ENDOCRINE SELF STUDY MODULE

Introduction to Medications for Diabetes Mellitus

Diabetes has often been described as "starvation in the midst of plenty." The adverse health effects of increased blood glucose occur either because there is too little insulin synthesized and released from the beta cells of the pancreas (type 1 diabetes) or because insulin receptors become insensitive and glucose transport into the cell is impaired (type 2 diabetes). It is now known that this is a gross oversimplification of the disease process. Most people with type 2 diabetes also experience reduced insulin secretion over time. Hormones other than insulin, such as glucagon, cortisol, and growth hormone (the so-called counterregulatory hormones), are involved as well. Serum potassium levels also play a role, because adequate levels of extracellular potassium are key in the ability of insulin to drive glucose into the cell.

Goals of Pharmacotherapy for Diabetes Mellitus

The primary goal of pharmacotherapy for diabetes is to maintain "tight control" of plasma glucose levels. Maintaining the plasma glucose level as near normal as possible, in addition to treating hypertension and hyperlipidemia, helps postpone or even prevent both acute and long-term complications (sequelae).

Treatment Targets for Patients with Diabetes

Categories of Pharmacotherapeutic Agents for Diabetes

Pharmacotherapeutic agents for diabetes can be divided into the following categories:

Agents that stimulate insulin release Agents that stimulate insulin receptors Agents that decrease/delay glucose absorption Insulin replacement Agents that suppress glucagon Glucagon to counteract excess insulin Agents to prevent complications of diabetes Agents to treat complications of diabetes

Type 2 diabetes accounts for more than 90% of patients with diabetes. Epidemiologists estimate that at the current rate of increase in disease incidence, 50% of Americans more than age 50 will have diabetes by 2050. Type 2 diabetes is now increasingly common, even among children as young as age 10. However, the American Diabetes Association estimates that more than 90% of cases of type 2 diabetes could be prevented with diet, exercise, and weight control. Researchers are studying whether pharmacotherapy can delay or prevent type 2 diabetes in individuals at high risk.

Agents that Stimulate Insulin Release

Individuals with type 2 diabetes are typically obese at the time of diagnosis. Usually they secrete sufficient insulin. In fact, development of type 2 diabetes is often preceded by years of hyperinsulinemia due to consumption of large, frequent meals. Over time, the insulin receptors downregulate, and eventually the individuals become insulin resistant. Drugs that stimulate insulin release were once the mainstay of pharmacotherapy for type 2 diabetes. Today, they are step 1 drugs only for individuals with type 2 who are lean, a small minority of these patients. Single-drug therapy is rarely effective over the long term, however, and many obese patients take an agent to stimulate insulin release in addition to other drugs.

Agents that stimulate insulin release include:

Sulfonylureas: first and second generations Meglitinides: repaglinide (Prandin) and nateglinide (Starlix)

Categories of Pharmacotherapeutic Agents for Diabetes

Agents that Stimulate Insulin Release

Sulfonylureas

Sulfonylureas are chemically related to sulfonamide antibiotics ("sulfa drugs"). They increase beta-cell insulin release and decrease glycogenolysis. When taken for a long time, they may also increase insulin receptor sensitivity.

There are two generations of sulfonylureas. Although these two generations have equal therapeutic efficacy, the second-generation agents are more potent and have the following advantages:

Longer duration of action (once-daily dosing convenience) Less likely to cause disulfiram-like reactions with alcohol Less likely to be involved in cross-sensitivity in people allergic to sulfonamides Less potential for fluid retention (they have diuretic properties) Less risk of UVA/UVB photosensitivity

All sulfonylureas share the following potential adverse effects and drug interactions:

Hypoglycemia

Hypoglycemia may develop in individuals who tend to eat sporadically or who miss meals when ill, because insulin will be released throughout the day, not just in response to food.

Displacement from plasma proteins by other drugs

Drugs such as warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfonamides compete to bind to plasma albumin. The resulting increased free levels of the sulfonylurea may result in hypoglycemia.

Inhibition of hepatic metabolism by other drugs

Drug inhibitors—such as cimetidine, omeprazole (Prilosec), and antifungal drugs—can reduce hepatic biotransformation of sulfonylureas. Increased free levels of the sulfonylurea may result in hypoglycemia.

