Drug Criteria & Outcomes

Exenatide (Byetta) Drug Evaluation

Part 2 of 2: Clinical trial summary, Cost comparison, and Recommendation

By Steven Higginbotham, PharmD Candidate
Harrison School of Pharmacy, Auburn (AL) University

Clinical trial summary

Trial 1: Buse JB, Henry RR, Han J, et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with Type 2 diabetes. Diabetes Care 2004;27:2,628-2,635.

Objective: To evaluate the ability of exenatide to improve glycemic control in patients with Type 2 diabetes who have not achieved control with maximally effective doses of a sulfonylurea.

Study design: A triple-blind, randomized, placebo-controlled, 30-week study conducted at 101 sites in the United States.

Treatment regimen: After a four-week, single-blind, placebo lead-in period, 377 subjects were randomized and began four weeks of 5 mcg subcutaneous exenatide twice daily (before breakfast and dinner; in arms A or B) or placebo. The exenatide dose for arm B was then increased to 10 mcg twice daily while arm A remained at 5 mcg twice daily for the duration of the study.

Study population

• The study included males and females (age range 22-76 years) with Type 2 diabetes.

• Of the 377 patients randomized, 123 received a placebo, 125 received exenatide 5 mcg BID, and 129 received exenatide 10 mcg BID.

Inclusion criteria

• Type 2 diabetes treated with maximum doses of a sulfonylurea for at least three months prior to screening.

• Fasting plasma glucose level < 240mg/dL, body mass index (BMI) 27-45 kg/m2, and HbA1c 7.1-11%.

• Stable weight (±10%) for three months prior to screening.

• No clinically relevant abnormal laboratory test values (for Type 2 diabetes) defined as > 25% outside normal range.

• Females were either postmenopausal, surgically sterile, or used contraceptives for at least three months prior to screening.

Exclusion criteria

• Use of metformin, thiazolidinediones, meglitinides, a-glucosidase inhibitors, exogenous insulin, or weight-loss drugs within three months prior to screening.

• Therapy with corticosteroids, drugs that alter GI motility, transplantation medications, or investigational drugs.

• Evidence of any clinically significant comorbid condition.

Study endpoints

Primary endpoint

— Evaluation of glycemic control based primarily on HbA1c.

— Safety profile based on adverse events, clinical lab test, physical examination, 12-lead electrocardiogram, and vital signs.

Secondary endpoint

— Fasting plasma glucose concentrations.

— Changes in weight.

— Fasting concentrations of circulating insulin, proinsulin, and lipid.

Results

• More patients being treated with exenatide achieved an HbA1c ≤ 7% than those receiving placebo (10 mcg group 41.3%, 5 mcg group 32.6%, placebo 8.8%; P ≤ 0.0002).

• No clear safety concerns were identified.

• Fasting plasma glucose concentrations were decreased in the exenatide groups and increased in the placebo group. [10 mcg (-0.6 ± 0.3), 5 mcg (-0.3 ± 0.2), placebo (+0.4 ± 0.3); P < 0.05 vs. placebo for the 10-mcg arm only].

• All patients experienced weight loss during the study period, with the exenatide group losing the most [10 mcg (-1.6 ± 0.3 kg), 5 mcg (-0.9 ± 0.3 kg), placebo (-0.6 ± 0.3 kg)].

• No significant differences in fasting insulin concentrations in any of the groups.

• There was a significant decrease in proinsulin reduction compared with baseline and placebo.

• No significant changes in lipids were noted in any of the groups.

Strengths

• Balanced, randomized, and placebo-controlled.

• Triple-blinded

• Conducted at 101 sites across the United States.

• Two separate laboratories were used to analyze blood test.

• Used intention-to-treat analysis.

• Accounted for dropouts.

• Several outcomes measured.

• All baseline measurements were similar.

Weaknesses

• Only 260 of the original 377 completed the trial.

• Diet and exercise were not controlled.

• Self-administered injection.

Authors’ conclusions

• Exenatide reduced HbA1c and was associated with sustained weight loss.

• Exenatide generally is well tolerated and appears to be a safe drug.

• Long-term use of exenatide is likely a good choice for Type 2 diabetics who are uncontrolled with sulfonylurea agents.

Trial 2: Defronzo RA, Ratner, Han J, et al. Effects of exenatide (Exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1,092-1,100.

Objective: To evaluate the ability of exenatide to improved glycemic control in patients with Type 2 diabetes who failed to achieve control with maximally effective doses of metformin.

