Selected Updates in Diabetes Therapeutics

 from the ACCP 2012 Annual Meeting

By Mark Malak, PharmD

What do I need to know about Exenatide LAR (once-weekly GLP-1 agonist)?

Exenatide LAR offers a long-acting GLP-1 agonist injected once weekly as opposed to current exenatide therapy, which is administered bid, and liraglutide, which is administered once daily.  Exenatide LAR has not yet been approved in Canada as of November 2012.

How does Exenatide LAR (2 mg/week) compare vs. current exenatide therapy  (10 mcg bid)?

The 2 agents have been compared in the Duration 1 and Duration 5 trials.

Duration 1: Exenatide LAR produced a greater A1c reduction in comparison to current exenatide therapy (A1c reduction of 1.9% vs. 1.5%, p < 0.0023).  Whether or not there is a clinically significant difference in this is open to debate.  Exenatide LAR offers better reductions in FPG and PPG than bid therapy.  A lower incidence of GI adverse events, particularly nausea (26.4% vs. 34.5%) and vomiting (10.8% vs. 18.6%) was seen with LAR therapy vs. bid therapy.  The overall weight change between the two drugs was similar and there was no significant difference in hypoglycemia.
(Drucker DJ, et al.  Lancet 2008;372:1240-50)

Duration 5:
Exenatide LAR (2 mg/week) produced a greater A1c reduction than exenatide 10 mcg bid (1.6% vs. 0.9%, p < 0.0001).  It produced a greater reduction in FPG, a similar reduction in weight, and no difference in hypoglycemia.  Exenatide LAR was again better tolerated with a lower incidence of nausea (14% vs. 35%) and vomiting (4.7% vs. 8.9%).
(Blevins T, et al.  J Clin Endocr Metab 2011;1-10)

How does Exenatide LAR (2 mg/week) compare with high-dose liraglutide (1.8 mg daily)?

The results of this trial have not been published yet, but results are available from the abstract presented at a meeting.  Both drugs produced clinically similar reductions in A1c (1.28% vs. 1.48%).  This difference was said to be statistically significant but the p values were not reported.  The difference in A1c reduction between the 2 drugs would not drive selection of a specific agent given lack of a clinically significant difference.  Subjects experienced a greater reduction in weight with liraglutide than with exenatide LAR (-3.58 kg vs. -2.68 kg), but the p value has not been reported.  How this “difference” in weight reduction extrapolates to a longer-term clinical effect remains unknown.  There was no difference in hypoglycemia between the two agents.  Exenatide LAR was better tolerated with a lower incidence of nausea (9.3% vs. 20.4%) and vomiting (3.7% vs. 10.7%), but the incidences of these ADRs are lower than that seen in the trials reported above.
(Buse JB, et al.  EASD meeting.  September 2011: abstract 75)

How does Exenatide LAR (2 mg/week) compared to daily insulin glargine? 

The Duration 3 trial demonstrated clinically similar A1c reductions between exenatide LAR and daily insulin glargine (1.5% vs. 1.3%, p = 0.017).  As expected, insulin glargine had a better reduction in FPG compared to exenatide LAR and was also associated with slight weight gain.  Exenatide LAR as expected, had a higher incidence of nausea (13% vs. 1%) and vomiting (4% vs. 1%).  There was less overall minor hypoglycemia with exenatide LAR (8% vs. 26%).
(Diamant M, et al.  Lancet 2010;375:2234-43).

Brief summaries of other data were presented which demonstrated superiority of exenatide LAR over sitagliptin and comparative efficacy with pioglitazone and metformin.

In summary, exenatide LAR is more effective for A1c reduction in type 2 diabetics than bid exenatide or sitagliptin. It provides similar A1c reductions to metformin, pioglitaztone, and glargine, and has a better short-term tolerability profile compared to bid exenatide.