Diabetes Mellitus, Type 2 - A Review

Technorati Tags: diabetes,type 2 DM,insulin,sulfonilurea,metabolic syndrome

Scott R Votey, MD, Assistant Dean for Graduate Medical Education, Professor of Medicine/Emergency Medicine, David Geffen School of Medicine at UCLA, UCLA Medical Center
Anne L Peters, MD, CDE, Director of Clinical Diabetes Programs, Professor, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, Los Angeles County/University of Southern California Medical Center

Introduction

Background

Diabetes mellitus is a chronic disease that requires long-term medical attention both to limit the development of its devastating complications and to manage them when they do occur. It is a disproportionately expensive disease; in 2002, the per-capita cost of healthcare was $13,243 for people with diabetes, while it was $2560 for those without diabetes.

This article focuses on the ED evaluation and treatment of the acute and chronic complications of diabetes other than those directly associated with hypoglycemia and severe metabolic disturbances such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). (Please see Hypoglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Nonketotic Coma for more information on these disorders.)

Pathophysiology

The 2 basic types of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is reviewed more fully in a separate eMedicine article (see Diabetes Mellitus, Type 1 - A Review).

Type 2 diabetes mellitus was once called adult-onset diabetes. Now, because of the epidemic of obesity and inactivity in children, type 2 diabetes mellitus is occurring at younger and younger ages. Although type 2 diabetes mellitus typically affects individuals older than 40 years, it has been diagnosed in children as young as 2 years of age who have a family history of diabetes.

Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. For type 2 diabetes mellitus to develop, both defects must exist: all overweight individuals have insulin resistance, but only those with an inability to increase beta-cell production of insulin develop diabetes. In the progression from normal glucose tolerance to abnormal glucose tolerance, postprandial glucose levels first increase. Eventually, fasting hyperglycemia develops as inhibition of hepatic gluconeogenesis declines.

About 90% of patients who develop type 2 diabetes mellitus are obese. Because patients with type 2 diabetes mellitus retain the ability to secrete some endogenous insulin, those who are taking insulin generally do not develop DKA if it is stopped. Therefore, they are considered to require insulin but not to depend on insulin. Moreover, patients with type 2 diabetes mellitus often do not need treatment with oral antidiabetic medication or insulin if they lose weight or stop eating.

Maturity-onset diabetes of the young (MODY) is a form of type 2 diabetes mellitus that affects many generations in the same family with an onset in individuals younger than 25 years. Several types exist. Some of the genes responsible can be detected by using commercially available assays.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. GDM is a complication in approximately 4% of all pregnancies in the United States, though the rates may be 1-14% depending on the population studied. Untreated GDM can lead to fetal macrosomia, hypoglycemia, hypocalcemia, and hyperbilirubinemia. In addition, mothers with GDM have increased rates of cesarean delivery and chronic hypertension. To screen for GDM, a 50-g glucose screening test should be done at 24-28 weeks of gestation. This is followed by a 100-g, 3-hour oral glucose tolerance test if the patient's plasma glucose concentration at 1 hour after screening is greater than 140 mg/dL.

Frequency

United States

In 2005, people with diabetes were estimated to account for 7% of the US population, or approximately 20.8 million people. Of these 20.8 million people, 14.6 million have a diagnosis of diabetes, and diabetes is undiagnosed in another 6.2 million. Approximately 10% have type 1 diabetes, and the rest have type 2. Additionally, an estimated 54 million people have pre-diabetes. Pre-diabetes, as defined by the American Diabetes Association, is that state in which blood glucose levels are higher than normal but not high enough to be diagnosed as diabetes.

Mortality/Morbidity

The morbidity and mortality associated with diabetes are related to the short- and long-term complications. Complications include the following:

• Hypoglycemia and hyperglycemia
• Increased risk of infections
• Microvascular complications (eg, retinopathy, nephropathy)
• Neuropathic complications
• Macrovascular disease (eg, coronary artery disease, stroke)

Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and end-stage renal disease (ESRD).

Race

Type 2 diabetes mellitus is more prevalent among Hispanics, Native Americans, African Americans, and Asians/Pacific Islanders than in non-Hispanic whites.

Sex

The incidence is essentially equal in women and men in all populations.

Age

• Type 2 diabetes mellitus is becoming increasingly common because people are living longer, and the prevalence of diabetes increases with age.
• It is also seen more frequently now than before in young people, in association with the rising prevalence of childhood obesity.
• Although type 2 diabetes mellitus still occurs most commonly in adults aged 40 years or older, the incidence of disease is increasing more rapidly in adolescents and young adults than in other age groups.

Clinical

History

Correctly determining whether a patient has type 1 or type 2 diabetes is important because patients with type 1 diabetes are dependent on a continuous source of exogenous insulin and carbohydrates for survival. Patients with type 2 diabetes may not need treatment for hyperglycemia during periods of fasting or decreased oral intake. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 diabetes. A lean patient who has had diabetes since childhood, who has always been dependent on insulin, or who has a history of DKA almost certainly has type 1 diabetes.

Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and are young but clinically appear to have type 2 diabetes and (2) older patients with late onset of diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 diabetes. (This latter group is now said to have latent autoimmune diabetes of the adult [LADA]). When in doubt, treat the patient with insulin and closely monitor his or her glucose levels. Some adolescents or young adults, mostly Hispanic or African American patients, who present as with classic DKA are subsequently found to have type 2 diabetes.

Many patients with type 2 diabetes are asymptomatic, and their disease is undiagnosed for many years. Studies suggest that the typical patient with new-onset type 2 diabetes has had diabetes for at least 4-7 years before it is diagnosed. Among patients with type 2 diabetes, 25% are believed to have retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis.

Pre-diabetes often precedes overt type 2 diabetes. Pre-diabetes is defined by a fasting blood glucose level of 100-125 mg/dL or a 2-hour post oral glucose tolerance test (OGTT) glucose level of 140-200 mg/dL. Patients who have pre-diabetes have an increased risk for macrovascular disease as well as diabetes.

Often confused with pre-diabetes is the metabolic syndrome (also called syndrome X or the insulin-resistance syndrome). Metabolic syndrome, thought to be due to insulin resistance, can occur in patients with overtly normal glucose tolerance, prediabetes, or diabetes. It is characterized by central obesity, then by dyslipidemia. Hypertension is a common feature. Eventually, clinically apparent insulin resistance develops. Unfortunately, insulin resistance is not measured clinically, except in research settings. An elevated fasting blood glucose level is the first indication of insulin resistance, but fasting insulin levels are generally increased long before this occurs. Measurement of fasting insulin levels are not yet recommended for the diagnosis of insulin resistance. An effort to standardize insulin assays is underway and may allow for the use of fasting insulin levels to diagnose insulin resistance in the future.

See Workup for more information on diagnosis of diabetes. See Diabetes Mellitus, Type 1 - A Review for more information on the symptomatic patient with diabetes.

During history taking, inquire about the type and duration of the patient's diabetes and about the care the patient is receiving for diabetes.

• Type and estimated duration of diabetes: This information helps to determine if the patient is insulin dependent. The diagnosis is based on history, therapy, and clinical judgment, as described above.
• Diabetes care: Inquire about the patient's current treatment of diabetes and about his or her usual blood glucose levels based on self-monitoring and/or recent measurements of hemoglobin A_1C (A _1C , an indicator of long-term glucose control).

