Clinical Review
	This article is recommended by the Commission for Certification in Geriatric Pharmacy as a certification examination study resource.

The American Diabetes Association estimates that there are currently 16 million people in the United States with diabetes—about 4% of the general population. With a large population of “baby boomers” approaching an age when many are or will be developing diabetes, there promises to be a dramatic increase in the number of patients with diabetes in long-term care facilities. Of all patients with diabetes, approximately 10% are classified as having type 1 diabetes (no β-cell insulin production) and the remainder have type 2 diabetes (minimal or ineffective insulin production). The old terminology of “insulin-dependent diabetes mellitus” (IDDM), or “juvenile diabetes,” for type 1 diabetes and “non–insulin-dependent diabetes mellitus” (NIDDM), or “adult-onset diabetes,” for type 2 diabetes should not be used. The patient’s age or use of insulin does not determine the type of diabetes. An individual with type 2 diabetes now requires insulin therapy, but this does not mean type 1 diabetes has developed. These individuals still produce some insulin, which will substantially reduce the risk for developing some acute complications.

Currently, the health care costs for patients with diabetes account for about 14% of the total health care budget nationwide.¹ Advances in diabetes care will mean patients will live longer, but the likelihood of developing complications also increases. Availability of progressive treatments and education today does not guarantee that patients will be healthier longer. Large segments of the population have not had the opportunity or the motivation to improve their diabetes management. These individuals are still affected by long-term complications at relatively young ages. The overall cost to the health care system of diabetes treatment is surely going to increase, and the chronic complications of diabetes already account for about 40% of the excess cost of diabetes. With this in mind, the health care industry is finally turning its focus to prevention.^2,3 Unfortunately, change takes time, and not all health care providers appear to be aware of or willing to support new guidelines for tighter blood glucose control, especially in long-term care facilities.⁴

New Guidelines for Control

Table 1. Glycemic Control for People with Diabetes
			Additional
Biochemical Index	Normal	Goal	Action Suggested
Average preprandial glucose (mg/dL)	< 110	80–120	< 80 > 140
Average bedtime glucose (mg/dL)	< 120	100–140	< 100 > 160
HbA1c (%)	< 6	< 7	> 8
Note: The values shown in this table are by necessity generalized to the entire population of individuals with diabetes. Patients with comorbid diseases, young and older adults, and others with unusual conditions or circumstances may warrant different treatment goals. These values are for nonpregnant adults. “Additional action suggested” depends on individual patient circumstances. Such actions may include enhanced diabetes self-management education, comanagement with a diabetes team, referral to an endocrinologist, change in pharmacological therapy, initiation of or increase in self-monitored blood glucose, or more frequent contact with the patient. HbA1c is referenced to a nondiabetic range of 4.0%–6.0% (mean 5.0%, SD 0.5%). Values reported as plasma glucose for whole blood subtract 10%. Source: Adapted from American Diabetes Association.28,29

Diabetes management is complicated, especially when patients are likely to present with any number of comorbidities, including heart disease, hypertension, kidney disease, and chronic obstructive pulmonary disease (COPD). For the purpose of this article, we limit the discussion to those issues directly associated with and affecting diabetes management as it relates to complications. The consultant pharmacist is encouraged to develop a thorough understanding of hypertension, heart disease, lipid therapy, and kidney disease. These conditions will frequently mask the symptoms of complications, affect their treatments, and lead to development of other diabetes complications. However, they are much too complicated in and of themselves to be thoroughly addressed within the context of this article. Early recognition of acute problems and initiation of treatment are especially important in patients with long-term complications, because acute complications can also exacerbate other patient comorbidities. For example, the patient with severe cardiovascular disease (CVD) is at greater risk for stroke or heart attack if subjected to severe hypoglycemia.

Acute Complications

• Decreasing recognition of hunger and/or thirst
• Altered senses such as vision, taste, and smell
• Psychosocial stresses such as depression and anxiety
• Chronic diseases such as arthritis, COPD, and coronary artery disease (CAD)

Remember that patients will often lose the ability to recognize symptoms of acute complications and, therefore, not request or initiate treatment. The patient with long-term diabetes may also exhibit signs of long-term complications, such as neuropathy, which further diminishes the ability to recognize or handle acute complications. Therefore, it is of utmost importance that the consultant pharmacist and attending staff be aware of precipitating factors and symptoms, as well as treatments necessary for acute conditions.⁶

Hypoglycemia

On the other hand, patients managed properly with tighter blood glucose control by a staff adequately trained to recognize and handle hypoglycemia should be less of a burden than their uncontrolled counterparts; that is, if hypoglycemia is detected quickly and treated properly. Early recognition of hypoglycemia and recommendations for treatment become especially important in patients experiencing long-term complications, because hypoglycemia can also exacerbate other patient comorbidities, as mentioned earlier.