Decreased action from drugs that cause hypokalemia

Drugs such as thiazide diuretics and oral corticosteroids deplete potassium, as do drugs and diets high in sodium. Hypokalemia impairs insulin release and insulin-receptor function.

Decreased action from drugs that cause hyperglycemia

Drugs such as corticosteroids, estrogen-based contraceptives, thiazide diuretics, nicotinic acid, phenytoin, and some calcium-channel blockers can increase blood glucose levels. As a result, sulfonylureas may be less effective, especially as monotherapy.

Reduced efficacy with long-term use

Sulfonylureas continue to stimulate insulin secretion even when the patient is fasting. Over time, this leads to so-called pancreatic burnout and reduced capacity of the pancreas to synthesize insulin.

Meglitinides: Repaglinide (Prandin) and Nateglinide (Starlix)

Meglitinides are about as effective as sulfonylureas and share the same mechanism of action. Repaglinide (Prandin) and nateglinide (Starlix), however, differ from sulfonylureas in the following ways

Short half-life (1 hour)

Meglitidines are taken immediately before a meal or as long as 30 minutes after eating to treat postprandial (after-meal) hyperglycemia.

Less likely to cause hypoglycemia

Metaglinides have short half-lives and are administered with meals. Hypoglycemia can occur if the patient fails to eat after taking the drug.

Less likely to cause pancreatic burnout

A low drug level between meals allow the pancreas to rest and recover. Pancreatic burnout may be delayed or prevented.

Metabolized by CYP 3A4

Drugs that are CYP 3A4 inducers, such as St. John's wort, will increase hepatic metabolism of the drug. CYP 3A4 inhibitors, such as the antifungal drug ketoconazole, can reduce hepatic metabolism of meglitinides.

Agents that Stimulate Insulin Receptors

Biguanides: Metformin (Glucophage)—Actions and Advantages

Metformin is chemically related to a naturally occurring substance called guanidine. Plants containing guanidine were used in medieval times to treat diabetes. Metformin requires sufficient levels of insulin to exert its action, so it is used to treat only type 2 diabetes. The FDA also recommends that all patients taking oral corticosteroids for prolonged periods also take metformin. Corticosteroids deplete potassium and increase muscle catabolism, resulting in

hyperglycemia and insulin resistance. Metformin has been shown to prevent impaired glucose tolerance in patients taking corticosteroids. Other studies suggest that metformin can prevent type 2 diabetes in patients at high risk for the disease when combined with lifestyle changes (exercise, diet, weight control).

Metformin's actions

Increases the number of insulin receptors Increases insulin receptor sensitivity Increases cellular uptake of glucose As a result of increased hepatic insulin receptor sensitivity, reduces hepatic

gluconeogenesis (formation of glycogen from fatty acids and proteins) Reduces gastrointestinal (GI) glucose absorption

Metformin's advantages

Does not cause hypoglycemia Decreases plasma lipids (low-density lipoprotein [LDL], triglycerides) Decreases blood pressure in obese patients (about 2%) Decreases weight in obese patients Not bound to plasma proteins; no drug displacement interactions Not metabolized in the liver; no CYP–drug interactions

Biguanides: Metformin (Glucophage)—Side Effects and Adverse Reactions

Metformin has few drug interactions or adverse side effects, but there are several important nursing considerations.

Metformin increases risk of lactic acidosis

A biguanide called phenformin was removed from the market because of fatalities from lactic acidosis. Phenformin inhibits enzymes that metabolize lactic acid in patients with renal impairment (eg, in advanced age, shock, sepsis, acute myocardial infarction, acute heart failure, and alcoholism). Metformin does not increase risk of lactic acidosis as long as the patient has normal renal and hepatic function, does not have sepsis, dehydration, or acute heart failure, and avoids alcohol. Patients with chronic heart failure have longer survival rates with metformin than with sulfonylureas. Patients should immediately report signs of lactic acidosis, including myalgia, malaise, and extreme somnolence.

Metformin should be avoided with renal impairment.

