Medical Management of Type 2 Diabetes

By American Diabetes Association

Medical Management of Type 2 Diabetes provides health care providers with all of the answers to their questions about implementing scientifically proven clinical care for their patients with type 2 diabetes.

As type 2 diabetes continues its disturbing rise in prevalence worldwide, there is an increasing need to study the disease and describe successful treatment regimens. There are several options for treatment, including oral medications, diet and lifestyle modification, and insulin therapy. Knowing which treatment method to select for a patient and how to apply it relies on several clinical guidelines that are updated every year by the American Diabetes Association.

This new edition features:

• Details on the newest agents for the treatment of type 2 diabetes
• Expanded information on pharmacological intervention
• Updated data on chronic and acute complications
• The latest standards of medical care from the American Diabetes Association

This essential resource will enhance the clinical knowledge of type 2 diabetes and bolster the skills necessary to care for patients with diabetes. p>

• Language: English
• Publisher: American Diabetes Association
• Release date: Mar 29, 2023
• ISBN: 9781580406970

Book preview

Diagnosis and Classification

Highlights

Definition of Diabetes

Diagnosis of Diabetes

Classification of Diabetes

Type 1 Diabetes

Type 2 Diabetes

Gestational Diabetes Mellitus

Other Specific Types of Diabetes

Stage of Disease

Screening for Diabetes

Categories of Increased Risk for Diabetes

Metabolic Syndrome

Evaluation and Classification of Patients Before Treatment

Highlights

Diagnosis and Classification

Diabetes is diagnosed by one of the following, confirmed by repeat testing in the absence of unequivocal hyperglycemia:

Hemoglobin A1c (A1C) ≥6.5% (48 mmol/mol) by laboratory method; point-of-care A1C assays are not sufficiently accurate to use for diagnostic purposes

Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)

2-h plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT)

Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia (polydipsia, polyuria, unintentional weight loss) or hyperglycemic crisis.

The two most common types of diabetes are type 1 diabetes, which has absolute insulin deficiency and propensity to develop ketoacidosis, and type 2 diabetes, which has relative insulin deficiency combined with defects in insulin action. Type 2 diabetes accounts for 90%-95% of the incidence of the disease in Western societies and is most often (but not always) associated with obesity.

Prediabetes describes individuals with plasma glucose or A1C levels higher than normal but lower than those diagnostic of diabetes. Such individuals are at higher risk for both progression to type 2 diabetes and cardiovascular disease. Diagnostic criteria for prediabetes include:

A1C 5.7%-6.4% (39-46 mmol/mol)

FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L), also known as impaired fasting glucose (IFG)

2-h plasma glucose during the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L), also known as impaired glucose tolerance (IGT).

Gestational diabetes mellitus (GDM) is defined as hyperglycemia diagnosed during the second or third trimesters of pregnancy. It affects approximately 6% of all pregnancies in the U.S. As many as 50% of women with GDM later develop type 2 diabetes. If diabetes is diagnosed at the initial prenatal visit within the first trimester, using standard criteria for diabetes, it should be classified as diabetes complicating pregnancy.

Screening for GDM is recommended between the 24th and 28th week of pregnancy for all women who are not known to have diabetes. The two approaches used in the U.S. include the following:

One-step approach with 75-g OGTT with plasma glucose measurement of fasting at 1 h and 2 h. GDM is diagnosed if

FPG ≥92 mg/dL (≥5.1 mmol/L), or

1-h plasma glucose ≥180 mg/dL (≥10.0 mmol/L), or

2-h plasma glucose ≥153 mg/dL (≥8.5 mmol/L).

Two-step approach with a 50-g nonfasting screen, which if abnormal is followed by 100-g OGTT.

All women diagnosed with GDM should be screened at 4-12 weeks postpartum for diabetes or prediabetes using usual nongestational glycemic criteria and rescreened periodically (at least every 3 years) thereafter.

Diagnosis and Classification

Sadia Ali, MD

DEFINITION OF DIABETES

Diabetes is a group of chronic metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. These defects result in abnormalities in carbohydrate, protein, and fat metabolism from deficient action of insulin on target tissues.¹

Chronic, sustained exposure to hyperglycemia is associated with long-term damage, dysfunction, and failure of various organs leading to microvascular complications (e.g., retinopathy, nephropathy, and neuropathy), as well as macrovascular complications (e.g., stroke, myocardial infarction, and peripheral arterial disease).²,³

Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes polyphagia, and blurred vision. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or hyperglycemia hyperosmolar nonketotic syndrome.

