Achieving Adequate Glycemic Control in Diabetes Patients

Diabetes mellitus, which affects 6% of the US population, is a group of disorders characterized by hyperglycemia caused by inadequate insulin secretion and/or inadequate insulin effect due to resistance. Although there are many types of diabetes, the most common are type 1 and type 2 diabetes, as classified by the American Diabetes Association Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.¹ Type 1 diabetes, caused by an absolute deficiency in insulin secretion, typically presents itself during childhood or early adulthood. The lack of insulin results from the autoimmune destruction of the beta cells of the pancreas and the islet cells.

Type 1 diabetes accounts for 10% of all cases. Type 2 diabetes, accounting for more than 90% of cases, is caused by a combination of insulin resistance and inadequate insulin secretion. The incidence of type 2 diabetes has tripled during the past 30 years. Type 2 diabetes typically develops during adulthood, but it is often present and causing organ and tissue damage many years before it is diagnosed.

The National Institutes of Health estimates that 18 million Americans aged 20 years or older have diabetes, including 8.6 million aged 60 and older.² The International Diabetes Federation predicts that the number of patients with diabetes could soon reach 472 million, because the number of cases increased by 33% between 1990 and 1998.³ A recent survey conducted by the Centers for Disease Control and Prevention indicated that 1 in 3 Americans born in the year 2000 would develop diabetes.⁴ According to the survey, the lifetime risk of developing diabetes in that population was 33% for males and 39% for females. The survey estimates an even higher risk among Hispanics, at 45% for males and 53% for females. Diabetes remains more prevalent among African Americans, Hispanics, American Indians, and Asian Americans. The incidence of diabetes in children and teenagers continues to rise, due in part to the rising incidence of obesity.

Due to chronic hyperglycemia, diabetes can have devastating complications. These long-term complications lead to a decreased quality of life and increased health care costs. Diabetes remains the seventh leading cause of death in the United States, the leading cause of blindness in adults aged 20 to 74, and the leading cause of end-stage renal disease. Nearly 65% of patients with diabetes will succumb to heart disease and stroke.²

With adequate glycemic control, many diabetic complications are avoidable. A 1% reduction in hemoglobin A_1c provides a 21% reduction in the risk of diabetes-related mortality. Researchers at George Washington University in Washington, DC, confirmed that tight glycemic control of type 1 diabetes could reduce complications, even in patients with a history of poor control.⁵ The study showed that the group of patients who underwent intensive control had reduced incidence of atherosclerosis, compared with patients who never achieved control. These results were consistent even in patients with less than adequate control for the 8 years preceding the study.

A study published in the January 30, 2003, New England Journal of Medicine reported that patients receiving intensive treatment for 8 years showed a reduced risk of complications.⁶ The type 2 diabetes patients in the intensive-treatment arm received multifactorial intervention, combining individual risk assessment, patient education, drug therapy, and regular clinical evaluation. These patients showed a 47% reduction in risk for cardiovascular disease, a 39% lower risk of nephropathy, a 42% lower risk for retinopathy, and a 37% lower risk of autonomic neuropathy.

Treatment

Insulin

The onset and duration of insulin products range from ultrashort to long. Ultrashort-acting insulins, lispro (Humalog) and aspart (Novo Rapid), are administered immediately before meals to closely mimic normal insulin response. Regular insulin also can be used to control postprandial hyperglycemia. It is rarely used alone for maintenance therapy, however, because its duration is too short to provide a basal insulin level.

Two intermediate-acting insulins are available, NPH and Lente. These agents are administered once or twice daily, providing a basal insulin level. These agents can cause allergic reactions due to zinc and protamine in the suspension.

Ultralente and insulin glargine (Lantus) are long-acting insulins. Ultralente is typically administered once a day to provide a steady basal insulin level. Insulin glargine is intended for once-daily subcutaneous administration at bedtime.

Sulfonylureas

Sulfonylureas increase secretion of insulin by inhibiting adenosine triphosphate (ATP)-dependent potassium (K⁺) channels. They also may produce a gradual but limited increase in insulin sensitivity (Table 1).

Common side effects include weight gain, hypoglycemia, dermatologic reactions, gastrointestinal distress, and photosensitivity. Sulfonylureas also can cause disulfiram-like reactions with alcohol.

