Vol. VIII, No. 1
  January/February 2005

  Marc A. Earl, Pharm.D.

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 Pharmacotherapy
 Update Index

Emerging Therapies in the Treatment of Type 2 Diabetes

Introduction: In the United States, 1.3 million people are newly diagnosed with type 2 diabetes annually and as of 2002, 18.2 million people have been diagnosed.¹ These patients have a reduced ability to utilize insulin present in the body, which eventually results in a decreased function of ß-cells in the pancreas to secrete a sufficient amount of insulin. This causes an alteration in blood glucose control that has been shown to increase both microvascular (i.e., retinopathy, neuropathy, and nephropathy) and macrovascular (i.e., cardiovascular disease and stroke) complications, resulting in a high degree of morbidity and mortality for patients with diabetes.²

The prevention of diabetic complications is based on the control of blood glucose. Current goals have been developed by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE).^3,4 Blood glucose values can be measured through daily self-monitoring or a hemoglobin A_1c (HbA_1c) test which is a reflection of the average blood glucose over a 3-month period (See Table 1).

Clinical trials have demonstrated that a decrease in HbA_1c can reduce the incidence of complications associated with type 2 diabetes. A 1% absolute reduction in HbA_1c can provide a 35% risk reduction in the development of microvascular complications which has resulted in the development of multiple oral medications (See Table 2).⁵ Despite the different combinations of oral therapies available to regulate blood glucose, many patients do not have adequate control of their disease. Over time, the ß-cells of patients with type 2 diabetes lose the ability to produce insulin, therefore, control of blood glucose with current oral agents becomes difficult. These agents also produce undesirable side effects such as edema, weight gain, and gastrointestinal intolerance which may result in noncompliance with therapy. Because of these problems, investigators have focused on new agents with novel mechanisms of action (e.g., glucagon-like peptide-1 agonists, dipeptidyl peptidase-IV inhibitors, and amylin analogs) to control blood glucose.

Glucagon-Like Peptide-1 (GLP-1) Agonists: In response to the intake of food, GLP-1 is produced and secreted in the gastrointestinal tract. The increase of GLP-1 results in additional insulin secretion from ß-cells of the pancreas by increasing ß-cell differentiation, growth, and lifespan. It also contributes to additional glucose control by delaying gastric emptying, decreasing appetite, and increasing the feeling of fullness while ingesting a meal.^6,7 The overall effect of GLP-1 is to assist in the control of blood glucose, especially after the ingestion of a meal. The half-life of GLP-1 in the body is less than 2 minutes due to rapid degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV). To increase the effects of GLP-1 in patients with type 2 diabetes, GLP-1 analogs, that are not as susceptible to DPP-IV, have been developed. Agents such as exenatide and liraglutide have a longer half-life than endogenous GLP-1 and prolonged glucose-lowering effects.⁶

Exenatide
Exenatide is a GLP-1 agonist that is produced from the venom of the Gila Monster. It is more resistant to DPP-IV than endogenous GLP-1 and is 3000-times more potent at causing glucose-dependent insulin release from the pancreas. On April 28, 2005, exenatide (Byetta™; Amylin Pharmaceuticals, Inc.) received approval from the FDA for use as adjunctive therapy to improve glycemic control in patients with type 2 diabetes receiving metformin, a sulfonylurea, or both. Exenatide is administered by subcutaneous (SC) injection, has a half-life of 2.4 hours, and is cleared renally.⁸

Fineman and colleagues conducted a randomized, parallel-group, placebo-controlled study in patients with type 2 diabetes (n=116) to assess glucose control and safety of exenatide.⁸ Patients enrolled in the study were on a regimen of a sulfonylurea alone (20%), metformin alone (22%), or a sulfonylurea plus metformin (58%). The primary endpoint was the mean change from baseline to day 28 in HbA_1c (mean baseline HbA_1c was 9.3%). Secondary endpoints included post-prandial glucose, body weight, and fasting lipids. After a single week of placebo, patients were randomized to one of four groups and exenatide was dosed as a 0.08 mcg/kg SC injection. Group 1 received exenatide SC twice daily (BID) with breakfast and dinner, Group 2 received exenatide SC BID with breakfast and at bedtime, Group 3 received exenatide SC three times daily (TID) at breakfast, dinner, and bedtime, and Group 4 received placebo. Post-prandial blood glucose testing was conducted after similar standardized meals. At Day 28, there was a statistically significant reduction in HbA_1c values for all patients receiving exenatide compared to placebo, and the HbA_1c was reduced by 1.1%, 0.7%, and 1% in Groups 1, 2, and 3, respectively. Additionally, 15% of the exenatide-treated patients had a HbA_1c <7% compared to 4% of placebo patients. There was also a significant decrease in post-prandial plasma glucose concentrations in all patients receiving exenatide compared to placebo (p<0.004). However, there was no difference in the average reductions in body weight or fasting lipid levels from baseline between the groups. The most frequently reported side effects with exenatide were nausea (31%) and hypoglycemia (15%). The authors concluded that exenatide 0.08 mcg/kg administered SC BID to TID is associated with a marked reduction in HbA_1c in patients who are not adequately controlled on a sulfonylurea, metformin, or a combination of both.

