFG refer to a metabolic stage intermediate between normal glucose homeostasis and diabetes. This stage includes individuals who have IGT and individuals with fasting glucose levels >110 mg/dl (6.1 mmol/l) but <126 mg/dl (7.0 mmol/l) (IFG). The term IFG was coined by Charles et al. (115) to refer to a fasting plasma glucose (FPG) level >110 mg/dl (6.1 mmol/l) but <140 mg/dl (7.8 mmol/l). We are using a similar definition, but with the upper end lowered to correspond to the new diagnostic criteria for diabetes. A fasting glucose concentration of 109 mg/dl (6.1 mmol/l) has been chosen as the upper limit of "normal." Although it is recognized that this choice is somewhat arbitrary, it is near the level above which acute phase insulin secretion is lost in response to intravenous administration of glucose (116) and is associated with a progressively greater risk of developing micro- and macrovascular complications (117121).

Note that many individuals with IGT are euglycemic in their daily lives (122) and may have normal or near normal glycated hemoglobin levels (123). Individuals with IGT often manifest hyperglycemia only when challenged with the oral glucose load used in the standardized OGTT.

In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes and cardiovascular disease (117). They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with the insulin resistance syndrome (also known as syndrome X or the metabolic syndrome), which consists of insulin resistance, compensatory hyperinsulinemia to maintain glucose homeostasis, obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-HDL type, and hypertension (124). Insulin resistance is directly involved in the pathogenesis of type 2 diabetes. IFG and IGT appear as risk factors for this type of diabetes at least in part because of their correlation with insulin resistance. In contrast, the explanation for why IFG and IGT are also risk factors for cardiovascular disease is less clear. The insulin resistance syndrome includes well-recognized cardiovascular risk factors such as low HDL levels and hypertension. In addition, it includes hypertriglyceridemia, which is highly correlated with small dense LDL and increased plasminogen activator inhibitor-1 (PAI-1) levels. The former is thought to have enhanced atherogenicity, perhaps as a result of its greater vulnerability to oxidation than normal LDL. PAI-1 is a cardiovascular risk factor probably because it inhibits fibrinoloysis. Thus, the insulin resistance syndrome contains many features that increase cardiovascular risk. IFG and IGT may not in themselves be directly involved in the pathogenesis of cardiovascular disease, but rather may serve as statistical risk factors by association because they correlate with those elements of the insulin resistance syndrome that are cardiovascular risk factors.

DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS

The new criteria
The diagnostic criteria for diabetes mellitus have been modified from those previously recommended by the NDDG (1) or WHO (2). The revised criteria for the diagnosis of diabetes are shown in Table 3. Three ways to diagnose diabetes are possible, and each must be confirmed, on a subsequent day, by any one of the three methods given in Table 3. For example, one instance of symptoms with casual plasma glucose >200 mg/dl (11.1 mmol/l), confirmed on a subsequent day by 1) FPG >126 mg/dl (7.0 mmol/l), 2) an OGTT with the 2-h postload value >200 mg/dl (11.1 mmol/l), or 3) symptoms with a casual plasma glucose >200 mg/dl (11.1 mmol/l), warrants the diagnosis of diabetes.

For epidemiological studies, estimates of diabetes prevalence and incidence should be based on an FPG >126 mg/dl (7.0 mmol/l). This recommendation is made in the interest of standardization and also to facilitate field work, particularly where the OGTT may be difficult to perform and where the cost and demands on participants' time may be excessive. This approach will lead to slightly lower estimates of prevalence than would be obtained from the combined use of the FPG and OGTT (Table 4).

The Expert Committee recognizes an intermediate group of subjects whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered altogether normal. This group is defined as having FPG levels >110 mg/dl (6.1 mmol/l) but <126 mg/dl (7.0 mmol/l) or 2-h values in the OGTT of >140 mg/dl (7.8 mmol/l) but <200 mg/dl (11.1 mmol/l). Thus, the categories of FPG values are as follows:

  • FPG <110 mg/dl (6.1 mmol/l) = normal fasting glucose;
  • FPG >110 (6.1 mmol/l) and <126 mg/dl (7.0 mmol/l) = IFG;
  • FPG >126 mg/dl (7.0 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above).