Renal function and lactate levels should be routinely monitored.

Alcohol potentiates the effect of metformin on lactate metabolism

Alcohol consumption should be limited to one standard drink per day.

Metformin decreases absorption of folate and vitamin B12

Folate and vitamin B12 depletion results in increased levels of homocysteine. Homocysteine levels are correlated with an increased risk of cardiovascular disease, the number-one cause of death in people with diabetes. Patients taking metformin should also take a vitamin supplement containing folate and vitamin B12.

Metformin is withheld before administration of a contrast agent.

Metformin can cause acute renal failure in patients undergoing radiologic studies in which a contrast agent is given (eg, renal angiography, computed tomography). Metformin must be discontinued 48 hours before and after the contrast agent is administered.

Metformin causes GI distress and metallic taste

Warn patients starting metformin therapy that they may experience nausea, diarrhea, and a metallic taste. These side effects usually disappear with time

Agents that Stimulate Insulin Receptors

Thiazolidinediones (Glitazones): Pioglitazone (Actos), Rosiglitazone (Avandia)

Glitazones ("get in the zone" with "glitazones") activate a gene that decreases insulin resistance in patients with type 2 diabetes. They increase insulin receptor number and sensitivity. They also decrease hepatic gluconeogenesis. They have none of the side effects of metformin and have no effect on hepatic liver enzymes. Remember the following points about glitazones:

Glitazones cause fluid retention and edema. Glitizones are contraindicated in patients with heart failure, because the edema will aggravate dyspnea and fatigue. The FDA has a "black box" warning stating that these agents may worsen heart failure.

Research is ongoing to determine if rosiglitazone (Avandia) is associated with an increased risk of angina or myocardial infarction.

Pioglitazone (Actos) increases high-density lipoprotein (HDL) and decreases triglycerides. These beneficial lipid effects may help decrease the risk of heart disease, the most common cause of death in patients with type 2 diabetes. Rosiglitazone (Avandia) does not have these lipid benefits because it increases triglycerides and does not increase HDL as much. Both drugs increase LDL slightly.

Check serum alanine transaminase (ALT) at baseline and every 3 to 6 months. The first glitazone (troglitazone [Rezulin]) was removed from the market because of hepatoxicity. Neither of the two glitazones currently on the market has been shown to cause hepatoxicity, but the recommendation to monitor ALT remains. Fewer than 0.5% of patients (5 in 1000) exhibit increased ALT.

Glitazones are associated with an increased risk of fractures in the distal extremities (forearm, hand, wrist, foot, ankle, fibula, tibia) in women.

Agents that Decrease/Delay Glucose Absorption

Alpha-Glucosidase Inhibitors: Acarbose (Precose), Miglitol (Glyset)

As mentioned earlier, metformin (Glucophage) decreases glucose absorption in addition to its other effects on insulin receptors and hepatic gluconeogenesis.

Acarbose (Precose) and miglitol (Glyset) work by inhibiting the intestinal brush-border enzyme that breaks off glucose molecules from carbohydrates (both complex carbohydrates and sugar) before absorption. As a result, carbohydrate (glucose) absorption is slower and the postprandial increase in plasma glucose is less. These agents have minimal systemic effects as less than 2% is absorbed.

Adverse effects are flatulence, cramps, abdominal distention, and diarrhea

Gas is produced by the fermentation of unabsorbed carbohydrates by GI bacteria

Iron absorption is reduced. Periodically assess patients for iron deficiency. Iron supplements may be needed.

Sugar cannot be used to treat hypoglycemia.

These drugs do not cause hypoglycemia. If the patient also takes insulin or a sulfonylurea, however, hypoglycemia may develop. Sugar is an ineffective treatment because hydrolysis of sugar and absorption of glucose is too slow. Patients must understand that only glucose should be used to treat hypoglycemia.

Avoid use with metformin.Alpha-glucosidase inhibitors decrease metformin absorption. Also, the combined GI side effects of the alpha-glucosidase inhibitors and metformin are poorly tolerated.

Monitor liver function in patients taking acarbose (Precose).

Liver function should be checked every 3 months for the first year. Miglitol (Glyset) has not been shown to be hepatotoxic.