Furthermore, Phase III trials demonstrated that in patients with poorly controlled type 2 diabetes, exenatide 5 mcg SC BID was effective at reducing HbA_1c an additional 0.46% to 0.55% when current maximum doses of a sulfonylurea, metformin, or both were ineffective (p<0.01 vs. placebo).^9-11 These trials also demonstrated that when exenatide was dosed at 10 mcg SC BID, there were larger reductions of HbA_1c (0.77% to 0.9%). A significantly higher percentage of patients receiving exenatide therapy achieved a HbA_1c <7% when compared to placebo. In addition, exenatide therapy was associated with a significant reduction in weight. Finally, mild-to-moderate hypoglycemia was the most frequent adverse event reported in these trials.

Since exenatide slows gastric emptying it reduces the extent and rate of absorption of orally administered drugs. Therefore, it should be used cautiously in patients receiving 1) oral medications that require rapid gastrointestinal absorption and 2) oral medications that are dependent on specific blood concentrations (e.g., digoxin and phenytoin). It is recommended that these medications be administered 60 minutes prior to exenatide injection.¹²

Exenatide should be initiated at 5 mcg SC BID at least 60 minutes prior to morning and evening meals. The dose can be increased to 10 mcg SC BID at 1 month if glycemic control has not been met. The SC injection may be administered in the thigh, abdomen, or upper arm. When exenatide is added to sulfonylurea therapy, a reduction in the sulfonylurea dose should be considered to reduce the risk of hypoglycemia; however, a dose reduction of metformin may not be necessary when exenatide is added to therapy. Byetta™ is commercially available as a prefilled pen that delivers either a 5- or 10-mcg dose and provides a 30-day supply (60 doses per pen).¹⁰ The prefilled pen should be stored in the refrigerator, protected from light, and discarded 30 days after its first use. The average wholesale price (AWP) of the 1.2 ml prefilled pen (5 mcg dose) is $179.34, while the 2.4 ml prefilled pen (10 mcg dose) is $210.45.¹³ Exenatide has not been requested or reviewed for addition to the CCF Formulary of Accepted Drugs.

Liraglutide
Liraglutide (NN2211; Novo Nordisk) is a derivative of GLP-1 and acts as an agonist on GLP-1 receptors. The liraglutide molecule is combined with albumin, which provides a slow release from SC tissue after the drug is injected. Compared to endogenous GLP-1, it has an extended half-life (10-13 hours), thereby allowing for once daily administration. The duration of action is also increased because the molecule is resistant to breakdown by DPP-IV.¹⁴ Single-dose trials have shown that liraglutide increases insulin production resulting in decreased fasting and post-prandial blood glucose values. Current Phase II trials in patients with type 2 diabetes are nearing completion and Phase III trials are expected to begin later in 2005.

Harder and coworkers conducted a randomized, parallel-group, placebo-controlled trial to assess the effect of liraglutide on glycemic and body weight control in patients with type 2 diabetes (n=33) that were diet-controlled and/or receiving monotherapy with a sulfonylurea or repaglinide (Prandin®).¹⁵ The primary endpoint was the mean change in HbA1c from baseline to 8 weeks (mean baseline HbA1c was 7.5%). Secondary endpoints included change in body weight and total fat mass. Patients were randomized to receive liraglutide 0.6 mg SC once daily in the morning or placebo. There was a significant decrease in HbA1c of 0.8% in patients receiving liraglutide compared to a decrease of 0.09% in the placebo group (p=0.028). There was no significant difference in weight gain between the groups (liraglutide -0.7 kg vs. placebo -0.9 kg, p=0.756) or change in overall fat mass (liraglutide -1% vs. placebo -0.1%, p=0.088). There were no instances of hypoglycemia in either group, however, transient nausea and diarrhea was reported more often with liraglutide therapy. The authors concluded that liraglutide therapy, when given to patients with type 2 diabetes, resulted in increased glycemic control without significant weight gain or adverse effects.

Dipeptidyl Peptidase-IV (DPP-IV) Inhibitors: Another novel mechanism for the treatment of type 2 diabetes is DPP-IV inhibitors. They decrease the breakdown of GLP-1 by extending the half-life of endogenous GLP-1. Investigational DPP-IV inhibitors offer an advantage over other novel therapies (e.g., GLP-1 agonists and amylin analogs) since they can be administered orally.¹⁶ There are various DPP-IV inhibitors in Phase I, II, and III trials. Novartis Pharmaceuticals has a DPP-IV inhibitor (NVP DPP728) that is beginning Phase II trials and is targeted for FDA submission in the year 2006.