Biguanides

Metformin (Glucophage) works by inhibiting glucose release from the liver, enhancing peripheral muscle glucose uptake, and increasing insulin sensitivity. The usual dose is 500 to 2250 mg/day. The most common adverse effects are gastrointestinal, with nearly 30% of patients developing diarrhea, flatulence, nausea, and a metallic taste in the mouth. Initiating the drug at lower doses, then titrating slowly, minimizes these adverse effects. Although structurally similar to phenformin, the ability of metformin to induce lactic acidosis is much lower. Metformin should be avoided in patients with a serum creatinine level of >1.5 mg/dL.

Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors work by reversibly inhibiting intestinal brush border enzymes, thus delaying the breakdown of ingested carbohydrates and allowing sufficient time for insulin release (Table 2). The most common adverse effects are flatulence, diarrhea, and abdominal cramps, due to gas production from bacterial action on carbohydrates. These agents are not recommended for patients with inflammatory bowel disease or cirrhosis.

Thiazolidinediones

The primary action of this class, also known as glitazones, is to increase sensitization of peripheral tissue to the effects of insulin by binding to intracellular peroxisome proliferator-activated receptor-gamma (Table 3). They also decrease insulin resistance, lower hepatic glucose output, and alter lipid profiles. Common side effects of these agents include weight gain, fluid retention, and edema. They should be avoided in patients with Class III or IV heart failure.

Meglitinides

The most recent additions to the US market are meglitinides, or insulin secretagogues (Table 4). Similar to sulfonylureas, these agents prevent the activation of ATP-sensitive K⁺ channels and increase intracellular calcium (Ca²⁺), thus increasing insulin secretion through an insulinotropic action. Because of their short duration of action, they should be taken immediately before meals to reduce postprandial glucose levels. Adverse effects include hypoglycemia, gastrointestinal disturbances, and arthralgias.

Products in the Pipeline

Several companies have new products in the pipeline to treat and prevent diabetes. Among the products for insulin therapy are inhaled insulin and products for liposomal administration. Inhaled powdered insulin, currently in phase 3 trials, may prove as effective as injectable insulin, according to earlier studies. The use of liposomes is under investigation to allow oral administration of insulin and for administering compounds that increase insulin sensitivity.

Multiple pharmaceutical companies currently have gut hormone analogues in clinical trials. Gut hormones are known to stimulate insulin release, increase insulin receptor affinity, enhance incorporation of fatty acids into triglycerides, and reduce food intake. Unfortunately, gut hormones break down quickly in the blood, so pharmaceutical companies have had to create analogues that would not degrade as quickly. The phase 2 and 3 clinical trials of these analogues have shown positive results.

Gene therapy research also is currently being conducted. The first area of research involves the conversion of stem cells to insulin-producing islet cells. Gene research is underway to promote inactivation of SHIP2, a gene that increases insulin sensitivity.

Opportunities for the Pharmacist

In the community setting, when the pharmacist notes that a patient is filling prescriptions for diabetes medications, he or she should assess the effectiveness of the therapy, the patient's compliance with it, and the presence of any adverse effects. Reviewing the frequency at which medications are refilled is a simple tool to gauge the patient's compliance. The refilling of glucagon or purchasing of glucose tablets should prompt the pharmacist to question the patient about side effects or difficulties with the therapy.

Because a patient often visits the pharmacist more often than the physician, the pharmacist can offer to review the patient's log of daily glucose readings. If the pharmacist notes erratic control, he or she can offer options to improve adherence to therapy or recommend an appointment with the physician to alter the treatment plan.

When the pharmacist notices that a patient is filling prescription for diabetes medications for the first time, the pharmacist can play a crucial role in educating the patient about diabetes. Patients often have heard about diabetes but will have many questions that the pharmacist can help answer. Patients who know more about their disease are better prepared to play a role in the decision-making process and in establishing goals of therapy with their physician.

According to an Institute for Safe Medication Practices study, 11% of serious medication errors are due to insulin misadministration.⁷ The pharmacist should educate the patient about the type of insulin used, including the brand, duration of action, onset of action, and proper storage. Patients should demonstrate to the pharmacist that they are able to accurately measure insulin in the syringe. If a patient uses multiple insulins and is required to mix them, the pharmacist should ensure that the patient demonstrates the correct technique. The pharmacist also should educate the patient on which insulins never should be mixed.

Dr. Schlesselman is a clinical pharmacist based in Niantic, Conn.

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.