A focused diabetes history should include the following questions:

• Is the patient's diabetes generally well controlled (with near-normal blood sugar levels)? Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications.
• Does the patient have severe hypoglycemic reactions? If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness, this possibility must be addressed, especially if the patient drives.
• Does the patient have peripheral neuropathy?
• Does the patient have any unrecognized foot ulcers or lesions that need treatment?
• Does the patient have diabetic nephropathy that might alter use of medications or intravenous radiographic contrast material?
• Does the patient have macrovascular disease, such as coronary artery disease (CAD), that should be considered in the ED?

As circumstances dictate, additional questions may be warranted.

• Diabetes care
  • What is the patient's diet? Does he or she use oral antidiabetic agents, insulin, or both? If so, what are the doses and frequencies of the medications?
  • Does the patient self-monitor his or her glucose levels? If yes, what is the frequency and the usual range of values at each time of day?
  • When was the patient's A _1C level last measured? What was it?
  • Does the patient adhere to a specific diet or exercise regularly?
• Hyperglycemia: Ask about polyuria, polydipsia, nocturia, weight loss, and fatigue.
• Hypoglycemia
  • Does patient have episodes of hypoglycemia? Are these episodes explicable? Are these episodes mild or severe?
  • Does the patient require the assistance of another person for treatment?
  • When and how often do these episodes occur? How does the patient treat them?
  • Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia)? Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia.
• Microvascular complications
  • Retinopathy: When was the patient's last dilated eye examination? What were the results? Any recent deterioration in vision?
  • Nephropathy: Does the patient have known kidney disease? What were the results and dates of the last measurements of urine protein and serum creatinine levels? If urine protein has been negative to trace, has a microalbumin-to-creatinine ratio been assessed within the past year?
• Neuropathy: Does the patient have any history of neuropathy or symptoms of peripheral neuropathy or autonomic neuropathy (including impotence if the patient is male)?
• Macrovascular complications
  • Hypertension: Does the patient have hypertension (defined as a BP of >130/80 mm Hg)? What medications are taken?
  • CAD: Does the patient have CAD? Does the patient have a family history of CAD?
  • Peripheral vascular disease: Does the patient have symptoms of claudication or a history of vascular bypass?
  • Cerebrovascular disease: Has the patient had a stroke or transient ischemic attack?
  • Hyperlipidemia: What are the patient's most recent lipid levels? Is the patient taking lipid-lowering medication?
• Diabetic foot disease: Does the patient have a history of foot ulcers or amputations? Are any foot ulcers present?
• Infections: Are frequent infections a problem? At what site?

Physical

A diabetes-focused examination includes vital signs, funduscopic examination, limited vascular and neurologic examinations, and a foot assessment. Other organ systems should be examined as indicated by the patient's clinical situation.

• Assessment of vital signs
  • Is the patient hypertensive or hypotensive? Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy.
  • If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered immediately, and appropriate tests ordered.
• Funduscopic examination
  • The funduscopic examination should include a careful view of the retina, including both the optic disc and the macula.
  • If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, especially if the patients' pupils are not dilated.
• Foot examination
  • The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections because poor lower-extremity blood flow can delay healing and increase the risk of amputation.
  • Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient's ability to protect the feet and ankles. This can be assessed with a monofilament, or more readily by assessment of reflexes, position, and vibration sensation.
  • If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation.

Causes

The major risk factors for type 2 diabetes mellitus are the following:

• Age - Older than 45 years (though, as noted above, type 2 diabetes mellitus is occurring with increasing frequency in young individuals)
• Obesity - Weight greater than 120% of desirable body weight (true for approximately 90% of patients with type 2 diabetes mellitus)
• Family history of type 2 diabetes in a first-degree relative (eg, parent or sibling)
• Hispanic, Native American, African American, Asian American, or Pacific Islander descent
• History of previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
• Hypertension (>140/90 mm Hg) or dyslipidemia (high-density lipoprotein [HDL] cholesterol level <40 mg/dL or triglyceride level >150 mg/dL)
• History of GDM or of delivering a baby with a birth weight of >9 lb
• Polycystic ovarian syndrome (which results in insulin resistance)

Differential Diagnoses

Diabetes Mellitus, Type 1 - A Review
Diabetic Ketoacidosis
Hyperosmolar Hyperglycemic Nonketotic Coma
Hypoglycemia

Workup

Laboratory Studies

• A fingerstick glucose test is appropriate in the ED for virtually all patients with diabetes. All other laboratory studies should be individualized to the clinical situation.
• In patients who present with symptoms of uncontrolled diabetes (eg, polyuria, polydipsia, nocturia, fatigue, weight loss) with a confirmatory random plasma glucose level of >200 mg/dL, diabetes can be diagnosed.
• In asymptomatic patients whose random serum glucose level suggests diabetes (>140 mg/dL), a fasting plasma glucose (FPG) concentration should be measured. The oral glucose tolerance test no longer is recommended for the routine diagnosis of diabetes.
  • An FPG level of >126 mg/dL on 2 separate occasions is diagnostic for diabetes.
  • An FPG level of 100-125 mg/dL is considered impaired IFG.
  • An FPG level of <100 mg/dL is considered normal glucose tolerance.
• A fasting C-peptide level >1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes (ie, residual beta-cell function).
• Autoantibodies can be useful in differentiating between type 1 diabetes and type 2 diabetes. 
  • Islet-cell autoantibodies (IA2) are present in children with new-onset type 1 diabetes but not type 2 diabetes. These antibodies are positive for approximately 6 months after diagnosis.
  • Anti-GAD65 antibodies are present in 80% of adult patients with new-onset type 1 diabetes (known as latent autoimmune diabetes of the adult [LADA]). These antibodies remain positive over time.

Other Tests

• A glucose tolerance test usually is not necessary, except when GDM or IGT is being diagnosed.

Treatment

Emergency Department Care

The ED care of patients with type 2 diabetes requires attention to both the patient's glycemic control and any of the numerous complications of diabetes the patient may have.