NVP DPP728
Ahren and colleagues conducted a randomized, double-blind, placebo-controlled, multicenter trial in patients with diet-controlled type 2 diabetes (n=93) to assess the efficacy and safety of NVP DPP728.¹⁷ The primary endpoint was the change in mean 24-hour glucose compared to placebo. Secondary endpoints were mean 24-hour insulin, fasting plasma glucose, and post-prandial glucose excursion (defined as the difference between maximal glucose observed in the 4-hour post-breakfast period minus the mean pre-breakfast measurement). Since patients were only followed for 4 weeks, HbA_1c was not an endpoint (mean baseline HbA_1c was 7.2%). Patients were randomized to receive NVP DPP728 100 mg orally TID, 150 mg orally BID, or placebo. At baseline and 4 weeks, patients underwent a 24-hour study with equivalent meals and frequent testing of blood glucose and insulin levels. At week 4, there was a significant decrease in 24-hour plasma glucose levels in patients receiving NVP DPP728 compared to placebo. The average glucose reduction in patients taking both NVP DPP728 regimens was 18 mg/dL (p<0.001). There were also statistically significant reductions in circulating insulin and fasting blood glucose levels in both groups. In addition, the post-prandial glucose levels were significantly reduced in both treatment groups. Adverse effects included hypoglycemia, nasopharyngitis, and pruritus. These events were mild and transient and did not result in cessation of therapy. The authors concluded that using a DPP-IV inhibitor in patients with type 2 diabetes is feasible and may lead to better control of diabetes. Further studies are needed to evaluate the long-term adverse effects of continued therapy as well as long-term glucose control.

Amylin Analogs:
The hormone amylin is secreted from the ß-cells of the pancreas in combination with endogenous insulin. Both hormones are secreted in equal molar amounts and have a secretion pattern that is increased with food intake and reduced during periods of fasting. Amylin decreases the release of glucagon, slows the rate of gastric emptying, and increases satiety, which in conjunction with insulin leads to a reduction in blood glucose values. Blood glucose reductions are greater with the combination of amylin and insulin compared to insulin alone. In patients with insulin insufficiency, there is reduced amylin secretion. Exogenous amylin has been investigated in patients requiring insulin to obtain better glucose control than with insulin administration alone.¹⁸

Pramlintide
Pramlintide is a derivative of the hormone amylin and demonstrates similar actions. On March 16, 2005, pramlintide (Symlin®; Amylin Pharmaceuticals, Inc.) was approved by the FDA for use in patients with type 2 diabetes who have failed to obtain desired glucose control with insulin therapy, with or without a sulfonylurea or metformin. It is also approved in patients with type 1 diabetes that have not achieved desired glucose control despite optimized insulin therapy. Pramlintide is administered by SC injection, has a half-life of approximately 50 minutes, and is cleared renally.¹⁸

Hollander and colleagues conducted a randomized, multicenter, double-blind, placebo-controlled trial in patients with type 2 diabetes requiring insulin (n=656) to assess the long-term efficacy and safety of pramlintide.¹⁹ The primary endpoint was the change in HbA_1c from baseline to 26 weeks (mean baseline HbA_1c was 9.1%). Secondary objectives included changes in HbA_1c at 52 weeks, changes in body weight from baseline at 26- and 52-weeks, and the percentage of patients who achieved a HbA_1c of <7%. Inclusion criteria included age >18 years, type 2 diabetes treated with insulin for at least 6 months, a HbA_1c > 8%, and stable insulin dosing (+10%) for at least 2 months prior to enrollment. Patients were given SC injections of either pramlintide 60 mcg SC TID, 90- or 120-mcg SC BID, or placebo TID 15 minutes before a meal. During the study, it was determined that 60 mcg TID was less effective than the 90- and 120-mcg doses and hence was excluded from statistical analysis. Patients were able to maintain the use of insulin, and either metformin alone, a sulfonylurea alone, or both metformin and a sulfonylurea throughout the study. At 26- and 52-weeks, the 90 mcg pramlintide group had a 0.54% and 0.35% decrease in HbA_1c, respectively, which was not significantly different compared to placebo. The 120 mcg group had a significant reduction in HbA_1c from baseline of 0.68% and 0.62% (p<0.05) at 26- and 52-weeks, respectively, compared to placebo. The percentage of patients with a HbA_1c <7% at 52 weeks was greater in the pramlintide 90 mcg group (9.4%) and the 120 mcg group (12.2%) when compared to placebo (4.1%). At 26 weeks, both the 90- and 120-mcg groups experienced significant weight loss compared to placebo (p<0.05). There was a mean 0.7 kg loss in the 90 mcg group and a 1.1 kg loss in the 120 mcg group. At 52 weeks, only the 120 mcg group continued to experience significant weight loss compared to placebo (mean: 1.4 kg, p<0.05). Adverse effects that occurred in >10% of patients were nausea and headache. Severe hypoglycemia was present in patients using 120 mcg of pramlintide during the first 4 weeks of the study. After 4 weeks, there was no significant difference in severe hypoglycemia between pramlintide and placebo. The authors concluded that pramlintide 120 mcg, administered around mealtime as an adjunct to insulin, appears to be effective and safe in improving long-term glycemic and weight control in patients with type 2 diabetes.