Because the syndrome of diabetes encompasses many disorders that differ in pathogenesis, natural history, and responses to treatment, it is important that clinicians and researchers use commonly accepted terminology as well as standardized classification and diagnostic criteria when categorizing patients with glucose intolerance.

Following the findings of the Diabetes Prevention Program, recognition of degrees of carbohydrate intolerance led to the description of categories of increased risk for diabetes as well as cardiovascular disease (prediabetes). The designation encompasses the previously described impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and individuals with A1C of 5.7%-6.4% (39-46 mmol/mol). Identification of such individuals should facilitate efforts to intervene early and reduce the incidence of diabetes and cardiovascular disease.

The Hyperglycemia and Adverse Pregnancy Outcomes Study (HAPO)⁴ demonstrated an increased risk of adverse maternal, fetal, and neonatal outcomes of pregnancy as a function of maternal glycemia at 24-28 weeks’ gestation even within ranges previously considered normal for pregnancy. As a result the American Diabetes Association developed revised criteria for the diagnosis of gestational diabetes mellitus (GDM), which will significantly increase the prevalence of GDM, but with appropriate treatment, should optimize gestational outcomes for women and their babies.

DIAGNOSIS OF DIABETES

According to current American Diabetes Association criteria, diabetes may be diagnosed based on fasting plasma glucose (FPG) ≥126 mg/dL (≥7.0 mmol/L), a 2-h oral glucose tolerance test (OGTT) ≥200 mg/dl (≥11.1 mmol/L), or A1C ≥6.5% (≥48 mmol/mol) (Table Except for patients in hyperglycemic crisis or with classic hyperglycemia symptoms associated with a random plasma glucose ≥200 mg/dL (≥11.1 mmol/L), diagnosis requires a second test for confirmation of diabetes⁵; this could be two different tests from the same sample (i.e., A1C and FPG) or a repeat test on a different day (same or different lab test). In patients where diabetes is diagnosed on the basis of symptoms and a random glucose ≥200 mg/dL, a confirmatory A1C adds additional value in terms of initial treatment options.

When comparing different tests, the A1C has several advantages over OGTT and FPG, including greater convenience as the patient does not need to fast, less day-to-day variation, and greater pre-analytic stability. Relative disadvantages include lower sensitivity of A1C at the designated cut point, greater cost, limited availability of A1C testing in certain regions of the developing world, and the imperfect correlation between A1C and average glucose in certain individuals.⁶ National Health and Nutrition Examination Survey (NHANES) data indicate that an A1C cut point of ≥6.5% (≥48 mmol/mol) identifies a prevalence of undiagnosed diabetes that is one-third of that using glucose criteria.⁷

In addition, A1C may not accurately reflect glycemic exposure in patients with certain hemoglobinopathies, thalassemia syndromes, states of increased red cell turnover—including those related to hemolysis, cytotoxic chemotherapy, erythropoietin therapy, or transfusion—and in patients with iron deficiency. Uremia and hyperbilirubinemia may also interfere with some assays. In such patients, the diagnosis of diabetes must employ other glycemic criteria.

The FPG and the 2-h OGTT are the other two tests that may be used to diagnose diabetes. The FPG and 2-h OGTT tests do not always match in diagnosing diabetes; the same is true of the A1C test and either glucose-based test (FPG or OGTT). Numerous studies have confirmed that compared with FPG and A1C cut points, the 2-h OGTT value is more sensitive and diagnoses more people with diabetes.⁸ Therefore, OGTT could be considered in patients with elevated but nondiagnostic A1C or FPG in whom there is a high index of suspicion for diabetes (e.g., in patients with evidence of cardiovascular disease or microvascular complications). The OGTT is not required for patients with symptoms and concurrent random glucose levels ≥200 mg/dL (≥11.1 mmol/L), A1C ≥6.5% (≥48 mmol/mol), or fasting glucose level ≥126 mg/dL (≥7.0 mmol/L).

