The major study behind the FDA approval for the use of exenatide as an adjunct to insulin glargine was conducted by Buse et al.17
This was a randomized, double-blind, placebo-controlled, parallel group, multicenter, 30-week trial (). Patients with age at least 18 years, T2DM (A1c 7.1%–10.5%), BMI ≤45 kg/m2
and stable weight (<5% weight change in body weight over 3 months) who were treated with insulin glargine (minimum of 20 units per day) with or without metformin and/or pioglitazone for at least 3 months were included in this study. The primary end point was change in A1c from baseline at 30 weeks.
A total of 259 participants were randomized and received exenatide titrated to 10 mcg twice daily (n = 137) or matching placebo (n = 122) injections. Glargine doses were prospectively reduced by 20% in those with a baseline A1c ≤8%. After 5 weeks, all study participants used the treat-to-target algorithm to adjust glargine to achieve fasting glucose of <5.6 mmol/L.18
Baseline characteristics between exenatide and placebo groups were similar, with the exceptions of sex (females 49% vs 36%, respectively) and use of prestudy oral antihyperglycemic agents (metformin 66% vs 75%; pioglitazone 2% vs 5%; both 17% vs 7%, respectively).
At the end of the study, A1c was reduced to a greater extent in the exenatide group than in the placebo group (−1.74% [95% CI −1.91% to −1.56%] vs −1.04% [−1.22% to −0.86%]; between-group difference, −0.69% [−0.93% to −0.46%]; P < 0.001). Participants in the exenatide group achieved A1c ≤7.0% more frequently when compared to placebo (60% [51%–69%] vs 35% [25%–45%]; between-group difference, 25% [12%–39%]; P < 0.001). In addition, A1c ≤6.5% was achieved more often in the exenatide group over placebo (40% [30%–49%] vs 12% [6%–17%]; between-group difference, 28% [17%–39%]; P < 0.001). Insulin doses were increased to a greater extent in the placebo group compared to the exenatide group (20 units/day [16–24 units/day] vs 13 units/day [9–17 units/day]; between-group difference, −6.5 units/day [−12.3 to −0.8 units/day]; P = 0.03). The decrease in FPG was similar for both the exenatide and placebo groups (−1.6 mmol/L [−1.9 to −1.3 mmol/L] vs −1.5 mmol/L [−1.8 to −1.2 mmol/L]; between-group difference, −0.1 mmol/L [−0.52 to 0.32 mmol/L]; P = 0.63). Self- monitored blood glucose levels were lower with exenatide at the morning 2-hour postprandial time point (between-group difference, −1.8 mmol/L [−2.5 to −1.2 mmol/L]; P < 0.001) and evening 2-hour postprandial time point (betweengroup difference, −1.7 mmol/L [−2.3 to −1.1 mmol/L]; P < 0.001), but not at the midday 2-hour postprandial time point (between-group difference, −0.3 mmol/L [−0.8 to 0.3 mmol/L]; P = 0.32). Weight loss with exenatide was greater than that observed with placebo (−1.8 kg [−2.5 to −1.1 kg] vs +1.0 kg [0.2 to 1.7 kg]; between-group difference, −2.7 kg [−3.7 to −1.7 kg]; P < 0.001). At 30 weeks, triglycerides, HDL, LDL, and non-HDL cholesterol did not differ between groups. The exenatide group demonstrated a greater decrease in systolic and diastolic blood pressures compared to placebo (between-group difference, −4.4 mmHg [−7.8 to −1.0 mmHg]; P = 0.01 and −3.4 mmHg [−5.2 to −1.6 mmHg]; P < 0.001, respectively), but heart rate was increased (between-group difference, 3.0 beats/minute [0.8–5.2 beats/minute]; P < 0.01).
Hypoglycemic events per participant per year as well as minor hypoglycemic events did not significantly differ between groups (P = 0.49). Minor hypoglycemic episodes were defined as self-treated or self-limiting symptomatic episodes with a corresponding blood glucose level < 3 mmol/L. No participants reported major hypoglycemic episodes in the exenatide group, compared to one participant in the placebo group. Major hypoglycemic episodes were defined as prompt recovery from loss of consciousness or seizure with the administration of glucagon or glucose, with a blood glucose level <3 mmol/L. Alternatively, a major episode could have been presumed if severe impairment in consciousness or behavior occurred and required third-party assistance. There was a higher withdrawal rate from the study for adverse events in the exenatide group compared to the placebo group (9% vs 1%; P < 0.01). The following adverse events occurred significantly more frequently with exenatide compared to placebo: nausea, diarrhea, vomiting, headache, and constipation.
Another study conducted by Arnolds et al examined the addition of exenatide or dipeptidyl-peptidase-4 (DPP-IV) inhibitor, sitagliptin, to existing therapy with glargine and metformin compared to continuation of glargine and metformin alone ().19
This was a randomized, parallel group, single-center, open-label, active-comparator-controlled, 4-week study. Participants were between the ages of 35 and 70 years, had duration of T2DM between 6 months and 10 years (A1c 7–10), and were treated with a stable regimen of metformin with or without a sulfonylurea, or a long or intermediate insulin (glargine, detemir, or NPH) with or without metformin. Additional criteria were BMI between 21.0 and 39.9 kg/m2
, a minimum of 3 months of stable therapy with antihypertensives or lipid-lowering agents, and lack of other clinically relevant medical conditions. The primary end point was the 6-hour postprandial blood glucose excursion following consumption of a standardized breakfast (618.2 kcal, 99.4 g of carbohydrates, 11.9 g of lipids, and 26.2 g of protein) after 4 weeks.
