Pharmaceutical Care and the Patient with Diabetes: Interventions to Help Control Diabetes and Its Related Comorbidities

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Discuss the impact of obesity on the development of diabetes.
• Identify the therapeutic goals of diabetes management.
• Select an appropriate pharmacologic intervention for the management of a patient with diabetes.
• List the key monitoring parameters for both efficacy and toxicity to be employed in evaluating a patient's diabetes drug-therapy regimen.
• Counsel patients on nonpharmacologic interventions??namely, diet, exercise, and home blood glucose monitoring??to help them achieve better control of their diabetes.
• Advise patients on the steps they can take to reduce the incidence of diabetes, control the progression, and manage diabetes-related complications, including heart disease, nephropathy, neuropathy, and retinopathy.

Diabetes is a chronic illness that is receiving much attention from both the medical community and the lay population. Some of the reasons for this interest are the increasing prevalence of the disease, its relationship to other comorbid conditions, an increased awareness of the impact of glucose control on the disease and on these related conditions, and the cost of the disease to society.

In 1996, 8.5 million adults were reported to have diabetes.¹ This number increased to 13 million in 2002. Furthermore, in 2002 it was estimated that another 5.2 million people had the disease but had not been diagnosed.² When limiting the numbers to adults affected by this disease, 18 million are age 20 years or older.²

Increased attention to and surveillance of diabetes, as well as an increased prevalence of obesity, are factors in the swelling numbers of patients with this disease. This continuing education article will discuss the relationship between obesity and diabetes and the impact that lifestyle modifications can have on this disease. It will discuss the various pharmacologic interventions that can be employed and what the pharmacist should know about the complications.

Obesity

As the prevalence of diabetes has increased over the past decade, so, too, have the numbers of patients classified as either overweight or obese.³ From 1991 to 2001, the percentage of obese adults in the United States increased by 74%.³ Comparably, from 1990 to 2001, the percentage of adults with diabetes increased by 67%.³

Obesity as a risk factor for the increasing development and identification of diabetes can be explained by its inclusion in the metabolic syndrome. In particular, abdominal obesity and its excess adipose tissue release products including nonesterified fatty acids (NEFA), cytokines, plasminogen activator inhibitor-1, and adiponectin.⁴ High NEFA levels have been found, by overloading the muscle and liver with lipid, to contribute to insulin resistance.⁴ It is, then, this insulin resistance and subsequent hyperinsulinemia that contribute to the development of diabetes (notably, type 2) and further weight gain (particularly in the abdominal region). Therefore, by combating obesity, insulin resistance would decline, and the progression to the diagnosis of diabetes (Table 1) would be slowed.

Research has demonstrated that a loss of 5% to 7% of body weight can result in the prevention or delay of the onset of diabetes in patients considered to be at risk.⁶ Over a 3- to 4-year period of lifestyle modifications, the risk of developing diabetes in high-risk patients was observed to decline by as much as 60%.⁷ Patients included in this research were considered to be at high risk for developing diabetes if they met the following criteria: ??25 years old; body mass index (BMI) of ??24 kg/m² (??22 kg/m² for Asian Americans); and impaired glucose tolerance (IGT).⁷ These patients with IGT or impaired fasting glucose (IFG) are considered, by definition, to have prediabetes. Lifestyle modifications, close monitoring, and routine screening for the presence of diabetes should be implemented in these patients. Table 2 gives the diagnostic thresholds for identifying patients with IGT and IFG.

Diabetes Management

There is a clear relationship between glucose control (or a lack thereof) and the development of diabetes complications. Furthermore, diabetes is a disease with large societal impact??both in terms of human lives and economically. As a cause of death, diabetes was ranked seventh on US death certificates in 1996.² Despite the increased awareness of the impact that glucose control has on the development and progression of diabetes and its related complications,^9,10 diabetes has now climbed to sixth place.¹ From an economic standpoint, the estimated total cost (direct and indirect) of diabetes in the United States in 2002 was $132 billion.¹¹ Secondary to the increasing prevalence of this disease, it is estimated that this number has the potential to increase to $156 billion by 2010.¹¹

Therefore, for these reasons, it is imperative that glucose control be stressed in all patients with diabetes. Patients need to understand and know their blood glucose goals. Table 3 identifies the current guidelines for glucose control in adults with diabetes. This control is achievable, and this fact needs to be relayed to patients. Moreover, patients need to "buy in" to this endeavor, and health care providers??especially pharmacists??should provide continued encouragement.