The corresponding categories when the OGTT is used are the following:

  • 2-h postload glucose (2-h PG) <140 mg/dl (7.8 mmol/l) = normal glucose tolerance;
  • 2-h PG >140 (7.8 mmol/l) and <200 mg/dl (11.1 mmol/l) = IGT;
  • 2-h PG >200 mg/dl (11.1 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above).

Since the 2-h OGTT cutoff of 140 mg/dl (7.8 mmol/l) will identify more people as having impaired glucose homeostasis than will the fasting cutoff of 110 mg/dl (6.1 mmol/l), it is essential that investigators always report which test was used.

Rationale for the revised criteria for diagnosing diabetes
The revised criteria are still based on measures of hyperglycemia. Whereas many different diagnostic schemes have been used, all have been based on some measurement of blood or urine glucose, as reviewed by McCance et al. (125). The metabolic defects underlying hyperglycemia, such as islet cell autoimmunity or insulin resistance, should be referred to independently from the diagnosis of diabetes, i.e., in the classification of the disease. Determining the optimal diagnostic level of hyperglycemia depends on a balance between the medical, social, and economic costs of making a diagnosis in someone who is not truly at substantial risk of the adverse effects of diabetes and those of failing to diagnose someone who is (126). Unfortunately, not all these data are available, so we relied primarily on medical data.

Plasma glucose concentrations are distributed over a continuum, but there is an approximate threshold separating those subjects who are at substantially increased risk for some adverse outcomes caused by diabetes (e.g., microvascular complications) from those who are not. Based in part on estimates of the thresholds for microvascular disease, the previous WHO criteria defined diabetes by FPG >140 mg/dl (7.8 mmol/l), 2-h PG >200 mg/dl (11.1 mmol/l) in the OGTT, or both. These criteria effectively defined diabetes by the 2-h PG alone because the fasting and 2-h cutpoint values are not equivalent. Almost all individuals with FPG >140 mg/dl (7.8 mmol/l) have 2-h PG >200 mg/dl (11.1 mmol/l) if given an OGTT, whereas only about one-fourth of those with 2-h PG >200 mg/dl (11.1 mmol/l) and without previously known diabetes have FPG >140 mg/dl (7.8 mmol/l) (127). Thus, the cutpoint of FPG >140 mg/dl (7.8 mmol/l) defined a greater degree of hyperglycemia than did the cutpoint of 2-h PG >200 mg/dl (11.1 mmol/l). It is the consensus of the Expert Committee that this discrepancy is unwarranted and that the cutpoint values for both tests should reflect a similar degree of hyperglycemia and risk of adverse outcomes.

Under the previous WHO and the NDDG criteria, the diagnosis of diabetes is largely a function of which test is performed. Many individuals who would have 2-h PG >200 mg/dl (11.1 mmol/l) in an OGTT are not tested with an OGTT because they lack symptoms or because they have an FPG <140 mg/dl (7.8 mmol/l). Thus, if it is desired that all people with diabetes be diagnosed and the previous criteria are followed, OGTTs must be performed periodically in everyone. However, in ordinary practice, not only is the OGTT performed infrequently, but it is usually not used even to confirm suspected cases (128). In summary, the diagnostic criteria are now revised to 1) avoid the discrepancy between the FPG and 2-h PG cutpoint values and 2) facilitate and encourage the use of a simpler and equally accurate test—fasting plasma glucose—for diagnosing diabetes.

The cutpoint for the 2-h PG has been justified largely because at approximately that point the prevalence of the microvascular complications considered specific for diabetes (i.e., retinopathy and nephropathy) increases dramatically. This property of the 2-h PG has been compared with the FPG in population studies of the Pima Indians in the U.S., among Egyptians, and in the Third National Health and Nutrition Examination Survey (NHANES III) in the U.S. In other studies, the relationships between glycemia and macrovascular disease have also been examined.