Patients with long-standing type 1 diabetes are generally much more prone to hypoglycemia. This is the result of a diminished capacity to produce glucagon, the counter-regulatory hormone produced by a-cells in the pancreas. A complete loss of glucagon secretory capacity is thought to occur after as little as 5–10 years of type 1 diabetes.⁷ As a result, these patients may not respond well to injected glucagon because of impaired glycogenolysis.⁸ Alternative therapies such as injectable glucose solution should be available in the event a patient is unresponsive to glucagon injection.

Although patients with type 2 diabetes are less likely to suffer from severe hypoglycemia, they are still prone to experience this complication when hypoglycemic agents are used. Patients taking sulfonylureas or insulin are particularly at risk.^9,10 Hypoglycemic episodes may be more prolonged with oral hypoglycemic agents because of these agents’ much longer duration of activity, especially when diminished renal function is present. Treatment should therefore reflect this possibility. Patients with type 2 diabetes can also experience rebound hyperglycemia, especially during the night. This phenomenon is reflected in high (persistent or increasing) fasting blood glucose levels when afternoon doses of hypoglycemic medications are added or increased. This is a result of blood glucose levels reaching hypoglycemic levels during sleep, which then triggers counter-regulatory hormone release (glucagon and adrenaline), stimulating liver glycogen breakdown. Patients experiencing symptoms of hypoglycemia during the night and/or elevated fasting blood glucose levels should have blood glucose levels taken at 3:00 a.m. to rule out this phenomenon.

Initial symptoms of mild hypoglycemia are generally cholinergic in nature and may include the following:^5,11

• Numbness or tingling (especially in mouth or fingers)
• Hunger
• Sweating
• Anxiety or nervousness
• Irritability
• Shakiness
• Pallor
• Palpitations/tachycardia
• Nausea

If unrecognized and not treated quickly, hypoglycemia usually will worsen, causing neuroglucopenia with more pronounced central nervous system symptoms such as:

• Inability to concentrate
• Confusion/irrational behavior
• Slowed reaction times
• Extreme fatigue

If hypoglycemia continues or becomes more severe, patients may:

• Become unresponsive
• Develop amnesia
• Suffer convulsions
• Lose consciousness

Note that patients with very tight blood glucose control whom frequently experience hypoglycemic blood glucose levels or have a long history of diabetes may not experience the pronounced symptoms of hypoglycemia. The usual symptoms may not appear at all, or if they do, not until blood glucose levels are well below the clinical threshold of 70 mg/dL.⁵ These patients will often have had long-standing diabetes (30 years or more) and are thought to lose the adrenaline-mediated responses, which include more visible warning signs such as anxiousness, sweating, shakiness, and pallor.¹² These patients and those with more advanced autonomic complications may experience hypoglycemia unawareness. In these cases, only very slight symptoms, if any, are present during hypoglycemic episodes, increasing the risk of much lower blood glucose levels and the possible loss of consciousness. Target blood glucose levels and relative risk times for hypo- and hyperglycemia, based on insulin and/or oral medication dose responses, should be determined and addressed to minimize these risks (Figure 1, Table 2).

Table 2. Oral Agent Hypoglycemia Risks and Recommended Blood Glucose Testing
Medication	Blood Glucose Most Affected	Testing to Recommend	Greatest Risk for Hypoglycemia
Sulfonylureas	Fasting and postprandial	2–3 times per day, especially fasting	4–6 hour p.c. and fasting
Biguanide	Fasting	Fasting	None
Thiazolidinedione	Fasting and postprandial	2–3 times per day, especially fasting	Post-exercise
Alpha-glucosidase inhibitor	Postprandial	2 hour p.c	None
Meglitinide	Postprandial	2 hour p.c.	2–3 hour p.c.
Source: The Diabetes Center, Old Saybrook, Connecticut, 1999.

Patients with hypoglycemia unawareness will generally develop neuroglycopenia and become lethargic, irritable, and confused, and lose consciousness or have a seizure while experiencing minimal cholinergic-type symptoms.¹³ However, these patients can learn to recognize when they are becoming hypoglycemic by being trained to recognize properly very subtle symptoms, such as tingling in fingertips, tongue or lips; slight pain in areas of peripheral neuropathy; blurred vision; or headache. If possible, patients should frequently self-monitor blood glucose, or have it monitored for them, during higher-risk times to identify these or other signs of impending hypoglycemia.

