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Clinical Efficacy

BYETTA vs insulin lispro

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Study design

Study design

4B study: BYETTA BID vs insulin lispro TID

4B : Basal Insulin Glargine, Exenatide BID, and Metformin Therapy or Basal Insulin Glargine, Bolus Insulin Lispro, and Metformin Therapy

Objective: Compare the efficacy and safety of BYETTA (extenatide) injection, a shortacting GLP-1 receptor agonist, or bolus insulin lispro in patients inadequately controlled on a regimen of titrated insulin glargine plus metformin.

4B study design4B study design
Abbreviations: FPG, fasting plasma glucose; IG, insulin glargine; IL, insulin lispro; ITT, intent to treat; Met, metformin; PP, per-protocol population; SU, sulfonylurea.
  • Insulin glargine titration1,2: The INITIATE (INITiate Insulin by Aggressive Titration and Education) algorithm2 was utilized for IG titration during the BIO phase and following the initial IG reductions at randomization. At randomization, the daily IG dose in the BYETTA group was reduced up to 10% or more when A1C was ≤8%; in the IL group, the daily IG dose was reduced by one-half or one-third at the investigator’s discretion. In both groups, bedtime IG dose was titrated to an FPG of 100 mg/dL or lower without hypoglycemia (ie, glucose <54 mg/dL), based on self-monitored blood glucose and the use of a patient dosing aid.
    Patients were instructed to take IG at bedtime and record daily date, time, and dose/units in a diary. Based on the average of 3 consecutive FPG values, doses of IG were increased when FPG exceeded 100 mg/dL. If fasting blood glucose was less than 72 mg/dL with symptomatic hypoglycemia, which occurred without reason, patients decreased the glargine dose.
  • Insulin lispro titration1: IL was titrated to a premeal glucose of 100 to 108 mg/dL based on self-monitored blood glucose and the use of a patient dosing aid. Patients were instructed to record date, dose, time of dose, and dose/units in a diary and test blood glucose immediately before injections and starting a meal. If premeal glucose was >108 mg/dL, IL doses were increased based on the dosing aid.

Mean baseline characteristics at randomization

  • BYETTA arm: 52% male, 90% Caucasian; age, 60 years (mean); A1C, 8.3%; weight, 91.1 kg (200.4 lb); FPG, 7.1 mmol/L (127.8 mg/dL); metformin daily dose, 2038 mg; insulin glargine, 61.5 U/day; median duration of diabetes, 12 years.
  • Insulin lispro arm: 51% male, 87% Caucasian; age, 59 years; A1C, 8.2%; weight, 89.4 kg (196.7 lb); FPG, 7.1 mmol/L (127.8 mg/dL); metformin daily dose, 1998 mg; insulin glargine, 61.1 U/day; median duration of diabetes, 11 years.
  • Baseline insulin dosing: At the start of the BIO phase, the insulin glargine dose was 40.7 U/day in the enrolled population (N = 917), 34.5 U/day among the responders (N = 92 with A1C ≤7%), and 40.6 U/day among nonresponders (N = 652 with A1C >7%). At the end of the BIO phase, the insulin dose had been titrated to 56.8 U/day, 47.3 U/day, and 58.0 U/day in the enrolled, responder, and nonresponder population, respectively.

Select Important Safety Information: Warnings and Precautions

  • Renal Impairment: Should not be used in patients with severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or when initiating or escalating the dose in patients with moderate renal failure. Postmarketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation.
  • Gastrointestinal Disease: Because exenatide is commonly associated with gastrointestinal adverse reactions, BYETTA is not recommended in patients with severe gastrointestinal disease (eg, gastroparesis).
  • Immunogenicity: Patients may develop antibodies to exenatide. In 3 registration trials, antibody levels were measured in 90% of patients, with up to 4% of patients having high-titer antibodies and attenuated glycemic response. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy.
  • Hypersensitivity: Postmarketing reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYETTA and other suspect medications and promptly seek medical advice.


A1C reduction

A1C reduction

In appropriate adult patients with type 2 diabetes uncontrolled on insulin glargine and metformin in addition to diet and exercise

BYETTA (exenatide) injection provided powerful A1C reductions similar to insulin lispro at 30 weeks

Primary endpoint: change in A1C from baseline at 30 weeks
  • Abbreviations: BL, baseline; LS, least squares; PP, per-protocol population; SE, standard error.
  • Primary endpoint was change in A1C from randomization to 30 weeks with a noninferiority margin of 0.4% in the PP population.

BYETTA 5 mcg BID for 1 month, followed by BYETTA 10 mcg BID for the remainder of the 30-week study.

  • BYETTA® (exenatide) injection met the primary endpoint of noninferiority to insulin lispo1
  • BYETTA BID reduced A1C by -1.13% vs -1.10% for insulin lispro TID1
 


Weight loss

Additional benefit of weight loss*

 

Secondary endpoint: change in body weight* at 30 weeksSecondary endpoint: change in body weight* at 30 weeks
  • Abbreviations: BL, baseline; Ls, least squares; PP, per-protocol population; SE, standard error.
  • At 30 weeks, BYETTA treatment resulted in a 5.5-lb reduction of body weight compared to insulin lispro, which increased body weight by 4.6 lb1

BYETTA is not indicated for weight loss.

*Weight reduction was a secondary end point

Select Important Safety Information: Warnings and Precautions

  • Hypoglycemia: Increased risk of hypoglycemia when used in combination with a sulfonylurea (SU) or when used with a glucose-independent insulin secretagogues (eg, meglitinides). Clinicians may consider reducing the SU dose in patients receiving BYETTA to reduce the risk of hypoglycemia. When used with insulin, evaluate and consider reducing the insulin dose in patients at increased risk of hypoglycemia.
  • Renal Impairment: Should not be used in patients with severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or when initiating or escalating the dose in patients with moderate renal failure. Postmarketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation.
  • Gastrointestinal Disease: Because exenatide is commonly associated with gastrointestinal adverse reactions, BYETTA is not recommended in patients with severe gastrointestinal disease (eg, gastroparesis).

VIEW SAFETY PROFILE


Clinical summary

Clinical summary

  • Significantly greater A1C reduction of 1.7% compared to 1.0% for titrated insulin glargine alone.*
  • Helped 57% of patients get to an A1C < 7% compared to 30% of patients on insulin glargine alone, and provided the potential for weight loss.
  • Rate of hypoglycemia for BYETTA plus titrated insulin glargine vs placebo plus titrated insulin glargine was 24.8% vs 29.5%, respectively.
  • Nausea, the most common adverse event, was 41% for BYETTA vs 8% for placebo.

BYETTA provided powerful A1C reductions similar to mealtime insulin with the additional benefit of weight loss1*

In a head-to-head study vs mealtime insulin, BYETTA demonstrated:

  • Powerful A1C reductions similar to insulin lispro at 30 weeks (-1.13% vs -1.10%, respectively)
  • The additional benefit of weight loss* vs insulin lispro, with a 10-lb difference between groups
  • Lower incidences of minor hypoglycemia (BYETTA, 30%; insulin lispro, 41%) and major hypoglycemia (BYETTA, 0.6%; insulin lispro, 2.2%)

BYETTA is not indicated for weight loss.

*Weight reduction was a secondary end point

  • Baseline: BYETTA, 8.3%; insulin lispro,
  • 8.2%.
  • Reference: 1. Diamant M, Nauck MA, Shaginian R, et al; for the BYETTA vs mealtime insulin Study Group. Glucagon-like peptide-1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care. 2014;37(10):2763-2773.