TABLE 16-2 Ocular and Periocular Manifestations of DM

Patients >10 years of age with type 1 diabetes should have an initial dilated and comprehensive eye examination within 3 to 5 years after the onset of diabetes, and at least every year thereafter.
Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination shortly after diagnosis, and at least every year thereafter.

Demographics

TABLE 16-3 Comparison of the Essential Features of Type 1 and Type 2 DM

Significant History

• Age (type 2 DM is more common in people greater than 45 years of age; however, it is becoming increasingly more common in younger individuals, even adolescents)
  
• Family history (FH) of DM in a first-degree relative; if FH is positive for DM, determine age of onset, whether it was associated with obesity, and form of treatment. FH is much stronger in type 2 (70% to 80%) versus type 1 (20%)
  
• Diabetic patients with family members who have had severe retinopathy are more likely than other diabetics to have more severe retinal disease
  
• Unexplained weight loss (type 1) or visceral obesity and increased BMI (type 2)
  
• Physical inactivity
  
• Polyuria, polydipsia, polyphagia may be reported with marked hyperglycemia
  
• Chronic or recurrent infections
  
• Gestational diabetes, or having delivered a baby weighing greater than 9 lb
  
• Long or highly irregular menstrual cycles
  
• Member of a high-risk ethnic population
  
• Systemic hypertension, smoking, dyslipidemia, use of oral contraceptives, or other factors that increase cardiac risk

Ancillary Tests

The risk of developing type 2 diabetes is increased with plasma glucose (PG) levels well below the current cut-point for defining impaired fasting glucose (IFG), which is 100 to 125 mg/dL. Fasting plasma glucose (FPG) levels, even as low as 90 mg/dL, have been shown to be associated with an increased risk for type 2 diabetes. However, diabetes risk associated with fasting glucose should be viewed in the context of other risk factors such as systemic hypertension, dyslipidemia, and obesity. While the definition or cut-point of DM may change with time, the conventional criteria are as follows:

A diagnosis of DM, in nonpregnant adults, is appropriate in one of the following circumstances. Each must be confirmed on a subsequent day unless unequivocal symptoms of hyperglycemia are present:

• Symptoms of diabetes plus casual PG concentration ≥ 200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
  
• FPG ≥ 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours. If the FPG level is over 126 mg/dL on more than one occasion, further evaluation of the patient with a glucose challenge is unnecessary.
  
• 2-h PG ≥ 200 mg/dL during an oral glucose tolerance test.

Note: The International Expert Committee and the American Diabetes Association (ADA) have revised the recommendations listed above to include an A1c value of 6.5% or greater in the diagnosis of diabetes. A1c tests are now reproducible, standardized between labs, and are more convenient for patients as the test does not require overnight fasting. Compliance with screening may therefore be improved using the A1c test, which can be determined from a single nonfasting blood sample. However, A1c testing is more expensive than FPG, and values may vary with age, ethnicity, anemia, renal insufficiency, and certain infections. A cut-point of ≥6.5% was selected to diagnose diabetes, in that it tightly correlates with the risk of developing retinopathy.

Values between 5.7% and 6.4% are considered “prediabetic” as they are likely at the highest risk for progression to diabetes, as are patients with IFG and impaired glucose tolerance (IGT). Like other diagnostic tests for diabetes, an abnormal value should be confirmed with a repeat test.

If a diagnosis of DM is made, other baseline tests, procedures, and examinations should be performed. These assessments may reveal coexistent disorders, document preexisting target organ damage (TOD), and help guide future management. Evaluations include

• Fasting plasma triglycerides
  
• Total cholesterol, HDL cholesterol, LDL cholesterol
  
• Electrocardiography (ECG)
  
• Renal function studies
  
• Peripheral pulses (to detect peripheral artery disease or PAD)
  
• Neurologic, podiatric, and eye examinations

Self-monitoring of blood glucose (SMBG) is sometimes employed in the management of diabetes. Most would agree that SMBG is associated with better glycemic control, especially in insulin-treated diabetics or when adding to or modifying oral therapy.