Furthermore, pramlintide decreases HbA_1c by 0.4% to 0.6% when used in patients with type 2 diabetes that require insulin. When used for 1 year, the use of pramlintide is associated with an average weight loss of approximately 1.4 kg. A similar trial has been conducted in patients with type 1 diabetes. The reduction in HbA_1c was similar to that noted in patients with type 2 diabetes, ranging from -0.4% to -0.7%, and was not associated with weight gain.¹⁹

Similarly to exenatide, pramlintide affects gastric emptying and therefore should not be used by patients currently taking agents that alter gastrointestinal motility (e.g., anticholinergic agents) or agents that slow the intestinal absorption of nutrients (e.g.,α-glucosidase inhibitors).²⁰ Pramlintide also has the potential to delay the absorption of other oral medications, therefore, when the rapid onset of a concomitantly administered oral agent is essential, the agent should be administered at least 1 hour prior to or 2 hours after pramlintide injection.

Pramlintide dosage differs depending on whether the patient has type 1 or type 2 diabetes.²⁰ Initially, prior to pramlintide therapy, a dose reduction of insulin is required of all patients (type 1 and type 2) to reduce the risk of hypoglycemia. Patients receiving regular, short-acting, rapid-acting, and fixed-mix (70/30) insulin should decrease their dose by 50% when initiating pramlintide therapy. Once the target dose of pramlintide has been achieved, insulin doses may be readjusted by a health care professional to optimize glycemic control. Additionally, blood glucose should be monitored frequently, including pre- and post-meals and at bedtime. Patients with type 1 diabetes should be initiated on pramlintide at a dose of 15 mcg SC immediately prior to major meals and then titrated at 15 mcg increments to a maintenance dose of 30- or 60-mcg, as tolerated. Patients with type 2 diabetes should be initiated on pramlintide at a dose of 60 mcg SC immediately prior to major meals and increased to a dose of 120 mcg, as tolerated. Dose increases of pramlintide should only occur when no clinically significant nausea has occurred for at least 3 days. The SC injection may be administered in the thigh or abdomen.

There are potential medication safety issues with the use of pramlintide. First, since pramlintide is not available as a prefilled syringe, there is an increased risk of overdose.²¹ For example, pramlintide is ordered as "mcg", but is drawn up into an insulin syringe as "units" (i.e., 30 mcg is the intended dose, but 30 units is prepared and administered instead of 5 units; See Table 3). Second, since insulin and pramlintide will be administered at approximately the same time, by the same route, in the same physical location, and with the same type of syringe, the risk of confusing the dose of pramlintide with an insulin dose is greatly increased.

Symlin® is commercially available as a 5 ml vial, containing 0.6 mg/ml, for use with an insulin syringe (preferably a 0.3 ml size).²⁰ Symlin® should not be mixed with insulin in the same syringe. Unopened vials should be refrigerated and protected from light. Opened vials can be stored in the refrigerator or at room temperature and must be used within 28 days. The AWP for one 5 ml vial of Symlin is $96.99.¹³ To date, pramlintide has not been requested or reviewed for addition to the CCF Formulary of Accepted Drugs.

Conclusion: Patients with diabetes have many therapeutic options to assist in glucose control; however, even with the available drug therapy regimens, most patients in the United States have poor diabetes control. There are many novel therapies currently being investigated and some have recently been FDA-approved (e.g., exenatide and pramlintide). Finally, these new modalities complement the effectiveness of both insulin and oral hypoglycemic agents and will help patients achieve better control of diabetes and decrease associated morbidity and mortality.

References

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16. Rothenberg P, Kalbag J, Smith H, Gingerich R, Nedelman J, Villhauer E, et al. Treatment with a DDP-IV inhibitor, NVP-Dpp728, increases prandial intact GLP-1 levels and reduces glucose exposure in humans. Diabetes 2000;49 (Suppl 1): A39.
17. Ahren B, Simonsson E, Larsson H, Landin-Olsin M, Torgeirsson H, Jansson P, et al. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type II diabetes. Diabetes Care 2002;25:869-75.
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19. Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes. Diabetes Care 2003;26:784-790.
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21. ISMP Medication Safety Alert! June 16, 2005 Vol. 10, Issue 12.