• New-onset diabetes
  • Most patients with diabetes have type 2, and most of those are asymptomatic at diagnosis. Initial treatment of these patients is a trial of medical nutrition therapy (MNT, diet therapy) plus metformin. Therefore, if an asymptomatic patient is incidentally found to have an elevated blood glucose level in the ED, the patient's primary care provider can perform follow-up. Patients with mild symptoms of poorly controlled and previously undiagnosed diabetes can usually be treated on an outpatient basis.
  • The treatment of markedly symptomatic patients with newly discovered type 2 diabetes and glucose levels greater than 400 mg/dL is controversial. If close follow-up can be arranged, maximal doses of a sulfonylurea agent can be started, and they can be treated on an outpatient basis. Patients generally feel better in 1-2 days, and in a week, their blood glucose levels are markedly lower. The sulfonylurea dose can be tapered as they comply with MNT and metformin is added; in some, diabetes can be controlled with diet alone. Patients who cannot drink adequate amounts of fluid, those with serious coexisting medical conditions (eg, myocardial infarction [MI], systemic infection), and those without reliable follow-up should generally be hospitalized to start therapy. Alternately, insulin therapy can be initiated and doses adjusted in either an inpatient setting or an outpatient setting.
• Abnormalities caused by hyperglycemia
  • Acute hyperglycemia, even when not associated with DKA or hyperglycemic hyperosmolar nonketotic syndrome (HNKS), is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose, an osmotic diuresis ensues, with loss of glucose, electrolytes, and water. Hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection, and hyperglycemia may impair wound healing.
  • In patients with known type 2 diabetes that is poorly controlled, no absolute level of blood glucose elevation requires admission to the hospital or administration of insulin in the ED. If the patient is severely symptomatic or if the precipitating cause of hyperglycemia cannot be treated adequately in the ED, the patient may need to be admitted. In general, lowering the patient's blood glucose level in the ED does not correct the underlying cause and has no long-term effects on the patient's blood glucose levels. Therefore, a plan for lowering and monitoring the patients' glucose levels is needed. Adequacy of follow-up is extremely important. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis.
• Hyperglycemia during medical illness and surgery
  • Serious medical illness and surgery produce a state of increased insulin resistance. Hyperglycemia can occur, even in patients who do not have diabetes, because of stress-induced insulin resistance plus the use of dextrose-containing intravenous fluids. Increases in glucagon, catecholamines, cortisol, and growth hormone levels antagonize the effects of insulin, and the alpha-adrenergic effect of increased catecholamine levels inhibits insulin secretion. Counterregulatory hormones also directly increase hepatic gluconeogenesis.
  • Increasing evidence shows the benefits of treatment of hyperglycemia in severely ill patients with or without preexisting diabetes. In ICU patients, in patients before and after coronary artery bypass grafting (CABG), and in those with an acute MI, morbidity and mortality are reduced when they receive glucose-insulin-potassium infusion (GIK infusion) designed to maintain glucose levels in the reference range. Many hospitals are implementing GIK-infusion protocols for patients in ICU, surgical ICU, and critical care unit (CCU) settings.
  • Treatment regimens must be modified for patients not requiring an ICU setting to compensate for both decreased caloric intake and increased physiologic stress. Blood glucose levels of 100-150 mg/dL should be maintained in medical and surgical patients with diabetes for the following reasons:
    • To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis
    • To prevent the impairment of leukocyte function that occurs when blood glucose levels are elevated
    • To prevent the impairment of wound healing that occurs when blood glucose levels are elevated
  • Cardiovascular disease (CVD) or renal dysfunction increases surgical morbidity and mortality in patients with or without diabetes, and diabetic autonomic neuropathy increases the risk of cardiovascular instability. The ED clinician caring for the patient with diabetes who requires emergency surgery must notify the surgeon and the anesthesiologist of the patient's condition, consult medical specialists when appropriate, and promptly initiate a thorough medical evaluation to avoid delaying surgery.
• Infections in general
  • Infections cause considerable morbidity and mortality in patients with diabetes. Infections may precipitate metabolic derangements and, conversely, the metabolic derangements of diabetes may facilitate infection.
  • A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes. Infections, such as staphylococcal sepsis, occur more frequently and result in greater mortality in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and others the same.
  • Hyperglycemia and acidemia exacerbate impairments in humoral immunity and polymorphonuclear leukocyte and lymphocyte functions but are substantially, if not entirely, reversed when pH and blood glucose levels return to normal. Although the exact level above which leukocyte function is impaired is not defined, in vitro evidence suggests that glucose levels greater than 200 mg/dL impair leukocytic function.
  • Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resulting poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury.
• Ear, nose, and throat infections
  • Two head and neck infections that are associated with high rates of morbidity and mortality are malignant otitis externa and rhinocerebral mucormycosis; these are seen almost exclusively in patients with diabetes.
  • Malignant or necrotizing otitis externa principally occurs in patients with diabetes who are older than 35 years and is almost always due to Pseudomonas aeruginosa.
    • Infection starts in the external auditory canal and spreads to adjacent soft tissue, cartilage, and bone. Patients typically present with severe ear pain and otorrhea. Although they often have preexisting otitis externa, progression to invasive disease is usually rapid.
    • Examination of the auditory canal may reveal granulation tissue, but spread of infection to the pinna, preauricular tissue, and mastoid often makes the diagnosis apparent. Involvement of the cranial nerves, particularly the facial nerve, is common; when infection extends to the meninges, it is often lethal.
    • CT helps define the extent of disease.
    • Prompt surgical consultation is mandatory for malignant otitis externa because surgical debridement is often an essential part of therapy. Intravenous antipseudomonal antibiotics should be started immediately in patients with invasive disease. Patients with diabetes with severe otitis externa but no evidence of invasive disease can be treated with an otic antibiotic drop and oral ciprofloxacin; they require close follow-up.
  • Mucormycosis collectively refers to infections caused by various ubiquitous molds. Invasive disease occurs in patients with poorly controlled diabetes, especially with DKA. Organisms colonize the nose and paranasal sinuses, spreading to adjacent tissues by invading blood vessels and causing soft tissue necrosis and bony erosion.
    • Patients usually present with periorbital or perinasal pain, swelling, and induration. Bloody nasal discharge may be present. Involvement of the orbits, with lid swelling, proptosis, and diplopia, is common.
    • The nasal turbinates may appear dusky red or frankly necrotic. Black necrotic tissue is an important visual clue. The infection may invade the cranial vault through the cribriform plate, resulting in cerebral abscess, cavernous sinus thrombosis, or thrombosis of the internal carotid artery.
    • Wet smears of necrotic tissue often reveal broad hyphae and distinguish mucormycosis from severe facial cellulitis. CT helps delineate the extent of disease.
    • Treatment consists of controlling the predisposing hyperglycemia and acidemia, administering intravenous amphotericin B, and immediate surgical debridement. Until the diagnosis is confirmed, antistaphylococcal antibiotic therapy is appropriate.
• Urinary tract infections
  • Patients with diabetes have increased risk of cystitis and, more important, of serious upper urinary tract infection. Intrarenal bacterial infection should be considered in the differential diagnosis of any patient with diabetes who presents with flank or abdominal pain.
  • The treatment of cystitis is essentially the same as that in patients without diabetes, except that longer courses of therapy are generally recommended (eg, 7 d for uncomplicated cystitis). Individuals with a neurogenic bladder due to diabetic neuropathy may not empty their bladder well and may require urologic referral. Sulfonamide antibiotics can cause hypoglycemia in patients taking sulfonylurea agents by displacing the sulfonylurea agents from their binding sites and increasing their hypoglycemic effect.
  • Treatment of pyelonephritis does not differ for patients with diabetes, but a lower threshold for hospital admission is appropriate. First, pyelonephritis makes control of diabetes more difficult by causing insulin resistance; in addition, nausea may limit the patient's ability to maintain normal hydration. The ensuing hyperglycemia further compromises their immune response. Second, patients with diabetes are more susceptible than others to the complications of pyelonephritis (eg, renal abscess, emphysematous pyelonephritis, renal papillary necrosis, gram-negative sepsis).
  • More than 70% of cases of emphysematous pyelonephritis occurred in patients with diabetes. Emphysematous pyelonephritis is an uncommon necrotizing renal infection caused by Escherichia coli, Klebsiella pneumoniae, or other organisms capable of fermenting glucose to carbon dioxide. The presentation is usually similar to that of uncomplicated pyelonephritis, and the diagnosis is established by identifying renal gas on plain radiography or sonography. Surgery is indicated at diagnosis.
• Skin and soft tissue infections
  • Sensory neuropathy, atherosclerotic vascular disease, and hyperglycemia all predispose patients with diabetes to skin and soft tissue infections. These can affect any skin surface but most commonly involve the feet.
  • Blood glucose levels greater than 250 mg/dL significantly increase a patient's risk of soft tissue infection.
  • Cellulitis; lymphangitis; and, most ominously, staphylococcal sepsis can complicate even the smallest wound. Minor wound infections and cellulitis are typically caused by Staphylococcus aureus or hemolytic streptococci. Treatment with a penicillinase-resistant synthetic penicillin or a first-generation cephalosporin has been effective for the outpatient treatment of minor infections, but the increasing prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) must now be considered when selecting an antibiotic. Patients with diabetes do not appear to have a higher prevalence of CA-MRSA than comparable patients without diabetes.