For most patients with type 1 diabetes, SMBG is recommended three or more times daily. The optimal frequency and timing of SMBG for patients with type 2 diabetes on oral therapy is not known but may be incorporated in order to facilitate reaching glucose goals. However, for well-controlled patients with noninsulin treated type 2 diabetes, home monitoring of blood glucose is of questionable value, is expensive, and may increase the risk of depression.

The accuracy of data obtained by any glucose monitoring system requires proper instruction of the patient in sampling and measuring procedures as well as proper calibration of the instruments. Audible glucose monitoring devices, in both English and Spanish, are available for diabetics who are visually impaired.

Daily blood glucose levels should be less than 110 mg/dL before eating breakfast (preprandial) and less than 140 mg/dL 2 hours after eating a meal (postprandial). In addition, measurement of 1,5-anhydroglucitol (1,5-AG) levels in serum can be used to monitor postprandial glycemic control in patients with moderately well-controlled diabetes. The 1,5-AG serum assay (GlycoMark) can be used to measure postprandial glucose levels over 1 to 2 weeks.

Continuous glucose monitoring devices, which measure interstitial glucose via subcutaneous sensors, may be particularly beneficial for diabetics who are at risk for nocturnal hypoglycemia. These devices have alarms that can awaken a patient and prevent a seizure. However, this monitoring system is expensive, has some accuracy limitations, and requires patient motivation. Although this method is appealing theoretically, the extent to which it will improve long-term clinical outcomes remains to be determined.

TABLE 16-4 HbA1c Percentage and Corresponding Estimated Average Glucose Level

Urine strips are a precise and convenient method to detect glucosuria (Diastix are sensitive to as little as 0.1% glucose in urine). However, the renal threshold for PG is approximately 180 mg/dL, thus urine glucose is not the method of choice for monitoring diabetic control.

Urine testing for ketones (Acetest or Ketostix) is important for type 1 diabetics when they are ill, under stress, or when their blood glucose exceeds 240 mg/dL.

Note: A noninvasive imaging device that identifies elevated levels of flavoprotein autofluorescence in retinal tissue, which is caused by increased metabolic stress, may provide evidence of diabetes or diabetic eye disease before neuronal loss is evident. This technology may allow clinicians to diagnose diabetes earlier and to initiate glycemic control before extensive ocular tissue damage occurs.

The Treatment

Diabetes care is complex and requires that many health-related issues, beyond glycemic control, be addressed. A complete medical evaluation should be performed to detect the presence of diabetic complications, to formulate a management plan, and to provide a basis for continuing care. Currently, the treatment objectives for both type 1 and 2 are similar and that is to maintain glycemic control as close to normal as possible, while avoiding undue risk for adverse events or placing an unacceptable burden on the patient. Treatment strategies should be individualized based on the type of diabetes, comorbidities, life expectancy, and the specific requirements of each patient.

The management of DM involves lifestyle adaptations such as diet and exercise, to improve glucose levels, blood pressure (BP), lipid levels, and weight control. Bariatric surgery is a very effective treatment option for type 2 diabetics who are morbidly obese. Studies show improved survival from heart disease and cancer in patients following bariatric surgery for morbid obesity, but also report a 73% remission in type 2 diabetes compared with nonsurgical treatments.

TABLE 16-5 Oral Antidiabetic Drugs

TABLE 16-6 Insulin Preparations

The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, times indicated above should be considered general guidelines only.
There are a number of different types of injected insulin, which can be used to comprise a regimen that can approximate the normal response of the beta cell.
Rapid-acting insulins can be used at meals to control postprandial glucose. Longer-acting insulins, including NPH, glargine, and detemir, provide basal or background insulin. NPH is intermediate-acting insulin given twice daily; glargine and detemir have 24-hour profiles and are given once daily.
Premixed insulins are a fixed combination of a long-acting and rapid-acting insulin and may be given twice daily. These premixed formulations actually show an asymmetric peak, with a skewing toward the longer acting insulin.
Continuous infusion of insulin (insulin pump) usually achieves slightly better glycemic control than does an optimized-injection regimen. However, it is not clear whether insulin pumps are cost effective and they are usually reserved for patients in whom injection regimens do not provide adequate control.