Blood glucose control can be achieved through lifestyle modifications (notably dietary interventions, weight loss, exercise, and home blood glucose monitoring) and with the addition, as necessary, of pharmacologic agents. Therefore, keeping this multifactorial approach to blood glucose control in mind, one can see why it is important for the pharmacist to be educated about all of the interventions??not just pharmacologic.

Nondrug Interventions

As noted, lifestyle changes such as dietary interventions, weight loss, and exercise are all imperative to achieving control of one's diabetes. The American Diabetes Association has termed dietary interventions as medical nutrition therapy, or MNT. In general, the goals of MNT are to aid in achieving and maintaining normal blood glucose levels, to positively impact both lipid levels and blood pressure, and to improve overall health.¹² MNT focuses on the intake of carbohydrates and fats (Table 4).

It is important for all patients to be aware of portion sizes and food choices. Patients often are surprised to learn that a portion of pasta, for example, should be 1/2 cup. Good carbohydrates??such as fruits, vegetables, and whole grain breads??should be stressed, because of their increased fiber content as well as their greater vitamin and mineral content. Less nutritive carbohydrates??such as white breads, pasta, and rice??should be limited. Patients also should be aware of the types of fats they ingest. Saturated fats, such as fats derived from animals, contribute greatly to coronary heart disease (CHD).

The American Diabetes Association utilizes and encourages the use of the Diabetes Food Pyramid to guide healthy eating among patients with diabetes.¹⁴ The bottom of this pyramid consists of breads, grains, and starchy vegetables such as beans; the 2 components of the second level are fruits and vegetables; the third level consists of milk and meat, meat substitutes, and other proteins; the top of the pyramid??the smallest component??is made up of fats, oils, and sweets. This pyramid stresses eating a wide variety of foods every day and eating high-fiber foods by getting the most servings from the bottom 2 levels.

Incorporating some of these dietary interventions into one's lifestyle will help in obtaining better glucose control; it also may contribute to weight loss. In addition, exercise can contribute to weight loss and improved glycemic control. Thirty accumulated minutes of moderate exercise on most days of the week is recommended for all people.¹³

For patients with diabetes, however, a thorough evaluation is very important prior to embarking on any type of exercise regimen. If it is discovered that a patient already has begun to develop some of the complications of diabetes??notably cardiovascular disease, peripheral arterial disease, neuropathy, and retinopathy??then the exercise regimen may need to be changed or limited (Table 4).¹³

Along with diet and exercise interventions, another major component of diabetes self-management is home blood glucose monitoring (HBGM; Table 4). Clear benefits from HBGM include immediate feedback relative to the influence of diet and exercise on one's blood glucose. Furthermore, it allows a patient to see, over time, the effect that the addition of medication(s) has on glucose control. For HBGM to have optimal impact, patients need to know what their blood glucose goals are (Table 3) and how to interpret the values they obtain.

Drug Therapy

Despite maximum patient effort relative to diet and exercise, the addition of pharmacologic agents often is necessary. Although the use of diet and exercise contribute to overall glucose control in patients with type 1 diabetes, their survival depends on the use of insulin from the point of diagnosis. In patients with type 2 diabetes, diet and exercise may be sufficient to control glucose for a period of time. Typically, there comes a point, however, when the addition of drug therapy is necessary to help maintain this same level of glucose control. For patients with type 2 diabetes, the armamentarium of drug therapy has ballooned in the past decade. As a result, there are now several pharmacologic options to employ prior to initiating insulin therapy.

Insulin

In the past, insulin was derived from either cows or pigs (beef or pork insulin). Limitations to its use included rejection and reactions by patients, because these proteins were not identical to human insulin. Today these sources of insulin are no longer used, as recombinant DNA technology has allowed for the mass production of insulin identical to human insulin. Insulin, regardless of the type (Table 5), works by allowing the entry of glucose into the cells of the body for energy.

Different types of insulin generally are used in combination??short-acting along with intermediate- or long-acting??in order to attempt to achieve insulin levels similar to what is observed with endogenous insulin secretion. Endogenous insulin secretion includes a continuous low level of secretion (basal insulin production). Following the ingestion of food, endogenous insulin secretion is increased, resulting in "peaks" of insulin production. Some combinations of therapy include NPH insulin twice daily to provide "basal" coverage and short-acting insulin prior to meals to mimic the "peaks" Other combinations include the use of 1 dose of a long-acting insulin and dosing of a short-acting insulin prior to meals. The use of HBGM is imperative in patients requiring insulin therapy as a means of helping to adjust specific doses, so as to maintain glucose control while avoiding episodes of hypoglycemia.

