Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes

A Review of Current Literature

Courtney Aavang Tibble; Tricia Santos Cavaiola; Robert R Henry

Disclosures

Expert Rev Endocrinol Metab. 2013;8(3):247-259. 

In This Article

Exenatide Once Weekly (Bydureon)

The first LA GLP1-RA to come to the US market was Bydureon (once-weekly exenatide), which was approved by the US FDA in January 2012. Its label indications are the same as those of exenatide b.i.d., which has been on the market for 7 years, and for which published data on efficacy and side effects are fairly extensive. The exenatide molecule used in EQW formulation is identical to that used in the exenatide b.i.d. formulation. However, in EQW, the exenatide molecules are further embedded in biodegradable polymeric microspheres that allow for slow release of the drug, resulting in gradual delivery to the bloodstream at a controlled rate.[23] Early trials showed that EQW at a dose of 2 mg weekly resulted in therapeutic concentrations of exenatide within 2 weeks, as well as steady-state levels of the drug (comparable with the maximum concentration achieved with a one-time 10-µg injection of exenatide) within approximately 6 weeks.[10]

In a Phase II trial published by Kim et al. in 2007, a multicenter, double-blind study compared EQW at various doses with placebo in patients on diet or metformin monotherapy. After 15 weeks, EQW 0.8- and 2-mg groups showed a change in mean A1c of -1.4 and -1.7%, respectively, compared with +0.4% with placebo (p < 0.0001 for EQW groups vs placebo). The only group to exhibit weightloss was the EQW 2-mg dose (mean weight reduction of -3.8 kg), whereas both placebo and EQW 0.8-mg groups had no significant change in bodyweight. As with exenatide b.i.d., the most common reported adverse event was nausea; but, no episodes of severe nausea were reported and no one withdrew from the study.[10]

Subsequently, a series of Phase III trials were published looking at EQW against a variety of other approved therapeutic agents. These registration trials were entitled 'DURATION' trials, which are summarized in the following subsections and in Table 2.

DURATION-1

This was a 30-week, randomized, noninferiority, open-label study comparing exenatide 2 mg once in a week (EQW) versus exenatide 10 µg b.i.d. in 295 patients with T2D on 0–2 oral medications, with an average A1c of 8.3%. Patients treated with EQW had a significantly greater reduction in A1c than those treated with exenetide b.i.d., (-1.9 vs -1.5%, respectively; p = 0.0023) and significantly greater proportion of patients reaching goal A1c <7% (77 vs 61%, respectively; p = 0.0039). Bodyweight decreased to a similar degree in both groups, with mean weight change from a baseline of -3.7 kg with EWQ versus -3.6 kg with exenatide b.i.d. The reduction in fasting plasma glucose (FPG) concentration from baseline was significantly greater in EQW group (-2.3 mmol/l) than in the exenatide b.i.d. group (-1.4 mmol/l), while the change in 2-h postprandial glucose concentration from baseline was greater in the exenatide b.i.d. group (-6.9 mmol/l) than in the EQW group (-5.3 mmol/l). Gastrointestinal (GI) side effects were less prevalent in the EQW group with 39% reporting nausea and 16% reporting vomiting, compared with the exenatide b.i.d. group with 50% reporting nausea and 27% reporting vomiting.[11]

In a 22-week extension study, subjects in the EQW arm continued on their existing EQW medication regimen and those in the exenatide b.i.d. group were switched to EQW. A total of 258 out of the original 295 (87%) subjects continued. After 22 weeks, the EQW group maintained the A1c reduction of nearly 2%, while those previously on exenatide b.i.d. switched to EWQ improved their A1c from 30 weeks (average of those continuing in study was -1.8%) to 52 weeks, with average reduction in A1c from baseline by end of study period -2%. Of note, there was some transient worsening of control during the switch over period in this group as EQW takes up to 6 weeks to achieve peak plasma concentration.[12]

DURATION-2

This was a 26-week randomized double-blind trial comparing EQW head-to-head to both sitagliptin and pioglitazone as add-on therapy to metformin in T2D patients with a mean A1c of 8.5%. Subjects were randomized to EQW, pioglitazone or sitagliptin, and also stratified by A1c >9 and <9%.[14] After 26 weeks of therapy, the mean A1c reductions for EQW, pioglitazone and sitagliptin were -1.5, -1.2 (p = 0.0165 compared with EQW) and 0.9% (p < 0.0001 compared with EQW), respectively. EQW also had significantly greater reductions in A1c compared with pioglitazone and sitagliptin in the A1c >9% group. However, in the A1c group <9%, EQW produced a significant reduction in A1c over sitagliptin, but not over pioglitazone. Weightloss at the end of 26 weeks was significantly greater with EQW (-2.3 kg) than with either pioglitazone (+2.8 kg) or sitagliptin (-1.5 kg).[13]