Patients with long-standing diabetes experiencing hypoglycemia unawareness may also have some degree of autonomic neuropathy. This chronic condition alters gastric emptying times, clinically defined as gastroparesis. It can lead to decreases in the rate of absorption of food and/or drugs from the digestive track, which will make predicting effects much more difficult. Gastroparesis can also cause irregular responses to the oral supplements used to treat hypoglycemia. Treatment of hypoglycemia should therefore consist of glucose products rather than complex carbohydrates to ensure consistent and rapid absorption.

Symptoms of gastroparesis (which may not cause any symptoms) are:

• Heartburn
• Reflux
• Early satiety
• Nausea
• Abdominal bloating
• Erratic blood glucose levels

Early recognition of hypoglycemic symptoms through more frequent blood glucose monitoring and identification of high-risk times and individuals is especially important with elderly patients. As mentioned earlier, many hypoglycemic symptoms are also associated with the aging process and, therefore, are attributed to other causes and not addressed appropriately. The best treatment always starts with prevention, and prevention starts with education.

Precipitating factors for hypoglycemia in long-term care facilities often include:

• Diminished appetite
• Increased activity (such as physical therapy, which can lower blood glucose levels for up to 24 hours)
• Decreasing renal function, delaying drug clearance
• Weight loss without insulin or hypoglycemic agent dosage adjustments
• Addition of medications, leading to a decrease in blood glucose levels (Table 2)

Although the general rule of treatment is applicable to all forms of hypoglycemia and includes the treatments in Table 3, optimal treatment should be based on an accurate patient assessment. Factors that should be considered when determining the most appropriate treatment of hypoglycemia are:

• When was the last meal or food eaten, and when is the next meal?
• Does the patient have any gastrointestinal (GI) disorders that will affect carbohydrate absorption?
• When was the last dose of hypoglycemic medication taken, what type of medication was it, and how much was taken?
• When was the last physical activity, how strenuous was that activity, and how long did the activity last?

Table 3. Suggested Treatments for Hypoglycemia
Glucose Source	Dose (15 g Carbohydrate	Comments
Glucose tablets	3–4 tablets p.o.	Don’t use if patient can’t chew.
Glucose gel	1–2 tubes p.o.	Maybe placed in cheek if minimally responsive.
Lifesavers	6	Should be chewed; dissolving may delay relief.
Raisins	2 tbsp.
Table sugar	1 tbsp.	Best if dissolved in small amount of liquid.
Fruit juice	1/2 cup
Soda	1/2 cup	Must not be sugar free.
Milk	1 cup	Protein content provides more prolonged effect.
Source: Adapted from Santiago JV. Medical management of insulin-dependent (type 1) diabetes. 2nd ed. Alexandria, VA: American Diabetes Association; 1994.

Treatment of Hypoglycemia

Severe hypoglycemia, characterized as a patient being unconscious or unresponsive or unwilling to take carbohydrate orally, should be treated initially using glucagon. Glucagon should be available on all units of the long-term care facility for emergency use, and staff should be trained on proper reconstitution and administration before an emergency happens. An adult dosage is 1 mg SQ, with the patient regaining responsiveness within 20 minutes. Vomiting can occur after glucagon is administered; therefore, appropriate measures should be taken to prevent aspiration of stomach contents. Additional carbohydrate should be consumed (Table 3) when responsiveness returns, and the cause of hypoglycemia should be determined to prevent or minimize future episodes.

If hypoglycemia is a recurring problem, the glycemic medication(s) dose-response profile should be considered and changes made to those medications causing the hypoglycemia. This will minimize the risks during times when patients are more prone to hypoglycemia (Tables 2 and 4, Figure 1). Changes that should be considered are (1) decreasing the dose of the causative oral agent or insulin, (2) adding a snack before activities and during times of high risk, and (3) scheduling activities for times when hypoglycemic risk is lower.