The pharmacist should be familiar with certain educational points in order to provide the patient with accurate information, in an attempt to produce maximum therapeutic results. These points include insulin storage and handling, compatibility of insulin mixtures in the same syringe, and insulin administration.

With regard to storage and handling, because insulin is a protein, it loses potency if it is exposed to high temperatures. Unopened bottles should be stored in the refrigerator until they are used, and they should be discarded on passage of the expiration date. An opened bottle can be stored at room temperature without loss of potency for 1 month.

Room-temperature insulin is preferred because it causes less discomfort on injection.

From a compatibility standpoint, glargine is not compatible with any of the other available types of insulin. The short-acting insulins are all compatible in the same syringe with NPH. Regular insulin also is compatible with Lente and Ultralente. Lispro is compatible with Ultralente. Any combination containing Lispro, however, should be used within 5 minutes of mixing. Lente and Ultralente can be combined.

Regarding insulin administration, patients should be aware that the primary injection sites include the abdomen, upper arms, thighs, and buttocks. Injections are made into a "pinched" area of the subcutaneous fat layer at a 90-degree angle. Because absorption varies from these different sites, it is important that the patient know that the same dose (eg, the breakfast dose, the dinner dose, etc) should be injected into the same anatomical area (eg, the abdomen, an arm, a thigh, etc) daily. In using the same anatomical area, however, it is important to rotate the injection site within the area. Each injection should be an inch or more away from the previous injection site, to reduce the likelihood of developing local irritation or lipodystrophy. The development of lipodystrophy, atrophy, or hypertrophy of the skin may result in erratic absorption if that area is used for insulin administration. This erratic absorption can change the expected onset/peak times for the activity of the insulin, which may increase the risk for poor control and/or of hyper- or hypoglycemia.

Hypoglycemia (defined as a blood glucose level of <70 mg/dL) is the most common side effect of insulin therapy. Either too much insulin or too little food can cause this effect. Exercise, particularly in the absence of adequate food intake, also can contribute. It is important for patients to know the symptoms of hypoglycemia: shaking/tremor, tachycardia, perspiration, and confusion. If hypoglycemia is suspected, patients should be instructed to check their blood glucose and to know how to treat it??without overtreating it. Treatment for hypoglycemia includes ingestion of 15 g of carbohydrate (eg, 3 teaspoonfuls of sugar or the appropriate number of glucose tablets, depending on their content, or 1/2 cup of sweetened fruit juice or soda). The blood glucose level should be rechecked in 15 minutes. If this recheck reveals persistent hypoglycemia, an additional 15 g of carbohydrate is given, and the process is repeated until the blood glucose is within the normal range. When the results are within the normal range, the patients need to decide whether the next meal is close enough or whether they need a snack containing both carbohydrate and protein to hold them over until that next meal.

Oral Agents

The cornerstone of drug therapy in type 2 diabetes is the available oral agents. As noted previously, several classes of agents are now available, each with a unique mechanism of action.

The beauty of this variety, beyond simply extending the time until the use of insulin is required, is that they can be used individually or in combination. With varying mechanisms of action, their combined use results in greater blood glucose control.

Sulfonylureas

The original class of oral agents, the sulfonylureas, exerts its effects by stimulating the pancreas to produce insulin. Agents within this class can be divided into either first- or second-generation agents. The only first-generation sulfonylurea still available is chlorpropamide. This agent is much less potent than the second-generation agents, and it can exert hypoglycemic activity for >48 hours.¹⁵ Because it is a renally excreted agent, this duration of effect can be even longer in patients who have renal dysfunction. In comparison, the duration of action of the second-generation agents??glimepiride, glipizide, and glyburide??does not exceed 24 hours.¹⁵

Given the mechanism of action of this class of agents, the primary side effect is hypoglycemia. If it occurs, patients should manage it in the same way as previously noted for hypoglycemia associated with insulin. Another negative consequence of sulfonylurea therapy is weight gain. Weight gain also is observed in patients starting insulin therapy. The mechanism for this weight gain stems from insulin's natural function of energy storage??including the preservation and laying down of fat tissue. This is particularly bothersome, because many type 2 diabetes patients already are overweight or obese. For this reason, other treatment options now are often employed for diabetes management in overweight/obese type 2 patients.