CLASSIFICATION OF DIABETES

Having established a diagnosis of diabetes, the next task is to classify the type. The purpose of classification is to differentiate and identify the various forms of the disease, as the treatment approach will vary for different types of diabetes. Of note, a number of individuals do not fit into a single class at time of diagnosis.¹

The first generally accepted classification system was developed by the National Diabetes Data Group (NDDG) and published in 1979.⁹ The World Health Organization (WHO) Study Group on Diabetes Mellitus endorsed the substantive recommendations of the NDDG in 1980 and 1985.¹⁰ These groups recognized two major forms of diabetes, which they termed insulin-dependent diabetes mellitus (IDDM, type I diabetes) and non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes). In 1997, the American Diabetes Association Expert Committee on the Diagnosis and Classification of Diabetes Mellitus recommended modifications to this classification system. The revised classification scheme was designed to reduce some of the confusion created by the previous scheme and to reflect both etiology and stage of disease. The terms insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) and their acronyms were eliminated, as they frequently resulted in classifying patients based on treatment rather than etiology, and substituted with the terms type 1 diabetes and type 2 diabetes, respectively.

Diabetes is now generally classified into the following categories (see Table 1.2):

    1.  Type 1 diabetes (due to destruction of pancreatic β-cells, usually leading to absolute insulin deficiency).

    2.  Type 2 diabetes (due to a combination of loss of β-cell insulin secretion and insulin resistance).

    3.  GDM (diabetes diagnosed in the second and third trimester of pregnancy in a woman without a prior diagnosis of diabetes).

    4.  Other specific types of diabetes from various causes, e.g., monogenic diabetes syndromes (from genetic defects of β cell function and defects in insulin action), diseases of the exocrine pancreas (e.g., cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (from glucocorticoid use, HIV/AIDS treatment, or after organ transplantation).¹

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important in determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 at the time of diagnosis. The traditional paradigms of type 1 occurring only in children and type 2 occurring only in adults are no longer accurate, as both diseases occur in any age group.

TYPE 1 DIABETES

Type 1 diabetes accounts for 5%-10% of all diabetes and results from cell-mediated destruction of pancreatic β-cells, leading to absolute insulin deficiency. These individuals are prone to develop ketoacidosis. This form includes cases resulting from both autoimmune process (type 1A) and those for which an etiology is unknown (type 1B, idiopathic). Autoimmune markers of this process include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD), the tyrosine phosphatases IA-2 and IA-2B, and zinc transporter (ZnT8).¹⁹ One or more autoantibodies is present in ≤90% of individuals with type 1 immune-mediated diabetes at diagnosis. Patients with type 1 immune-mediated diabetes are prone to other autoimmune disorders, including autoimmune thyroid disease, celiac disease, Addison disease, autoimmune gastritis, and vitiligo. In these patients, the prevalence of positive antithyroid antibodies can be ≤20%, hypothyroidism 2%-5%, and hyperthyroidism <1%.²⁰-²⁷ For other autoimmune disorders, the prevalence of positive anti-endomysial or tissue transglutaminase is ≤10%, biopsy proven celiac disease 5%,²⁸-³¹ autoimmune gastritis 5%-10%, pernicious anemia 2%-4%,³²-³⁴ Addison disease <1%, and positive 21-hydroxylase antibodies ≤2%.³⁵

In addition, this type of diabetes has strong HLA associations, which can be either predisposing (DR3/DR4) or protective.¹ Type 1A (autoimmune) diabetes is currently classified into three stages that reflect the onset of autoimmunity, the development of dysglycemia (IGT or IFG), and eventually the progression to symptomatic hyperglycemia (see Table 1.3).³⁶,³⁷

Immune-mediated type 1 diabetes commonly occurs in childhood and adolescence but can occur at any age. The rate of β-cell destruction is quite variable. In general, it is more rapid in children and slower in adults. This may explain why children present with ketoacidosis as the first manifestation of disease, and adults may retain sufficient β-cell function to prevent ketoacidosis for many years. Although patients are often not obese when they present with type 1 diabetes, the presence of obesity is not incompatible with the diagnosis, especially given the increased prevalence of obesity in the general population. In the late stages of type 1 immune-mediated diabetes, there is little or no insulin secretion as manifested by low or undetectable levels of plasma C-peptide in the setting of hyperglycemia.

