Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial.

Context Does exenatide improve glycemic control in patients with type 2 diabetes that is already being treated with insulin? Contribution Adults receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents) were randomly assigned to twice-daily injections of exenatide or placebo for 30 weeks. Exenatide reduced hemoglobin A1c levels and body weight more than placebo, but it caused nausea, diarrhea, vomiting, and headache. Rates of hypoglycemia seemed to be similar for both groups. Caution More exenatide recipients than placebo recipients withdrew from the study. Implication Adding exenatide improved glycemic control without increased hypoglycemia or weight gain in diabetic patients already treated with insulin, but it caused nausea, diarrhea, and vomiting. The Editors Glycemic control in type 2 diabetes mellitus becomes increasingly challenging with longer duration of disease. Progressive decline in -cell function and insulin resistance, combined with increased hepatic glucose output due to glucagon dysregulation, lead to elevations in both fasting and prandial glucose levels. Pharmacologic treatment of diabetes usually involves the sequential addition of oral antihyperglycemic agents according to a target-driven strategy, usually followed by the addition of basal insulin and then prandial insulin (1). This progression, despite increasing numbers and doses of therapeutic agents, is generally associated with persistently elevated hemoglobin A1c (HbA1c) levels and decreased likelihood of achieving glycemic targets with longer duration of diabetes (15). Several studies have demonstrated that basal insulin replacement can attain HbA1c targets in 50% to 60% of patients when the insulin dose is systematically adjusted by following structured titration regimens (612). Prandial replacement is often required in patients with HbA1c levels greater than 7.0% and long-standing type 2 diabetes (13, 14). Glucagon-like peptide-1 receptor agonists are associated with improved glycemic control without increased risk for hypoglycemia, and weight loss also usually occurs (15, 16). The rationale for combining twice-daily exenatide with basal insulin is thus based on complementary pharmacologic effects on prandial and fasting glycemia (17). The use of exenatide and insulin in combination is not an approved regimen. Published supporting evidence of combining exenatide and insulin is limited to a short-term, small-scale, randomized, controlled clinical trial (18); a small, short-term, randomized trial comparing exenatide with sitagliptin added to optimized insulin glargine (19); 2 uncontrolled, nonrandomized, retrospective reports derived from clinical practice (20, 21); a trial in which reduction in insulin dose and weight were the primary outcomes (22); and a recent summary report of small, observational studies and trials, which showed reductions in HbA1c, body weight, and insulin dose (23). We tested whether twice-daily exenatide injections result in greater reductions in HbA1c level than placebo at 30 weeks in persons receiving insulin glargine. Methods Study Design Our 30-week, randomized, double-masked, parallel, placebo-controlled study was conducted in 59 centers in 5 countries (Greece, Israel, Mexico, United Kingdom, and United States) from 29 October 2008 to 4 January 2010. Participants, investigators, and other personnel involved in the conduct of the study were blinded to individual treatment assignments for the duration of the study. The primary objective was to determine whether exenatide injection, 10 g twice daily, was superior to placebo, as measured by change in HbA1c level, in participants with type 2 diabetes who were receiving insulin glargine with or without metformin or pioglitazone (or both agents). Secondary outcome measures included the percentage of participants with HbA1c levels of 7.0% or less and 6.5% or less; 7-point self-monitored blood glucose (SMBG) profiles; change in body weight, waist circumference, and insulin dose from baseline; and safety (measured by self-reported hypoglycemic events and treatment-emergent adverse events). Exploratory measures included 1,5-anhydroglucitol level at baseline, week 18, and week 30. The study was approved at each site by an institutional review board in accordance with principles described in the Declaration of Helsinki (24). All participants gave written informed consent before participating. No data safety monitoring board was involved, and no interim analyses were performed. Setting and Participants Participants were at least 18 years of age; had type 2 diabetes; had been receiving insulin glargine at a minimum of 20 U/d without any other insulin, alone or in combination with a stable dose of metformin or pioglitazone (or both agents) for at least 3 months; and had an HbA1c level of 7.1% to 10.5%, body mass index of 45 kg/m2 or less, and stable body weight (less than 5% change over 3 months). Participants were