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Exenatide is an incretin mimetic with potential gluco-regulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy [...]

Background: Patients with type 2 diabetes (T2DM) are at risk of long-term vascular complications. In trials, exenatide once weekly (ExQW), a GLP-1R agonist, improved glycemia, weight, blood pressure (BP), and lipids in patients with T2DM. We simulated potential effects of ExQW on vascular complications, survival, and medical costs over 20 years versus standard therapies. Patients and methods: The Archimedes model was used to assess outcomes for ~25,000 virtual patients with T2DM (NHANES 1999-2006 [metformin ± sulfonylureas, age 57 years, body mass index 33 kg/m2, weight 94 kg, duration T2DM 9 years, hemoglobin A1c [A1C] 8.1%]). The effects of three treatment strategies were modeled and compared to moderate-adherence insulin therapy: advancement to high-adherence insulin at A1C ~8% (treat to target A1C , 7%) and addition of pioglitazone (PIO) or ExQW from simulation start. ExQW effects on A1C, weight, BP, and lipids were modeled from clinical trial data. Costs, inflated to represent 2010 $US, were derived from Medicare data, Drugstore.com, and publications. As ExQW was investigational, we omitted ExQW, PIO, and insulin pharmacy costs. Results: By year 1, ExQW treatment decreased A1C (~1.5%), weight (~2 kg), and systolic BP (~5 mmHg). PIO and high-adherence insulin decreased A1C by ~1%, increased weight, and did not affect systolic BP. After 20 years, A1C was ~7% with all strategies. ExQW decreased rates of cardiovascular and microvascular complications more than PIO or high-adherence insulin versus moderate-adherence insulin. Over 20 years, ExQW treatment resulted in increased quality-adjusted life-years (QALYs) of ~0.3 years/person and cost savings of $469/life-year versus moderate adherence insulin. For PIO or high-adherence insulin, QALYs were virtually unchanged, and costs/life-year versus moderate-adherence insulin increased by $69 and $87, respectively. Conclusions: This long-term simulation demonstrated that ExQW treatment may decrease rates of cardiovascular and some microvascular complications of T2DM. Increased QALYs, and decreased costs were also projected. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D), obesity, and nonalcoholic fatty liver disease (NAFLD) are emerging public health concerns that often co-exist, with diabetes and obesity the two most important risk factors for NAFLD. Because exenatide is associated with improvement in glycemic control and weight reduction, we evaluated the effects of the incretin mimetic exenatide over 3y in T2D patients not achieving glycemic control with MET and/or a SFU. Patients were enrolled in 30-wk, placebo-controlled trials followed by open-label extensions (64% M, 58±10 y, 99±18 kg, BMI 34±5 kg/m², A1C 8.2±1.0% [mean±SD]). In this ad-hoc analysis, 217 patients were evaluated for ALT and AST stratified by baseline ALT (normal: F ≤19 IU/L, M≤30 IU/L) as surrogate markers of NAFLD. Patients completing 3 y on exenatide had reductions in A1C (-1.0±0.1%; p<0.0001), weight (-5.3±0.4 kg; p<0.0001), fasting plasma glucose (-24±4 mg/dL; p<0.0001), and ALT (-4.5±1.1 IU/L; p<0.0001) [mean±SE]. Exenatide was generally well tolerated. The correlation coefficient for ALT change vs. A1C change was r=0.25, and for ALT change vs. weight change was r=0.31. Patients with normal baseline ALT (21.3±0.5 IU/L; n=101; -0.9±0.1% A1C) had minimal increases in ALT (+2.3±1.2 IU/L; p=0.06) or AST (+3.0±0.6 IU/L; p<0.0001). In contrast, patients with elevated baseline ALT (38.4±1.5 IU/L; n=116; -1.0±0.1% A1C) had reductions in ALT (-10.4±1.5 IU/L; p<0.0001) and AST (-4.1±1.0 IU/L; p<0.0001). There was a difference in 3-y weight change for normal vs. elevated baseline ALT (-4.4±0.5 kg vs. -6.1±0.6 kg; p--0.03). Patients with elevated baseline ALT in the weight change quartile with the greatest weight loss (n=29) had the greatest ALT reduction (-16.3±3.1 IU/L; baseline 37.2±2.9 IU/L) coupled with -2.0±0.2% A1C and - 13.9±0.7 kg. In conclusion, T2D patients treated with exenatide for 3 years had improvements in hepatic biomarkers, with reductions in A1C and weight. These data support further investigations into possible improvements in NAFLD with exenatide treatment. [ABSTRACT FROM AUTHOR]