Patients that present with ketoacidosis and have no evidence of autoimmunity and no clear etiology are classified as having idiopathic type 1 diabetes; other terms include type 1B or 1.5 diabetes, atypical diabetes, Flatbush diabetes, or ketosis-prone type 2 diabetes. These patients are insulinopenic and are prone to episodic ketoacidosis. This form of diabetes is thought to account for 25%-50% of new diabetic ketoacidosis presentations in African American and Hispanic individuals and has also been described in Asian populations.³⁸ While it is not HLA associated, the majority of patients have a family history of type 2 diabetes and are overweight or obese. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. An absolute requirement for insulin replacement therapy in affected patients may come and go. Fasting C-peptide levels >0.33 nmol/L collected 1 week after resolution of ketoacidosis or >0.5 nmol/L at 6-8 weeks following the acute event are predictive of remission to near-normal glycemia.³⁸

TYPE 2 DIABETES

Type 2 diabetes accounts for 90%-95% of all diabetes diagnosed in adults and is characterized by both impairment of insulin secretion and defects in insulin action. Although patients with this type of diabetes may have insulin levels that appear normal or elevated, insulin levels are low relative to the ambient hyperglycemia. Thus, insulin secretion is defective in these patients and insufficient to compensate for the degree of insulin resistance. Although the specific etiology of type 2 diabetes is unknown, autoimmune destruction of β-cells does not occur. Type 2 diabetes is often associated with a strong genetic predisposition; however, the genetics of this form of diabetes are complex and not clearly defined.

The risk of type 2 diabetes increases with age, obesity, and physical inactivity. Although type 1 diabetes remains the most common type of diabetes in children and adolescents, type 2 diabetes now accounts for one-quarter to one-third of diabetes in adolescents, particularly in racial and ethnic minority populations. Patients with type 2 diabetes who are not obese by traditional weight criteria (e.g., Asian populations) may have an increased percentage of body fat distributed predominantly in the intra-abdominal region.³⁹,⁴⁰ Type 2 diabetes occurs more frequently in women with prior gestational diabetes and in individuals with hypertension and dyslipidemia. Its frequency varies in different racial and ethnic groups. Diabetic ketoacidosis seldom occurs spontaneously in type 2 diabetes, but it can be seen in association with the stress of another illness such as infection or use of certain other drugs (e.g., corticosteroids, atypical antipsychotics, and sodium-glucose transporter 2 inhibitors).⁴¹,⁴²

GESTATIONAL DIABETES MELLITUS

GDM is defined as diabetes diagnosed in the second or third trimester of pregnancy that was not present prior to pregnancy;¹ in the past, GDM had been defined as glucose intolerance that was first recognized during pregnancy,⁴³ regardless of whether the condition may have predated pregnancy. Approximately 6% of pregnant women in the U.S. have GDM,⁴⁴ while global estimates of GDM vary from 10% to 25% depending on different regions, populations, and methods of diagnosis.⁴⁵

GDM carries risks for mother and neonate. Both the size of the baby and need for a first cesarean delivery are related to the degree of maternal hyperglycemia. The HAPO study⁴ demonstrated that the risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24-28 weeks of gestation, even within ranges previously defined as normal. These results emphasize the importance of recognition and treatment of GDM, with a focus on glycemic control as it reduces the risk of adverse outcomes in the mother and the fetus.

Screening for diabetes is recommended for all pregnant women, starting at the first prenatal visit. Women at high risk of diabetes should be screened immediately, using standard diagnostic criteria including A1C, fasting, or post-glucose-load glucose level. Diabetes diagnosed at this stage is considered to have preceded pregnancy. Women not found to have overt diabetes at that first prenatal visit should undergo further testing to rule out GDM at 24-28 weeks’ gestation. Currently there are two approaches to diagnose GDM in the U.S. (Table 1.4):¹ one-step 75-g OGTT or two-step approach with a 50-g (nonfasting) screen followed by a 100-g OGTT for those who screen positive.