  • Outpatient treatment of minor infections is appropriate for patients who are reliable, who monitor their blood glucose, and who have access to close follow-up.
  • Necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle can also complicate wounds and particularly cutaneous ulcers. These infections are typically polymicrobial, involving group A streptococci, enterococci, S aureus, Enterobacteriaceae, and various anaerobes. Radiographs of any spreading soft tissue infection in a patient with diabetes should be obtained to look for the soft tissue gas that characterizes necrosis. Surgical debridement is necessary for necrotizing infections. Gram stains and surface cultures are not helpful; antibiotic coverage should reflect the range of potential pathogens.
• Osteomyelitis
  • Contiguous spread of a polymicrobial infection from a skin ulcer to adjacent bone is common in patients with diabetes.
  • In one study, osteomyelitis was found in the bone under 68% of diabetic foot ulcers, and findings on physical examination and plain radiographs did not help in diagnosing one half of the cases. Unfortunately, these diagnostic modalities are often the only ones available in the ED, and the diagnosis might be suspected but not established. MRI, if available on an emergent basis, has better sensitivity and specificity in diagnosing osteomyelitis. 
  • If osteomyelitis is apparent on radiography or physical examination (eg, if the wounds are deep enough to expose tendons or bone), the patient should be admitted for intravenous antibiotics. If osteomyelitis is suspected but the soft tissue infection or metabolic disturbances do not warrant admission, the patient can be discharged for outpatient workup.
• Other infections
  • Although cholecystitis is probably no more common in patients with diabetes than in the general population, severe fulminating infection, especially with gas-forming organisms, is more common. The early clinical manifestations of emphysematous cholecystitis are indistinguishable from those of usual cholecystitis. The diagnosis can be made by finding gas in the gallbladder lumen, wall, or surrounding tissues. Even with immediate surgery, the rate of mortality is high. Clostridial species are found in more than 50% of cases.
  • The incidence of staphylococcal and K pneumoniae infections is greater in people with diabetes than people without diabetes.
  • Diabetes is a risk factor for reactivation of tuberculosis.
  • Cryptococcal infections and coccidioidomycoses are more virulent in patients with diabetes than in others.
• Ophthalmologic complications
  • Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to come to the ED. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period.
  • Patients with diabetes also tend to develop senile cataracts sooner than persons without diabetes, though this is not related to the degree of glycemic control.
  • Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control maintained. Because the diagnosis of type 2 diabetes often is delayed, 20% of these patients have some degree of retinopathy at diagnosis. The following are the 5 stages in the progression of diabetic retinopathy:
    1. Dilation of the retinal venules and formation of retinal capillary microaneurysms
    2. Increased vascular permeability
    3. Vascular occlusion and retinal ischemia
    4. Proliferation of new blood vessels on the surface of the retina
    5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous
  • The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy.
    • Initially, the retinal venules dilate, then microaneurysms, (tiny red dots on the retina that cause no visual impairment) appear.
    • As the microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting the leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears.
    • Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina.
    • The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision.
  • Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts caused by capillary occlusion and appear as patches that range from off-white to gray and have poorly defined margins.
  • Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous. Patients may notice a small hemorrhage, which appears as a floater, though a large hemorrhage may result in marked visual loss.
  • Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation because laser therapy can be effective in this condition, especially before actual hemorrhage occurs. Patients with retinal hemorrhage should be advised to limit their activity and to keep their head upright (even while sleeping) so that the blood settles to the inferior portion of the retina, minimizing obscuration of their central vision.
  • Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents.
• Nephropathy
  • Patients with type 2 diabetes account for most patients with diabetes with ESRD. All patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Therefore, extreme care should be exercised when using any nephrotoxic agent in a patient with diabetes.
  • The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Caution should be used when contrast-enhanced studies are being considered in patients with diabetes with a creatinine level greater than 2 mg/dL; such studies should absolutely be avoided in patients with a creatinine level greater than 3 mg/dL. Although most recover within 10 days, some develop irreversible renal failure. Patients with diabetes who must undergo such studies should be well hydrated before, during, and after the study, and their renal function should be carefully monitored. A better solution is to seek equivalent clinical information by using an alternative study that does not require the use of contrast material (eg, sonography, noncontrast CT, MRI).
  • Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced dosage as appropriate to the patient's serum creatinine level.
  • Because chronically elevated blood pressure contributes to the decline in renal function, hypertensive patients with diabetes must be referred for long-term management of the blood pressure. If antihypertensive therapy is started in the ED, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) are recommended because these agents decrease proteinuria and slow decline in renal function independent of their effect on blood pressure. ACE inhibitors and ARBs tend to increase the serum potassium level and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels.
• Neuropathy
  • Of the many types of peripheral and autonomic diabetic neuropathy, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most frequent. Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.
  • Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear). Patients can present with diplopia and eye pain.
  • In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases.
  • Consideration of nondiabetic causes of cranial nerve palsies is important because 42% are due to causes other than diabetes. Therefore, evaluation should include nonenhanced and contrast-enhanced CT or, preferably, MRI. Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies.
  • Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations. Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, or symptomatic orthostatic hypotension.
    • Treatment of gastroparesis is symptomatic, and symptoms tend to wax and wane. Patients with gastroparesis may benefit from metoclopramide or erythromycin. Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used.
    • Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone.
    • Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating and requires a long-term treatment plan with input from all of the patient's healthcare team.
• Diabetic foot disease
  • About 50-70% of all nontraumatic lower-extremity amputations occur in patients with diabetes. The insensate, poorly perfused foot is at risk for ulcers from pressure necrosis or inflammation from repeated skin stress and unnoticed minor trauma. These can evolve into cellulitis, osteomyelitis, or nonclostridial gangrene and end in amputation.
  • Patients with diabetes who present with wounds, infections, or ulcers of the foot should be treated intensively. In addition to appropriate use of antibiotics, avoidance of further trauma to the healing foot is mandatory. This can be achieved by immobilization in a boot and/or using crutches, a wheelchair, or bed rest. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease. If bone or tendon is visible, osteomyelitis is present, and hospitalization for intravenous antibiotics is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing.
  • Because curing ulcers and foot infections is difficult, their prevention is extremely important. At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. ED clinicians can facilitate this practice by briefly inspecting the feet of each patient with diabetes and by educating them about the need for proper foot care. Patients with distal sensory neuropathy to pinprick or light touch, decreased peripheral pulses, moderate-to-severe onychomycosis, or impending skin breakdown should be referred to a podiatrist.
• Macrovascular disease
  • This is the leading cause of death in patients with diabetes, causing 75% of deaths in this group but approximately 35% of deaths in people without diabetes. Diabetes increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well. The risk of stroke in patients with diabetes is double that of people without diabetes, and the risk of peripheral vascular disease is 4 times that of people without diabetes. Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. Therefore, lipid abnormalities must be treated aggressively to lower the risk of serious atherosclerosis. Findings suggest that statin therapy should be started in all patients with type 2 diabetes, regardless of their lipid levels, to lower their risk of CVD.
  • Hypertension, which also increases the risk of atherosclerosis, is twice as common in patients with type 2 diabetes as in persons without diabetes. In patients with diabetes, hypertension must be treated aggressively to lower their risk of serious atherosclerosis. ACE inhibitors and angiotensin II–receptor blockers (ARBs) may also reduce CVD risk independent of its effects on blood pressure. Many advocate their use, in addition to statins, in most patients with type 2 diabetes.
  • Patients with diabetes may have an increased incidence of silent ischemia. However, silent ischemia is common in many patients with CAD, and the apparently increased incidence may be because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, an ECG is prudent in patients with diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not expected to be due to myocardial ischemia.
  • Diastolic dysfunction is common in patients with diabetes and should be considered in the patient with symptoms of congestive heart failure and a normal ejection fraction.