Meglitinides

Another class of agents that works very similarly to the sulfonylureas is the recently added meglitinides. Repaglinide and nateglinide are the 2 agents, to date, within this class. Whereas their mechanism of action is similar to that of the sulfonylureas in that they stimulate insulin secretion, they differ in that their peak effects occur within 1/2 to 1 hour of dosing, and their duration of activity is only approximately 5 hours.¹⁵ Therefore, their use is reserved for mealtime administration as a means of helping to control postprandial hyperglycemia.

Biguanides

The only biguanide currently available in the United States is metformin. It exerts its activity primarily by reducing hepatic glucose production. It also reduces blood glucose levels, however, by increasing the sensitivity of muscle tissues to insulin.¹⁷ Thus, when used as monotherapy, it is not likely to contribute to hypoglycemia. In addition to the positive impact of metformin on blood glucose, other benefits include modest weight loss and improvement in the lipid profile. It is used quite frequently as the drug of first choice in obese type 2 diabetes patients.

Metformin typically is administered twice daily with meals to help reduce the occurrence of diarrhea.¹⁷ Another potential side effect of metformin therapy is lactic acidosis. Although this metabolic condition can be fatal, its actual incidence is very low. In fact, when the recommended contraindications to its use are adhered to, there is no greater association with the occurrence of this condition than with other antihyperglycemic treatments.¹⁸ These suggested contraindications include serum creatinine level of ??1.5 mg/dL in males and ??1.4 mg/dL in females.¹⁹ Furthermore, close monitoring of renal function via serum creatinine levels is suggested for all patients undergoing radiologic studies requiring the use of intravenous contrast media that are known to have acute, negative effects on renal function. It is prudent to withhold treatment of metformin on the day of such studies and to reintroduce it after determining that renal function has not been affected or has returned to baseline.

As noted previously, the beauty of the various mechanisms of action among the different classes of drugs used in the management of diabetes is their increased efficacy when used in combination. Although individual agents can be given separately, because of the benefits of combination therapy and the importance of adherence to the drug therapy regimen, combination agents have been developed. To date, there are 2 different combination products that utilize a sulfonylurea and metformin. Metaglip combines glipizide and metformin in formulations containing either 2.5 mg or 5 mg glipizide and either 250 mg or 500 mg of metformin. Similarly, Glucovance combines glyburide and metformin in formulations containing 1.25 mg, 2.5 mg, or 5 mg of glyburide and either 250 mg or 500 mg of metformin.

Thiazolidinediones

Pioglitazone and rosiglitazone are the 2 available agents in this class. The maximal glucose-lowering effects observed with these agents do not occur quickly, but rather approximately 4 to 6 weeks or more after therapy initiation or dose escalation. Their mechanism of action includes increasing the sensitivity of muscle tissue to the effects of endogenous or exogenously administered insulin by affecting the makeup of the cells. When these agents are added to insulin regimens in patients with type 2 diabetes, it often is possible to reduce the insulin dose.

The side effect of most concern with this class of agents is hepatotoxicity.¹⁷ Although its occurrence with pioglitazone and rosiglitazone is extremely rare, experts recommend that baseline liver tests be performed at the start of therapy and that periodic evaluation be done throughout therapy. This class of agents also may contribute to fluid retention and is, therefore, contraindicated in patients with New York Heart Association stages III and IV congestive heart failure.²⁰

Because of the varying mechanisms of action and the increased glucose control when agents are combined, a combination product containing the thiazolidinedione rosiglitazone and metformin has been developed. It is marketed under the brand name Avandamet, and it contains either 2 mg or 4 mg of rosiglitazone and 500 mg or 1000 mg of metformin. The same monitoring needs to be performed for the combination as would be performed for the 2 agents used individually.

Alpha-Glucosidase Inhibitors

Acarbose and meglitol are the 2 agents in this class. Like the meglitinides, these agents are intended primarily to impact postprandial hyperglycemia. They exert their activity in a very different way, however. Instead of stimulating insulin secretion, acarbose and meglitol inhibit the release and function of alpha-glucosidase. This is the enzyme that is responsible for the breakdown of dietary starches and some sugars. As the breakdown of these products is slowed, the usually occurring spike in glucose following a meal is blunted. For these agents to achieve their maximum benefit, they must be taken with the first bite of a meal.