Approximately 5%-10% of women with GDM are diagnosed with type 2 diabetes in the postpartum period, and ≤50%-70% develop type 2 diabetes within 15-25 years.⁴⁸ Because of this increased risk, women with GDM should be retested for diabetes or prediabetes 4-12 weeks postpartum and every 1-3 years thereafter.¹ A 2-h 75-g OGTT is recommended postpartum because A1C levels may still be impacted by increased red blood cell turnover or delivery-related blood loss; the results are interpreted using nonpregnancy criteria.⁴⁹ Thereafter, an A1C, FPG, or 2-h OGTT can be used for screening purposes. Women with a history of GDM found to have prediabetes should receive education about intensive lifestyle interventions or metformin to prevent diabetes.¹

OTHER SPECIFIC TYPES OF DIABETES

In the current classification scheme, the class of other specific types of diabetes includes the following categories: 1) genetic defects of β-cell function; 2) genetic defects in insulin action; 3) diseases of the exocrine pancreas; 4) endocrinopathies; 5) drug- or chemical-induced diabetes; 6) infections; 7) uncommon forms of immune-mediated diabetes; and 8) other genetic syndromes sometimes associated with diabetes. These categories may represent <5% of all people with diabetes. Nevertheless, correct identification of these patients is important because their treatment and prognosis may differ. Recognition of patients with other specific types of diabetes requires clinical alertness to identify the history or physical features that lead to the correct diagnosis.

Monogenic Diabetes Syndromes

A small number of cases of diabetes (<5%) result from monogenic defects in β-cell function. About 80%-85% cases of neonatal or congenital diabetes, which is diagnosed <6 months of age, is monogenic in cause.⁵⁰ Maturity-Onset Diabetes of the Young (MODY) is monogenic diabetes that presents with hyperglycemia at a younger age (generally <25 years, although diagnosis may occur at older age). MODY is inherited in an autosomal dominant pattern and is characterized by impaired insulin secretion with minimal or no defects in insulin action.¹ Abnormalities in ≥13 genes on different chromosomes have been identified to date, the most common of which are GCK (glucokinase gene)-MODY (MODY 2), HNF1A (hepatic nuclear factor)-MODY (MODY 3), and HNF4A-MODY (MODY 1). Rare forms of MODY include defects in PDX1(IPF1) and NEUROD1.¹ A diagnosis of MODY should be suspected in younger and thinner patients diagnosed with diabetes who also have multiple family members affected by the disease. Correctly diagnosing MODY can result in simplification of treatment approaches and in identification of other affected family members.⁵¹ For example, no treatment is usually indicated for GCK-MODY, while HNF1A- and HNF4A-MODY often respond to sulfonylurea therapy.¹ These individuals should be referred for consultation to a center specializing in diabetes genetics for further evaluation, treatment, and genetic counseling.

Diseases of the Exocrine Pancreas

Any process that causes diffuse and extensive injury of pancreatic tissue can cause diabetes. Diabetes in the context of disease of the exocrine pancreas has been termed pancreoprivic diabetes.¹ Acquired causes include pancreatitis, infection, trauma, pancreatectomy, and pancreatic carcinoma. Pancreatic carcinoma at earlier stages can also cause diabetes from a mechanism different from β-cell destruction. In earlier stages of pancreatic cancer, new onset diabetes can occur from increased insulin resistance. Extensive cystic fibrosis and hemochromatosis can also cause β-cell damage and impaired insulin secretion.

Cystic Fibrosis-Related Diabetes

Diabetes is a common complication seen in patients with cystic fibrosis, mainly due to β-cell deficiency (due to destruction of pancreatic islets) and exacerbated by the insulin resistance associated with infection and inflammation common in cystic fibrosis.⁵² Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in people with cystic fibrosis, with a prevalence of ∼20% in adolescents and 40%-50% in adults.⁵³ OGTT is the recommended screening test; however, some recent publications suggest using an A1C cut point <5.4% (<5.8% in second study) would detect >90% of cases and reduce patient screening burden.¹,⁵⁴,⁵⁵ Screening for diabetes <10 years old can identify the risk for progression to CFRD in those with abnormal glucose tolerance.¹ Annual screening for CFRD with OGTT is recommended to start at age 10 years in all patients with cystic fibrosis not previously diagnosed with CFRD.¹ CFRD is associated with a decline in pulmonary function, poor nutritional status, and an increase in mortality.⁵⁶,⁵⁷ Insulin is the recommended therapy for treatment of hyperglycemia in patients with CFRD.⁵⁸