Medication

Target glucose levels

Chronic hyperglycemia is associated with an increased risk of microvascular complications, as shown in the Diabetes Control and Complications Trial (DCCT) in individuals with type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in people with type 2 diabetes. In the DCCT, intensive therapy to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, and neuropathy over 7 years.
The ongoing Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993. Intensive therapy was not associated with increased mortality or incidence of major macrovascular events and did not decrease the quality of life, though it did increase the likelihood of severe hypoglycemic episodes. Furthermore, in the EDIC study, a long-term follow-up of the DCCT, over time those who had been in the intensively treated group had a reduction in the risk of CVD compared with those in the conventionally treated group.

In the UKPDS, more than 5000 patients with type 2 diabetes were followed up for up to 15 years. Those in the intensely treated group had a significantly lower rate of progression of microvascular complications than that of those receiving standard care. Rates of macrovascular disease were not altered except in the metformin-monotherapy arm in obese individuals, in which the risk of MI was significantly decreased. Moreover, severe hypoglycemia occurred less often than it did in patients with type 1 diabetes in the DCCT.

Kooy et al found an improved body weight, glycemic control, and insulin requirements when metformin was added to insulin in type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. Because of these sustained beneficial effects, it is important to support the policy to continue metformin treatment after the introduction of insulin in type 2 diabetes mellitus unless contraindicated.¹
The goal of oral antidiabetic therapy is to lower blood glucose levels to near-normal (preprandial levels of 90-130 mg/dL and A_1C levels <7%) and to maintain them in this range for the patient's lifetime. Optimal diabetic control requires self-monitoring of blood glucose levels.

The Agency for Healthcare Research and Quality (AHRQ) reviewed the published evidence (from short-term studies but applicable to long-term use) regarding the comparative effectiveness of oral diabetes medications in controlling blood glucose levels and other aspects of diabetes. The AHRQ found little evidence to support predictions of whether a particular medication is more likely to be effective in a given patient subgroup or to cause adverse effects in a particular patient. The AHRQ concluded that, when used as monotherapy, most oral diabetes medications (with the exception of the less-effective nateglinide and alpha-glucosidase inhibitors) produce similar reductions in HbA1c, and that older medications (eg, metformin and second-generation sulfonylureas) can reasonably be used before newer ones (eg, glitazones or meglitinides), especially when cost is a factor.²

Patients with no or mild symptoms should initially be treated with MNT (diet therapy) plus metformin, and MNT should be encouraged throughout treatment. In the ED, drugs are typically started only when a patient presents with moderate-to-marked symptoms of diabetes, but it is also reasonable to initiate metformin (after ensuring that the serum creatinine level is <1.5 [men] or <1.4 [women]) in moderately hyperglycemic asymptomatic individuals if appropriate follow-up can be arranged.

Treatment of type 2 diabetes is aimed at lowering insulin resistance and increasing function of beta cells. In many patients, beta-cell dysfunction worsens over time, necessitating exogenous insulin. Because patients with type 2 diabetes have both insulin resistance and beta-cell dysfunction, oral medication to increase insulin sensitivity (eg, metformin or a thiazolidinedione [TZD]) is often given with an intermediate-acting insulin (eg, neutral protamine Hagedorn [NPH]) at bedtime or a long-acting insulin (eg, glargine [Lantus] insulin or insulin detemir [Levemir]) given once daily; glargine can be given in either the morning or the evening; detemir should be given in the evening.) An insulin secretagogue, such as a sulfonylurea agent, can also be given to increase preprandial insulin secretion.

The US Food and Drug Administration (FDA) has issued an early communication to health care practitioners regarding 4 recently published observational studies that describe the possible association of insulin glargine (Lantus) with an increased risk of cancer.³ Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

• The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than what is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raise further questions about the risk that actually exists and therefore warrants further evaluation.
• The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

The goal of these combined daytime oral agent plus once-a-day insulin is to lower the fasting glucose level to 100 mg/dL by titrating the insulin. When this target is achieved, the oral agents can be effective in maintaining preprandial and postprandial blood glucose levels throughout the day. If a regimen combining oral agents and insulin fails to lower glucose levels into the normal range, patients should be switched to a daily multiple-injection schedule with a premeal rapid-acting insulin and a longer-acting basal insulin.
Throughout treatment for type 2 diabetes, adherence to MNT and exercise should be stressed because behavior modification can have a large effect on the degree of diabetic control they achieve.

Some patients should not aim for near-normal blood glucose levels. In elderly patients who have a life expectancy of less than 5 years or in any patient with a terminal disease, tight control may be unnecessary. Patients with known CAD or cerebrovascular disease also may need higher preprandial blood glucose targets (eg, 100-160 mg/dL) to prevent extreme hypoglycemia. Patients with advanced microvascular and neuropathic diabetic complications may not particularly benefit from maintenance of near-euglycemia.
Additionally, patients with alcoholism or other serious substance abuse, and patients with severe uncontrolled mental illness may be unable to effectively participate in the care of their diabetes, placing them at high risk for severe hypoglycemic reactions if near-normal glucose levels are targeted. Finally, patients with hypoglycemia unawareness (ie, lack adrenergic warning signs of hypoglycemia) or those with recurrent episodes of severe hypoglycemia (ie, hypoglycemia requiring treatment by another person) should also have high target levels at least temporarily.
Although ED clinicians rarely start new therapy for diabetes, being acquainted with the drugs used and their adverse effects and contraindications is useful. The AHRQ has reviewed the adverse effects associated with oral diabetes medications and assessed the relative risks of such effects with particular medications. For descriptions of insulins, see Diabetes Mellitus, Type 1 - A Review.

Sulfonylurea Agents

These agents reduce serum glucose concentrations by increasing insulin secretion from pancreatic beta cells in patients with residual beta cell function. All are well absorbed; half-life and duration of action vary. These agents are classified as first generation (acetohexamide, chlorpropamide, tolazamide, tolbutamide; not described below), second generation (glipizide, glyburide), and third generation (glimepiride). All may cause hypoglycemia.

Glipizide (Glucotrol, Glucotrol XL)

Second-generation sulfonylurea; stimulates insulin release from pancreatic beta cells.

Dosing

Adult

5 mg/d PO initially in untreated patients with symptomatic hyperglycemia; not to exceed 40 mg/d PO; daily doses >20 mg given in divided doses bid; Glucotrol XL not to exceed 20 mg/d PO
Start at 2.5 mg/d PO for elderly patients and patients with hepatic or renal disease; may start at higher doses in patients with severe hyperglycemia or symptoms, if home glucose monitoring and close follow-up can be arranged

Pediatric

Not established

Interactions

Numerous possible, few clinically significant; sulfonamides may enhance hypoglycemic effect

Contraindications

Documented hypersensitivity; DKA; type 1 diabetes mellitus

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic or renal impairment; cardiovascular disorders may occur; other risk factors are older age, malnutrition, and irregular eating (if prolonged or recurrent, consider admission); may cause rash, nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (rare), intrahepatic cholestasis (rare), disulfiramlike reaction, flushing, headache, and SIADH causing hyponatremia

Glyburide (DiaBeta, Micronase, PresTab, Glynase)

Second-generation sulfonylurea agent; increases insulin secretion from pancreatic beta cells.