The relationships of FPG and 2-h PG to the development of retinopathy were evaluated in Pima Indians over a wide range of plasma glucose cutpoints (Fig. 2A) (129). Both variables were similarly associated with retinopathy, indicating that by this criterion, each could work equally well for diagnosing diabetes. The authors concluded that both measures were equivalent in terms of the properties previously used to justify diagnostic criteria.

Figure 2—Prevalence of retinopathy by deciles of the distribution of FPG, 2-h PG, and HbA1c in Pima Indians (A) described in McCance et al. (129), Egyptians (B) described in Engelgau et al. (130), and in 40- to 74-year-old participants in NHANES III (C) (K. Flegal, National Center for Health Statistics, personal communication). The x-axis labels indicate the lower limit of each decile group. Note that these deciles and the prevalence rates of retinopathy differ considerably among the studies, especially the Egyptian study, in which diabetic subjects were oversampled. Retinopathy was ascertained by different methods in each study; therefore, the absolute prevalence rates are not comparable between studies, but their relationships with FPG, 2-h PG, and HbA1c are very similar within each population.

These findings were confirmed in a similar study in Egypt, in which the FPG and 2-h PG were each strongly and equally associated with retinopathy (Fig. 2B) (130). For both the FPG and the 2-h PG, the prevalence of retinopathy was markedly higher above the point of intersection of the two components of the bimodal frequency distribution (FPG = 129 mg/dl [7.2 mmol/l] and 2-h PG = 207 mg/dl [11.5 mmol/l]).

In the NHANES III, 2,821 individuals aged 40–74 years received an OGTT, a measurement of HbA1c, and an assessment of retinopathy by fundus photography (K. Flegal, personal communication). Figure 2C shows that all three measures of glycemia (FPG, 2-h PG, and HbA1c) are strongly associated with retinopathy, which is similar to the relationships found in the Pima Indians (129) and Egyptians (130), although the relationship was strongest for 2-h PG. As in other studies, the prevalence rose dramatically in the highest decile of each variable, corresponding to FPG >120 mg/dl (6.7 mmol/l), 2-h PG >195 mg/dl (10.8 mmol/l), and HbA1c >6.2%. As in the Pima Indian (129) and Egyptian (130) studies, estimates of these "thresholds" for retinopathy are somewhat imprecise. More precision cannot easily be obtained by using narrower glycemic intervals (e.g., 20 instead of the 10 shown in Fig. 2) because of the limited numbers of cases of retinopathy in each sample (32 cases in the Pima study, 146 in the Egyptian study, and 111 in NHANES III). There are no absolute thresholds because some retinopathy occurred at all glucose levels, presumably because of measurement or disease variability and because of nondiabetic causes of retinopathy.

The associations between FPG and 2-h PG and macrovascular disease have been examined in adults without known diabetes (131). The 2-h PG was somewhat more closely associated with major coronary heart disease, but there was no significant difference in the association of the FPG or the 2-h PG with other indexes of macrovascular disease. Similarly, the relationship between glycemia and peripheral arterial disease was studied in 50- to 74-year-old Caucasians (132). The prevalence of arterial disease was strongly related to the FPG and 2-h PG. The associations appeared to be of the same strength for both variables.

In a recent analysis of the Paris Prospective Study, the incidence of fatal coronary heart disease was related to both FPG and 2-h PG determined at a baseline examination (118). Incidence rates were markedly increased at FPG >125 mg/dl (6.9 mmol/l) or 2-h PG >140 mg/dl (7.8 mmol/l). Similarly, the incidence of coronary artery disease and the all-cause mortality rates were predicted by the FPG in the Baltimore Longitudinal Study of Aging (R. Andres, C. Coleman, D. Elahi, J. Fleg, D.C. Muller, J.D. Sorkin, J.D. Tobin, personal communication). The incidence rates of both these outcomes increased markedly and almost linearly above FPG levels in the range of 110–120 mg/dl (6.1–6.7 mmol/l). In conclusion, both the FPG and 2-h PG provide important information regarding risk of both micro- and macrovascular disease, and the approximate thresholds for increased risk correspond with those for retinopathy and with the revised diagnostic criteria.