Subsequently, 319 out of 491 randomized patients continued in a 26-week, open-label extension trial examining continuation of EQW versus switching from pioglitazone or sitagliptin to EQW. Patients receiving the full 52 weeks of EQW maintained their A1c reduction (least square mean of -1.6%). Those switched from pioglitazone to EQW also maintained their A1c reduction to -1.6% (with a trend toward improving), while those who switched from sitagliptin to EQW significantly improved their A1c reduction to -1.4 from -0.9% (p = 0.001).[14]

DURATION-3

This was a 26-week open-label study comparing EQW head-to-head with once-daily glargine in subjects with T2D on 1–2 oral medications. Subjects were randomized to receive either EQW 2 mg weekly or insulin glargine 10 units (titrated to achieve target fasting glucose levels of 4–5.5 mmol/l). After 26 weeks, patients in the exenatide arm showed a greater change in A1c (-1.5%) compared with those in the glargine arm (-1.3%), p = 0.017. Mean FPG was lower in the glargine group (-2.8 vs -2.1 mmol/l), but postprandial glucose concentrations were significantly lower in the EQW group. Significant differences were also seen in bodyweight with a mean change of -2.6 kg in the subjects receiving EQW in contrast to +1.4 kg in those receiving insulin. Rates of confirmed minor hypoglycemia were significantly lower at all times of day in patients treated with EQW (8% of subjects) compared with patients treated with glargine (26% of subjects).[15]

DURATION-4

This was the first study looking at EQW versus pioglitazone, metformin or sitagliptin as a monotherapy inT2D patients uncontrolled with lifestyle modification and mean A1c of 8.4–8.6%. There were significant A1c reductions seen in all four study arms, with least-squares mean A1c change in EQW (-1.53%) being superior only to sitagliptin (-1.15%), noninferior to metformin (-1.48%), while not reaching noninferiority measure with pioglitazone (-1.63%). Similar results were seen in reductions in FPG and seven-point self-monitored blood-glucose profiles. EQW therapy was associated with a more significant decrease in weight (-2 kg) compared with pioglitazone (+1.5 mg) and sitagliptin (-0.8 kg), but was equal to metformin (-2 kg). Reports of adverse events in all groups were low, with nausea being the most common treatment-emergent event in the EQW group at 11.3% of patients.[16]

DURATION-5

This study re-examined the comparison made in the DURATION-1 trial, looking at effects of EQW compared with standard dosing of exenatide b.i.d. This was a 24-week, open-label study in T2D with mean A1c of 8.4% who were treatment naive or treated with one to two oral agents. Change in A1c from baseline was significantly greater in all patients receiving EQW than in those receiving exenatide b.i.d. (-1.6 vs 0.9%; p < 0.0001) as well as those in the various subgroup analyses. EQW was also associated with greater improvement in FPG (-35 vs -12 mg/dl). In contrast to equivalent weightloss seen in DURATION-1, EQW subjects showed a significantly greater weightloss as 24 weeks (-2.3 kg) than exenatide b.i.d. subjects (-1.4 kg), p < 0.05. Nausea was significantly less at 14% in EQW versus 35% in exenatide b.i.d..[17]

DURATION-6

The DURATION-6 study was designed to compare EQW head-to-head with liraglutide. This was a 26-week trial enrolling 911 patients with mean A1c of 8.5% on mono- and combination-therapies with metformin, sulfonylurea and pioglitazone. Subjects were randomized to receive either EQW 2 mg or liraglutide 1.8 mg daily. Results showed that patients receiving EQW had change in A1c from baseline of -1.28%, while patients receiving liraglutide had a change in A1c of -1.48% with a difference of 0.21% (95% CI: 0.08–0.34). Therefore, the analysis concluded that EQW did not meet the prespecified end point of noninferiority to liraglutide (upper limit of CI <0.25%), the reasons for which are unclear. Weightloss was greater for the liraglutide group (-3.57 kg) compared with the exenatide group (-2.68). The most common adverse events (nausea, vomiting and diarrhea) were less frequent in the exenatide group.[24]

Overall published studies, to date, have demonstrated a consistent A1c reduction of -1.3 to -1.9% with EQW,[10–17,24] which surpasses the average A1c reduction of -0.8 to -1.2% seen with exenatide b.i.d. in most studies.[25–28] This improvement in A1c has been attributed to continuous exposure to exenatide resulting in suppressed glucagon and lower fasting glucose. EQW has shown to be equally efficacious to exenatide b.i.d. in producing an average 2–3 kg weightloss.[11–17,24] Studies have also shown a decreased incidence in nausea and vomiting in the once-weekly formulation of exenatide compared with b.i.d. formulation, which is also attributed to continuous steady stimulation of GLP-1 receptors as opposed to intermittent peaks of activity. The incidence of minor hypoglycemia in subjects on EQW remains low, and major hypoglycemic events were virtually nonexistent, similar to the findings reported in studies of exenatide b.i.d..[10–17,24–28] In addition, patients previously treated with exenatide b.i.d. and switched to EQW have reported increased treatment satisfaction and improvement in QoL scores.[29]

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