The article presents the findings of research that aims to examine changes in insulin-sensitizing hormone adiponectin (ADPN) in patients with evaluable plasma samples completing 2 to 2.5 y of exenatide treatment in open-label extension studies. It mentions the association of decreased circulating concentration of ADPN with increased risk of cardiovascular disease. A table showing improvements in glycemic control and weight reduction is presented.

Traditional antidiabetic therapies often fail to maintain glycemic control over time. In this retrospective analysis using a large, national commercial health care claims database, we describe baseline characteristics, comorbidities, and concomitant therapies in patients prescribed exenatide in the first 13 months following FDA approval. A total of 3578 patients were identified who had a prescription claim for exenatide between May 1, 2005 and May 31,2006, ≥12 months of pre-index eligibility (first claim defined as index date), and were ≥18 years old. Of these, 3454 patients (96.5%) had a pre-index diagnosis for type 2 diabetes based on diagnosis code and/or meditation use. Mean (±SD) age was 54.24±10.0 years; 49.7% were female and 12.7% were ≥65 years of age. Baseline A1C values obtained within 100 days before the index date were available for 340 patients (mean±SD = 8.04±1.6%). The most common comorbidities associated with diabetes reported in the 12 months prior to the index date were dyslipidemia (87.7%), hypertension (64.3%), other cardiovascular disease (27.7%), and obesity (17.7%). Most patients analyzed (94.2%) were treated with at least one other antidiabetic medication at baseline; 22.1% with one drug, 34.3% with 2 drugs, and 37.8% with ≥3 drugs. Metformin was the most common baseline therapy (74.5%), followed by thiazolidinediones (50.6%), sulfonylureas (49.0%), and insulin (29.7%). This study provides the first nonclinical trial population analysis of the baseline A1C, demographics, comorbidities, and concomitant diabetes therapies in patients initiated on exenatide. The mean baseline A1C indicates that these patients were not achieving glycemic control as defined by current guidelines, supporting the notion that diabetes remains a difficult disease in which to achieve therapeutic goals. In the first 13 months since FDA approval, exenatide was predominantly prescribed to patients with type 2 diabetes who were failing to achieve glycemic control with prior antidiabetic therapy. [ABSTRACT FROM AUTHOR]

Postprandial hyperglycemia contributes significantly to A1C and is an independent risk factor for long-term morbidity and mortality in diabetes. Exenatide, an incretin mimetic, has been shown to lower postprandial glucose (PPG) concentrations. The plasma 1,5-anhydroglucitol (1,5-AG; GlycoMark) assay, which increases with lower PPG, has been shown to reflect PPG more robustly than A1C. In this post-hoc analysis of a randomly selected subset of patients with type 2 diabetes (T2DM) with evaluable samples from three placebo-controlled studies (N=144; age 57.2±10.0y; A1C 8.2±1.0%; weight 96.4±20.9kg; mean±SD), plasma 1,5-AG was measured in patients treated for 30 weeks with either exenatide (5 or 10µg) or placebo. At 30 weeks, A1C was significantly reduced in patients treated with exenatide (10µg) compared to placebo (-0.9±0.1; P<0.01). Consistent with the known improvement in PPG in patients with T2DM treated with exenatide, 1,5-AG increased in patients treated with both 5µg (+2.7±0.6µg/mL; +45.3±11.9%; P<0.05 compared to placebo; mean±SE) and 10µg (+2.9±0.6µg/mL; +69.4±14.6%; P<0.01 compared to placebo) of exenatide. Changes in 1,5-AG were significantly correlated with A1C change from baseline (r=-0.74; P<0.0001) and fasting plasma glucose (FPG) change from baseline (r=-0.54; P<0.0001). Moreover, analysis of 1,5-AG changes grouped by A1C change tertiles indicated that patients with larger A1C changes from baseline had larger 1,5-AG changes from baseline. Previous studies have shown that as A1C nears 7%, PPG becomes the major contributor to overall glycemic control. As such, 1,5-AG may be a useful complement to A1C to reflect PPG in patients with T2DM treated with agents that target PPG. In this post-hoc analysis, the increase in 1,5-AG confirms previously reported improvements in PPG in exenatide-treated patients. [ABSTRACT FROM AUTHOR]