Study design: A 30-week, triple-blind, randomized, placebo-controlled study consisting of 336 patients at 82 sites across the United States.

Treatment regimen: All patients were given placebo for the first four weeks of the study. Patients were then given either exenatide 5 mcg or placebo BID for four weeks. Thereafter, patients either received exenatide 5 mcg, 10 mcg, or placebo for the remainder of the study. All patients continued metformin.

Study population

• Males and females (age range 19-78 years) with Type 2 diabetes being treated with metformin monotherapy were included.

• Of the 336 patients, 113 were given placebo, 110 exenatide 5 mcg, and 113 exenatide 10 mcg.

Inclusion criteria

• Type 2 diabetes being treated with monotherapy.

• Fasting plasma glucose level < 240mg/dL, BMI 27-45 kg/m2, and HbA1c 7.1-11%.

• Metformin dose was > 1,500 mg/day for three months prior to the study.

• Stable weight (± 10%) for three months prior to screening.

• No clinically relevant abnormal laboratory test values (for Type 2 diabetes) defined as > 25% outside normal range.

• Females were either postmenopausal, surgically sterile, or used contraceptives for at least three months prior to screening.

Exclusion criteria

• Use of sulfonylureas, thiazolidinediones, meglitinides, a-glucosidase inhibitors, exogenous insulin, or weight-loss drugs within three months prior to screening.

• Therapy with corticosteroids, drugs that alter GI motility, transplantation medications, or investigational drugs.

• Evidence of any clinically significant comorbid condition.

Study endpoints

Primary endpoint

— Glycemic control assessed by efficacy and safety.

Secondary endpoint

— Patients (%) achieving HbA1c ≤ 7% by week 30.

— Effect of exenatide on glucose concentrations.

— Weight changes.

— Concentrations of insulin, fasting proinsulin, and lipids.

Results

• Forty percent of subjects in the 10 mcg group, 27% in the 5 mcg group, and 11% in the placebo group reached an HbA1c ≤ 7% by week 30. This was statistically significant (P < 0.001).

• Fasting plasma glucose levels were lower in the exenatide groups [10 mcg (-10.1 ± 4.4 mg/dL), 5 mcg (-7.2 ± 4.6 mg/dL), placebo (+14.4 ± 4.2 mg/dL), P < 0.005].

• All patients with baseline BMI ≥ 30 kg/m2 lost weight over the study period. Patients in the exenatide group lost slightly more that those in the placebo group. In patients with a baseline BMI < 30 kg/m2, only those in the exenatide group lost weight (approximately 1-3 kg).

• No significant changes in insulin concentrations were noted.

• A significant reduction in proinsulin was observed in the exenatide group vs. placebo.

• No lipid changes were noted in any group.

Strengths

• Balanced, randomized, and placebo-controlled.

• Triple-blinded.

• Conducted at 82 sites across the United States.

• Intent-to-treat analysis was used.

• Dropouts were explained.

• Baseline measurements were similar.

• Multiple outcomes were measured.

• Only people using metformin were included.

Weaknesses

• Relatively small number of participants.

• Diet and exercise were not controlled.

• Self-administered injection.

Authors’ conclusions: Exenatide was effective in lowering HbA1c in patients who failed to achieve glycemic control with metformin monotherapy. Exenatide was not associated with weight gain or increased risk of hypoglycemia.

Trial 3: Whitehouse FW, Kruger DF, Fineman MF, et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 2002;25:724-730.

Objective: To assess the effects of mealtime pramlintide on long-term glycemic and weight control in patients with Type 1 diabetes.

Study Design: A 52-week, double-blind, randomized, placebo-controlled, multicenter study involving 480 patients.

Treatment regimen: Patients were started on either 30 mcg pramlintide or placebo preprandial QID. After 20 weeks, the pramlintide patients were re-randomized to 30 or 60 mcg pramlintide QID if decreases from baseline HbA1c were less than 1%. Of the 342 patients who completed the 52-week study, 236 (~70%) volunteered to participate in a one-year, open-label extension in which all received 30 or 60 mcg pramlintide QID.

Study population: 16- to 70-year-old males and females with a history of Type 1 diabetes.

Inclusion criteria

• Type 1 diabetes for at least one year.

• C-peptide concentration ≤ 1 and a baseline HbA1c value between 7% and 13%.

• Hypoglycemia- and hyperglycemia-free for at least two weeks.

• Insulin dose not adjustedby ± 10% during the one week prior to the study.

• Women were surgically sterile, postmenopausal, or using effective contraception.

