Ted Okerson

Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study.

BACKGROUND Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents. OBJECTIVE The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. METHODS This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged >or=18 years with type 2 diabetes were randomly assigned to receive exenatide 5 microg, exenatide 10 microg, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA(1c)); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA(1c) values <or=6.5% and <or=7.0%; weight; and homeostasis model of beta-cell function (HOMA-B, a clinical measure of pancreatic beta-cell function). Tolerability measures included patient-reported adverse events, hypoglycemia, and blood pressure. RESULTS A total of 232 patients were included in the intent-to-treat population (130 men, 102 women; 68% white; mean [SD] age, 54 [10] years; duration of type 2 diabetes, 2 [3] years; weight, 86 [16] kg; body mass index, 31 [5] kg/m(2); HbA(1c), 7.8% [0.9%]). At end point, least-squares mean (SE) HbA(1c) reductions (%) from baseline were significantly greater with exenatide 5 and 10 microg than placebo (-0.7 [0.1] and -0.9 [0.1] vs -0.2 [0.1]; P = 0.003 and P < 0.001, respectively), as were FSG reductions (mg/dL) (-17.5 [4.0] and -18.7 [4.0] vs -5.2 [4.0]; P = 0.029 and P = 0.016, respectively). Changes in daily mean postprandial glucose excursions (mg/dL) from baseline to end point were significantly greater with exenatide 5 and 10 microg than placebo (-21.3 [2.7] and -24.7 [2.7] vs -8.3 [2.5]; both, P < 0.001). With exenatide 5 and 10 microg, 31% and 35% of patients achieved HbA(1c) <or=6.5% at end point versus 19% with placebo (P = NS and P = 0.026, respectively), while 48% and 46% versus 29% achieved HbA(1c) <or=7.0% (P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with exenatide 5 and 10 (2)g than placebo (-2.8 [0.3] and -3.1 [0.3] vs -1.4 [0.3]; P = 0.004 and P < 0.001, respectively). HOMA-B values increased from baseline to end point by 32% and 28% in the exenatide 5- and 10-microg groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with exenatide 5 and 10 microg than placebo (P = 0.002 and P = 0.010, respectively). Significant improvements in mean systolic and diastolic blood pressure (mm Hg) from baseline to end point were also observed with exenatide (systolic, both 5 and 10 microg, -3.7 [1.2] [P = 0.037]; diastolic, 10 microg, -2.3 [0.7] [P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported >or=1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 microg, 3%; 10 microg, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-microg and placebo groups, respectively (P = NS), with no incidents of severe hypoglycemia reported. CONCLUSIONS In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA(1c), improved fasting and postprandial glucose control, reduced weight, improved beta-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.

Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study.

ABSTRACT Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients. Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 ± 5 kg/m2; HbA1c: 8.5 ± 1.2%; 2-h PPG: 245 ± 65 mg/dL. Patients received exenatide (5 µg BID for 1 week, then 10 µg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581). Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 ± 6 mg/dL versus 208 ± 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 ± 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by −76 ± 10 mg/dL. Postprandial glucose parameters (AUC, Cave, Cmax) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (−15 ± 4 mg/dL vs. −19 ± 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 ± 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 ± 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 ± 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 ± 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (−134 ± 97 kcal vs. +130 ± 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature. Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.

Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes.

BACKGROUND The majority of patients with type 2 diabetes mellitus have blood pressure (BP) exceeding the recommended value of <130/80 mm Hg. Optimal control of hyperglycemia and hypertension has been shown to reduce the incidence of macrovascular and microvascular complications due to diabetes. Treatment with the GLP-1 receptor agonist exenatide, previously demonstrated to reduce hemoglobin A(1C) and weight in subjects with type 2 diabetes, was associated with BP reduction in several studies. METHODS This analysis explored the effects of exenatide vs. placebo or insulin on BP measurements in pooled data from six trials including 2,171 subjects studied for at least 6 months. RESULTS Overall, 6 months of exenatide treatment was associated with a significantly greater reduction in systolic BP (SBP) compared with placebo (least squares mean (s.e.): difference of -2.8 mm Hg (0.75); P = 0.0002) or insulin (difference of -3.7 mm Hg (0.85); P < 0.0001). No significant intergroup differences in diastolic BP (DBP) were observed. The majority of the intergroup difference was observed in subjects with SBP > or = 130 mm Hg (difference of -3.8 mm Hg (1.08) from placebo: P = 0.0004; difference of -4.0 mm Hg (1.01) from insulin; P < 0.0001). The largest intertreatment differences between exenatide and comparators were observed in subjects with SBP >/=150 mm Hg. Similar responses were observed in African-American subjects. A weak correlation between the amount of weight lost and reduction in SBP was found (r = 0.09, P = 0.002) for exenatide-treated subjects. CONCLUSIONS These results support the need for a prospective, randomized, controlled study of BP changes during exenatide treatment in patients with hypertension and type 2 diabetes.

Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors.

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Effects of Exenatide on Diabetes, Obesity, Cardiovascular Risk Factors, and Hepatic Biomarkers in Patients with Type 2 Diabetes

Obesity increases the risk of diabetes up to 90-fold and worsens hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. For patients with type 2 diabetes, weight loss can trigger improvements in all these conditions and decrease the need for glucose-lowering agents. The incretin mimetic exenatide shares many glucoregulatory properties with native glucagon-like peptide-1, including enhancement of glucose-dependent insulin secretion, glucose-dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, and reduction of food intake in patients with type 2 diabetes. Exenatide treatment was associated with progressive weight loss in the majority of patients in clinical trials. In addition, patients with elevated markers of liver injury at baseline showed improvements. Therefore, exenatide represents a unique option for adjunctive therapy for patients with type 2 diabetes not achieving adequate glycemic control on oral antidiabetic agents, especially in patients for whom weight gain would be an additional contraindication.

Interim results at 48 weeks of LAP-BAND AP experience (APEX) study: prospective, multicenter, open-label longitudinal patient observational study.

BACKGROUND The development of laparoscopic adjustable gastric banding marked a breakthrough in minimally invasive bariatric surgery. The unique features of gastric banding, including device adjustability, lack of malabsorption, and easy reversibility, have contributed to its widespread use. Since Food and Drug Administration approval of the first laparoscopic adjustable gastric band, the device design has undergone engineering improvements. The LAP-BAND AP (LBAP) system received Food and Drug Administration approval in 2006. Little is known about the safety and efficacy of this new system. Our objective was to prospectively assess the efficacy and safety of the LBAP system in real-world clinical settings at 50 clinical centers throughout the United States. METHODS In an open-label 5-year evaluation, 508 severely or morbidly obese patients from 50 centers in the United States underwent surgery using the LBAP system. The present interim report describes the results from 323 patients after ≥ 48 weeks of follow-up. RESULTS By week 48, the patients had experienced a mean percentage of excess weight loss of 46% and a mean ± standard deviation reduction in the body mass index of 8.4 ± 3.69 kg/m(2). Sixteen patients (3.1%) experienced a severe device- or procedure-related adverse event. There were no deaths. CONCLUSION These 48-week interim data demonstrate that the LBAP system offers a safe and effective therapy to reduce weight in severely obese patients.

Prevalence of comorbidities and baseline characteristics of LAP-BAND AP® subjects in the Helping Evaluate Reduction in Obesity (HERO) study.

Objective To describe the baseline characteristics in patients who chose placement of a LAP-BAND AP® System (LBAP) and participated in the Helping Evaluate Reduction in Obesity (HERO) Study across regions. Patients and Methods HERO is a five- year, prospective, multicenter, international study of patients with LBAP placement between July 22, 2009 and January 31, 2011. In addition to baseline and peri-surgery clinical data, seven follow up visits are scheduled at 3, 6 and 12 months, and annually through year five. Data collection included family and medical history, clinical outcomes, laboratory data, health-related quality of life (HRQoL), productivity, healthcare resource utilization, and adverse events. Results LBAP were placed in 1106 enrolled patients; 56.6% from the US, 26.3% from Europe, 7.1% from Canada, and 10.0% from Australia. The majority were female (n = 877 (79.3%)) with a mean age of 43 years (s.d. = 11.4) and mean body mass index of 45.1 kg/m2 (s.d. = 6.9). The most common comorbidities were hypertension (HTN) (overall  = 42.9%) and diabetes (overall 22.2%, with 27% from the US and 14% from Europe). Overall, less than 5% had a history of cardiovascular disease. The prevalence rates of HTN, diabetes and cardiovascular disease were significantly (p<0.001) higher in men than in women across all regions. Overall HRQoL also worsened with increasing BMI. Conclusions The HERO study is the first large, multinational and long-term registry with the LBAP. This study will provide real-world outcomes data on LAGB that will help inform patient choice, clinician treatment strategies, and payer reimbursement decisions.