Hyperglycemia

Table 4. Insulin Onset, Duration, and Times of Hypoglycemia Risk
Human Insulin	Onset	Peak	Effective Duration	Maximal Duration	Hypoglycemia Risk
Lispro Premeal	< 15 min.	1–2 hr.	2–4 hr.	3–5 hr.	Just after injection
Regular Premeal	0.5–1 hr.	2–4 hr.	3–6 hr.	4–8 hr.	Prior to next meal or during night
NPH b.i.d.	2–4 hr.	4–10 hr.	10–16 hr	14–18 hr.	Afternoon or during night
Lente b.i.d.	3–4 hr.	4–12 hr.	12–18 hr.	16–20 hr.	Afternoon or during night
UltraLente	6–10 hr.	None	18–20 hr.	20–30 hr.	Cumulative effect
NPH with R b.i.d.	0.5–1hr.	2–10 hr.	10–16 hr.	14–18 hr.	Prior to next meal afternoon and during night
Note: Hypoglycemia can be caused by many factors and is not confined to any specific time period. This information is intended only as a guide to possibly help isolate a cause of repeated hypoglycemia and/or prevent future hypoglycemia through adjustment of the correct insulin dose. Source: Adapted from the Diabetes Center, Old Saybrook, Connecticut, 1999.

In cases of intermittent or mild hyperglycemia, simple adjustments in medication may be needed to bring a patient’s blood glucose levels under control within a relatively short period of time. In many cases, placing the patient on insulin therapy provides greater flexibility and allows for p.r.n. dosing to correct blood glucose excursions. Insulin therapy allows for more accurate dosing, better blood glucose control, and tailoring of therapy to fit the patient’s blood glucose pattern. Unfortunately, insulin therapy also requires more involvement of facility staff and more frequent blood glucose testing. This provides an opportunity for the consultant pharmacist to become involved in blood glucose pattern management by monitoring the patient, providing education in-services on insulin dose-response issues, and actual dose regulation input.

Insulin doses should be adjusted based on the result of blood glucose testing, keeping in mind that the last insulin dose is affecting the current blood glucose level. Most inexperienced staff and patients will increase or decrease the current insulin dose based on current blood glucose levels. This “chasing” of blood sugars can place the patient at risk for hypoglycemia or continued hyperglycemia, because the problem began with the last insulin dose, not the current one. For example, a patient taking just neutral protamine Hagedorn insulin (NPH) once a day will often have the morning NPH increased when blood glucose levels are elevated at this time. The patient then experiences hypoglycemia later in the day, which is treated by providing carbohydrate. This causes blood glucose levels to be higher the following morning, to which the staff responds by further increasing the insulin dose.

Frequent adjustments of insulin doses are encouraged with most patients, especially when using rapid-acting insulins (Figure 2). Unlike regular insulin, which can take as much as 30 minutes to begin working and has a duration of action of 4–8 hours, insulin lispro has a relatively short onset and duration of action and a more predictable dose-response profile. Lispro begins working within minutes of injecting, and its effect generally last only 2–4 hours. This is especially useful in patients with unpredictable eating patterns. Lispro can be given just after the meal in doses based on what the patient actually ate. This reduces the risk of hypoglycemia by matching the dose to food intake, while the rapid onset reduces the risk of postprandial hyperglycemia. It is also useful for those patients taking regular insulin at supper and frequently experiencing nocturnal hypoglycemia. Since lispro only has a duration of action of a few hours, by the time the patient goes to sleep, it is no longer working and therefore not adding to the effect of longer-acting insulins such as NPH if given together. The greatest advantage of its rapid onset and short duration is that lispro can easily be used on a p.r.n. basis to bring hyperglycemia under control. When using lispro, insulin sensitivity should be determined based on the patient’s actual insulin responses. A patient’s response can be roughly estimated by taking the patient’s total daily caloric intake and dividing it by the usual total daily dose of insulin. For example, a patient with a total calorie intake of 1,500 calories per day is taking 24 U 70/30 insulin in the morning and 12 U before supper. This patient’s insulin sensitivity would be 1,500/(24 + 12) = 42. In other words, 1 U of insulin is expected to decrease the patient’s blood glucose levels by 42 mg/dL.¹⁴

The repeated or frequent need for these additional doses of insulin should be recognized as an indication of a problem with the routine insulin doses, which should then be adjusted accordingly.

Dehydration

Table 5. Signs of Possible DKA

Hyperglycemia with its manifestations (polyurea, polydipsia, polyphagia, blurred vision) Hyperpnea (deep respirations) Acetone (fruity) breath due to excretion of acetoacetate by the lungs Dehydration Acute abdominal tenderness with nausea or vomiting Sudden mentation changes

Diabetic Ketoacidosis

During these times of insulin deficiency, hepatic glucose output increases as a result of gluconeogenesis, with the subsequent release of free fatty acids. This leads to ketogenesis in the liver, which increases concentrations of acetoacetate and beta-hydroxybutyrate.¹⁵ As these metabolic by-products accumulate in the blood, causing acidosis to develop, there is a pronounced increase in serum ketone concentrations, and these by-products then begin to appear in the urine. As blood glucose levels continue to rise from hepatic glucose output, hyperglycemia worsens, causing more frequent urination and pronounced dehydration via osmotic diuresis. This potentiates the electrolyte imbalance and the acidosis.¹⁶ Acidosis then leads to rapid respiration (Kussmaul’s) or hyperventilation. This causes partial respiratory alkalosis as the body tries to correct the acidosis state.