In clinical trials, exenatide improved glycemic control and was associated with weight reduction and improvement in several cardiovascular risk factors. In this retrospective analysis using a large, national commercial health care claims database, we describe changes in concomitant diabetes therapies in patients with type 2 diabetes who had a prescription claim for exenatide in the first 13 months following FDA approval. A total of 1637 patients were ≥18 years old, had type 2 diabetes, had an initial (index) claim for exenatide between May 1,2005 and May 31, 2006, and had 12 months of pre-index and 6 months of post-index eligibility. Baseline diabetes therapies were defined as prescriptions filled 100 days pre-index through 15 days post-index; post-index therapies were defined as any prescriptions filled ≥16 days to 180 days post-index. In the post-index period, the number of patients with prescription claims for metformin, thiazolidinediones, and sulfonylureas decreased by 14.3% (P<0.0001), 16.0% (P<0.0001), and 25.0% (P<0.0001), respectively. Patients with prescription claims for both metformin and a sulfonylurea declined by 25.9% (P<0.0001) and patients with prescriptions claims for the combination of metformin, a thiazolidinedione, and a sulfonylurea decreased by 40.1% (P<0.0001). The percentage of patients with prescription claims for insulin was similar between baseline and post-index periods. This study provides the first nonclinical trial population analysis of changes in concomitant diabetes therapies following initiation of exenatide therapy, and demonstrates that exenatide initiation was associated with a significant reduction in prescription claims for other diabetes therapies. [ABSTRACT FROM AUTHOR]

In two comparator trials (10µg exenatide BID vs. either insulin glargine or mixed insulin), both exenatide and insulin treatment achieved similar reductions in A1C for approximately 6 months, while exenatide was associated with weight loss and insulin associated with weight gain. Data were pooled from these two studies (N=1050) to examine whether patient's baseline characteristics (A1C, fasting serum glucose (FSG), weight, age, duration of diabetes, origin, and gender) were associated with a final A1C of ≤6.5% and ≤7%, for exenatide or insulin treatment on background of metformin (MET) and a sulphonylurea (SFU). Mean (±SD) baseline A1C (8.4±1.0%) was similar for both treatment groups and treatment was not a significant predictor for achieving an A1C ≤7%. However, the odds of exenatide patients achieving an A1C ≤6.5% were 1.69 (95% CI 1.21-2.35) times greater than insulin patients (p=.002). For exenatide patients, lower baseline A1C (odds ratio 0.40 [95% CI 0.29-0.54]) and lower baseline FSG (0.87 [0.78-0.96]) were significant predictors for achieving A1C ≤6.5%; lower baseline HbA1c (odds ratio 0.47 [0.36-0.62]), lower baseline FSG (0.87 [0.79-0.96]), and older age (1.04 [1.01-1.06]) were significant predictors for achieving A1C ≤7%. For insulin patients, lower baseline A1C was the only significant factor associated with reaching an A1C ≤6.5% (odds ratio 0.36 [0.27-0.50]) or A1C ≤7% (odds ratio 0.30 [0.23-0.40]). In patients with type 2 diabetes failing on SFU and MET in whom the next step may be insulin, exenatide treatment was associated with a greater percentage of patients achieving an A1C ≤6.5% than insulin, with no increase in overall hypoglycemia. In these trials, exenatide was associated with a lower rate of nocturnal hypoglycemia and mean weight reduction, while insulin patients gained weight. Irrespective of treatment, a lower baseline A1C value was associated with a higher probability of achieving glycemic targets. [ABSTRACT FROM AUTHOR]