Endocrinopathies

Several hormones, including growth hormone, cortisol, glucagon, and epinephrine, can impair insulin action. Endocrinopathies, which lead to excessive production of these hormones (e.g., acromegaly, Cushing syndrome, glucagonoma, and pheochromocytoma), can cause diabetes. Somatostatinoma and primary hyperaldosteronism can also cause diabetes by the hypokalemia-induced inhibition of insulin secretion. Hyperglycemia is generally resolved when hormone excess is corrected.¹

Drug- or Chemical-Induced Diabetes

Many drugs can impair insulin secretion and can lead to diabetes in individuals with underlying insulin resistance. One of the newer categories recently added includes immune checkpoint inhibitors used for cancer treatment.⁵⁹ This is a relatively new cancer treatment modality and is becoming more widely utilized as new U.S. Food and Drug Administration approval for drugs and cancer treatment indications are added. The mechanism of diabetes with these drugs is autoimmune mediated, and insulin and islet cell antibodies have been identified in individuals with new onset diabetes on immune checkpoint inhibitors. Corticosteroids are known to increase insulin resistance and can uncover underlying β-cell insufficiency or cause stress-related hyperglycemia at high doses. Atypical antipsychotics can be associated with weight gain, insulin resistance, and hyperglycemia, at times presenting as diabetic ketoacidosis.⁶⁰ Protease inhibitors used for HIV/AIDS can also be associated with hyperglycemia and diabetes.

Infections

Certain viral infections have been associated with β-cell destruction leading to certain cases of diabetes. These include rubella, coxsackie virus B, cytomegalovirus, adenovirus, and mumps.

Posttransplantation Diabetes

Patients after transplant are at an increased risk for developing diabetes.⁶¹,⁶² Hyperglycemia is common in the few weeks following transplant, but in most cases stress or steroid-induced hyperglycemia resolves.⁶³ Patients should be screened for diabetes following organ transplantation once the patient is stable on maintenance immunosuppressive therapy.¹ While the 2-h OGTT is the gold standard to screen for diabetes following transplant, an FPG or A1C test can identify high-risk patients requiring further assessment. Several terms have been used in literature to describe post-organ transplantation diabetes, including new onset diabetes after transplantation (NODAT).¹ Currently, the term posttransplantation diabetes mellitus (PTDM) is favored⁶⁴ as it describes all diabetes diagnosed after a transplant irrespective of the time of onset of hyperglycemia (i.e., some people may have had undiagnosed diabetes prior to their transplant). Diagnosis of diabetes is made using the same diagnostic criteria as for nontransplant patients.

Risk factors for PTDM include both the traditional risk factors for diabetes (e.g., age, family history of diabetes, ethnicity, obesity) as well as transplant-specific factors, such as use of immunosuppressive agents like glucocorticoids and calcineurin inhibitors.⁶⁵

Insulin is the agent of choice for glycemic management in the inpatient setting. In the outpatient setting, the choice of glycemic agent can be assessed based on patient condition, side effect profile of medication, and possible interaction with immunosuppressive regimen, with particular attention given to changes in glomerular filtration rate commonly seen in transplant patients.⁶⁵ Metformin was reported to be safe for use in renal transplant recipients in a small short-term pilot study, but its safety has not been studied in other types of organ transplant.⁶⁶ Thiazolidinediones have been successfully used in people with liver and kidney transplants; however, they have been associated with side effects, including fluid retention, heart failure, and osteopenia.⁶⁷,⁶⁸ Dipeptidyl peptidase-4 inhibitors have demonstrated safety in small clinical trials for transplant patients.⁶⁹,⁷⁰

