New Pharmacotherapeutic Approaches for Diabetes Mellitus

Case Scenarios: Diabetes MellitusDiabetes mellitus is a disease characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both.1 An alarming 7% of Americans, or approximately 21 million individuals, have diabetes; of these individuals, 90% to 95% are diagnosed with type 2 diabetes. The Centers for Disease Control and Prevention predicts a 165% increase in the incidence of Americans with diabetes between 2000 and 2050.2 The direct and indirect medical costs related to diabetes reached $132 billion in 2002.3 Numerous updates in diabetes care have taken place. Recently, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) collaborated to produce a guideline for initiating therapy in patients with newly diagnosed type 2 diabetes.4 Since the turn of the century, 5 new insulin products, including inhaled insulin, have been approved by the FDA (Table 1). Furthermore, added to the list of available diabetes treatments are 3 notable medications: exenatide (Byetta), pramlintide acetate (Symlin), and sitagliptin (Januvia), all with new mechanisms of action.New Pharmacologic Agents Exenatide (Byetta)

Exenatide injection was introduced into the market in 2005 as adjunctive therapy for patients with type 2 diabetes who have failed treatment with oral antihyperglycemic agents.^{5,6 It is a synthetic version of a naturally occurring peptide called exendin-4, which binds to and activates the glucagon-like peptide-1 (GLP-1) receptor.}5,7 The subcutaneous injectable exenatide is available as a prefilled pen with fixed dosing for all patients. It requires refrigeration prior to dispensing but may be stored at room temperature for up to 30 days once opened. Dosing should begin at 5 mcg twice daily (administered 60 minutes before a meal) and may be increased to 10 mcg twice daily 1 month after initiating therapy.Exenatide has been studied in patients treated with either a sulfonylurea, thiazolidinedione, metformin with sulfonylurea, or metformin alone in double-blind, placebo-controlled trials.8-11 Results have shown that the addition of exenatide to a regimen already containing metformin, sulfonylurea, or thiazolidinedione decreases hemoglobin A1C (HbA1C) levels by 0.9% to 1%.^{9,11 While progressive reductions in weight have been observed, the most common adverse reaction reported has been nausea, which is dose-limiting and eventually subsides with time.}8,9,12 Additionally, significant rates of hypoglycemia have not been noted for patients on regimens with or without metformin. Presently, exenatide is not recommended for initial drug therapy but should be considered as add-on therapy for patients unable to take other oral antihyperglycemic agents and those with postprandial hyperglycemia.Pramlintide Acetate (Symlin)

Another new class of antidiabetic agents on the market is the amylin agonist. Pramlintide is a synthetic analog of human amylin that is secreted by the pancreatic beta cells. It is approved for use as an adjunct therapy for patients with type 1 or 2 diabetes who have not achieved glucose control on optimal insulin therapy with or without metformin and/or sulfonylurea.13 Taken subcutaneously at mealtime, pramlintide slows down gastric emptying and prevents postprandial glucagon rise. Patients receiving pramlintide may require a decrease in their insulin dose by as much as 50%, because higher rates of hypoglycemia have been observed with pramlintide use.^{14,15 Patients also may experience weight loss, but the most common side effects observed have been nausea and vomiting.}14 Due to its mechanism of action, pramlintide should be avoided in patients with gastroparesis. Pramlintide is available in a 5-mL vial containing 0.6 mg/mL of active drug and requires refrigeration and protection from light for storage.13 Starting doses for patients with type 1 and type 2 diabetes are 15 mcg and 60 mcg, respectively, and can be administered concurrently with insulin (as separate injections and via distinct injection sites) as a subcutaneous injection immediately prior to each meal.Inhaled Insulin: (insulin human [rDNA origin]) Inhalation Powder (Exubera)

Exubera is the first dry-powder inhaled insulin, approved by the FDA in January 2006 for the treatment of type 1 and type 2 diabetes in adults. Inhaled insulin delivers regular human insulin in a dry-powder formulation and is available in 1- and 3-mg blister packs.16 Each milligram is equivalent to 2 to 3 units of regular subcutaneous insulin and should be administered up to 10 minutes before a meal. Inhaled insulin has been shown to have similar effects on HbA1C when compared with neutral protamine Hagedorn and Ultralente insulin regimens in studies. ^{17,18 The inhalation form of insulin peaked as rapidly as the subcutaneous insulin but had a more rapid clearance, thus causing less postprandial hypoglycemia.}16,18 Weight gain with inhaled insulin has been comparable with that with subcutaneous insulin.^{19 Patients who smoke may experience higher rates of hypoglycemia, because smoking increases the drug?s absorption, and thus inhaled insulin should be avoided in current smokers or those who have quit within the past 6 months.}20,21 Also, it is contraindicated in patients with poorly controlled asthma and chronic obstructive pulmonary disease. Therefore, all patients should undergo spirometric testing prior to initiation of treatment, as well as 6 months after treatment. If a =20% decline in forced expiratory volume in 1 second occurs from the baseline, inhaled insulin should be discontinued.Sitagliptin (Januvia)

