Larry Z. Shen

DURATION-1: Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks

OBJECTIVE In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks. RESEARCH DESIGN AND METHODS In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. RESULTS Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. CONCLUSION Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes

Exenatide (exendin‐4) exhibits dose‐dependent glucoregulatory activity, but causes dose‐limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose‐escalation methodology.

Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial

Aims  The autoimmune‐mediated destruction of pancreatic β‐cells in Type 1 diabetes mellitus renders patients deficient in two glucoregulatory peptide hormones, insulin and amylin. With insulin replacement alone, most patients do not achieve glycaemic goals. We aimed to determine the long‐term efficacy and safety of adjunctive therapy with pramlintide, a synthetic human amylin analogue, in patients with Type 1 diabetes.

Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes

It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m2), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (≤1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies.Keywords: GLP-1 receptor agonist, diabetes, cardiovascular safety

Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing.

Background and ObjectivesExenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus.Patients and MethodsPatients with type 2 diabetes participated in either a single-dose trial (n=62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER.ResultsExenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6–7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (−42.7 ±15.7 mg/dL with the 0.8mg dose and −39.0±9.3mg/dL with the 2mg dose; both p<0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC50) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2mg doses of exenatide ER). The 2 mg dose reduced bodyweight (−3.8 ± 1.4kg; p<0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbAlc) levels were reduced with the 0.8 mg dose (−1.4±0.3%; baseline 8.6%) and with the 2mg dose (−1.7 ± 0.3%; baseline 8.3%) [both p<0.001 vs placebo]. Adverse events were generally transient and mild to moderate in intensity.ConclusionThese studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss.[Clinicaltrials.gov Identifier: NCT00103935]

Enhanced Weight Loss Following Coadministration of Pramlintide With Sibutramine or Phentermine in a Multicenter Trial

Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo‐controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1‐week placebo lead‐in, 244 obese or overweight, nondiabetic subjects (88% female; 41 ± 11 years; BMI 37.7 ± 5.4 kg/m2; weight 103 ± 19 kg; mean ± s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 µg t.i.d.), pramlintide sc (120 µg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 µg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single‐blind for subjects receiving subcutaneous medication only and open‐label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 ± 1.1% with pramlintide + sibutramine, 11.3 ± 0.9% with pramlintide + phentermine, −3.7 ± 0.7% with pramlintide; −2.2 ± 0.7% with placebo; mean ± s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 ± 1.2 beats/min, P < 0.05; 2.7 ± 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 ± 1.3 beats/min, P < 0.01; 3.5 ± 1.2 mm Hg, P < 0.001) using 24‐h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide‐containing combination treatments for obesity.

Addition of pramlintide to insulin therapy lowers HbA1c in conjunction with weight loss in patients with type 2 diabetes approaching glycaemic targets

Aim:  Two long‐term, randomized, double‐blind, placebo‐controlled clinical trials in insulin‐using patients with type 2 diabetes, spanning a wide range of baseline glycaemic control, have shown that the addition of pramlintide, an analogue of the β‐cell hormone amylin, to pre‐existing insulin regimens results in reductions in HbA1c that are accompanied by weight loss.

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects

Aims Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc. Methods Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. Results Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). QTcP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔQTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. Conclusions These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

Sample size determination for controlling the upper confidence limit of incidence rate of a binomial endpoint

Assume that in a comparative clinical study the primary endpoint is a binary event, such as life or death. A new treatment or therapy is tested for a significant reduction of the incidence of the binary event compared with a control group. Another objective is to ensure that the incidence in the new treatment group is below some clinically acceptable value. This is done by calculating the exact upper 95% confidence limit for the probability of the event. The study is considered successful if the upper confidence limit is lower than a historical threshold, as well as if there is a significant reduction in the incidence of the event by the new treatment. In this article, we provide an exact method for calculating the sample size so that there will be adequate power to ensure that the exact upper confidence limit is below the threshold. Based on this we can design a study to achieve both objectives.

A practical and efficient approach to database quality audit in clinical trials

In clinical trials, data quality is one of the key factors in determining the success or failure of a drug development program. Data audit is an important step in assessing and ensuring the quality of clinical databases. However, despite the availability of many sophisticated statistical methodologies in analyzing clinical data, there are few data audit methods that are both efficient and statistically sound. A frequent method is auditing data for a fixed percentage of the subjects in a clinical study. Such a method either wastes too many resources or lacks statistical rigor in determining the quality status of a database. In this article, we give a short review of some recent developments and provide an example of database audit strategy. The methodology was developed for, and applied to, a real clinical study. Such a method is both statistically sound and efficient in saving resources needed for the conduct of the audit.