Note: There is some controversy that the glitazone drugs (i.e., rosiglitazone and pioglitazone) may increase the risk of developing macular edema (ME) in some diabetic patients. The most current studies (ACCORD) show that these drugs appear to be safe to use in diabetic patients without contributing to this important complication of the disease.

Several newer drugs include:

Exenatide (Byetta) and liraglutide (Victoza) are incretin mimetics (a glucagon-like peptide or GLP-1 agonist) used as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who have not achieved adequate control with metformin, a thiazolidinedione, and/or a sulfonylurea. These drugs may be well suited for patients with hazardous jobs that would make hypoglycemia particularly dangerous and in those that need to lose weight and in whom the HbA1c level is close to target (<8%). The drugs are available as a prefilled pen injector device.

Sitagliptin (Januvia) and saxagliptin (Onglyza) are oral dipeptidyl peptidase-4 (DPP-4) inhibitors and may be appropriate for select patients with type 2 diabetes. Blocking the action of DPP-4 prolongs the activity of the incretin proteins, leading to better insulin release, suppressing the release of glucagon, and delaying gastric emptying, which collectively results in better blood glucose control.

Note: Neither GLP-1 agonists nor DPP-4 inhibitors cause hypoglycemia unless used with other agents known to increase risk.

Pramlintide (Symlin) is a synthetic analog of the β cell co-secreted pancreatic hormone amylin. This medication is injected subQ just before meals with insulin, in a different syringe from the insulin syringe. Symlin lowers postprandial blood glucose by slowing gastric emptying, by suppressing glucagon secretion, and by modulating the appetite, which may lead to weight loss.

The Food and Drug Administration (FDA) approved Exubera, an inhaled insulin, in January 2006. Unfortunately, due to the poor level of adoption by both physicians and patients, the manufacturer removed it from the market in October 2007. Other formulations of inhaled insulin and their delivery systems appear very promising (i.e., technosphere insulin—Afresa).

Coexistent disorders such as smoking, obesity, arterial hypertension, and/or dyslipidemia must be addressed as they may increase the risk and accelerate the progression of diabetic complications (i.e., retinopathy, neuropathy, nephropathy, and peripheral vascular disease). If no contraindications exist, enteric-coated aspirin (75 to 162 mg/d) is reasonable for older diabetic adults who are at increased CV risk and/or in patients with symptomatic CV disease. The risk of ischemic heart disease is two to four times greater in diabetics, occurs at a younger age, and is much higher in women with diabetes.

DR, even in its mildest form, is an independent predictor of kidney disease and of the risk for HF. A careful cardiac assessment is recommended for patients with DR to allow detection of subclinical HF or left ventricular dysfunction.

The Diabetes Control and Complications Trial (DCCT) demonstrated that “tight” metabolic control, geared toward maintaining near normal glucose levels, had a definite and beneficial effect on the development and progression of long-term diabetic microvascular complications in type 1 diabetics. In addition, the Epidemiology of Diabetes Interventions and Complications (EDIC) study showed a reduction in the risk of both microvascular and macrovascular events resulting from intensive therapy, which persisted for years, despite increasing levels of blood glucose.

Note: Intensive regulation of blood glucose is difficult at best and glycemic controls should always be realistic. In some patients (e.g., small children, the elderly, those with advanced renal disease), the criteria for optimal control may need to be adjusted upward as the detrimental risks of hypoglycemia may outweigh the benefits of tight glycemic control.

