Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea

Oregon Health and Science University, Portland, Oregon, United States
Diabetes Care (Impact Factor: 8.42). 06/2005; 28(5):1083-91. DOI: 10.2337/diacare.28.5.1083
Source: PubMed


This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy.
A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 +/- 10 years, BMI 33.6 +/- 5.7 kg/m(2), A1C 8.5 +/- 1.0%; means +/- SD) randomized to 5 microg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 microg b.i.d. and arm B escalated to 10 microg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea.
Week 30 A1C changes from baseline (+/-SE) were -0.8 +/- 0.1% (10 microg), -0.6 +/- 0.1% (5 microg), and +0.2 +/- 0.1% (placebo; adjusted P < 0.0001 vs. placebo), yielding placebo-adjusted reductions of -1.0% (10 microg) and -0.8% (5 microg). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C < or =7% than placebo-treated subjects (34% [10 microg], 27% [5 microg], and 9% [placebo]; P < 0.0001). Both exenatide arms demonstrated significant weight loss (-1.6 +/- 0.2 kg from baseline each exenatide arm, -0.9 +/- 0.2 kg placebo; P < or = 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 microg), 19% (5 microg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment.
Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.

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Available from: Julio Rosenstock, Jul 23, 2015
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    • "In the series of 3 trials, in which exenatide was added to a sulfonylurea agent, or metformin, or to metformin plus sulfonylurea; patients were randomized to placebo or exenatide injection twice daily[33],[34,35]. The authors found that patients in the 3 groups had a decrease level of HbAlc levels while weight loss was seen in patients who were on metformin monotherapy when the exenatide was started333435. Although exenatide is only approved for use with metformin and/or sulfonylurea agent, there is no pharmacologic reason to believe that it can't be used as monotherapy or in combination with all agents for treating diabetes, including thiazolidinediones and insulin. "
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    ABSTRACT: Incretins are hormones produced from the gastrointestinal tract that works to lower glucose level in a glucose-dependent fashion without causing hypoglycemia, but with gradual weight loss due to a decrease in caloric intake. Incretin mimetics or GLP-1 analogs are a new class of pharmacological agents that mimics some effect of endogenous incretin hormones. The incretin mimetics seem to possess a spectrum of beneficial actions for patients with type 2 diabetes. Their particular virtue is their ability to produce durable improvement in glycaemic control combined with a sustained and progressive weight loss. GLP-1 based therapies operate through multiple novel mechanism of action that addresses many of the pathophysiological disturbances in type 2 diabetes. DPP-4 inhibitors short-acting GLP-IR agonists and long-acting GLP-IR agonists each have unique attributes. Short-acting, GLP-IR agonist should be used to target post prandial hyperglycemia as monotherapy or as part of a combination requirement with oral or basal insulin if fasting hyperglycemia is also present. DPP-4 inhibitors or GLP-IR agonists should be used if fasting hyper glycaemia is the main target of therapy. Long-acting GLP-IR agonists appear to be most Potent HbAIC lowering agent of the GLP-1 based therapy and thus may be the best choice for patients that are far from glycemic goals. However, the benefits and risks of these agents require further evaluation.
    Full-text · Article · Jan 2016
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    • "Exenatide, exenatide LAR, and lixisenatide are synthetic peptides based on exendin-4, which is found in the saliva of the Gila monster lizard. Exendin-4 has homology of 53% to the human GLP-1 with equal power in the GLP-1 receptor and is resistant to degradation by serine protease enzyme dipeptidyl peptidase-4 (DPP-4)[36]. Other GLP-1 RAs synthetic peptides are modified GLP-1 naturally occurring, where the amino acid substitution has been used to protect the GLP-1 molecule to be broken by DPP-4[35]. "

    Full-text · Article · Jan 2016 · Open Journal of Endocrine and Metabolic Diseases
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    • "Among antidiabetic agents, GLP-1 agonists such as exenatide, liraglutide, and lixisenatide are known to have benefits for weight loss, and their use is expected to have a direct and indirect effect on reducing CVD risks[29]. Several studies were conducted using GLP-1 agonists, and the effects of glycemic control and weight reduction were proven in most studies3031323334353637. However, in Korea, reimbursements by national medical insurance system are only available for T2DM patients with BMI ≥30 kg/m 2 . "
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    ABSTRACT: Background: The present study aimed to investigate the clinical characteristics of type 2 diabetes mellitus (T2DM) in Korean adults according to Body Mass Index (BMI) and to analyze the association with cardiovascular disease (CVD). Methods: We conducted a cross-sectional study of data from the Korea National Health and Nutrition Examination Survey from 2007 to 2011. A total of 3,370 patients with T2DM were divided into categories according to BMI. We conducted a comparison of the T2DM patient population composition by BMI category between different countries. We investigated the prevalence of awareness, treatment, and target control of T2DM according to BMI. Results: Patients with T2DM had a higher BMI, and were more likely to have a history of CVD than healthy controls. For Korean adults with T2DM, 8% had BMI ≥30 kg/m². By contrast, the population of patients with T2DM and BMI ≥30 kg/m² was 72% in patients in the USA and 56% in the UK. The rate of recognition, treatment, and control has worsened in parallel with increasing BMI. Even in patients with BMI 25-29.9 kg/m², the prevalence of CVD or high risk factors for CVD was significantly higher than in patients with BMI 18.5-22.9 kg/m² (OR 2.07). Conclusion: Korean patients with T2DM had lower BMI than those in Western countries. Higher BMI was associated with lower awareness, treatment, and control of diabetes, and a positive association was observed between CVD or high risk factors for CVD and BMI, even for patients who were overweight but not obese.
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