Insulin Replacement

Insulin used to be extracted from beef and pork pancreas. Today insulin identical to human insulin is manufactured with the use of recombinant DNA technology in a weakened strain of Escherichia coli. Manufactured human insulin can be chemically modified to form human insulin analogs (chemical compounds similar in structure but differing in effect) that have different times of onset and duration of action.

Insulin can be divided into the following categories:

Short-acting o Rapid onset/short durationo Slower onset/short duration

Intermediate-acting Long-acting

Except for NPH insulin, all insulins manufactured today are clear, colorless solutions. This point must be emphasized to patients because, previously, when insulin from beef and pork was used, only rapid-onset/short-duration insulins were clear.

Insulin Replacement

Rapid Onset/Short Duration: Injected Insulin—Insulin Lispro, Insulin Aspart, Insulin Glulisine

These insulins are clear solutions that are injected subcutaneously in the 15 minutes before or immediately after a meal to control postprandial glucose. They are used in both type 1 and type 2 diabetes. In people with type 1 diabetes, additional intermediate- or long-acting insulin must be taken to provide glycemic control between meals and at night. Patients with type 2 diabetes may need an additional oral hypoglycemic. rapid-onset/short-duration insulins:

Insulin lispro (Humalog)

Because the order of two amino acids in insulin (lysine and proline) is switched, the resulting insulin analog acts within 15 to 30 minutes and lasts 3 to 6 hours. Regular insulin takes 30 to 60 minutes to take effect.

Insulin aspart (Novolog)

Because aspartic acid is switched for the amino acide proline in one position of the insulin molecule, the resulting insulin analog acts within 10 to 20 minutes and lasts 3 to 5 hours

Insulin glulisine (Apidra)

With two amino acid differences from human insulin, insulin glulisine has the fastest onset of action—10 to 15 minutes. It must be given no more than 15 minutes before or 20 minutes after a meal. The duration is 3 to 5 hours.

Insulin Replacement

Rapid Onset/Short Duration: Inhaled Insulin—Exubera

Exubera is an insulin inhalation system that delivers powdered regular insulin to the lungs. It has a rapid onset (30 minutes) and lasts 6.5 hours. It is taken within 10 minutes of a meal. As with rapid-onset/short-duration injected insulins, patients with type 1 diabetes must take an additional intermediate- or long-acting insulin to provide glycemic control between meals and at night. Patients with type 2 diabetes need an additional oral hypoglycemic.

Here are some important points about Exubera:

Exubera is FDA approved for patients over age 18 only. It is not for use by smokers.

o Smokers have greater absorption than nonsmokers between cigarettes and thus greater risk for hypoglycemia.

o Smokers have less absorption than nonsmokers immediately after a cigarette and thus greater risk for hyperglycemia.

Long-term effects on pulmonary function are unknown. Exubera is expensive (new delivery system; only 6% to 10% bioavailability).

*In October 2007, Pfizer decided to withdraw Exubera from the market because too few patients were using the drug and other drugs are available with which to reduce blood glucose levels.

Insulin Replacement

Slower Onset/Short Duration: Regular Insulin—Humulin R, Novolin R

Regular insulin (Humulin R, Novolin R) is approved to be given by way of subcutaneous injection, subcutaneous infusion, IM injection, and inhalation.

Use of regular insulin IV in an emergency is an off-label use. This is not FDA approved because insulin adsorbs to IV infusion sets in an unpredictable manner. Close glycemic monitoring is essential! No other insulin types are given IV or by way of inhalation.

Regular insulin takes between 30 and 60 minutes to take effect because the insulin molecules aggregate under the skin and this slows absorption. It peaks in 1 to 5 hours and can last as long as 10 hours. Typically, regular insulin is taken in either or both of the following ways:

Subcutaneous injection 30 to 60 minutes before meals Subcutaneous infusion to provide a lower basal insulin level all day

Regular insulin is a clear solution and comes in 100 units/mL (U-100; available without a prescription) and 500 units/mL (U-500; prescription only). Only patients with insulin resistance use U-500 insulin.