Further electrolyte imbalances can occur as a consequence of the acidosis itself. As hydrogen ion levels increase (pH levels drop), some ions move intercellularly, causing potassium to move out into the bloodstream. This leads to pronounced hyperkalemia and subsequent potassium dumping in the urine. Although initial blood work (Table 6) may show normal potassium levels or a state of hyperkalemia, during treatment it is especially important to monitor electrolyte levels and cardiac function, since severe drops in potassium (hypokalemia) are possible with the reinitiation of insulin therapy.¹⁷ Failure to recognize and treat DKA will lead to decreasing mental status and, eventually, coma and death.

Table 6. Initial Laboratory Values for Patients in DKA
Blood Test	Initial Value	Comments
Glucose	Greater than 250 mg/dL	Not related to severity of DKA
Ketones	Strong in undiluted plasma
Bicarbonate	0–15 mEq/L
pH	< 7.2
Potassium	May be low, normal, or high	Extracellular K+ excreted in urine; levels decline further with treatment, as it re-enters cells
Sodium	May be low, normal, or high	Levels depend on total body water, depletion with dehydration
Phosphate	Usually normal or slightly elevated	Due to phosphaturia; levels decline with treatment
Creatinine, BUN	Usually slightly elevated
Hemoglobin, hematocrit, total protein	Often increased	Secondary to concentrated plasma volume
Source: Adapted from Funnell M.6

Treatment of DKA

Patients will need to receive 3–5 oz of fluid per hour given p.o. in small doses every 20–30 minutes. Adequate insulin therapy should then be initiated, which is generally 10%–20% greater than the usual daily dose, depending on the patient’s individual sensitivity to insulin. This additional insulin may be administered in the form of short-acting insulin given every three to six hours. Extreme caution should be used if rapid-acting insulin is administered, because hypokalemia may develop rapidly. Patients should be monitored closely to maintain hydration and watched for signs of hypokalemia, with potassium supplements being available if needed. Symptoms of hypokalemia include skeletal weakness leading to paralysis, rapid diminution or absence of deep tendon reflexes, arrythmias, and shallow respiration. It is important to determine the cause of the ketotic state and correct it if possible. Insulin doses may also need to be modified, based on the patient’s response to treatment, to prevent hypoglycemia or further hyperglycemia. Blood glucose levels should return to normal within 12–24 hours, but urine ketone levels may remain positive for several days.¹⁸

In cases where more severe DKA is present or the patient is unable to take or retain fluids, more immediate emergency treatment is required in an acute-care hospital. Because patients are often quickly discharged to long-term care facilities after episodes of DKA, the consultant pharmacist should be aware of general treatment protocols. In almost all cases, hypovolemia becomes critical, and fluid volume replacement must be initiated as soon as possible. Obtaining the following test results is also recommended: level of hyperglycemia, urine ketones, serum ketones, serum bicarbonate levels, and arterial pH. The following baseline laboratory values should be obtained: electrolyte levels, including calcium, phosphorus, and serum ketone concentration; arterial blood gases; blood urea nitrogen and creatinine levels; and creatinine clearance (Table 6).

Initial fluid replacement usually begins with one-half normal to normal saline I.V. in the amount of 1–2 L (or 15–20 mL/kg) in the first 1–2 hours, depending on the patient’s level of dehydration and cardiovascular status. Rehydration of the patient will begin lowering blood glucose concentrations via simple dilution. Once blood glucose levels have decreased to less than 300 mg/dL, intravenous fluids should be changed to contain insulin and glucose, with electrolyte and volume levels determined by the patient’s status. In the case of potassium, when the level is less than 3.0 mEq/L, which, as mentioned earlier, can occur with initiation of insulin, the patient should also be placed on a cardiac monitor and observed for signs of hypokalemia.¹⁸

Protocols for initiation of insulin in cases of DKA varies considerably depending on the institution, but the following principles usually apply. Use of short- or rapid-acting insulin in a low-dose continuous I.V. infusion containing glucose is encouraged. This reduces the risk of sudden hypoglycemia and hypokalemia and offers a more predictable decrease in glucose and potassium levels than injected insulin. It is also thought to reduce the risk of cerebral edema associated with sudden drops in blood glucose levels.