Reproducibility is another important property of a diagnostic test, a property for which the FPG appears to be preferable. When OGTTs were repeated in adults during a 2- to 6-week interval, the intra-individual coefficients of variation were 6.4% for the FPG and 16.7% for the 2-h PG (133).

It is important to review the rationale for retaining the diagnostic cutpoint of 200 mg/dl (11.1 mmol/l) for the 2-h PG. This cutpoint was originally adopted for three reasons (1,2). First, 200 mg/dl (11.1 mmol/l) has been found to approximate the cutpoint separating the two components of the bimodal distribution of 2-h PG. Second, in several studies, the prevalence of microvascular disease sharply increased above 2-h PG levels of ~200 mg/dl (11.1 mmol/l). Third, an enormous body of clinical and epidemiological data has been collected based on the 2-h PG cutpoint of 200 mg/dl (11.1 mmol/l). Thus, this value has been retained for the diagnosis of diabetes because it would be very disruptive, and add little benefit, to alter the well-accepted 2-h PG diagnostic level of >200 mg/dl (11.1 mmol/l).

Changing the diagnostic cutpoint for the FPG to 126 mg/dl (7.0 mmol/l) is based on the belief that the cutpoints for the FPG and 2-h PG should diagnose similar conditions, given the equivalence of the FPG and the 2-h PG in their associations with vascular complications and their discrimination between two components of a bimodal frequency distribution (129,130). McCance et al. (129) computed the FPG level equivalent (in sensitivity and specificity for retinopathy) to the 1985 WHO criterion of the 2-h PG >200 mg/dl (11.1 mmol/l) and found it to be an FPG of >123 mg/dl (6.8 mmol/l) (Table 5). Finch et al. (134) approached the problem in each of 13 Pacific populations surveyed with OGTTs by determining the value in the FPG that, when used alone as a diagnostic criterion, gave the same prevalence of diabetes as did 2-h PG >200 mg/dl (11.1 mmol/l). The summary estimate from all these populations was a cutpoint of 126 mg/dl (7.0 mmol/l). The same method was applied to data derived from the Pima Indians and resulted in an FPG cutpoint of 120 mg/dl (6.7 mmol/l). In NHANES III, the corresponding cutpoint was 121 mg/dl (6.7 mmol/l) (Table 5). These values and the 2-h PG cutpoint of 200 mg/dl (11.1 mmol/l) are also quite similar to the values of FPG 129 mg/dl (7.2 mmol/l) and 2-h PG 207 mg/dl (11.5 mmol/l) that separated the components of the bimodal frequency distributions and identified individuals with a high prevalence of retinopathy among Egyptians (130). Because the standard errors of these estimates are not known, the small differences in the estimates shown in Table 5 may be consistent with sampling variability.

We chose a cutpoint at the upper end of these estimates (FPG >126 mg/dl, 7.0 mmol/l). This value is slightly higher than most of the estimated cutpoints that would give the same prevalence of diabetes as the criterion of 2-h PG >200 mg/dl (11.1 mmol/l). That is, slightly fewer people will be diagnosed with diabetes if the new FPG criterion is used alone than if either the FPG or the OGTT is used and interpreted by the previous WHO and NDDG criteria (Table 4).

As noted above, although the OGTT is an acceptable diagnostic test and has been an invaluable tool in research, it is not recommended for routine use. Because of its inconvenience to patients and the perception by many physicians that it is unnecessary, the OGTT is already not widely used for diagnosing diabetes. In addition, it is more costly and time-consuming than the FPG, and the repeat test reproducibility of the 2-h PG is worse than that of the FPG (133). If the OGTT is used, either for clinical or research purposes, the test procedure methods recommended by the WHO (2) and the diagnostic criterion in Table 3 should be employed.

HbA1c measurement is not currently recommended for diagnosis of diabetes, although some studies have shown that the frequency distributions for HbA1c have characteristics similar to those of the FPG and the 2-h PG. Moreover, these studies have defined an HbA1c level above which the likelihood of having or developing macro- or microvascular disease rises sharply (Fig. 2) (129132). Furthermore, HbA1c and FPG (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 HbA1c. These observations have led some to recommend HbA1c measurement as a diagnostic test (126,135).