Slower Onset/Intermediate Duration: NPH Insulin, Insulin Detemir

NPH (which stands for neutral protamine Hagedorn) insulin is conjugated with protamine, a large protein that decreases the absorption of the insulin. Here are some important points about NPH insulin:

NPH insulin is injected subcutaneously twice a day to control blood glucose between meals and during the night.

NPH insulin is the only longer-acting insulin that can be mixed with short-acting insulin. Allergic reactions to protamine (a protein) are possible. NPH insulin is a cloudy suspension (regular insulin is clear). NPH insulin is available without a prescription.

Insulin detemir (Levemir) is a prescription-only insulin analog in which an amino acid has been removed and a fatty acid chain has been attached. These modifications to the molecule cause insulin detemir to form strongly bound aggregates that slow its absorption. The fatty acid chain causes insulin detemir to bind strongly to plasma albumin; this slows delivery of insulin detemir to tissues. Depending on the dose, insulin detemir can have a 12-hour (at 0.2 units/kg) to 24-hour (at 0.4 units/kg) duration. Subcutaneous injections are usually taken twice a day. It should never be mixed with any other insulin preparations and should never be used IV or in insulin pumps.

Long Duration: Insulin Glargine (Lantus)

Insulin glargine (Lantus) differs from regular insulin by three amino acids. One amino acid has been replaced with glycine (the gl in glargine), and two arginines have been added to the end of the protein chain (the argine in glargine). As a result, insulin glargine has at least a 24-hour duration of action and so can be taken as a subcutaneous injection once per day (eg, at bedtime). The risk of hypoglycemia and hyperglycemia is less than that with regular insulin because release of insulin glargine from the injection site is slow and constant (it has zero-order delivery and produces no peaks or troughs). Do not prefill syringes with insulin glargine (Lantus)! The insulin glargine is acidic and reacts with the plastic, causing turbidity.

Mixing Insulin Solutions

Many patients take a long-duration insulin for coverage between meals and at night and a rapid-onset/short-duration insulin at mealtime. Combining these in the same syringe is convenient, but insulin mixing is confusing. Some may be mixed, but others cannot or the absorption rate of the mixed insulins will be compromised.

Due to manufacturing difficulties, cromolyn (Intal) was unable to be reformulated to be CFC free. Therefore, cromolyn (Intal) inhalers are no longer available. Cromolyn is available in a nebulizer formulation only. Nedocromil (Tilade) is available in a CFC inhaler.

Some rules about insulin mixing are summarized below:

Only NPH insulin can be mixed with short-duration insulins (regular insulin, insulin lispro, insulin aspart, insulin glulisine).

Draw up the short-duration insulin first to avoid contaminating it with NPH insulin. Mixtures are stable for 28 days.

Insulin Pumps

Portable insulin pumps deliver a constant basal infusion of insulin (regular, lispro, aspart, or glulisine) through a subcutaneous needle placed in the abdomen. The patient pushes a button to deliver bolus doses with meals.

Because short-duration insulin is used, the pump should not be removed for more than 1 to 2 hours.

The infusion set and needle location must be changed every 1 to 3 days because insulin microdeposits may form at the infusion site, reducing insulin absorption.

Storage of Insulin

Always check the package insert to confirm the following guidelines from the American Diabetes Association's 2006 Resource Guide:

Unopened vials: Unopened vials should be stored at room temperature until the expiration date. Do not store below 36oF (2oC).

Opened vial: Store at room temperature (not above 86oF and away from direct sunlight) for as long as 1 month. Write an expiration date on the vial of 1 month from the time of opening.

Mixtures prepared in the vials: Store in refrigerator (not below 36oF [2oC]) for as long as 3 months or at room temperature for as long as 1 month.

Mixtures in prefilled syringes: Store in refrigerator for as long as 1 week with the needle pointing up. Agitate gently to resuspend the insulin before administration. Do not prefill syringes with insulin glargine (Lantus)! Insulin glargine is acid and reacts with the plastic, causing turbidity.

Insulin should be at room temperature before administration (administration of cold insulin is painful). All solutions (except NPH insulin) should be clear. There should be no particles, deposits, participates, or cloudy material floating in the solutions.

When in doubt—throw it out!