Response to therapy should target a drop in blood glucose concentrations of 75–100 mg/dL per hour until normal target levels are reached. Ketosis is generally reversed in 12–24 hours, but urine ketones may be present for several days.¹⁸

Hyperglycemic, Hyperosmolar, Nonketotic Syndrome

As mentioned earlier, most patients with type 2 diabetes still produce at least some insulin, and they generally do not progress to a ketotic state. However, DKA is possible in severe cases. Increases in hepatic glucose production and an altered sensation of thirst and taste, combined with higher renal thresholds for spilling glucose, predispose these patients to dehydration and further contribute to increasing plasma glucose concentrations. Treatment is often delayed because symptoms are less pronounced, develop slowly over time, are often misdiagnosed as dementia, are attributed to other disease states, or are simply attributed to the aging process. It is also possible for HHNS to go unrecognized simply because patients do not complain.

Staff at a long-term care facility should recognize that patients who are ambulatory or semi–self-sufficient often respond to thirst by choosing sweet juices. This results in an increase in their level of hyperglycemia, with all its adverse effects. The increasing hyperglycemia and subsequent dehydration will almost always worsen with time, thus setting the stage for HHNS. Although DKA is generally considered to be the more serious of the acute complications, HHNS actually has a higher mortality rate. As many as 10%–20% of patients with HHNS will die as a result, compared with only 3%–10% of patients with DKA.¹⁶

The primary treatment goals of HHNS are eliminating dehydration and normalizing blood glucose levels. If identified in a timely manner, treatment may be handled in the long-term care facility, thus eliminating the need for acute hospitalization. Acute hospitalization should be undertaken in severe cases of HHNS or when the patient has a previous history of severe cardiovascular disease or complications.

The underlying cause of HHNS should be determined and corrected. Frequent causes include infection or acute illness, recent surgery, decreased fluid intake, and declining blood glucose control. In-service education of staff is recommended, especially with respect to the recognition of both symptoms of and predisposing factors for HHNS.

Treatment of HHNS

Peri- and Postoperative Care

More frequent blood glucose monitoring should be established before surgical procedures to ensure that adjustments are made to therapy in the event of hyper- or hypoglycemia.

Minor surgical procedures being performed on patients with adequate blood glucose control (fasting blood glucose levels are less that 140 mg/dL) who are on oral diabetes agents often do not require extensive alterations in their oral diabetes medication. The changes in therapy recommended in Table 8 can often be used.

If more involved procedures are involved or protocol preferences require patients to be placed on insulin, the following should be considered:

• Discontinue oral medications as indicated above, then, using multiple doses of short-acting rather than longer-acting insulin to increase dosing flexibility (during the procedure patients are usually given rapid- or fast-acting insulin intravenously with glucose)
• Keep the patient on insulin after the procedure to promote healing and reduce the risks of HHNS if better blood glucose control can be maintained.
• Agents requiring titration should be reinitiated as soon after the procedure as possible to maintain effectiveness at the patient’s pre-procedure dose.

If transitioning back to oral agents:

• Insulin should be continued until the next regular dose of the oral medication.
• More frequent monitoring is recommended during this transition.
• Supplements of rapid-acting insulin may be needed while titrating back to oral agents to ensure that blood glucose target levels are maintained.

For insulin-dependent patients, protocols vary considerably, depending on the institution and diabetologist or endocrinologist involved. In cases of extended procedures, almost all protocols require insulin therapy to be adjusted, which includes intravenous glucose and insulin being supplied during the procedure. Adjustments are then made based on blood glucose monitoring. With short procedures where the patient is usually able to eat within a few hours, several approaches may be used. For example:

• Withhold the morning dose of short- or rapid-acting insulin, but give one-half of all the intermediate-acting insulin for basal insulin coverage. Then give rapid-acting insulin after the procedure, based on blood glucose monitoring to attain target levels. Normal insulin doses are re-initiated at the next regularly scheduled time.
• Withhold all intermediate-acting insulin and use short- or rapid-acting insulin every 3–4 hours or p.r.n., dosed according to blood glucose monitoring results to attain target levels. This is done until the next regularly scheduled dose of intermediate-acting insulin.