In addition, several recent trials (ADVANCE, ACCORD, and VADT) are consistent in showing no significant benefit of very tight glycemic control (HbA1c ≤ 6%) on macrovascular or microvascular events in older type 2 diabetics with established disease. However, the 10-year follow-up of the UKPDS suggested a definite benefit (or “legacy effect”) of tight glycemic control in patients with type 2 diabetes, which extended beyond a finite period of intensive management. The observations from the more recent trials suggest that intensive glucose-lowering therapy may hold more promise for younger, newly diagnosed type 2 diabetics—the analysis of data is ongoing.

In general, it is reasonable to conclude that multifactorial treatments such as glucose control that minimizes hypoglycemia (HbA1c ~7%), controlling BP (<140/80 mm Hg), and other risk factors (diet, exercise, smoking cessation, and lipid lowering) should be considered in most patients with diabetes, regardless of their age, in order to reduce the risk of CV mortality and all-cause mortality.

Transient worsening of retinopathy (and neuropathy) during the first 6 to 12 months of intensive therapy has been noted in several clinical trials and is referred to as “treatment-induced diabetic retinopathy or neuropathy.”

Systolic hypertension, in the elderly is due to age-related reductions in the elasticity (stiffening or fibrosis) of large and medium-sized arteries, leading to a progressive rise in the systolic BP. The diastolic blood pressure (DBP), on the other hand, tends to peak around age 50 and then begins to decrease with advancing years. This increasing difference between the systolic and diastolic BP causes the familiar widening of pulse pressure with age.

Etiology

In essential HTN, which accounts for 90% to 95% of cases, no specific etiology has been established. In addition to the potential factors listed above, chronic systemic inflammation and oxidative stress may also play a role in the development of essential HTN.

Causes of secondary HTN (those 5% to 10% of cases with an identifiable etiology) include:

• Obesity and obstructive sleep apnea
  
• Drug induced or drug related (i.e., NSAIDs, steroids, oral contraceptives, cyclosporine, cocaine, alcohol)
  
• Pregnancy (gestational hypertension)
  
• Renal parenchymal disease
  
• Renovascular hypertension (i.e., renal artery stenosis)
  
• Coarctation of the aorta
  
• Hyperaldosteronism (Conn’s syndrome)
  
• Cushing’s disease
  
• Hyperparathyroidism
  
• Hyperthyroidism
  
• Hypercalcemia
  
• Pheochromocytoma
  
• Acromegaly

Blood pressure (BP) rise and hypertension are not necessarily an inevitable consequence of aging; however, isolated systolic hypertension (ISH) frequently occurs in individuals over 60 years of age. ISH is defined as a systolic blood pressure (SBP) of 140 mm Hg or more and a DBP less than 90 mm Hg. ISH is related to loss of arterial elasticity (or compliance) of large arteries due to atherosclerosis and is often more resistant to treatment than essential hypertension. ISH is the most frequent form of uncontrolled hypertension in the United States. For individuals older than 50 years of age, the SBP is a more important predictor of CV disease than the diastolic pressure. Conversely, hypertensive individuals, younger than 50, may have isolated diastolic hypertension. Therefore, clinicians should focus equally on the management of an elevated systolic or diastolic reading.

The Patient

Clinical Symptoms

Probably, the greatest challenge for physicians treating high BP is the nonadherence to therapy as the condition is largely asymptomatic until there is end-organ damage. The major target organ damage (TOD) caused by systemic hypertension occurs in the heart, brain, kidney, peripheral arteries, and the retina. While uncommon, elevated BP may produce vague complaints such as suboccipital headaches, palpitations, facial flushing, lightheadedness, or fatigue. Accelerated hypertension may cause visual disturbances.

Clinical Signs

The threshold for the diagnosis of arterial hypertension is when the SBP exceeds 139 mm Hg or when the DBP is higher than 89 mm Hg. However, this definition is arbitrary, and in actuality, there is a continuous relationship with CV risk down to a level of 115/75 mm Hg.