Dosing

Adult

5 mg/d PO initially in untreated, symptomatic patients; not to exceed 20 mg/d PO
Start 2.5 mg/d PO for elderly patients and patients with hepatic or renal disease; may start at <20 mg/d in patients with severe hyperglycemia or symptoms, if home glucose monitoring and close follow-up can be arranged
Dosing for Glynase (micronized formulation) differs: 3 mg/d PO initially; not to exceed 12 mg/d

Pediatric

Not established

Interactions

Numerous possible, few clinically significant; sulfonamides may enhance hypoglycemic effect

Contraindications

Documented hypersensitivity; DKA; type 1 diabetes mellitus

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic or renal impairment; cardiovascular disorders may occur; other risk factors are older age, malnutrition, and irregular eating (if prolonged or recurrent, consider admission); may cause rash, nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (rare), intrahepatic cholestasis (rare), disulfiramlike reaction, flushing, headache, and SIADH causing hyponatremia

Glimepiride (Amaryl)

Third-generation sulfonylurea; increases insulin secretion from pancreatic beta cells.

Dosing

Adult

Usual starting dose is 1-2 mg PO qd with breakfast; usual maintenance dose is 1-4 mg PO qd; maximum dose is 8 mg PO qd

Pediatric

Not established

Interactions

NSAIDs, sulfonamides, chloramphenicol, probenecid, warfarin, MAOIs, beta-blockers, and miconazole produce increased hypoglycemic effects; thiazides, hydantoins, oral contraceptives, corticosteroids, phenothiazines, thyroid estrogen, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid produce decreased hypoglycemic effects; increases alcohol-related disulfiram reactions; increases warfarin effects

Contraindications

Documented hypersensitivity, diabetic ketoacidosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients predisposed to hypoglycemia, such as patients with liver disease, renal disease, and elderly patients

Meglitinides

These agents are short-acting insulin secretagogues. They act on the ATP-dependent potassium channels in pancreatic beta cells, allowing opening of calcium channels and increased insulin release.

Repaglinide (Prandin)

Stimulates insulin release from pancreatic beta cells.

Dosing

Adult

0.5-4 mg PO ac; may dose bid/qid preprandial, not to exceed 16 mg/d

Pediatric

Not established

Interactions

CYP3A4 inhibitors (eg, clarithromycin, ketoconazole, miconazole, erythromycin) decrease metabolism, increasing serum levels and effects; thiazides, diuretics, corticosteroids, estrogens, oral contraceptives, nicotinic acid, CCBs, phenothiazines, and thyroid products, may lower glycemic control; toxicity increased with highly protein-bound drugs (eg, NSAIDs, sulfonamides, anticoagulants, hydantoins, salicylates, phenylbutazone)

Contraindications

Documented hypersensitivity; DKA; type 1 diabetes mellitus

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypoglycemia, especially if carbohydrate not eaten after drug; caution in hepatic impairment

Nateglinide (Starlix)

Short-acting insulin secretagogue. Action is dependent upon functional beta-cells in pancreatic islets. Stimulates pancreatic insulin secretion within 20 min of oral administration.

Dosing

Adult

120 mg PO tid ac; may decrease to 60 mg PO tid ac

Pediatric

Not established

Interactions

Metabolized by cytochrome P450 isozyme CYP2C9 (70%) and CYP3A4 (30%); may inhibit CYP2C9; inhibitors of CYP2C9 (eg, NSAIDs, fluvoxamine, cimetidine) may decrease elimination; inducers of CYP2C9 (eg, carbamazepine, phenobarbital, phenytoin) may enhance elimination; coadministration with NSAIDs, salicylates, MAOIs, and non-selective beta-blocking agents may potentiate hypoglycemic effects; thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce hypoglycemic effects

Contraindications

Documented hypersensitivity; diabetic ketoacidosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Reduce dose in hepatic impairment; may cause hypoglycemia (monitor glucose level); may cause GI distress; hypersensitivity reactions have been reported

Biguanides

These agents increase sensitivity of insulin by decreasing hepatic gluconeogenesis (primary effect) and increasing peripheral insulin sensitivity (secondary effect). They do not increase insulin levels or cause weight gain. Alone, they rarely cause hypoglycemia.

Absorbed from intestine (bioavailability 50-60%). Not bound to plasma proteins, not metabolized; rapidly eliminated by kidneys. Levels increase markedly in renal insufficiency. Accumulates in intestine; may decrease local glucose absorption (may explain GI effects). At high levels (eg, in renal failure), accumulates in mitochondria; inhibits oxidative phosphorylation and causes lactic acidosis (potentiated by alcohol). This side effect is rare.

Metformin (Glucophage)

Monotherapy or with sulfonylurea, thiazolidinediones, or insulin. Take with food to minimize adverse GI effects.
Available in immediate-release and extended-release formulations as well as in combination with other antidiabetic drugs.

Dosing

Adult

Metformin immediate release: 500 or 850 mg/d PO with dinner; increase less than q2wk to desired effect (1 g PO bid), GI effects prevent increase, or 2550 mg/d

Pediatric

Not established

Interactions

Numerous possible, few (if any) clinically significant

Contraindications

Serum creatinine level >1.5 mg/dL (men) or >1.4 mg/dL (women); hepatic dysfunction; acute or chronic acidosis; local or systemic tissue hypoxia; excessive alcohol intake; drug therapy for CHF

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Fatal lactic acidosis if given with contraindication (rare without contraindication); discontinue before IV contrast enhancement, do not restart until creatinine level normal; withhold in acute hypoxia; check renal function regularly and discontinue if abnormal; adverse effects (including GI, especially diarrhea [30%]), may cause discontinuation (5%)

Thiazolidinediones

Thiazolidinedione derivatives improve glycemic control by improving insulin sensitivity. These drugs are selective agonists for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and hyperinsulinemia. Must be taken about 12-16 weeks to achieve maximal effect. These agents are used as monotherapy or with sulfonylurea, metformin, meglitinide, or insulin.
The US Food and Drug Administration issued an alert to patients and health care professionals on May 21, 2007, of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis (See rosiglitazone).
In the RECORD trial, cardiovascular outcomes were assessed after adding rosiglitazone to metformin or sulfonylurea regimens for type 2 diabetes mellitus.⁴ The study was a multicenter, open-label trial that included 4447 patients with mean HbA1c of 7.9%. Follow-up of the 2 combinations took place over 5-7 years. No difference was observed between the 2 groups for cardiovascular death, myocardial infarction, and stroke. Sixty-one patients who received rosiglitazone experienced heart failure that caused either hospital admission or death compared with 29 patients in the active control group (hazard ratio [HR] 2.10, 1.35-3.27 risk difference per 1000 person-years 2.6, 2.2-4.1).
Noncardiovascular adverse effects included increased upper and distal lower limb fracture rates, particularly in women. At 5 years, mean HbA1c was lower in the rosiglitazone group compared with the active control group. Results of the RECORD study found that use of rosiglitazone for type 2 diabetes mellitus increases risk of heart failure. Additionally, the risk for select fractures is increased, particularly in women. 
Troglitazone (Rezulin), another thiazolidinedione, was voluntarily withdrawn from the market by the manufacturer on March 21, 2000, following concerns about its hepatic toxicity.

Pioglitazone (Actos)

Insulin sensitizer; decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and possibly liver and adipose tissue.