If the patient must not eat beginning the day or night before the procedure, the following approach can be suggested:

• Withhold one-half of the evening or bedtime intermediate-acting insulin.
• Withhold the morning dose of intermediate-acting insulin and give rapid- or short-acting insulin, dosed according to blood glucose monitoring results to attain target levels. Short- or rapid-acting insulin is dosed in this same manner until the next scheduled dose of intermediate-acting insulin.

In all cases, should hypoglycemia develop before the procedure, oral glucose gel or injectable glucose is recommended for treatment to avoid adding contents to the stomach. After the procedure, more frequent blood glucose monitoring is always recommended. Temporary adjustments to insulin doses may be required as a result of factors such as increased stresses, decreased activity, or decreased appetite.

Chronic Complications

As documented in the UKPDS group, hypertension plays a major role in the development of complications and is a risk factor for development of diabetes itself. The medical staff should be encouraged to aggressively treat hypertension to minimize its impact. Blood pressures less than 130/85 mm Hg should be maintained in all patients with diabetes. What should be stressed to patients and caregivers is that even with good hypertension control, blood glucose control is the key to delaying or preventing long-term complications. The closer to normal a patient’s blood glucose levels are maintained, the less likely the long-term complications will develop and/or the slower the complications will progress.^23-26

Table 7. Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults

I. LDL cholesterol lowering* First choice HMG CoA reductase inhibitor (statin) Second choice Bile acid-binding resin or fenofibrate II. HDL cholesterol raisingBehavioral interventions such as weight loss, increased physical activity and smoking cessation may be useful Glycemic control Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates III. Triglyceride lowering glycemic control first priority Fibric acid derivative (gemfibrozil, fenofibrate) Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol IV. Combined hyperlipidemia First choice Improved glycemic control plus high-dose statin Second choice Improved glycemic control plus statin plus fibric acid derivative (gemfibrozil, fenofibrate) Third choice Improved glycemic control plus resin plus fibric acid derivative (gemfibrozil, fenofibrate) Improved glycemic control plus statin plus nicotinic acid (glycemic control must be monitored carefully) * Decision for treatment of high LDL before elevated triglycerides is based on clinical trial data indicating safety and efficacy of the available agents. The combination of statins with nicotinic acid and, especially, with gemfibrozil or fenofibrate may carry an increased risk of myositis. Source: Adapted from American Diabetes Association.28,29

Macrovascular Complications

TABLE 8. Changes in Therapy Prior to Minor Surgery
Medication	Therapy Alteration (simple morning procedure)
Sulfonylureas	Discontinue evening dose prior to surgery; reinitiate after procedure. Discontinue chlorpropamide 48-72 hours prior; reinitiate after procedure.
Metformin	Discontinue for 48 hours starting on day of procedure.
Glitazones	Discontinue morning of procedure, reinitiate after procedure.
Repaglinide	Not given unless patient is able to eat.
Alpha-glucosidase inhibitors	Not given unless patient is able to eat.

Microvascular Complications

When structural changes in the kidney begin to take place, the glomerular basement membrane thickens, mesangial expansion is observed, and the kidneys become enlarged. Initially, the patient’s glomerular filtration rate (GFR) increases, and over time, proteinuria develops, followed by a rising creatinine level and, finally, ESRD32 (Figure 3, Table 10). As with other complications of diabetes, treatment generally focuses on blood glucose and hypertension control. Although the addition of ACE inhibitors is accepted as the recommended therapy for treatment and prevention, the UKPDS also demonstrated an improvement when beta blockers were used. However, beta blockers should be used cautiously, as they are known to block autonomic responses to hypoglycemia.

Table 10. Lipid Level Risk Classification and Goals
Risk Factor	LDL	HDL	Triglycerides
High	≥ 130	< 35	≥ 400
Borderline	100–129	35–45	200–399
Low	≤ 100	> 45	< 200
Goal	> 35	< 200
With CHD, PVD, CVD	≤ 100	Initiate nutrition and drug therapy if LDL ≥ 100
Without CHD, PVD, CVD	≤ 100	Initiate nutrition and drug therapy if LDL ≥ 130
Source: Adapted from American Diabetes Association.28,29