Incretin Mimetics: Pramlintide (Symlin), Exenatide (Byetta)

The incretin hormones, GLP-1 and gastric inhibitory polypeptide (GIP), are released by the intestinal mucosa in response to increased blood glucose levels. The incretin GLP-1 suppresses

glucagon secretion and both incretin hormones, GIP and GLP-1, increase insulin synthesis and release.

Glucagon is a major counterregulatory hormone with effects that are the opposite of insulin's. Glucagon is secreted by the alpha cells of the pancreatic islets. It stimulates glycogenolysis and inhibits glycogen synthesis. As a result, it increases plasma glucose. It also relaxes smooth muscle in the GI tract. Some research suggests that excess glucagon is involved in the pathophysiology of both type 1 and type 2 diabetes. Pramlintide (Symlin) and exanatide (Byetta) are drugs that suppress glucagon by different mechanisms. Both are injected at mealtimes.

Pramlintide (Symlin)

Pramlintide (Symlin) is a synthetic analog of amylin, a peptide hormone released with insulin from the pancreas. Pramlintide and amylin suppress glucagon secretion and delay gastric emptying. Pramlintide is prescribed for patients in whom insulin therapy fails to achieve adequate glucose control.

Exenatide (Byetta)

Exenatide (Byetta) is a synthetic analog of glucagon-like peptide-1 (GLP-1). GPL-1 is secreted from the GI tract in response to a meal. GLP-1 stimulates gastric emptying and glucagon secretion. Exenatide blocks GLP-1 receptors. As a result, gastric emptying is slower and postprandial glucagon secretion is inhibited. It also stimulates postprandial insulin release and so is used in type 2 diabetes in patients whose diabetes is not well controlled with metformin or a sulfonylurea. A beneficial side effect for overweight patients is that it suppresses appetite, so many patients lose weight. Once weekly injections of exenatide have recently been shown to be as effective as twice daily injections.

Both pramlintide (Symlin) and exenatide (Byetta) have the following potential adverse effects, drug interactions, and contraindications.

Hypoglycemia

Dosages of rapid-acting insulin must be reduced by 50% when patients are started on pramlintide (Symlin) therapy. After the maintenance dosage of Symlin is reached, insulin dosage may be titrated up. Dosages of sulfonylureas must be reduced when patients are started on exenatide (Byetta) therapy and can be titrated up later when the maintenance dosage of Byetta is reached.

Nausea

Because these drugs slow gastric emptying, patients experience nausea when beginning therapy. Careful dose titration can reduce the severity of nausea.

Reduced absorption of oral drugs

Delayed gastric emptying can reduce the absorption of some oral drugs, such as oral contraceptives, antibiotics, and digoxin. Oral drugs should be taken at least 1 hour before injection of Symlin or Byetta.

Avoided in end-stage renal disease

Both drugs are cleared by the kidney and should not be used in patients with end-stage renal disease.

Pancreatitis

Exenatide (Byetta) has been associated with an increased risk of pancreatitis. Patients must be monitored for symptoms of acute pancreatitis such as persistent abdominal pain and elevated serum amylase and/or lipase levels.

Agents that Inhibit the Breakdown of Incretin Hormones: Sitagliptin (Januvia)

Sitagliptin (Januvia)

Sitagliptin (Januvia) inhibits an enzyme named dipeptidyl peptidase-4 (DPP-4) that breaks down incretin hormones. As a result, levels of GLP-1 and GIP incretin hormones are increased allowing more insulin production and release in response to meals and decreased glucagon mediated glucose synthesis (gluconeogenesis) in the liver. Sitagliptin is used alone (Januvia) or with metformin (Janumet).

No increased risk for hypoglycemia has been found with sitagliptin compared to placebo and the risk for gastrointestinal side effects is low. Sitagliptin is eliminated primarily by the kidneys and dosage adjustments must be made for patients with moderate to severe renal insufficiency.

Glucagon to Counteract Excess Insulin

Glucagon can be injected (IM, subcutaneous, or IV) to counteract insulin overdose (and severe hypoglycemia). It is ineffective, however, if the patient has no glycogen reserves because of starvation. Glucagon is a second choice and should be used only if oral glucose is ineffective or if IV glucose cannot be given. Typically it is used in emergency settings in the community when the patient is unconscious. Once consciousness returns, oral glucose is given.

