Diagnosis of Diabetes and the Metabolic Syndrome

Introduction

A diagnosis of diabetes can be suspected in the presence of the following signs and symptoms of hyperglycemia:

• Polydipsia (increased thirst)
• Polyuria (increased urinary frequency with increased volume)
• Fatigue
• Polyphagia (increased appetite), a rare but commonly mentioned symptom
• Weight loss
• Abnormal healing
• Blurred vision
• Increased occurrence of infections, particularly those caused by yeast.

Only a minority of adults who are diagnosed with type 2 diabetes (T2D) are symptomatic initially. Consequently, the onset of T2D may occur years before a diagnosis is made. Individuals who are asymptomatic tend to be diagnosed during a routine physical examination, during treatment for another condition, or through specific diabetes screening. The risk of diabetes is increased in asymptomatic individuals if any of the following risk factors are present:

• A strong family history of diabetes (first- and second-degree relatives)
• Obesity (body mass index [BMI] ≥25 kg/m²), particularly central adiposity
• Certain ethnic groups (American Indian, Hispanic, African American, Asian American, or Pacific Islander ancestry)
• Women with previous gestational diabetes mellitus (GDM) or a history of newborns ≥9 pounds at birth
• Previously identified impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)
• High-density lipoprotein (HDL) cholesterol ≤35 mg/dL and/or triglycerides ≥250 mg/dL
• Hypertension (blood pressure ≥140/90 mm Hg) or on hypertension therapy
• Polycystic ovary syndrome
• History of vascular disease
• Physically inactive
• Age ≥45 years
• Glycosylated hemoglobin (A1C) ≥5.7%
• Any other conditions associated with insulin resistance.

Diabetes is diagnosed and confirmed using either plasma glucose (PG) or glycosylated hemoglobin (A1C) criteria. Prediabetes can also be detected using these criteria. Normal A1C and plasma glucose values are presented in Table 4-1, and the ADA criteria for diagnosing diabetes and detecting prediabetes in nonpregnant adults are shown in Table 4-2.

Four approaches to glucose testing can be used to diagnose diabetes:

• Fasting plasma glucose (FPG) measurements
• 2-hour plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT)
• A1C assay certified by the National Glycohemo­globin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay
• Random plasma glucose measurements in patients with symptoms of hyperglycemia or hypoglycemia.

A1C measurement is often the preferred method of diagnosis because of convenience and greater reproducibility. Compared with the FPG cut point of ≥126 mg/dL, the A1C cut point of ≥6.5% identifies fewer cases of undiagnosed diabetes. However, the relative convenience of the A1C test may offset the lower sensitivity of the test. Additional factors can complicate the use of A1C as a diagnostic tool. These factors include age, race/ethnicity and hemoglobinopathies/anemias. Since A1C is an indirect measure of average blood glucose levels, discordance between A1C and PG levels should raise the possibility of A1C assay interference and use of a different assay without interference should be considered. However, the A1C can vary by as much as 0.8% within the same blood sample. Nevertheless, the A1C-Derived Average Glucose (ADAG) study demonstrated that A1C levels can serve as a useful proxy for estimated average glucose levels in most patients with T1D and T2D, and be expressed in the same units as used in day-to-day glucose monitoring. In the future, the FDA may acknowledge the 90 day GMI (glucose management indicator)-derived or -estimated A1C from a continuous glucose monitoring (CGM) data download as the most accurate measurement over laboratory A1C.

The studies establishing A1C as a diagnostic tool were performed using adult populations, so it is currently unclear if the same A1C diagnostic criteria can be used to diagnose diabetes in children and adolescents. In conditions where there is increased red blood cell turnover (such as during pregnancy), blood glucose criteria should be used instead of A1C during diagnosis.

Regardless of the test used, unless there is a clear clinical diagnosis the test should be repeated for confirmation. It is recommended the same test is used for confirmation and that diagnosis be made on the basis of the confirmed test. In cases where the second test is negative, patients should be followed closely and an additional test should be repeated in 3 to 6 months.