Neuropathy

• Polyol hypothesis—involves the nerve cell resorting to the polyol pathway to metabolize an excess of glucose in the cell. In this case, glucose is reduced to sorbitol via the enzyme aldose reductase. Sorbitol is then metabolized to fructose via the enzyme sorbitol dehydrogenase. However, this step takes place much slower than the conversion of glucose to sorbitol. The build up of sorbitol is thought to, among other effects, decrease myo-inositol levels and decrease Na+-K+-ATPase activity, causing nerve swelling and demyelination.
• Vascular hypothesis—involves structural abnormalities of the microvasculature, which are similar to those seen in retinopathy and nephropathy, whereby blood flow is reduced, resulting in ischemia and nerve death.
• Advanced glycosylation end-products—may also play a role in causing pathologic changes in tissue by interfering with key matrix molecules in nerve cells. This impedes cell-to-cell interactions and may alter intracellular protein function and may be responsible for some of the symptoms of neuropathy.
• Neuronal growth factors—promote maintenance and regeneration of neurons and have been recognized as deficient in patient with diabetes. A decrease in NGFs is thought to decrease skin axon reflex vasodilation and lower levels of sensory neuropeptide substance, contributing to small nerve fiber damage.33

Table 11. Definitions of Abnormalities in Albumin Excretion
Category	24-hour Collection (mg/24 hr.)	Timed Collection (pg/mm)	Spot Collection(ug/mg Creatinine)
Normal	< 30	< 20	< 30
Microalbuminuria	30-300	20-200	30-300
Clinical albuminuria	> 300	> 200	> 300
Note: Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, and marked hypertension may elevate urinary albumin excretion over baseline values. Source: Adapted from American Diabetes Association.28,29

Because the actual cause of neuropathy is probably a combination of these causes, therapy is best approached by prevention. Once again, the most critical components for prevention and treatment are tighter blood glucose and blood pressure control.^22,34

Acute treatments will depend on several factors, including the degree of patient discomfort and dysfunction. In cases where the presence of autonomic neuropathy has led to gastrointestinal or genitourinary dysfunction, orthostatic hypotension, or other vagus nerve–mediated abnormalities, treatments are generally considered separately and will vary depending on the degree of dysfunction and its related symptoms. Neuropathic pain is usually treated using a combination of different drug classes, including narcotics, antidepressants, and anticonvulsants. Unfortunately, treatments are often abandoned as ineffective because relief was not realized quickly. The clinical pharmacist should consistently remind patients and staff that treatment and pain relief depends largely on trial and error and that results often take time. Use of any one of several types of medications and gradual titration may be necessary, requiring several days to weeks before optimal effect is realized. Agents frequently used in the treatment of neuropathies, which the pharmacist should be familiar with, are listed in Table 12.

Table 12. Agents Used to Treat Neuropathies
Condition	Agents Frequently Used
Gastrointestinal dysfunction	Metoclopramide, cisapride, erythromycin,laxatives and/or anti-diarrheal agents as needed
Hypotension	Midodrine (high-salt diets and fludrocortisone should be avoided due to risk of edema, congestive heart failure, and supine hypertension)
Genitourinary	Bethanechol and other parasympathetic agonists
Neuropathic pain	Narcotics (any)* Tricyclic antidepressants (nortriptyline,* desipramine,** amitriptyline) Anticonvulsants (carbamazepine, phenytoin, gabapentin,* lamotrigine, capsaicin)
* For acute pain or breakthrough pain. ** Preferred agent(s) due to less adverse side effects or toxicity. Source: Adapted from The Diabetes Center, Old Saybrook, Connecticut, 1999.

New agents currently in development show promise in targeting the underlying pathogenesis of diabetic neuropathies. These agents include recombinant human nerve growth factor (rhNGF), aldose reductase inhibitors, protein kinase C inhibitors, and ACE inhibitors. Possible beneficial aldose reductase inhibitors include Sorbinil (Pfizer), Alconil (Alcon), Statil (ICI), and Tolrestat (Wyeth-Ayerst). Gangliosides include Cronussial (Fidia).

Conclusion

Consultant pharmacists can and should be offering viable suggestions for more effective drug therapy and, at the same time, be monitoring and providing insight into the diabetes disease state process, particularly with respect to complications. They should be providing in-service diabetes education to staff and patients, especially those patients eligible for and capable of discharge to self-care at home. Proper input and education can and will help minimize future adverse drug events, such as episodes of hypo- and/or hyperglycemia. It will also improve blood glucose control for all patients with diabetes, decrease the burden on staff, improve the patient’s short-term outcomes by decreasing acute-care hospitalizations, decrease their length of stay, and increase the patient’s overall quality of life.

With an aging population, the number of patients with diabetes residing in long-term care facilities is going to increase in spite of the many advances being made in diabetes treatments. Acute and chronic complications are still going to be present and need to be managed. Opportunity already exists for those consultant pharmacists ready and willing to become actively involved in the management of patients with diabetes. Any input provided will usually be welcomed, especially considering that even small improvements in blood glucose control reduce the risk of diabetes complications.

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