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

Dulaglutide Weekly Injection (LY2189265)

Dulaglutide (also referred to as LY2189265 in recent publications) is another LA GLP1-RA under investigation. This molecule is a GLP-1 analog with amino acid substitution, which renders it less susceptible to hydrolysis by DPP4. It is linked to an Fc fragment of human IgG4, which reduces immunogenicity and limits renal clearance.[19] Pharmacokinetic studies have shown a mean plasma half-life of 4 days with a steady-state trough reached by 2 weeks.[35] Early small studies examining various dosing of dulaglutide (0.1, 0.3, 1, 3, 6 and 12 mg weekly) in healthy subjects showed a significantly decreased glucose area under the curve following oral glucose tolerance test (29% decrease from baseline test) compared with placebo, p < 0.01 at doses of 1 mg and above. Nausea and dyspepsia were the most commonly reported side effects in all groups. Doses up to 6 mg daily were well tolerated, while doses of 12 mg weekly resulted in vomiting in nearly all subjects.[35]

Another trial in patients with T2D and mean A1c of 7.6%, previously treated with diet alone or single oral agent, showed that once-weekly dosing of dulaglutide significantly reduced both fasting and 2-h postprandial plasma glucose (p < 0.01) at doses of 1 mg weekly and above. These glucose effects remained consistent throughout the weekly dosing cycle. Subjects were randomized to receive five weekly injections of 0.05, 0.3, 1, 3, 5 or 8 mg of dulaglutide. At the end of 5 weeks, reductions in FPG were significant (p < 0.05) at all doses except 0.3 mg, at a mean of 31% decrease from baseline. Postprandial plasma glucose was also significantly decreased (p < 0.05) at all doses except the 0.05- and 0.3-mg dose. Significant weightloss of approximately 2–2.5 kg was seen only at the highest doses of dulaglutide (5 and 8 mg), but it is important to bear in mind that this study was only 5 weeks in duration. Overall the medication was well tolerated with nausea being the most commonly reported adverse reaction. Nausea occurred in increasing frequency with higher doses, with at least one episode of vomiting occurring in 50% of subjects on the 8-mg dose.[36]

One published Phase III trial on dulaglutide was a placebo-controlled, double-blind, parallel-group study. A total of 262 patients enrolled with a mean A1c of 8.24%, all patients were on two oral medications, with 88.5% of completing the study (n = 232). Subjects were randomized to one of four arms; placebo for 16 weeks (PL), dulaglutide 0.5 mg × 4 weeks escalated to 1 mg for 12 weeks (LY0.5/1), dulaglutide 1 mg for 16 weeks (LY1/1) or dulaglutide 1 mg × 4 weeks escalated to 2 mg for 12 weeks (LY1/2). The primary end point was change in A1c from baseline to 16 weeks. The least-squares mean change in A1c was significant compared with placebo in all three LY dosing groups: LY0.5/1 = -1.38%, LY1/1 = -1.32%, LY1/2 = -1.59%. The reduction seen with LY1/2 was also significantly greater than the other two LY dosing regimens (p < 0.05). Similar significant reductions were seen in fasting blood glucose, and glucose response to solid mixed meal test in all dulaglutide-treated groups (p < 0.001 vs placebo). Dulaglutide subjects showed significant weight change from baseline compared with the placebo group as well, -1.44, -1.34 and -2.55 kg for the LY0.5/1, LY1/1 and LY 1/2 arms, respectively. Nausea was the most commonly reported adverse event, and was similar in all dosing regimens (13.6–16.9% of patients). Diarrhea and abdominal distention were more common in the highest dose of LY (13.8%). Hypoglycemia was uncommon, with <0.8 episodes/patient/30 days.[37] Overall, dulaglutide shows a similar A1c reduction to EQW, with a seemingly lower rate of nausea when compared across clinical trials.

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