Exclusion criteria:

• Clinically significant ischemic heart disease, hypertension (> 150/95), gastrointestinal disease, renal disease, and unstable diabetic neuropathy.

• Treatment with drugs known to alter gastrointestinal motility (e.g., erythromycin, metoclopramide, cisapride, cholestyramine, or colestipol).

• Treatment with drugs that alter glucose metabolism (e.g., thiazide diuretics, corticosteroids, bile sequestering resins, acarbose, or metformin).

Study endpoints:

Primary endpoint

— Relative change in HbA1c from baseline to week 52.

— Number of patients with an HbA1c < 7% or < 8% depending on baseline.

Other endpoints

— Absolute changes in HbA1c and body weight from baseline to week 52.

— Relative change in insulin use from baseline.

Results

• Of the 480 patients enrolled, 342 completed the study.

• Patients in the pramlintide group has significant mean reductions in HbA1c (0.67%) compared with placebo (0.16%) from baseline to week 13 (P < 0.0001). A significant placebo-corrected treatment difference was sustained in favor of pramlintide through week 52 (-0.39 vs. -0.12%, P = 0.0071).

• Percent of patients who achieved an HbA1c of < 7% in patients who had a baseline ≥ 7% (25 vs. 11.3% for placebo, P = 0.01).

• Percent of patients who achieved an HbA1c of < 8% in patients who had a baseline ≥ 8% (58.6 vs. 35.1% for placebo, P = 0.04).

• Patients in the pramlintide group had a sustained mean reduction in weight; patients in the placebo group had a mean increase in weight.

• There was a slight increase of insulin use in both groups (+2.3% for pramlintide and +10.3% for placebo at week 52, P = 0.0176).

• There was no significant increase in the incidence of severe hypoglycemia in either group.

Strengths

• Double-blind, randomized, placebo-controlled, multicenter.

• All baseline values were similar.

• Used intent-to-treat analysis.

• HbA1c and weight were analyzed using a two-way ANOVA (analysis of variance).

• Dropouts were accounted for.

Weaknesses

• Insulin use was not controlled.

• Self-administered injection.

• Diet and exercise was not controlled.

Authors’ conclusions: Use of pramlintide at mealtime as an adjunct to insulin improved long-term glycemic control. Pramlintide did not cause weight gain or increase the incidence of severe hypoglycemia in Type 1 diabetics.

Cost comparison

Exenatide (Byetta)

• 300 mcg/1.2 mL pen containing 60 5-mcg doses — $147/month or $4.90/day (5 mcg BID).

• 600 mcg/2.4 mL pen containing 60 10-mcg doses — $172.50/month or $5.75/day (10 mcg BID).

• A pen containing a month’s supply of drug will have to be used for each patient; the company does not plan to manufacture a multidose vial.

Pramlintide (Symlin)

• 3 mg/ 5mL vial — $79.50.

• Type 1 diabetics $2.39- 4.77/day (30-60 mcg TID).

• Type 2 diabetics $4.77-9.54/day (60-120 mcg TID).

Recommendation

Exenatide and pramlintide both mimic natural peptides in the body that have a role in glucose control. Although both drugs have very similar effects on the body, they act by very different mechanisms. Trials indicate that both drugs effectively improve long-term glycemic control and do not cause weight gain. Exenatide is indicated for use in Type 2 diabetes, whereas pramlintide is indicated for Type 1 and Type 2 diabetes. Both drugs are given as SQ injections at multiple times throughout the day (BID for exenatide and TID-QID for pramlintide). Similar side effects have been observed with the drugs and they are both safe. The monitoring and storage requirements are similar for both drugs as well.

Pramlintide can be twice as expensive as exenatide. A month’s supply of exenatide will likely have to be purchased for each patient regardless of the length of stay because of the lack of a multidose vial. Because of the different mechanisms of action and slightly different indications, both drugs will be needed on the formulary. Pramlintide is a complicated drug to initiate; therefore, a protocol must be created for its use.

Resources

  • Amylin Pharmaceuticals. Byetta [package insert]. San Diego: April 2005.
  • Amylin Pharmaceuticals. Symlin [package insert]. San Diego: March 2005.
  • Klasco RK, ed. DRUGDEX® System. Thomson MICROMEDEX, Greenwood Village, CO (Edition expires 2005). Accessed June 13, 2005.
  • Personal Communication with Keith Moss. Pharmacy Buyer. Huntsville (AL) Hospital System Pharmacy. June 2005.
  • Hollander PA, Levy P, Fineman MS, 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.