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Byetta (Exenatide Injection) - Description and Clinical Pharmacology

 
 



DESCRIPTION

BYETTA (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors.

Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

BYETTA is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).

CLINICAL PHARMACOLOGY

Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.

BYETTA improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Pharmacodynamics

Glucose-dependent insulin secretion: BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, BYETTA does not impair the normal glucagon response to hypoglycemia.

First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of BYETTA at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p <0.001 for both).

Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of BYETTA or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects

Glucagon secretion: In patients with type 2 diabetes, BYETTA moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.

Gastric emptying: BYETTA slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.

Postprandial Glucose

In patients with type 2 diabetes, BYETTA reduces postprandial plasma glucose concentrations (Figure 2).

Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of BYETTAa Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)

Fasting Glucose

In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of BYETTA. Plasma glucose concentrations were significantly reduced with BYETTA compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of BYETTAa or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

Cardiac Electrophysiology

The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms. Thus, BYETTA (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.

Pharmacokinetics

Absorption

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or upper arm.

Distribution

The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.

Metabolism and Elimination

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.

Drug Interactions

Acetaminophen

When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA (0 h) and 1 hour, 2 hours, and 4 hours after BYETTA injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before BYETTA injection.

Digoxin

Administration of repeated doses of BYETTA (10 mcg BID) 30 minutes before oral digoxin (0.25 mg QD) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed.

Lovastatin

Administration of BYETTA (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of BYETTA, the use of BYETTA in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

Lisinopril

In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), BYETTA (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-h mean systolic and diastolic blood pressure.

Oral Contraceptives

The effect of BYETTA (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after BYETTA administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. BYETTA did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after BYETTA administration injection as compared to when the OC was given alone. The effect of BYETTA on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to BYETTA injection.

Warfarin

Administration of warfarin (25 mg) 35 minutes after repeated doses of BYETTA (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. BYETTA did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions].

Specific Populations

Renal Impairment

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function. [see Use in Specific Populations].

Hepatic Impairment

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment [see Use in Specific Populations].

Age

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population].

Gender

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

Race

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

Body Mass Index

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).

In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with SC doses of 6, 68 or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Reproductive and Developmental Toxicology

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

CLINICAL STUDIES

BYETTA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione.

Monotherapy

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg BID (n = 77), BYETTA 10 mcg BID (n = 78), or placebo BID (n = 77) was used as monotherapy in patients with entry HbA1c ranging from 6.5-10%. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% were West Asian, 3% were Hispanic, 3% were Black, and 0.4% were East Asian.

The primary endpoint was the change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 6).

Table 6: Results of 24-Week Placebo-Controlled Trial of BYETTA Used as Monotherapy
Placebo
BID
BYETTA
5 mcg
BID
BYETTA
10 mcgBYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals.
BID
BID = twice daily.
Intent-to-Treat Population (N) 77 77 78
HbA1c (%), Mean
  Baseline 7.8 7.9 7.8
  Change at Week 24 1 -0.2 -0.7 -0.9
  Difference from placebo(95% CI) -0.5 [-0.9, -0.2] 2 -0.7 [-1.0, -0.3]
Proportion Achieving HbA1c <7% 38% 48% 53%
Body Weight (kg), Mean
  Baseline 86.1 85.1 86.2
  Change at Week 24 -1.5 -2.7 -2.9
  Difference from placebo(95% CI) -1.3 [-2.3, -0.2] -1.5 [-2.5, -0.4]
Fasting Serum Glucose Measured using the hexokinase-based glucose method. (mg/dL), Mean
  Baseline 159 166 155
  Change at Week 24 -5 -17 -19
  Difference from placebo (95% CI) -12 [-23.2, -1.3] -14 [-24.5, -2.5]

1 Least squares means are adjusted for screening HbA1c strata and baseline value of the dependent variable.
2 p <0.01, treatment vs. placebo.

On average, there were no adverse effects of exenatide on blood pressure or lipids.

Combination Therapy With Oral Antihyperglycemic Medicines

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.

In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg BID, BYETTA 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) were Hispanic, and 174 (12%) were Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%.

In the placebo-controlled trial of 16 weeks duration, BYETTA (n = 121) or placebo (n = 112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving metformin. BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA1c values were 7.9% for BYETTA and placebo.

The primary endpoint in each study was the mean change in HbA1c from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30-week and 16-week clinical trials.

