Use of Twice-Daily Exenatide in Basal Insulin-Treated Patients With Type 2 Diabetes A Randomized, Controlled Trial

University of North Carolina School of Medicine, Chapel Hill, 27599, USA.
Annals of internal medicine (Impact Factor: 17.81). 01/2011; 154(2):103-12. DOI: 10.1059/0003-4819-154-2-201101180-00300
Source: PubMed


Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A₁(c) (HbA₁(c)) targets.
To test whether twice-daily exenatide injections reduce HbA₁(c) levels more than placebo in people receiving insulin glargine.
Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA₁(c) level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. ( registration number: NCT00765817)
59 centers in 5 countries.
Adults with type 2 diabetes and an HbA₁(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents).
Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks.
The primary outcome was change in HbA₁(c) level. Secondary outcomes included the percentage of participants with HbA₁(c) values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events.
112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA₁(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo.
The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA₁(c) levels, and more exenatide recipients than placebo recipients withdrew because of adverse events.
Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation.
Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.

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    • "These results have led some to suggest that the twice-daily formulation, which has its strongest effect on PPG, is a particularly ideal “fit” with basal insulin, which primarily affects FPG [38]. The hypothesis was confirmed in a recently published randomized clinical trial, which showed that the addition of exenatide BID to titrated basal insulin provided greater glycemic control than titrated basal insulin alone, and did so without an increase in hypoglycemic events and with modest weight loss [39]. Studies are currently ongoing to examine the effect of exenatide QW in combination with basal insulin. "
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    ABSTRACT: A new formulation of exenatide has become available recently that is the first antidiabetic medication for type 2 diabetes mellitus (T2DM) dosed on a weekly schedule. This review summarizes the pharmacology, efficacy, and safety of exenatide once weekly (exenatide QW). The results are interpreted in terms of the pathophysiology of T2DM, as well as the pharmacology of the new formulation. Relevant literature on exenatide QW and diabetes was identified through PubMed database searches from inception until September 2013. In the new once-weekly formulation of exenatide, the exenatide molecule is dispersed in microspheres. Following subcutaneous injection, these microspheres degrade in situ and slowly release active agent. In clinical trials, therapy with exenatide QW as monotherapy or in combination with other antidiabetic treatments was associated with reductions in glycated hemoglobin (-1.3% to -1.9%), fasting plasma glucose (-32 to -41 mg/dL), and body weight (-2.0 to -3.7 kg). These outcomes were achieved without an associated increase in the rate of hypoglycemic episodes, except when exenatide QW was used in combination with sulfonylureas. The primary tolerability issues in the trials were gastrointestinal adverse events, particularly during the first weeks of use, although the rate of nausea during startup with exenatide QW was lower than that with the related agents, exenatide twice daily and liraglutide once daily. Exenatide QW may be particularly well suited to patients who desire the benefits associated with glucagon-like peptide-1 receptor agonists, including significant glycemic control, low risk of hypoglycemia, and moderate weight loss, but prefer the convenience of once-weekly dosing.
    Advances in Therapy 02/2014; 31(3). DOI:10.1007/s12325-014-0101-4 · 2.27 Impact Factor
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    • "While insulin glargine primarily reduced fasting glucose levels and actually increased body weight, exenatide decreased fed glucose levels and body weight while also reducing risk of nocturnal hypoglycemia [44]. Furthermore, when exenatide was added to insulin glargine in patients with suboptimally controlled type 2 diabetes, it improved glycemic control without increasing risk of hypoglycemia or weight gain [45]. "
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    ABSTRACT: Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. It also slows gastric emptying, which contributes to decreased postprandial glycemic excursions. In the 1990s, chronic subcutaneous infusion of GLP-1 was found to lower blood glucose levels in patients with type 2 diabetes. However, GLP-1's very short half-life, arising from cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4) and glomerular filtration by the kidneys, presented challenges for clinical use. Hence, DPP-4 inhibitors were developed, as well as several GLP-1 analogs engineered to circumvent DPP-4-mediated breakdown and/or rapid renal elimination. Three categories of GLP-1 analogs, are being developed and/or are in clinical use: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different plasma half-lives, molecular size, and homology to native GLP-1, and consequently different characteristic effects on glucose metabolism. In this article, we review current clinical data derived from each class of GLP-1 analogs, and consider the clinical effects reported for each category in recent head to head comparison studies. Given the relatively brief clinical history of these compounds, we also highlight several important efficacy and safety issues which will require further investigation.
    12/2013; 28(4):262-274. DOI:10.3803/EnM.2013.28.4.262
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    • "Additionally, exendin-4 can ameliorate obesity via suppressing the gastric emptying rate and the appetite, which poses significant risks to T2DM patients [7] [8]. Therefore, the combination therapy of insulin and exendin-4 has been proposed as a potential treatment for T2DM patients [8]. Parenteral administration has been the prevalent means for administering insulin and exendin-4 to treat diabetic patients. "
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    ABSTRACT: Current insulin therapy via subcutaneous administration can lead to occasional hypoglycemia and peripheral hyperinsulinemia, due to its nonphysiological route. This study evaluates the feasibility of using bovine insulin and exendin-4 in a form of combination therapy, as orally delivered by nanoparticles composed of chitosan and poly(γ-glutamic acid) (CS/γPGA NPs), to control blood glucose levels in rats with type 2 diabetes mellitus (T2DM) undergoing the oral glucose tolerance test. Experimental results indicate that CS/γPGA NPs could enhance the intestinal paracellular permeation; consequently, the exogenous bovine insulin and exendin-4 could be delivered into the liver and pancreas, where they could elicit their glucoregulatory activities. In response to the stimulus of exogenously delivered bovine insulin and the endogenously secreted rat insulin stimulated by the ingested exendin-4, significant glucose utilizations were found in the cardiac and skeletal muscles, resulting in the glucose-lowering effect. Owing to its synergic stimulation effects, the hypoglycemic effect of oral ingestion of NPs containing bovine insulin and exendin-4 was significantly greater than that of the group solely treated with insulin NPs. Above results demonstrate that oral combination therapy with bovine insulin and exendin-4 improves the modulation of blood glucose levels in T2DM rats, making it highly promising for treating those T2DM patients not adequately controlled by the current insulin therapy.
    Biomaterials 07/2013; 34(32). DOI:10.1016/j.biomaterials.2013.07.021 · 8.56 Impact Factor
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