excluded if they had clinically significant hematologic, oncologic, renal, cardiac, hepatic, or gastrointestinal disease; had been in a weight-loss program in the 3 months before the study; received systemic glucocorticoid therapy in the 8 weeks before the study; had more than 1 episode of major hypoglycemia in the 6 months before the study; had an irregular sleepwake cycle; or had a history of pancreatitis. Duration of diabetes was by self-report. Randomization and Interventions Participants continued their prestudy doses of oral antihyperglycemic agents. A computer-generated, random-sequence interactive voice-response system was used to randomly assign participants in blocks of 4, stratified by HbA1c level (8.0% or >8.0%, as measured by a central laboratory; normal range, 4.3% to 6.1%), to receive exenatide (5 g twice daily for 4 weeks and 10 g twice daily thereafter) or placebo injections within 60 minutes before morning and evening meals. Placebo was indistinguishable from exenatide. At randomization, participants with HbA1c levels greater than 8.0% continued to receive their current insulin glargine dose; those with HbA1c levels of 8.0% or less decreased their dose by 20%. These doses were maintained for 5 weeks, after which participants began titration to achieve a fasting glucose level less than 5.6 mmol/L (<100 mg/dL), on the basis of the Treat-to-Target Trial algorithm (9). Investigators assessed participants' adherence to study medication, study diaries, and glycemic control at each visit. Participants recorded SMBG, and adjustments to insulin dose were made by the investigator on the basis of the algorithm at least weekly from week 5 to week 10, and every 2 weeks thereafter. Sites were responsible for assessing medication distribution and use. Adherence to the insulin glargine algorithm was reviewed by study monitors at scheduled visits. Outcomes and Follow-up The primary outcome of the study was HbA1c level at 30 weeks. Secondary and exploratory outcomes included fasting plasma glucose, lipid, and 1,5-anhydroglucitol levels measured at baseline and at 18 and 30 weeks; SMBG profiles were obtained during the week before these visits. Other secondary outcomesvital signs, weight, waist circumference, and insulin doseswere obtained at baseline and each postrandomization visit. Safety was monitored by site staff at telephone and office visits by diary review and participant interview. Hypoglycemic episodes were classified as minor (signs or symptoms associated with hypoglycemia and fingerstick blood glucose level <3 mmol/L [<54 mg/dL] that were either self-treated or resolved on their own) or major (blood glucose level <3 mmol/L [<54 mg/dL], resulting in loss of consciousness or seizure from which the participant promptly recovered in response to glucagon or glucose, or presumed hypoglycemia requiring the assistance of another person because of severe impairment of consciousness or behavior). All laboratory determinations were performed by a centralized laboratory (Quintiles Laboratories, Marietta, Georgia). Additional exploratory outcomes that we assessed were optional 72-hour continuous glucose monitoring at study beginning and end, and changes in levels of adiponectin and high-sensitivity C-reactive protein. These outcomes are not reported in this article. Statistical Analysis All statistical analyses were performed by using SAS software, version 9.1 (SAS Institute, Cary, North Carolina). Methods were documented in a prespecified analysis plan before unblinding. Post hoc analyses were conducted to support the prespecified analyses where appropriate. Analyses used 2-sided CIs where appropriate, and an level of 0.05 was considered significant. The analysis of efficacy and safety variables included data from all participants who received the study drug and had measurements at postbaseline visits. Baseline was defined as the last nonmissing value before randomization. The analysis of continuous variables used a mixed-model repeated-measures analysis with effects for treatment, visit, treatment-by-visit interaction, baseline HbA1c stratum (8.0% or >8.0%) (except for HbA1c analyses), baseline of the variable analyzed, and pooled investigative site, with an unstructured variancecovariance matrix to model the covariance structure among the repeated measurements by participant (25). All sites that enrolled 1 participant were pooled into a single group. Changes from baseline are summarized by least-squares means and 95% CIs from the mixed model. The hypoglycemia rate was analyzed by using a generalized linear negative binomial model with effects for HbA1c stratum and treatment, log of the number of days of follow-up as an offset, and a log link. The proportion of participants achieving HbA1c targets was analyzed by using multiple imputation assuming missing at random, followed by a generalized estimating equation analysis (26). The variables included in the multiple imputation model were baseline body weight, baseline