STAGE OF DISEASE

In addition to reflecting etiology, the American Diabetes Association classification system attempts to describe the stage of disease in relationship to glycemic exposure.¹ A disease process may be present but may not have progressed enough to cause hyperglycemia. For example, in type 2 diabetes, there may be insulin resistance with a compensatory increase in endogenous insulin secretion and maintenance of normoglycemia. Progressive β-cell dysfunction will lead to impaired fasting glucose or impaired glucose tolerance (prediabetes), which could progress to hyperglycemia diagnostic of diabetes. For type 1 diabetes, the early stages of the disease are characterized by the presence of autoimmune antibodies in the setting of normal glucose tolerance, which might progress to the loss of first-phase insulin release and presymptomatic impaired glucose tolerance and eventually frank symptomatic hyperglycemia (see Table 1.3).³⁶ The degree of residual β-cell function determines the need for exogenous insulin replacement. For type 2 diabetes or GDM, this may range from no need for insulin to insulin required for adequate glycemic control; for type 1 diabetes, most patients require insulin for survival.¹ The severity of the metabolic abnormality can progress or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying disease process more than the nature of the process itself. Thus, classification of type of diabetes can be made independent of stage.

SCREENING FOR DIABETES

Approximately one-quarter of Americans with diabetes and nearly half of Hispanic, Black non-Hispanic, and Asian non-Hispanic people with diabetes remain undiagnosed.⁷¹ Screening for diabetes has been recommended to identify individuals with previously undiagnosed diabetes so that they may receive appropriate medical care. Support for diabetes screening is not based on randomized, controlled clinical trials, but on observational studies that have found that people diagnosed with diabetes as a result of screening have lower A1C levels and better outcomes than those presenting spontaneously with diabetes. Most organizations, including the American Diabetes Association, recommend that at-risk individuals be screened periodically for diabetes as a part of their routine medical care (opportunistic screening).⁷² Few, if any, organizations recommend population screening.

Some additional factors to consider regarding testing for type 2 diabetes and prediabetes in asymptomatic individuals include age, BMI, ethnicity, and medications. Age is a major risk factor for diabetes. BMI ≥25 kg/m² is also a risk factor for diabetes; however, data suggest that the BMI cut-point should be lower for the Asian American population.⁷³,⁷⁴ WHO data also suggest using a BMI cut-off ≥23 kg/m² to define increased risk in Asian Americans.⁷⁵ Evidence suggests that other populations may also benefit from lower BMI cut-points. A large multiethnic cohort study showed that a BMI of 30 kg/m² in non-Hispanic whites was equivalent to a BMI of 26 kg/m² in African Americans, for an equivalent incidence rate of diabetes.⁷⁶

Criteria for testing for type 2 diabetes and prediabetes in asymptomatic adults are as follows:¹

Testing should be considered in individuals who are overweight or obese (BMI ≥25 kg/m² or ≥23 kg/m² in Asian Americans) and who have one or more of the following risk factors:

First-degree relative with diabetes

High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)

History of cardiovascular disease

Hypertension (≥140/90 mmHg or on therapy for hypertension)

HDL cholesterol level <35 mg/dL (<0.90 mmol/L) and/or a triglyceride

LDL cholesterol level >250 mg/dL (>2.82 mmol/L)

Women with polycystic ovary syndrome

History of physical inactivity

Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)

Patients with prediabetes (A1C ≥5.7% [≥39 mmol/mol], IFG, or IGT) should be tested yearly.

Women who were diagnosed with GDM should have lifelong testing ≤3-year intervals. For all other patients, testing for diabetes should begin at age 45 years.

If the results are normal, testing should be repeated at ≤3-year intervals, with consideration of more frequent testing depending on initial results and risk status.

The incidence of type 2 diabetes in children and adolescents has increased dramatically in the last decade, especially in minority populations.⁷⁷ Children and youth at increased risk for the presence or the development of type 2 diabetes should be tested within the healthcare setting, and testing should be repeated every 3 years. Beginning at age 10 years or at the onset of puberty (if puberty occurs at a younger age), children who are at risk based on the following criteria should be tested for diabetes.

Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical setting:¹

Testing should be considered in youth who are overweight (≥85th percentile) or obese (>95th percentile) and who have one or more additional risk factors based on strength of their association with diabetes:

Maternal history of diabetes or GDM during the child's gestation.

Family history of type 2 diabetes in first- or second-degree relative.

High-risk race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander).

Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome, or small-for-gestational-age birth weight).