Pregnant women with risk factors should undergo risk assessment for GDM at the first prenatal visit. Women at low risk for developing glucose intolerance during pregnancy need not be tested for GDM. Women at high risk (marked obesity, previous history of GDM, glycosuria, high-risk racial/ethnic groups, or strong family history of diabetes) should undergo glucose testing as soon as possible. Testing involves either a one- or two-step test, with data supporting both testing strategies. The one-step test employs a fasting 75-g OGTT. The clinical usefulness of CGM for diagnosis and treatment in GDM cannot be overstated.

Fasting, 1- and 2-hour plasma glucose concentrations of ≥92 mg/dL, ≥180 mg/dL and ≥153 mg/dL are considered positive readings, respectively. A diagnosis of GDM is made if any of these values are met. The two-step test first employs a nonfasting 50-g OGTT. If the PG level 1-hour after the 50-g load is ≥140 mg/dL, then it is followed by a fasting 100-g OGTT. Diagnosis of GDM is made if two or more of the fasting, 1-, 2- or 3-hour PG levels meet or exceed 95 mg/dL, 180 mg/dL, 155 mg/dL, or 140 mg/dL, respectively.

A complete medical evaluation is indicated following a positive diagnostic blood test for diabetes. Patients should not be diagnosed on the basis of age alone. The purpose of this evaluation is to:

• Appropriately classify the patient
• Detect any underlying diseases that may require further evaluation
• Determine whether any of the complications of diabetes are present.

The proper management of diabetes is important for the health of the patient. In addition to laboratory tests, management plans should take into account other components of a comprehensive diabetes evaluation, as shown in Figure 4-1. Treatment should be provided by a collaborative team with expertise in diabetes, possibly consisting of a physician, physician’s assistants, dietitians, nurses, nurse practitioners, mental health professionals and pharmacists.

A management plan for the patient should be created taking into consideration input from the healthcare team and information obtained from the family and patient. Figure 4-1 shows a Diabetes Warranty Program developed as a reference for patients, outlining evaluations at every visit and annually. The patient should also be encouraged to take an active role in their management plan; getting patients involved in their own care is an important tool for improving compliance and motivation.

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Diabetes and Cardiovascular Disease Risk Assessment

Diabetes is now recognized as a cardiovascular (CV) disease equivalent. That is, an individual with diabetes but without evidence of overt heart disease has the same risk of an MI as a nondiabetic individual who has had a previous CV event. Diabetes is an independent risk factor for CV disease in both men and women. Women lose the protective effect against CV disease when they develop diabetes. Of every three people with diabetes, two die of CV disease. Once a person with diabetes develops clinical evidence of CV disease, their likelihood of survival is worse than that of nondiabetics with CV disease.

Most patients with T2D have tissue resistance to insulin. The presence of insulin resistance is associated with and predisposes to both CV disease and T2D. Like T2D, insulin resistance is influenced by genetic susceptibility, obesity, physical inactivity and advancing age. Patients with insulin resistance tend to develop the metabolic or dysmetabolic syndrome. This is associated with:

• Abdominal obesity
• Dyslipidemia
• Hypertension
• Glucose intolerance
• A procoagulant state
• Evidence of vascular inflammation.

The 2018 Guidelines on the Management of Blood Cholesterol (published by 12 professional societies, including the ADA and the American Heart Association) consider T2D a high-risk factor for CV disease. The guidelines recommend a statin-based lipid-lowering strategy for all patients aged 40-75 with T2D, regardless of CV risk. The primary target of therapy and a major cause of coronary heart disease (CHD) is elevated low-density lipoprotein (LDL) cholesterol. A high-intensity statin therapy to lower LDL cholesterol by 50% or more is reasonable for patients with T2D and multiple risk factors or those 50-76 years of age. Numerous clinical trials clearly demonstrate that lowering LDL cholesterol reduces risk for CHD, including in individuals with T2D According to the 2018 Guidelines, independent diabetes-specific CV risk enhancers include:

• Duration ≥10 years for T2D and ≥20 years for T1D
• Albuminuria ≥30 mcg of albumin/mg creatinine
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²
• Retinopathy
• Neuropathy
• Ankle-brachial index (ABI) <0.9

The American Diabetes Association (ADA) lists the following as CV risk factors:

• High LDL cholesterol (≥100 mg/dL)
• Elevated triglycerides (≥150 mg/dL)
• Cigarette smoking
• Hypertension >120/80 mm Hg (patients should be advised of lifestyle changes)
• Hypertension >140/90 mm Hg (in addition to lifestyle changes patients should undergo prompt pharmacologic therapy)
• Low HDL cholesterol (men: <40 mg/dL; women: <50 mg/dL)
• Family history of premature heart disease
• Advancing age (≥40 years of age)
• The presence of albuminuria.