In October 2006, the FDA approved oral sitagliptin as adjunct therapy for type 2 diabetes, when it is uncontrolled by a single agent alone. The once-daily sitagliptin has a novel mechanism of action, which targets insulin release and hepatic glucose production. It is a potent, reversible inhibitor of dipeptidyl-peptidase-IV (DPP-4), an enzyme that rapidly degrades GLP-1. By inhibiting the DPP-4 enzyme, it prolongs the action of GLP-1 and subsequently results in an increase in insulin secretion from beta cells during hyperglycemia. In contrast to other incretin mimetics, weight loss has not been observed with sitagliptin, and hypoglycemia rates have been compared with placebo.^{7 The average dose of sitagliptin is 100 mg once daily (supplied in oral tablet form). Dose adjustment is required for patients with impaired renal function.}22,23How Health Systems Select Medications for Formulary

Health systems often utilize an internal Pharmacy and Therapeutics (PT) Committee to review new medications for consideration for their formulary. With the addition of 8 new agents since the turn of the century, it is important that these committees perform a thorough medication review with major emphasis on safety, efficacy, and cost. This balancing act is not always easy to manage, due to conflicting drug information, influences from industry representatives, unique patient populations, and time constraints. It is recommended that each drug being considered for formulary be reviewed by internal subcommittees of the PT Committee and presented in an unbiased fashion. Consideration of nursing time spent to administer medications such as insulin and time spent to monitor blood glucose should be taken into account. Furthermore, of the medications reviewed above, keep in mind that 2 are administered subcutaneously, 1 via inhalation, and 1 by mouth. These factors will affect patient adherence rates. Lastly, reduction in glycosylated HbA1C should be compared with that of existing agents, as Hb A1C control has been associated with a reduction in diabetes complications.24,25

Updated ADA Guidelines for Type 2 Diabetes

A consensus statement from the ADA and the EASD was released in August 2006.4 The guideline addresses issues regarding initiation of therapy for patients with type 2 diabetes using 3 simple steps. Step 1 includes recommending lifestyle modification of exercise and diet, together with initiating low-dose metformin (500 mg) taken once or twice daily with meals. If glycemic goals are not achieved within 2 to 3 months, step 2 is begun. Step 2 includes the addition of either a sulfonylurea, a thiazolidinedione, or basal insulin. The exact medication should be tailored to the individual patient, because no consensus exists as to which of the 3 agents is best. Keep in mind that the FDA has recently issued a safety alert for rosiglitazone, claiming that it may increase the risk of myocardial infarction and cardiovascular-related death. If step 2 fails, step 3 includes further adjustments in which insulin should be added, or if it is already on board, then dosing should be intensified. Moreover, if combination medications are to be added, the selection of agents with different mechanisms of action should be considered.

Before this guideline, pharmacotherapy initiation was always secondary, only after lifestyle modifications had failed. Large bodies of data suggest, however, that exercise and diet, although very effective in reducing HbA1C, often fail for most patients in the first year. The rationale as to why metformin was considered the first-line agent is due to several factors including, but not limited to:Strong effects on HbA1C reductionAbsence of weight gainAbsence of hypoglycemiaGenerally mild adverse effectsHigh level of acceptance

Low cost4

Although the new guideline is a more aggressive approach to treating type 2 diabetes, the hope is that it will lessen the serious complications associated with the disease. Health systems should attempt to adopt a protocol for all newly diagnosed patients with type 2 diabetes to prolong survival.

Conclusion

Diabetes is a serious, life-threatening disease if untreated. We have reviewed 4 new medications with differing mechanisms of action, routes of use, and adverse effects. With the addition of these medications and 4 insulin products approved by the FDA since the turn of the century, as well as new guidelines for clinicians on how to initiate treatment for patients with type 2 diabetes, health systems must keep abreast of this information to make sound and unbiased formulary decisions.

References

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