Their most common, therapy-limiting side effects are gas, loose stools, and diarrhea.¹⁷ Although it is not likely when used as monotherapy, when these agents are combined with other agents, such as the sulfonylureas, they may contribute to hypoglycemia. In this event, treatment is slightly different from what is employed with hypoglycemia associated with insulin or the sulfonylureas. With acarbose or meglitol, should hypoglycemia occur, the treatment includes the use of dextrose (found in glucose tablets) instead of sucrose (table sugar).

Drug-Therapy Monitoring

Regardless of the agent(s) used in the management of diabetes, patients should be encouraged to perform HBGM to see the effects that these agent(s) have on their glucose control. (See Table 3 for glucose goals.) In addition to measuring fasting and postprandial glucose values to monitor therapy, the use of the hemoglobin A_1C test (referred to as A_1C) is very useful. This test evaluates a patient's overall glucose control for the preceding 2 to 3 months. The American Diabetes Association recommends that this test be performed at least twice annually in patients who are meeting treatment goals, and quarterly in patients who are not meeting treatment goals or have had their therapy changed.⁵

Relative to the side effects to be monitored, each agent has its own specific "set" of side effects, as noted above. It is helpful if the pharmacist questions the patient about the occurrence of these side effects and if appropriate monitoring is done (eg, serum creatinine for metformin, baseline and periodic liver function tests for the thiazolidinediones, etc).

Comorbidities

Clearly, it is important to achieve and maintain the blood glucose levels recommended by the American Diabetes Association (Table 3) in order to prevent the "acute" occurrences of hypoglycemia and severe hyperglycemia. An equally if not more important reason for maintaining these levels, however, is to reduce the incidence of diabetes-related complications. Epidemiologic studies suggest a potential reduction in the macrovascular complication of CHD,5 whereas large, prospective, randomized, controlled trials have repeatedly illustrated the reduction in rates of the microvascular complications of nephropathy, neuropathy, and retinopathy.^9,10

Macrovascular Complication

CHD is the macrovascular complication related to diabetes. In fact, the relationship is so close that in 2001 the report of the National Cholesterol Education Program Expert Panel deemed diabetes a CHD risk equivalent.²¹ Thus, the risk of having a fatal myocardial infarction in patients with diabetes is the same as that observed in patients who already have established CHD. It is the leading cause of diabetes-related deaths.² Another way to look at this situation is that about 65% of deaths among patients with diabetes is related to CHD or stroke.²

The role that diabetes plays in increasing the risk of CHD stems from the relationship between hyperglycemia and the increase in intracellular oxidative stress.²⁰ Oxidative stress releases free radicals that initiate and perpetuate an inflammatory process within the vascular wall.²⁰ This inflammatory process creates the basis for the process of atherogenesis??or clogging of the arteries. Patients with diabetes experience these negative changes in their arterial walls very early in the metabolic disturbances associated with hyperglycemia.²⁰ They experience the changes so early, in fact, that accelerating vascular dysfunction may be occurring in those patients identified as having IGT...IFG??prediabetes. The plaques that line the vascular wall in patients with diabetes appear to be much more susceptible to rupture than in patients without diabetes.

One can see the extreme importance of diet, exercise, and weight loss in all patients in an attempt to stave off the diagnosis of diabetes, as well as to slow the damage being done to the vascular wall. In patients with diabetes, these lifestyle modifications are just as important in helping to maintain desirable glucose levels and, therefore, in reducing intracellular oxidative stress.

Once one is aware of the strong relationship between diabetes and CHD, it is clear to see why diabetes is considered a CHD risk equivalent and why it is so important to achieve and maintain the recommended blood glucose goals. In addition to good blood glucose control, however, there are other treatment goals to be aware of in diabetic patients. These include the goals for low-density lipoprotein (LDL) cholesterol and blood pressure. Given the fact that diabetes is considered a CHD risk equivalent, the goal LDL in patients with diabetes is <100 mg/dL. Recent data further suggest that treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (the "statins"??pravastatin, simvastatin, etc) in those whose LDL is already <100 mg/dL may be of benefit in reducing the risk of CHD even more.^22,23 It is recommended, then, that all diabetic patients >40 years old with a total cholesterol level of >135 mg/dL, regardless of current LDL level, should be prescribed a statin to try to achieve a lowering of LDL by ~30%.⁵