Diabetes is considered a CHD risk equivalent and therefore a major risk factor. An HDL cholesterol level ≥60 mg/dL represents a negative risk factor and negates one positive risk factor from the total count.

The 2018 Guidelines of the Management of Blood Cholesterol recommend an LDL cholesterol reduction of 30-49% in all patients with T2D, and consider a target reduction of 50% or more in patients with additional risk factors to be reasonable. The ADA has established similar guidelines, including recommended lifestyle modifications to improve the lipid profile of patients. Changes focus on reducing intake of certain lipids (saturated fat and cholesterol), avoiding trans fats, weight reduction (if indicated), and increased physical activity.

The Metabolic or Dysmetabolic Syndrome

The constellation of abnormalities that constitute the metabolic syndrome enhance the risk for CHD at any given LDL level. By the National Cholesterol Education Program (NCEP) criteria, the diagnosis of the metabolic syndrome requires three or more of the risk determinants shown in Table 4-3. Most individuals with T2D have multiple risk determinants of the metabolic syndrome. First-line therapy for all components of the metabolic syndrome involves weight reduction/control and increased physical activity. Other components of the syndrome (high triglyceride levels, low HDL cholesterol levels, dyslipidemia, glucose intolerance, a procoagulant state and hypertension) may require specific pharmacologic management to achieve adequate control. The ADA Standards of Medical Care recognize metabolic syndrome as a target of risk-reduction therapy in patients with moderate hypertriglyceridemia.

In 2005, the International Diabetes Federation (IDF) published their own definition of metabolic syndrome, which remains current to date (Table 4-3). Since abdominal obesity is highly correlated with insulin resistance, it is one of their requirement for diagnosis. Additionally, the IDF recognize the impact of ethnicity on the relationship between abdominal obesity and metabolic syndrome. For this reason, the criteria for abdominal obesity differ by nationality or ethnicity. When an individual meets this criteria, two additional factors are required for the diagnosis of metabolic syndrome. The other factors are identical to the NCEP definition.

The IDF recommend the following for the treatment of the individual components of metabolic syndrome:

• Elevated blood pressure: an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB) as initial therapy or hypertension and/or microalbuminuria
• Insulin resistance and hyperglycemia: metformin has been shown to delay the development of diabetes, thiazolidinedione can delay or prevent T2D in individuals with IGT and insulin resistance, and acarbose and orlistat can delay the development of T2D in people with IGT
• Atherogenic dyslipidemia: treatment options include fibrates, statins, ezetimibe, PCSK9 antagonists and bempedoic acid. Fibrates improve all components of atherogenic dyslipidemia, and reduce the risk of CVD, whereas statins reduce all ApoB-containing lipoproteins. Combinational therapy using both fibrates and statins may be complicated by side effects, and is generally recommended with caution. Ezetimibe (an inhibitor of cholesterol uptake from the small intestine), PCSK9 inhibitors (which promote the clearance of LDL particles from the blood by increasing expression of LDL receptors on the cell surface), and bempedoic acid (an inhibitor of cholesterol biosynthesis) are comparatively novel agents with proven efficacy in LDL cholesterol level reduction when used in combination with a maximally-tolerated statin. For patients with homozygous familiar hypercholesterolemia, the ANGPTL3 (angiopoietin-like 3) inhibitor evinacumab is another novel option for lowering LDL cholesterol levels.

The Centers for Disease Control (CDC) recognize metabolic syndrome with the ICD-10-CM diagnosis code of E88.81. The CDC and the American Heart Association use the same criteria as NCEP.

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