CATEGORIES OF INCREASED RISK FOR DIABETES

Prediabetes includes a category of individuals who are at an increased risk for developing diabetes and have glucose levels higher than normal but lower than those diagnostic of diabetes⁷⁸ (Table 1.5). This category includes individuals with IGT and /or IFG and/or A1C 5.7%-6.4 %. IGT is diagnosed by the 2-h 75-g OGTT, where FPG is <126 mg/dL (<7.0 mmol/L) and 2-h glucose is between 140 and 199 mg/dL (97.8-11.0 mmol/L).⁴³ IFG is defined by fasting blood glucose between 100 mg/dL and 125 mg/dL (5.6-6.9 mmol/L).¹

Prediabetes is associated with an increased risk for diabetes and cardiovascular disease.¹,⁷⁹-⁸¹ In general, the incidence of type 2 diabetes in individuals with IGT is 5% per year, with a range from 4% to 9% per year. Risk factors for progression to diabetes include higher 2-h post-glucose load glucose levels or A1C levels and Hispanic or Native American ethnicity. For example, a systematic review showed that individuals with A1C between 5.5% and 6.0% had an increased 5-year incidence of diabetes of 9%-25%, while for those with A1C 6.0%-6.5%, the 5-year risk of progression was between 25% and 50%.⁸² For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.

Individuals with IGT have a risk of cardiovascular disease and cardiovascular mortality approximately twofold higher than individuals with normal glucose tolerance and similar to individuals with type 2 diabetes. Hence, it is important to consider testing for prediabetes in high-risk individuals. Once identified, interventions should be considered, including lifestyle modifications and metformin use for select patients, and if appropriate treat other cardiovascular risk factors.

IFG is defined as FPG between 100 mg/dL and 125 mg/dL (5.6-6.9 mmol/L) and IGT with 2-h 75-g OGTT as blood glucose between 140 mg/dL and 199 mg/dL (7.8-11.0 mmol/L).¹,⁴³,⁷⁸ It is important to note that WHO and some other diabetes organizations use the cutoff at 110 mg/dL (6.1 mmol/L) to define IFG. Some data in literature support that subjects diagnosed with IFG are different from subjects with IGT and, in general, are at lower risk for both diabetes and cardiovascular disease.⁸³

METABOLIC SYNDROME

Glucose intolerance and type 2 diabetes may also be manifestations of an underlying disorder known as the metabolic syndrome. Individuals with the metabolic syndrome are at risk for type 2 diabetes and cardiovascular disease.⁸⁴-⁸⁶ There is no uniform definition of the metabolic syndrome, but there are similarities between the criteria proposed by the U.S. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III])⁸⁷,⁸⁸ and the WHO (Table 1.6). Data from the NHANES III, which used the ATP III criteria, found that the prevalence of the metabolic syndrome in the U.S. was ∼20%-25%.⁸⁹ The prevalence of the metabolic syndrome increases with age and is highest in Hispanic populations, affecting ≤50% of adults.⁹⁰

Controversy surrounding the metabolic syndrome has not disputed the clustering of cardiovascular risk factors, including central obesity, dyslipidemia, and hypertension, or the association of the metabolic syndrome with the risk of diabetes and cardiovascular disease. Instead, the controversy has focused on the etiology of the syndrome, how best to define it, how clinical decision making should be modified based on those definitions, and whether there are more effective ways to screen for the risk of diabetes and cardiovascular risk.

EVALUATION AND CLASSIFICATION OF PATIENTS BEFORE TREATMENT

Before therapy is initiated for diabetes, the patient should have a complete medical evaluation (see Chapter 3). The complete medical evaluation helps the physician classify the patient, detect the presence of complications and comorbidities associated with diabetes (see Chapter 5), and provide the basis for formulating a management plan. Table 3.1 (page 55) provides an outline for the initial medical evaluation.

A thorough history, physical exam, complete personal and family history, and the diagnostic test results can often lead to an initial classification of diabetes. Patients should not be classified on the basis of age alone or on whether or not they are taking insulin. If the diagnosis of diabetes had been made previously, an initial evaluation should also review the previous treatment and the past and present degrees of glycemic control. Laboratory tests appropriate to the evaluation of each patient's general medical condition should be performed.

It is sometimes difficult to assign the patient to a particular type of diabetes (i.e., type 1 or type 2) despite an initial work-up. For example, the normal-weight patient with type 2 diabetes who has been taking insulin may appear to have type 1 diabetes. Some patients with type 2 diabetes require insulin for glycemic control but do not depend on