Agents to Prevent Complications of Diabetes

Cardiovascular Disease

Statins (HMG CoA Reductase Inhibitors)

Cardiovascular diseases are the most common cause of morbidity and mortality in patients with type 2 diabetes. Research has shown that statins (eg, atorvastatin [Lipitor], simvastatin [Zocor])

can reduce cardiovascular events in patients with diabetes, regardless of their LDL cholesterol levels. Diabetes specialists now recommend that all adult patients with diabetes take a statin.

Nephropathy

Angiotensin-Converting Enzyme (ACE) Inhibitors/Angiotensin Receptor Blockers (ARBs)

Patients with both types of diabetes are at high risk for nephropathy. Nephropathy depicts the most common cause of morbidity and mortality in patients with type 1 diabetes. Monitoring for microalbuminuria (proteinuria with small amounts of albumin) is the key to early identification. Antihypertensive drugs in the ACE inhibitor and ARB categories protect against diabetic nephropathy. Consequently, these are the drugs of choice in treating hypertension in patients with diabetes. ACE inhibitors have also been found to slow the onset of type 2 diabetes in patients at high risk. Diabetes specialists recommend that all adult patients with type 1 diabetes (regardless of blood pressure) take either an ACE inhibitor or an ARB.

Agents to Treat Complications of Diabetes

Neuropathic Ulcers

Becaplermin (Regranex)

Diabetic foot ulcers are the most common reason for hospitalization of patients with diabetes—and the reason for 85% of the amputations in the US. Becaplermin (Regranex) is genetically engineered human platelet-derived growth factor that is grown in yeast. It is used to treat lower-extremity diabetic neuropathic ulcers in conjunction with débridement, anti-infectives, and remaining off the feet. Becaplermin attracts repair cells such as monocytes and fibroblasts to the wound and simulates synthesis of granulation tissue needed for repair. It is effective, however, only if there is adequate blood supply to the ulcer–and often patients with diabetes have foot ulcers in part because of small-vessel disease. It has not been studied in superficial (stage I and stage II) ulcers.

Neuropathic Pain

Pregabalin (Lyrica)

For years, gabapentin (Neurontin) has been used off-label (ie, in a manner that is not FDA approved) to treat pain associated with diabetic neuropathy. Gabapentin has significant side effects, including dizziness, peripheral edema, blurred vision, and somnolence. Pregabalin (Lyrica) is FDA approved for treatment of diabetic peripheral neuropathy. Pregabalin is more potent than gabapentin; patients take a smaller dose and experience fewer dose-related side effects. Gabapentin and pregabalin enhance GABA and inhibit glutamine release. They have analgesic, anxiolytic, and anticonvulsant activities. In patients with diabetes, these drugs can cause the following important side effects:

Weight gain in approximately 6% of patients

Increased blood glucose and HbA1c should be monitored closely

1. Which statement by a patient undergoing assessment for microvascular complications of diabetes mellitus reflects the greatest risk?

A. "I do not get enough exercise." B. "I wake up in the morning with a headache." C. "I have been insulin dependent for 10 years." D. "I need extra doses of regular insulin everyday." Microvascular complications are associated with frequent or sustained periods of

hyperglycemia. In the patient who has to take extra doses of regular insulin because of increases in the blood glucose levels, the risk of microvascular changes would be greatest.

2. Which of the following values in a patient being assessed for compliance with treatment for diabetes mellitus is indicative of prolonged hyperglycemia?

A. HbA1c of 12% B. Increased serum BUN C. Fasting glucose of 140 D. Positive result on serum ketone testing An increased HbA1c value provides an index of average glucose levels over the previous

2 to 3 months, and a level above 7% indicates poor blood glucose control. Measurement of HbA1c every 3 to 6 months provides a picture of long term glucose control.