The other CHD treatment goal to be aware of in patients with diabetes is that of blood pressure. Approximately 60% of patients with diabetes also have hypertension.²⁰ This high prevalence, like the increased risk of CHD, can be attributed not just to the comorbid disease of diabetes, but also to the related conditions such as obesity, insulin resistance, and increased incidence of renal disease. Knowing the role that elevated blood pressure plays in the development of CHD, and knowing the CHD risk acquired simply via the diagnosis of diabetes, it is understandable, then, that tight blood pressure control also is desired. Blood pressure control can reduce cardiovascular disease by approximately 33% to 50%, and for every 10-mm Hg reduction in systolic blood pressure a 12% reduction in risk of any diabetes-related complication is realized.²

In diabetic patients, it has been established that lowering the blood pressure to <130/80 mm Hg would be more desirable than lowering it to <140/90 mm Hg, which is the treatment goal for the general population.²⁴ Drug therapy is recommended for all diabetic patients with a blood pressure of >140/90 mm Hg.^5,25 For those patients whose blood pressure falls between 130/80 mm Hg and 140/90 mm Hg, lifestyle changes should be employed for a maximum of 3 months.^5,25 If the goal of <130/80 mm Hg is not met within that time frame, drug therapy is then employed.^5,25

The other major CHD intervention to be aware of, in addition to glucose control and lipid and blood pressure lowering, is antiplatelet therapy??namely aspirin. Aspirin therapy (75-162 mg/day) is recommended for the primary prevention of CHD in both type 1 and type 2 diabetics over the age of 40 years or in whom other CHD risk factors exist.⁵ It should be employed at this same dosage level for secondary prevention in all patients who already have CHD, regardless of their age.⁵ It should not be used in diabetic patients <21 years because of the increased risk of Reye's syndrome. In patients unable to take aspirin, the use of other antiplatelet agents such as clopidogrel should be considered. Table 6 summarizes 10 facts that the pharmacist should know about diabetes and CHD.

Microvascular Complications

Like the macrovascular complication of CHD, the microvascular complications of nephropathy, neuropathy, and retinopathy occur via similar mechanisms. Therefore, as with CHD, tight glucose control is imperative. It has been observed, however, that for every 1% reduction in HbA_1C the risk of developing any of these microvascular complications is reduced by ~40%.² Moreover, there is a relationship between blood pressure and these complications; controlled blood pressure may result in a 33% reduction in their occurrence.² Each microvascular complication will be discussed briefly. Table 7 summarizes 10 facts that the pharmacist should know about diabetes and microvascular complications.

Nephropathy

The development of nephropathy occurs as a result of uncontrolled blood glucose, with uncontrolled blood pressure having an additive effect. It is screened for and evaluated by measuring albumin in the urine. The earliest clinical evidence of nephropathy occurs with urinary excretion of albumin at levels of 30 to 299 mg/day.²⁶ This condition is referred to as microalbuminuria. Among patients with type 1 diabetes, ~80% of patients with microalbuminuria will develop overt nephropathy (>300 mg of albumin in the urine/day) over a period of 10 to 15 years.²⁶ Of these patients, approximately 50% will progress to end-stage renal disease (ESRD) within 10 years and 75% within 15 years.²⁶ Among patients with type 2 diabetes, 20% to 40% with microalbuminuria develop nephropathy, and ~20% of these patients will go on to develop ESRD.²⁶

Screening for nephropathy should occur annually for all patients with type 2 diabetes, beginning at the time of diagnosis.²⁶ This early screening is secondary to the fact that hyperinsulinism and have probably existed for quite some time before the actual diagnosis of diabetes was made. In patients with type 1 diabetes, annual screening should begin after 5 years' duration of the disease.²⁶ Screening can occur via spot collection, a 24-hour urine collection, or a timed collection (usually over 4 hr or overnight).²⁶ Before a definitive diagnosis is made, the test should be repeated at least 2 other times in the following 3 to 6 months.