Table 7: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA Used in Combination with Oral Antidiabetic Agents
Placebo
BID
BYETTA
5 mcg BID
BYETTA
10 mcg BID
In Combination With Metformin (30 Weeks)
BID = twice daily.
Intent-to-Treat Population (N) 113 110 113
HbA1c (%), Mean
  Baseline 8.2 8.3 8.2
  Change at Week 30 1 -0.0 -0.5 -0.9
  Difference from placebo (95% CI) -0.5 [-0.7, -0.2] 2 -0.9 [-1.1, -0.6]
Proportion Achieving HbA1c <7% 12% 32% 40%
Body Weight (kg), Mean
  Baseline 99.9 100.0 100.9
  Change at Week 30 -0.2 -1.3 -2.6
  Difference from placebo (95% CI) -1.1 [-2.2, -0.0] -2.4 [-3.5, -1.3]
Fasting Plasma Glucose 3 (mg/dL), Mean
  Baseline 169 176 168
  Change at Week 30 +14 -5 -10
  Difference from placebo (95% CI) -20 [-32, -7] -24 [-37, -12]
  In Combination With a Sulfonylurea (30 Weeks)
Intent-to-Treat Population (N) 123 125 129
HbA1c (%), Mean
  Baseline 8.7 8.5 8.6
  Change at Week 30 +0.1 -0.5 -0.9
  Difference from placebo (95% CI) -0.6 [-0.9, -0.3] -1.0 [-1.3, -0.7]
Proportion Achieving HbA1c <7% 10% 25% 36%
Body Weight (kg), Mean
  Baseline 99.1 94.9 95.2
  Change at Week 30 -0.8 -1.1 -1.6
  Difference from placebo (95% CI) -0.3 [-1.1, 0.6] -0.9 [-1.7, -0.0]
Fasting Plasma Glucose (mg/dL), Mean
  Baseline 194 180 178
  Change at Week 30 +6 -5 -11
  Difference from placebo (95% CI) -11 [-25, 3] -17 [-30, -3]
In Combination With Metformin and a Sulfonylurea (30 Weeks)
Intent-to-Treat Population (N) 247 245 241
HbA1c (%), Mean
  Baseline 8.5 8.5 8.5
  Change at Week 30 +0.1 -0.7 -0.9
  Difference from placebo (95% CI) -0.8 [-1.0, -0.6] -1.0 [-1.2, -0.8]
Proportion Achieving HbA1c <7% 8% 25% 31%
Body Weight (kg), Mean
  Baseline 99.1 96.9 98.4
  Change at Week 30 -0.9 -1.6 -1.6
  Difference from placebo (95% CI) -0.7 [-1.2, -0.2] -0.7 [-1.3, -0.2]
Fasting Plasma Glucose (mg/dL), Mean
  Baseline 181 182 178
  Change at Week 30 +13 -11 -12
  Difference from placebo (95% CI) -24 [-33, -15] -25 [-34, -16]
   In Combination With a Thiazolidinedione or a Thiazolidinedione plus Metformin (16 Weeks)
Intent-to-Treat Population (N) 112 Dose not studied 121
HbA1c (%), Mean
  Baseline 7.9 Dose not studied 7.9
  Change at Week 16 +0.1 Dose not studied -0.7
  Difference from placebo (95% CI) Dose not studied -0.9 [-1.1, -0.7]
Proportion Achieving HbA1c <7% 15% Dose not studied 51%
Body Weight (kg), Mean
  Baseline 96.8 Dose not studied 97.5
  Change at Week 16 -0.0 Dose not studied -1.5
  Difference from placebo (95% CI) Dose not studied -1.5 [-2.2, -0.7]
Fasting Serum Glucose (mg/dL), Mean
  Baseline 159 Dose not studied 164
  Change at Week 16 +4 Dose not studied -21
  Difference from placebo (95% CI) Dose not studied -25 [-33, -16]

1 Least squares means are adjusted for baseline HbA1c strata or value, investigator site, baseline value of the dependent variable (if applicable), and background antihyperglycemic therapy (if applicable).
2 p <0.01, treatment vs. placebo.
3 Measured using the hexokinase-based glucose method.

HbA1c

The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).

In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, BYETTA resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo (Table 7).

Postprandial Glucose

Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-h postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was -63 (65) mg/dL for 5 mcg BID (n = 42), -71 (73) mg/dL for 10 mcg BID (n = 52), and +11 (69) mg/dL for placebo BID (n = 44).

Combination with Insulin Glargine

A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of BYETTA (n = 137) versus placebo (n = 122) when added to titrated insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control.

All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients assigned to BYETTA had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA1c ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA1c ≥8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% were American Indian or Alaska Native, 9% were Black, 3% were Asian, and 0.8% were of multiple origins.

The primary endpoint was the change in HbA1c from baseline to Week 30. Compared to placebo, BYETTA 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 30 (Table 8) in patients receiving titrated insulin glargine.

Table 8: 30-Week Placebo-Controlled Trial of BYETTA Used in Combination with Insulin Glargine With or Without Metformin and/or Thiazolidinediones
Placebo BID + Titrated Insulin Glargine BYETTA
10 mcgBYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 5 months for the 30-week trial. BID + Titrated Insulin Glargine
BID = twice daily.
Intent-to-Treat Population (N) 122 137
HbA1c (%), Mean
  Baseline 8.5 8.3
  Change at Week 30 1 -1.0 -1.7
  Difference from placebo (95% CI) -0.7 [-1.0, -0.5] 2
Proportion Achieving HbA1c <7% 30% 57%
Body Weight (kg), Mean
  Baseline 93.8 95.4
  Change at Week 30 3 1.0 -1.8
  Difference from placebo (95% CI) -2.7 [-3.7, -1.7]
Fasting Serum Glucose (mg/dL), Mean
  Baseline 133 132
  Change at Week 30 -16 -23
  Difference from placebo (95% CI) -7 [-18, 3]

1 Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA1c value, and treatment by visit, where subject is treated as a random effect.
2 p <0.01, treatment vs. placebo.
3 Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA1c stratum, baseline value of the dependent variable (where applicable), and treatment by visit, where subject is treated as a random effect.

Table 9: Dosing Algorithm for Titration of Insulin GlargineAdapted from Riddle et al. 2003.
Fasting Plasma Glucose Values
(mg/dL)
Dose Change
(U)
Abbreviations: U = units.
<56 1 -4
56 to 72 -2
73 to 99 2 0
100 to 119 +2
120 to 139 +4
140 to 179 +6
≥180 +8
1 Value for at least 1 fasting plasma glucose measurement since the last assessment.
2 Based on the average of fasting plasma glucose measurements taken over the prior 3 to 7 days. The increase in the total daily dose should not have exceeded more than 10 units per day or 10% of the current total daily dose, whichever was greater.

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