On the other hand, there are many different methods for the measurement of HbA1c and other glycosylated proteins, and nationwide standardization of the HbA1c test has just begun (136). Studies of the utility of the test compared with the FPG and 2-h PG have used different assays, thereby making it difficult to assign an appropriate cutpoint. Also, the FPG, 2-h PG, and HbA1c tests are imperfectly correlated. In most clinical laboratories, a "normal" HbA1c is usually based on a statistical sampling of healthy, presumably nondiabetic individuals. In conclusion, HbA1c remains a valuable tool for monitoring glycemia, but it is not currently recommended for the diagnosis of diabetes.

The revised criteria are for diagnosis and are not treatment criteria or goals of therapy. No change is made in the American Diabetes Association's recommendations of FPG <120 mg/dl (6.7 mmol/l) and HbA1c <7% as treatment goals (137). The new diagnostic cutpoint (FPG >126 mg/dl [7.0 mmol/l]) is based on the observation that this degree of hyperglycemia usually reflects a serious metabolic abnormality that has been shown to be associated with serious complications. The treatment of nonpregnant patients with hyperglycemia near the cutpoint should begin with an individualized lifestyle-modification regimen (i.e., meal planning and exercise). Initiation of pharmacological therapy in these patients has not yet been shown to improve prognosis and may lead to an unacceptably high incidence of hypoglycemic reactions with certain drugs (e.g., sulfonylureas, insulin).

The new criteria have implications for estimates of the prevalence of diabetes. Although an FPG >126 mg/dl (7.0 mmol/l) and a 2-h PG >200 mg/dl (11.1 mmol/l) have similar predictive value for adverse outcomes, the two tests are not perfectly correlated with each other. A given person may have one glucose value above one cutpoint and another value below the other cutpoint. Thus, simultaneous measurement of both FPG and 2-h PG will inevitably lead to some diagnostic discrepancies and dilemmas. Although diagnosing diabetes by either test will result in a similar number of "cases," different individuals in different hyperglycemic stages may be identified. (This situation would be even more complicated if a third diagnostic test, such as HbA1c, were used.) However, according to the data reviewed above, there is no basis for concluding that the 2-h PG is more reliable than the FPG. Thus, the FPG alone should be used for estimating the comparative prevalence of diabetes in different populations.

Table 4 shows the effect of the new diagnostic criteria on the estimated prevalence of diabetes in the U.S. population aged 40–74 years using data from NHANES III. Diagnosing diabetes in those without a medical history of diabetes by using only the FPG test would result in a lower prevalence of diabetes than would using WHO criteria (4.35 vs. 6.34%). The total prevalence of diabetes (including those with a medical history) would be 12.27%, or 14% lower than the prevalence of 14.26% by the WHO criteria. Of note, these prevalence estimates refer to results of testing on one occasion. The prevalence of diabetes confirmed by a second test will be lower regardless of which criteria are used.

Widespread adoption of the new criteria may, however, have a large impact on the number of people actually diagnosed with diabetes. Presently, about half the adults with diabetes in the U.S. are undiagnosed (127), but many might now be diagnosed if the simpler FPG test were always used.