Dosing

Adult

15 or 30 mg PO qd; may increase prn; not to exceed 45 mg/d; maximal effect may not be achieved for up to 12 wk

Pediatric

Not established

Interactions

With insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk of hypoglycemia

Contraindications

Documented hypersensitivity; active liver disease, ALT level >2.5 times upper limits of normal; DKA; type 1 diabetes mellitus; congestive heart failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with edema; may worsen macular edema; may decrease hemoglobin, hematocrit, and WBC counts (dilution); effects on lipids neutral or beneficial (decreased triglyceride, increased HDL levels); may increase risk for distal fractures in women

Rosiglitazone (Avandia)

Insulin sensitizer; major effect in stimulating glucose uptake in skeletal muscle and adipose tissue. Lowers plasma insulin levels. Used to treat type 2 diabetes mellitus with insulin resistance.

Dosing

Adult

4-8 mg/d PO or divided bid

Pediatric

Not established

Interactions

With insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk of hypoglycemia

Contraindications

Documented hypersensitivity; active liver disease, ALT level >2.5 times upper limits of normal; DKA; type 1 diabetes mellitus; congestive heart failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in edema; may worsen macular edema; may decrease hemoglobin, hematocrit, and WBC counts (dilution); may increase HDL cholesterol, neutral effect on triglycerides; may increase risk for distal fractures in women
The US Food and Drug Administration issued an alert to patients and health care professionals on May 21, 2007, of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. A large-scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (theheart.org from WebMD) including the following articles: (1) Rosiglitazone increases MI and CV death in meta-analysis, (2) The rosiglitazone aftermath: Legitimate concerns or hype? and (3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers. Also see, the FDA's Information for Health Care Professionals updated August 14, 2007.

Dipeptidyl Peptidase IV (DPP-4) Inhibitors

These agents block the action of DPP-4, which is known to degrade glucagon-like peptide 1 (GLP-1), thereby increasing its concentrations. The levels of GLP-1 achieved enhance glucose-dependent insulin secretion and suppress elevated glucagon secretion.

Sitagliptin (Januvia)

Indicated for monotherapy or combined with metformin or a thiazolidinedione.

Dosing

Adult

100 mg PO qd
CrCl >30 to <50 mL/min: 50 mg PO qd
CrCl <30 mL/min: 25 mg PO qd

Pediatric

Not established

Interactions

Data limited; caution with other drugs that decrease glucose levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects include upper respiratory tract infection, nasopharyngitis, and headache; assess renal function before initiating therapy and periodically thereafter; decrease dose with moderate or severe renal insufficiency

Saxagliptin (Onglyza)

Dipeptidyl peptidase IV (DPP-4) inhibitors. Blocks the enzyme DPP-4, which is known to degrade incretin hormones. Increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Dosing

Adult

2.5-5 mg PO qd
CrCl <50 mL/min: 2.5 mg PO qd
Coadministration with strong CYP450 3A4/5 inhibitors: 2.5 mg PO qd

Pediatric

<18 years: Not established

Interactions

Coadministration with strong CYP3A4/5 inhibitors (eg, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) significantly increases serum concentration (do not exceed 2.5 mg/d with concurrent use of these drugs); concurrent use with CYP3A4/5 inducers (eg, rifampin) significantly decreases exposure, but not active metabolite AUC (dose adjustment not needed); coadministration with sulfonylureas increases risk of hypoglycemia (decrease dose of sulfonylurea); coadministration with thiazolidinedione (eg, rosiglitazone, pioglitazone) increases risk for peripheral edema

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects include upper respiratory tract infection, urinary tract infection, and headache; may cause peripheral edema (especially when coadministered with thiazolidinedione); hypoglycemia reported more often when coadministered with sulfonylurea; may cause hypersensitivity-related events (eg, urticaria, facial edema)

Incretin Mimetics

These agents mimic human incretin (glucagon-like peptide 1 [GLP-1]) and thereby enhances glucose-dependent insulin secretion, suppresses elevated glucagon secretion, delays gastric emptying, and promotes satiety. These agents may cause weight loss.

Exenatide (Byetta)

Indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin or a sulfonylurea, but have not achieved adequate glycemic control.
Available as 5-mcg and 10-mcg fixed-dose prefilled pens.

Dosing

Adult

5 mcg SC bid within 1 h ac in morning and evening; based on response, may increase to 10 mcg SC bid after 1 mo

Pediatric

Not established

Interactions

Data limited; may decrease absorption of orally administered drugs (take drugs requiring rapid absorption, eg, oral contraceptives, antibiotics, at least 1 h before exenatide); may prolong INR in patients taking warfarin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer in thigh, abdomen, or upper arm; may cause hypoglycemia, nausea, vomiting, diarrhea, jittery feeling, dizziness, headache, or dyspepsia; may develop antibodies to protein contents; mild-to-moderate nausea is common (in 30%), generally self-limited, typically resolving within 2 wk of therapy

Amylin Analogs

These agents have endogenous amylin effects; they delay gastric emptying, decrease postprandial glucagon release, and modulate appetite.

Pramlintide acetate (Symlin)

Synthetic analogue of human amylin, hormone made in beta cells. Slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake (centrally mediated appetite modulation). Indicated to treat type 1 or 2 diabetes mellitus, in conjunction with prandial and basal insulin. Given before meals in patients who have not achieved desired glucose control despite optimal insulin therapy. Helps lower glucose levels after meals, lowers fluctuation during day, and improves long-term control (A _1C ) as compared with insulin alone. Lowers insulin use and body weight.

Dosing

Adult

Dose for type 1 and type 2 diabetes differs
Treatment of patients with type 2 diabetes: 60 mcg SC ac initially; titrate up (if no significant nausea for >3 d) to maintenance dose of 120 mcg; premeal insulin dose is decreased by 50% when pramlintide is started, but the basal insulin dose is usually unchanged; after target dose of pramlintide is achieved, optimize insulin dose to maintain glycemic control

Pediatric

Not established

Interactions

May delay absorption of concomitant oral drug (administer other drug 1 h before or 2 h after)

Contraindications

Documented hypersensitivity to pramlintide, components, or metacresol; gastroparesis; hypoglycemia unawareness; drugs that slow gastric emptying (eg, anticholinergics, eg, atropine) or that slow intestinal nutrient absorption (eg, alpha-glucosidase)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of insulin-induced severe hypoglycemia, especially with type 1 diabetes mellitus or gastroparesis, rare in patients with type 2 diabetes mellitus; common adverse effects are GI complaints, especially nausea (decreased when dose increased gradually); always use separate insulin syringe to measure and administer, do not mix in same syringe (insulin alters pharmacokinetics); redness, swelling, or itching at injection site; do not administer without major meal (>250 cal or 30 g carbohydrates)

Alpha-glucosidase Inhibitors

These agents inhibit action of alpha-glucosidase (carbohydrate digestion), delaying and attenuating postprandial blood glucose peaks. Undigested sugars are delivered to the colon, where they are converted into short-chain fatty acids, methane, carbon dioxide, and hydrogen.

Alpha-glucosidase inhibitors (AGIs) do not increase insulin levels or inhibit lactase; their major effect is to lower postprandial glucose levels (lesser effect on fasting levels). They do not cause weight gain and may restore ovulation in anovulation due to insulin resistance. AGIs are not commonly used in the United States, but they are more commonly used in other countries.

Alone, AGIs do not cause hypoglycemia. Less than 2% is absorbed as active drug. They are used as monotherapy or with sulfonylurea, TZD, metformin, or insulin. Take with food to minimize GI effects.

Acarbose (Precose)

Delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. Inhibits metabolism of sucrose to glucose and fructose.