3. The nurse administers insulin lispro (Humalog) to a patient. The nurse checks for effects of this medication within:

A. 5 to 10 minutes of administration. B. 15 to 30 minutes of administration. C. 45 to 60 minutes of administration. D. 1 to 2 hours after administration. Insulin lispro is a rapid acting type of regular insulin. Effects begin within 15 to 30

minutes of subcutaneous injection and last for 3 to 6 hours.

4. The nurse is aware that which of the following is the only insulin that can be administered intravenously?

A. NPH insulin B. Insulin lispro (Humalog) C. Insulin aspart (NovoLog) D. Regular insulin Regular insulin is the only type of insulin that may be administered intravenously. When

administered by way of this route, it must be delivered with the use of an IV pump.

5. When mixing regular and NPH insulin, the nurse should draw up which insulin first?

A. NPH B. Regular When regular and NPH insulin are mixed, regular insulin should be drawn up first to

avoid contaminating the NPH with the regular insulin. Once drawn up, the mixtures are stable for 28 days.

6. The nurse checking the postmeal blood glucose level of a patient with diabetes expects it to be:

A. less than 90 mg/dL. B. between 90 and 130 mg/dL. C. between 120 and 180 mg/dL. D. greater than 190 mg/dL. In patients with a history of diabetes, the nurse would expect the blood glucose after a

meal to be 180 mg/dL or lower. The premeal blood glucose should be between 90 and 130 mg/dL.

7. In teaching an insulin-dependent patient about the clinical manifestations of hypoglycemia, what should the nurse include? (Choose all that apply.)

A. Headache B. Sweating C. Increased appetite D. Increased urination E. Thirst F. Increased heart rate Effects of hypoglycemia are largely attributable to stimulation of the central nervous

system, because the low blood glucose is a stress to the body. Clinical manifestations include tachycardia, palpitations, sweating, and nervousness.

8. Which order would the nurse reviewing the admission orders of a patient with insulin-dependent diabetes mellitus be the most concerned about in regard to increased serum glucose?

A. Beta-adrenergic blockers B. Sympathomimetics C. Sulfonylureas D. Meglitinides Sympathomimetics mimic effects of the sympathetic system and can cause an increase in

the blood glucose level. Other drugs that can increase the blood glucose level include thiazide diuretics and glucocorticoids. Sulfonylureas, meglitinides, and beta-blockers lower the blood glucose level.

9. The nurse understands that oral tolbutamide (Orinase) decreases the serum glucose level by:

A. moving glucose into the cell. B. decreasing glucose production in the liver. C. stimulating release of insulin from the pancreas. D. decreasing glucose absorption in the small intestine.

Tolbutamide is an oral hypoglycemic agent that stimulates the release of insulin from the pancreas. This drug cannot be used if the pancreas is unable to synthesize insulin. Metformin lowers the blood glucose level by decreasing glucose production in the liver.

10. A patient with insulin-dependent type 2 diabetes is prescribed metformin (Glucophage). Which finding would require the nurse to contact the healthcare provider before administration?

A. Low fasting blood glucose levels B. Increased serum creatinine C. Decreased serum ketones D. Increased liver enzymes Metformin can cause lactic acidosis. This risk of lactic acidosis is greater in the patient

with altered renal function. Because elevated serum creatinine is an indication of renal impairment, the nurse should notify the physician before administering metformin to a patient with increased serum creatinine.

11. The nurse administers repaglinide (Prandin) at 8 am and checks for the peak effects of this drug at what time?

A. 9 am B. 10 am C. 11 am D. 12 noon Repaglinide is a rapid acting oral hypoglycemic agent that peaks within 1 hour of

administration. If the drug is given at 8 am, the peak drug effects would be seen at 9 am.

12. In the patient receiving continuous intravenous insulin therapy for the treatment of diabetic ketoacidosis, the nurse should plan to hang a dextrose solution (D5NS) when the blood glucose level reaches:

A. 100 mg/dL. B. 150 mg/dL. C. 200 mg/dL. D. 250 mg/dL. The intravenous insulin is administered to reduce the blood glucose level. When the

serum glucose level reaches 250 mg/dL the nurse should change the IV solution to D5NS and administer it at a rate of 150 to 200 mL/hr. Insulin administration should continue to maintain the serum glucose level at 200 mg/dL until the acidosis resolves.