TESTING FOR DIABETES IN PRESUMABLY HEALTHY INDIVIDUALS — Type 1 diabetes is usually an autoimmune disease, characterized by the presence of a variety of autoantibodies to protein epitopes on the surface of or within the -cells of the pancreas. The presence of such markers before the development of overt disease can identify patients at risk (138). For example, those with more than one autoantibody (i.e., ICA, IAA, GAD, IA-2) are at high risk (139141). At this time, however, many reasons preclude the recommendation to test individuals routinely for the presence of any of the immune markers outside of a clinical trials setting. First, cutoff values for some of the assays for immune markers have not been completely established for clinical settings. Second, there is no consensus yet as to what action should be taken when a positive autoantibody test is obtained. Thus, autoantibody testing may identify people at risk of developing type 1 diabetes without offering any proven measures that might prevent or delay the clinical onset of disease. Of note, however, is that there are a number of ongoing well-controlled clinical studies testing various means of preventing type 1 diabetes. These studies conducted in high-risk subjects may one day offer an effective means to prevent type 1 diabetes, in which case screening may become appropriate. Last, because the incidence of type 1 diabetes is low, routine testing of healthy children will identify only the small number (<0.5%) who at that moment may be "prediabetic." Thus, the cost-effectiveness of such screening is questionable, at least until an effective therapy is available. For the above reasons, the clinical testing of individuals for autoantibodies related to type 1 diabetes, outside of research studies, cannot be recommended at this time. Similarly, antibody testing of high-risk individuals (e.g., siblings of type 1 patients) is also not recommended until the efficacy and safety of therapies to prevent or delay type 1 diabetes have been demonstrated. On the other hand, the autoantibody tests may be of value to identify which newly diagnosed patients have immune-mediated type 1 diabetes in circumstances where it is not obvious, particularly when therapies become available to preserve -cell mass.

Undiagnosed type 2 diabetes is common in the U.S. As many as 50% of the people with the disease, or about 8 million individuals, are undiagnosed (127). Of concern, there is epidemiological evidence that retinopathy begins to develop at least 7 years before the clinical diagnosis of type 2 diabetes is made (142). Because hyperglycemia in type 2 diabetes causes microvascular disease and may cause or contribute to macrovascular disease, undiagnosed diabetes is a serious condition. Patients with undiagnosed type 2 diabetes are at significantly increased risk for coronary heart disease, stroke, and peripheral vascular disease. In addition, they have a greater likelihood of having dyslipidemia, hypertension, and obesity (143).

Thus, early detection, and consequently early treatment, might well reduce the burden of type 2 diabetes and its complications. However, to increase the cost-effectiveness of testing undiagnosed, otherwise healthy individuals, testing should be considered in high-risk populations. Suggested criteria for testing are given in Table 6. Factors leading to these recommendations include: 1) the steep rise in the incidence of the disease after age 45 years, 2) the negligible likelihood of developing any of the complications of diabetes within a 3-year interval of a negative screening test, and 3) knowledge of the well-documented risk factors for the disease. Although the OGTT and FPG are both suitable tests, in clinical settings, the FPG is strongly recommended because it is easier and faster to perform, more convenient and acceptable to patients, more reproducible, and less expensive.


Acknowledgments — We gratefully acknowledge the invaluable assistance of Robert Misbin, MD, in the development of the manuscript; Katherine Flegal, PhD, for her analysis of the NHANES III data set; Reubin Andres, MD, for sharing unpublished data from the Baltimore Longitudinal Study of Aging; and Michael Engelgau, MD, for providing the raw data from the Egyptian Study (130).


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From the American Diabetes Association, Alexandria, Virginia. Originally approved 1997. Modified in 1999 based on the Proceedings of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus (Diabetes Care 21 [Suppl. 2]:B1–B167, 1998).

*Members of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: James R. Gavin III, MD, PhD (Chair), K.G.M.M. Alberti, MD, Mayer B. Davidson, MD, Ralph A. DeFronzo, MD, Allan Drash, MD, Steven G. Gabbe, MD, Saul Genuth, MD, Maureen I. Harris, PhD, MPH, Richard Kahn, PhD, Harry Keen, MD, FRCP, William C. Knowler, MD, DrPH, Harold Lebovitz, MD, Noel K. Maclaren, MD, Jerry P. Palmer, MD, Philip Raskin, MD, Robert A. Rizza, MD, and Michael P. Stern, MD.

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; FPG, fasting plasma glucose; GCT, glucose challenge test; GDM, gestational diabetes mellitus; HNF, hepatocyte nuclear factor; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; MODY, maturity-onset diabetes of the young; NDDG, National Diabetes Data Group; NHANES III, Third National Health and Nutrition Examination Survey; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; WHO, World Health Organization; 2-h PG, 2-h postload glucose.