It is recommended that optimal blood glucose and blood pressure levels be achieved and maintained, because these 2 measures have been illustrated to reduce the risk and slow the progression of nephropathy.²⁶ In patients with type 1 diabetes, angiotensin-converting enzyme (ACE) inhibitors have been proven to slow the progression of nephropathy in hypertensive patients. In patients with type 2 diabetes, both ACE inhibitors and angiotensin receptor blockers (ARBs) have been shown to have this effect.²⁶ Furthermore, ARBs have been shown, specifically, to delay the progression of nephropathy in type 2 patients with macroalbuminuria and a serum creatinine level of >2.5 mg/dL.²⁶ If the patient can tolerate neither of these 2 drug classes, then the use of non?Cdihydropyridine calcium channel blockers, beta-blockers, or diuretics should be considered.⁵

Neuropathy

As with the aforementioned complications of diabetes, the risk of developing neuropathy increases in patients who do not maintain good blood glucose control. The risk of foot ulcers and amputations, the most common consequences of diabetic neuropathy, is highest in patients who have had the disease for >10 years, are male, or have any of the other diabetes-related complications including CHD, nephropathy, or retinopathy.⁵ Therefore, in addition to glucose and blood pressure control to prevent the neuropathy initially, one of the best ways to reduce the risk of amputation is for providers and patients to be cognizant of proper foot care.

The utilization of comprehensive foot care programs has reduced amputation rates by 45% to 85%.² Such programs include comprehensive foot examinations by the provider and education of the patient regarding self-care behaviors. The foot examination should include checking pulses, checking sensation (using a monofilament), evaluating general foot structure and looking for bony deformities, and evaluating the skin and nails for abnormalities such as calluses and infection.^27,28 Patient education includes encouraging patients to wash, dry, and inspect the feet daily; wear "breathable" socks; wear shoes with adequate toe boxes; treat dry skin as needed but avoid the use of moisturizers between the toes; and cut toenails straight across, not at an angle, so as to avoid ingrown toenails.

Patients should be encouraged to seek care from their primary provider or podiatrist immediately if they have wounds or ulcers; pain, numbness, or tingling of the feet; or corns, calluses, bunions, or ingrown toenails.²⁷ Patients who smoke should be encouraged to quit, because doing so helps to reduce the risk of vascular complications that contribute to the development of foot wounds and, potentially, amputation.²⁸

Retinopathy

Just as diabetes is the leading cause of ESRD and is responsible for the majority of nontraumatic lower-limb amputations, it also is the leading cause of blindness among adults aged 20 to 74 years.^2,5 An estimated 12,000 to 24,000 new cases of blindness are identified each year in patients with diabetes.² As with the other microvascular complications of diabetes, blood glucose control is key to preventing or delaying blindness.⁵ Glucose control may reduce the risk of developing retinopathy by as much as 76%.²⁷ The risk is greater in patients with nephropathy and uncontrolled high blood pressure.

This complication is clearly related to the duration of diabetes. Knowing the level of risk that diabetic patients have relative to developing this complication has led to ever-improving screening and treatment strategies, however. The use of these strategies may actually delay or prevent blindness in ~90% of people with diabetes.²⁷

Patients diagnosed with type 2 diabetes should be screened for retinopathy via a dilated and comprehensive eye examination at the time of diagnosis. 5 Patients with type 1 diabetes need to have their first examination within 3 to 5 years of diagnosis.5 After the initial screen, all patients should have an examination performed annually. Every 2 to 3 years may be suggested, if the examination is normal. Should proliferative diabetic retinopathy develop, treatment includes retinal laser photocoagulation surgery that can reduce the risk of severe vision loss to 4% or less.²⁷

Elena M. Umland, PharmD: Associate Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia; Adjunct Clinical Assistant Professor of Family Medicine, Jefferson Medical College, Thomas Jefferson University Hospital

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.

CE REVIEW QUESTIONS (Based on the article starting on page 120.) Choose the 1 most correct answer.

1. Which of the following products is released by excess abdominal adipose tissue and contributes to insulin resistance and the development of diabetes?

• Nonesterified fatty acids
• Cytokines
• Plasminogen activator inhibitor-1
• Adiponectin

2. A loss of _____ of body weight can result in the prevention or delayed onset of diabetes in patients considered to be at risk.

• 1%-3%
• 3%-5%
• 5%-7%
• 7%-9%

3. What is the preprandial plasma glucose goal in patients with diabetes?

• 70-110 mg/dL
• 100-125 mg/dL
• 90-130 mg/dL
• 110-150 mg/dL

4. What is the hemoglobin A_1C (HbA_1C) goal in patients who have diabetes?

• <7%
• <8%
• <9%
• <10%

5. The American Diabetes Association Diabetes Food Pyramid focuses on _________.

• Avoiding white bread, rice, and pasta.
• Greatly limiting the daily intake of protein.
• Eating a wide variety of food and eating high-fiber foods.
• Reducing the intake of starchy vegetables such as beans.