Dosing

Adult

25 mg PO tid ac initially with first bite of food; adjust q4-8wk based on 1-h postprandial glucose levels and tolerance; may increase dose prn, not to exceed 100 mg PO tid

Pediatric

Not established

Interactions

Hypoglycemia with insulin or sulfonylurea agents (give glucose as dextrose, as absorption of long-chain carbohydrates is delayed); may decrease absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes (eg, amylase, pancreatin) may reduce effects

Contraindications

Documented hypersensitivity; DKA; cirrhosis; IBD; colonic ulceration; serum creatinine level >2 mg/dL; elevated liver enzyme levels; partial or predisposition to intestinal obstruction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

GI effects (eg, flatulence, diarrhea, abdominal discomfort) common, especially with metformin (17% discontinue); systemic accumulation at high doses and in renal dysfunction, with possible drug-induced hepatitis

Miglitol (Glyset)

Delays glucose absorption in small intestine; diminishes postprandial hyperglycemia.

Dosing

Adult

25 mg PO tid ac initially with first bite of food; increase to 50 mg tid after 4-8 wk; may increase prn; not to exceed 100 mg PO tid

Pediatric

Not established

Interactions

Hypoglycemia with insulin or sulfonylurea agents (give glucose as dextrose, as absorption of long-chain carbohydrates is delayed); may decrease absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes (eg, amylase, pancreatin) may reduce effects

Contraindications

Documented hypersensitivity; DKA; colonic ulceration; partial or predisposition to intestinal obstruction; IBD

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause GI symptoms; not recommended in significant renal dysfunction

Follow-up

Further Inpatient Care

• Inpatient care generally is warranted only for the management of major acute complications such as severe recurrent hypoglycemia, major infections, or HHS.

Further Outpatient Care

• Although a few of the complications require hospitalization, type 2 diabetes mellitus can usually be managed on an outpatient basis.

Deterrence/Prevention

• Moderation in diet, weight loss, and exercise are all important deterrents of type 2 diabetes mellitus. The ADA suggests that metformin can be used to help prevent the progression of prediabetes to diabetes.
• Risk for vascular complications and cardiovascular mortality in patients with diabetes mellitus is increased by poor glucose control. Loimaala et al evaluated the efficacy of a long-term exercise training program on metabolic control and arterial stiffness in patients with type 2 diabetes mellitus. The study showed that long-term endurance and strength training was effective and resulted in improved metabolic control of diabetes mellitus compared with standard treatment; however, significant cardiovascular risk reduction and conduit arterial elasticity did not improve.⁵

Complications

• The complications of diabetes include hypoglycemia and hyperglycemia, increased risk of infections, microvascular complications (ie, retinopathy, nephropathy), neuropathic complications, and macrovascular disease.
• Diabetes is the major cause of blindness in adults aged 20-74 years.
• Diabetes is the leading cause of nontraumatic lower-extremity amputation and ESRD.
• For a detailed discussion of complications, see Emergency Department Care.

Prognosis

• Patients with diabetes have a lifelong challenge to achieve and maintain blood glucose levels as close to the reference range as possible. With appropriate glycemic control, the risk of microvascular and neuropathic complications is decreased markedly. In addition, if hypertension and hyperlipidemia are treated aggressively, the risk of macrovascular complications decreases as well.
• These benefits are weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. Studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years after starting effective preventive care.
• With each healthcare system encounter, patients with diabetes should be educated about and encouraged to follow an appropriate treatment plan. Providers must ensure that the care for each patient with diabetes includes all necessary laboratory tests, examinations (eg, foot and neurologic examinations), and referrals to specialists (eg, ophthalmologist, podiatrist).

Patient Education

• For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetes.

Miscellaneous

Medicolegal Pitfalls

• Overtreatment or undertreatment of hypoglycemia such as premature discharge of a patient who develops hypoglycemia due to long-acting insulin
  • After an episode of severe hypoglycemia, patients should be discharged home with a prescription for glucagon.
  • If the hypoglycemia resulted in a loss of consciousness while driving, patients with diabetes should be educated about how to drive safely with their condition. In many states, a loss of consciousness while driving must be reported to the state department of motor vehicles, though if a patient has a monitored treatment plan for their diabetes, this notification may not be required.
• Failure to treat the blood glucose levels of patients with wounds or active infections when levels are greater than 200 mg/dL
• Underestimation of the severity of diabetic retinopathy on funduscopic examination because of a failure to dilate the pupils or the failure to urgently refer any patient with lesions near the macula to an ophthalmologist
• Failure to provide adequate hydration to patients with mild diabetic nephropathy before contrast material is given may precipitate acute renal failure
• Failure to examine the patient's feet and failure to detect small ulcers or underestimating their seriousness
• Failure to consider myocardial ischemia in patients with nonspecific symptoms

Special Concerns

• Pregnancy
  • MNT is the treatment of choice for GDM. If diet fails, the treatment is insulin.
  • In the past, oral antidiabetic agents were considered contraindicated in pregnancy. Glyburide is safe and effective in the treatment of GDM. Evidence suggests that metformin may be safe and effective in pregnancy as well. Studies are underway to assess their role in pregnant patients with increased insulin resistance.
  • Because patient education and ongoing glycemic control are essential to optimize fetal outcomes, consultation and specific follow-up are imperative.
• Childhood diabetes: Although the predominant form of diabetes in children is type 1, type 2 diabetes also may occur in children.

References

1. [Best Evidence] Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. Mar 23 2009;169(6):616-25. [Medline].

2. Agency for Healthcare Research and Quality. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults With Type 2 Diabetes. AHRQ: Agency for Healthcare Research and Quality. Available at http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=6&DocID=40. Accessed January 27, 2009.

3. US Food and Drug Administration. Early Communication About Safety of Lantus (insulin Glargine). July 1, 2009. [Full Text].

4. [Best Evidence] Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. Jun 20 2009;373(9681):2125-35. [Medline].

5. [Best Evidence] Loimaala A, Groundstroem K, Rinne M, Nenonen A, Huhtala H, Parkkari J, et al. Effect of long-term endurance and strength training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. Apr 1 2009;103(7):972-7. [Medline].

6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. Jan 2007;30 Suppl 1:S42-7. [Medline]. [Full Text].

7. American Diabetes Association. Standards of medical care in diabetes--2007. Diabetes Care. Jan 2007;30 Suppl 1:S4-S41. [Medline]. [Full Text].

8. Cefalu WT, Waldman S, Ryder S. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents. Clin Pharmacol Ther. May 2007;81(5):636-49. [Medline].

9. Centers for Disease Control and Prevention. National Diabetes Fact Sheet. United States. 2005. Available at http://www.cdc.gov/diabetes/pubs/general.htm.

10. DCCT Group. The Diabetes Control and Complications Trial Research Group: the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline].

11. Frank RN. Diabetic retinopathy. N Engl J Med. Jan 1 2004;350(1):48-58. [Medline].

12. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin North Am. Jul 2004;88(4):1001-36, xi. [Medline].

13. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. Oct 1 2004;39(7):885-910. [Medline].

14. Mokabberi R, Ravakhah K. Emphysematous urinary tract infections: diagnosis, treatment and survival (case review series). Am J Med Sci. Feb 2007;333(2):111-6. [Medline].

15. Peters AL, Davidson MB, Schriger DL, Hasselblad V. A clinical approach for the diagnosis of diabetes mellitus: an analysis using glycosylated hemoglobin levels. Meta-analysis Research Group on the Diagnosis of Diabetes Using Glycated Hemoglobin Levels. JAMA. Oct 16 1996;276(15):1246-52. [Medline].

16. Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. Jan 1 1996;124(1 Pt 2):136-45. [Medline].