After a 4–8-week run-in period, during which insulin glargine was continued or initiated and titrated and sulfonylureas were discontinued, 48 participants were randomized to receive exenatide (5 mcg twice daily for 2 weeks, then 10 mcg twice daily for 2 weeks) + glargine + metformin (n = 16), sitagliptin (100 mg/day) + glargine + metformin (n = 16), or the control of glargine + metformin (n = 16). During the run-in and treatment periods, glargine doses were adjusted using a modified treat-to-target algorithm to achieve a goal FPG of ≤5.6 mmol/L.18
Two days prior to the treatment phase, glargine doses for all participants were decreased by 20%. Baseline A1c was reported as 7.9% for both the sitagliptin and control groups and 8.4% for the exenatide group; this difference was not reported to be statistically significant. No differences were reported among baseline demographics ().
At the end of the study, blood glucose excursions after the standardized meal were decreased to a greater extent, with both the exenatide and sitagliptin groups compared to the control group (between-group difference, −17% [P = 0.0036] and −20% [P = 0.0008], respectively). The difference between the exenatide and sitagliptin groups was not significant (P = 0.57). A1c levels were decreased in the exenatide, sitagliptin, and control groups (−1.8% and −1.5% vs −1.2%, respectively; P = 0.015 for exenatide vs control). The target A1c level of <7% was met by 80% of the exenatide group, 88% of the sitagliptin group, and 63% of the control group (P < 0.05 for exenatide and sitagliptin groups compared to control). Insulin doses at baseline were similar to end-point doses in the exenatide (40.3 units/day [0.60 ± 0.25 units/day] vs 41.1 units/day [0.42 ± 0.18 units/day]) and sitagliptin groups (33.4 units/day [0.50 ± 0.20 units/day] vs 35.0 units/day [0.36 ± 0.17 units/day]), and were increased in the control group (32.3 units/day [0.50 ± 0.21 units/day] vs 37.9 units/day [0.42 ± 0.20 units/day]). End-of-treatment FBG levels were significantly decreased from baseline in both the exenatide (from 5.2 to 4.6 mmol/L; P = 0.0018) and sitagliptin (from 5.3 to 4.7 mmol/L; P = 0.0016) arms but not in the control group (from 5.2 to 4.9 mmol/L; P = 0.21). Patients measured 7-point BG levels once a week and at the end of the study; these profiles were lower with both the exenatide and sitagliptin groups compared to the control group (P < 0.05 for both). Body weight changed −0.9 ± 1.7 kg in the exenatide group, 0.1 ± 1.6 kg in the sitagliptin group and +0.4 ± 1.5 kg in the control group (P = 0.038 for exenatide vs control). Significant decreases in total cholesterol were observed in the exenatide and sitagliptin groups when compared to control (−0.24 ± 0.48 mmol/L and −0.27 ± 0.61 mmol/L vs 0.30 ± 0.52 mmol/L [P < 0.01 for both, respectively]). LDL cholesterol was also significantly decreased when compared to control in the exenatide and sitagliptin groups (−0.30 ± 0.46 mmol/L and −0.28 ± 0.42 mmol/L vs 0.09 ± 0.36 mmol/L [P < 0.05 for both], respectively). No changes in HDL cholesterol were observed.
Minor hypoglycemia was experienced by five, two, and six subjects in the exantide, sitagliptin, and control groups, respectively. Minor episodes were defined as self-treatable episodes with or without blood glucose readings < 2.78 mmol/L, or blood glucose levels > 2.78 mmol/L with symptoms only. Hypoglycemia occurred at rates of 10.1 events/person-year in the exenatide group, 3.3 events/person-year in the sitagliptin group, and 1.6 events/person-year in the control group. No major hypoglycemic episodes were reported in any group. Major episodes were defined as subjects not being able to treat the episode on their own. Gastrointestinal side effects accounted for 56.3%, 18.8%, and 6.3% of adverse events experienced in the exenatide, sitagliptin, and control groups, respectively. There was one dropout in the exenatide group due to gastrointestinal side effects.
Riddle et al conducted a randomized, double-blind, placebo- controlled, parallel group, 24-week trial, which is available as an abstract ().20
Patients treated with metformin and one additional oral agent or insulin (<0.4 units/kg) were included in the study. During an 8-week run-in period, metformin was continued and the additional agent was switched to open-label exenatide 5–10 mcg twice daily. A total of 34 subjects were randomized to replace open-label exenatide with double-blind exenatide (n = 17) or placebo (n = 17). Insulin glargine was also initiated and titrated in all patients at randomization.
At the end of the 24 weeks, median A1c was 6.45% (5.7%–9.3%) in the exenatide group and 7.30% (5.7%–9.8%) in the placebo group (P = 0.06). More participants in the exenatide group achieved A1c <7.0% and <6.5% compared to placebo (76.5% vs 23.5%; P = 0.003; and 47.1% vs 11.8%; P = 0.03, respectively). The average insulin glargine dose in the exenatide group was 0.50 ± 0.33 units/kg/day and 0.56 ± 0.29 units/kg/day in the placebo group. Median difference in FPG was not significantly different between groups. Weight gain was observed to a lesser extent in the exenatide group versus the placebo group (+0.4 ± 1.1 vs +4.1 ± 0.6 kg; P < 0.01).
Mild hypoglycemia was defined as a symptomatic episode or blood glucose less than 3.89 mmol/L, and occurred in 53% of patients in the exenatide group and 41% of those in the placebo group (P < 0.05). No moderate or severe hypoglycemic episodes were reported. Moderate was defined as BG < 2.78 mmol/L, and severe episodes required third-party assistance. Withdrawals due to adverse events or gastrointestinal side effects were not presented.