6. Which of the following is a specific benefit of exercise in patients with diabetes?

• It acutely increases blood glucose.
• It improves insulin sensitivity.
• It directly slows the progression of retinopathy.
• It directly slows the progression of nephropathy.

7. The evaluation of a patient's blood glucose monitoring technique should be done _______.

• Initially only.
• Initially and at regular intervals.
• Every 5 years.
• At every appointment.

8. A patient comes to your pharmacy with a prescription for insulin glargine as well as regular insulin. Which of the following is true regarding these agents?

• Glargine and regular insulin cannot be combined in the same syringe.
• Once opened, they can be stored at room temperature until their expiration dates.
• The anatomic site for the morning dose should vary on a daily basis.
• Glargine and regular insulin can be combined in the same syringe but should be used within 5 minutes of mixing.

9. Which of the following is a common side effect of sulfonylurea therapy?

• Hepatotoxicity
• Lactic acidosis
• Diarrhea
• Hypoglycemia

10. Which of the following antidiabetic agents specifically lowers postprandial blood glucose levels?

• Glipizide
• Chlorpropamide
• Repaglinide
• Metformin

11. Which of the following agents would be the most appropriate firstline agent in an obese, 40-year-old patient recently diagnosed with type 2 diabetes?

• Acarbose
• Glyburide
• Metformin
• Nateglinide

12. A 32-year-old obese patient with type 2 diabetes has recently had acarbose added to her diabetes regimen of glimepiride. She has been experiencing hypoglycemic episodes about 1 hour following her meals. She has tried treating these episodes with 1/2 cup regular soda; however, her glucose level does not appear to respond well. At this time, you instruct the patient to:

• Eat more at mealtimes.
• Treat the episode with 1 cup of regular soda.
• Make an appointment with her provider for next week.
• Treat the episode with glucose tablets that she can purchase at the pharmacy.

13. Patients prescribed _________ should be instructed that the maximum glucose-lowering effects may not be realized for 4 to 6 weeks.

• Acarbose
• Glyburide
• Metformin
• Pioglitazone

14. A 42-year-old man has recently had his metformin dose increased from 500 mg po bid to 850 mg po bid as a result of his HbA_1C test. When should the next HbA_1C test be performed?

• 1 month
• 3 months
• 6 months
• 12 months

15. Which of the following is a macrovascular complication of diabetes?

• Coronary heart disease (CHD)
• Nephropathy
• Neuropathy
• Retinopathy

16. The American Diabetes Association recommends a low-density lipoprotein (LDL) goal of _______ and a blood pressure goal of _______ in all patients with diabetes.

• <70 mg/dL; <120/80 mm Hg
• <100 mg/dL; <130/80 mm Hg
• <130 mg/dL; <140/90 mm Hg
• <160 mg/dL; <145/95 mm Hg

17. Which class of lipid-lowering drugs, when added to patients whose LDL is already at or below their goal, has been shown to further reduce their risk of CHD?

• Bile acid sequestrants
• Fibric acid derivatives
• HMG-CoA reductase inhibitors
• Niacin

18. A reduction of HbA_1C by 1% has been shown to reduce the risk of ____________ by ~40%.

• Nephropathy
• Neuropathy
• Retinopathy
• All of the above

19. Screening for nephropathy and retinopathy should begin at the time of diagnosis for _________.

• Patients with type 1 diabetes.
• Patients with type 2 diabetes.
• All patients with diabetes.
• Any patient with an HbA_1C level of >7.5% at the time of diagnosis.

20. All patients with diabetes and a history of CHD should be taking _________.

• Aspirin.
• Clopidogrel.
• Insulin.
• Niacin.

CE ANSWER FORM INSTRUCTIONS

TESTING AND GRADING PROCEDURES

• Each participant achieving a passing grade of 70% or higher on any examination will receive a statement of credit giving the number of CE credits earned. This form should be safeguarded and may be used as documentation of credits earned.
• Participants receiving a failing grade on any exam will be notified and permitted to take 1 reexamination at no extra cost.
• All answers should be recorded on the answer form attached. For each question, decide which choice is the best answer, and circle the letter of the response representing your choice.
• Mail your completed exam form to the following address: Pharmacy Times, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432.

NEW SCORING OPTIONS

• Mail
• Fax: 703-404-1801
• This lesson is $5 on-line; receive instant grading, as well as download your certificate??www.pharmacytimes.com

Please print clearly??certificate will be issued from information given.

Please mail completed forms with your payment to: Pharmacy Times CE Department, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432