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


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

In This Article

Expert Commentary & Five-year View

The once- and twice-daily GLP-1 RAs are now well established for their glycemic efficacy in T2D, their low risk of hypoglycemia, effects on satiety and weightloss, and significant potential for both direct and indirect CV benefits. Further development of these compounds reveals a general trend of structures with longer duration of therapy following subcutaneous administration ranging from weeks to months and possibly as long as a year. In addition to the reduced frequency of administration, the available data for the LA GLP1 RAs suggest that they may have somewhat greater glycemic efficacy and/or a better tolerated side-effect profile than the once- or twice-daily injected forms. Many of the benefits and side effects of GLP-1 RAs appear to be related to changes of circulating GLP-1 levels. To this end, except for the ITCA 650 pump delivery system, the LA GLP-1 RAs achieve steady-state plasma GLP-1 levels more slowly, possibly to higher absolute levels and with less daily fluctuation than the shorter-acting preparations.

LA GLP1-RAs have now been shown in several randomized controlled trials to be as effective as second- and third-line agents for treatment of uncontrolled T2D, and in the DURATION-4 trial, EQW was also efficacious as a first-line agent. The LA GLP1-RAs have the benefit of weightloss rather than weight gain, with a low incidence of hypoglycemia. They also have a consistently lower incidence of nausea and vomiting when compared head-to-head with the commonly used formulation of exenatide b.i.d. While EQW is the only LA GLP1-RA approved by the FDA currently, there are several other formulations being developed and studied, which are showing early promise, each with unique properties that portend potential advantage to certain patient groups.

Although EQW was found to be inferior to liraglutide in DURATION-6, EQW compared with exenatide b.i.d. has been shown in most studies to result in a greater reduction of A1c and FPG. While it has not been compared head-to-head with the other LA GLP1-RAs in development, studies published to date show an average weightloss with EQW that is greater than that seen with albiglutide or dulaglutide. Albiglutide weekly injection is coupled with human albumin and has shown similar A1c reduction to exenatide b.i.d., and data thus far show seemingly less nausea than other GLP1-RA formulations. More long-term studies are needed to further elucidate the efficacy of this therapy. Dulaglutide (LY2189265) weekly injection is linked to an Fc fragment of human IgG4. It has similar efficacy to other GLP1 agonists, with seemingly lower incidence of nausea. Another important distinction to make with dulaglutide is that there is no evidence of antidrug Ab formation. Thus, it may be a good option for patients who develop high Ab titers or recurrent injection site reactions to other formulations of LA GLP1 agonists. Abstracts published on semaglutide suggest a greater number of patients reaching target A1c than with liraglutide, and initial reports also showed an average weightloss of nearly 5 kg, which is greater than that demonstrated by most LA GLP1-RAs to date. Preliminary data suggest ITCA 650 osmotic minipump results in A1c improvements similar to EQW while delivering continuous medication for 3–12 months without injections. Ensured adherence with ITCA 650 may improve long-term outcomes and provide an effective early treatment when combined with metformin or other oral antidiabetic medications. The ability to remove ITCA 650 with prompt reduction in exenatide concentrations is a significant advantage if side effects such as pancreatitis occur.

Another important factor to reflect on when considering therapy with LA GLP1-RAs is the potential for CV benefit. It has been demonstrated the LA GLP1-RAs tend toward improved lipid profile and lower SBP. This, in addition to the effect of weightloss and low incidence of hypoglycemia, all of which have been shown as risk factors for CV events probably combine to make GLP-1 RAs protective against CV events. However, recent small studies on both animals and humans have also shown that there are other aspects of GLP-1 that may independently contribute to endothelial vasodilation, protecting cardiomyocytes from ischemic damage, and improving contractile function in CHF.

Finally, one must not neglect the topic of cost–effectiveness in the current healthcare climate. A recent cost analysis looked at the potential economic benefits of EQW compared with sitagliptin and pioglitazone. Based on projected lifetime clinical outcomes and complication effects, it was found that EQW increased life expectancy while reducing lifetime per-patient complication costs over a period of 35 years.[65] A similar simulation analysis assessed projected outcomes after 20 years of therapy with EQW compared with intensive insulin therapy or pioglitazone, taking into account estimated A1c, weight, and SBP changes over time. This study also found an increase in quality-adjusted life-years and decrease in yearly healthcare costs with EQW compared with insulin and pioglitazone.[66]

Overall, the LA GLP1-RAs show a greater average A1c reduction with an overall greater reduction in fasting glucoses compared with exenatide b.i.d. The same effect has not been demonstrated in the randomized controlled trials comparing EQW and albiglutide head-to-head with liraglutide. LA GLP1-RAs have similar side-effect profiles as exenatide b.i.d. and liraglutide, but rates of nausea and vomiting are consistently lower with the LA formulations than with exenatide b.i.d. LA GLP1-RAs also result in weightloss and very low rates of hypoglycemia, which make them attractive compared with commonly used second-line oral agents such as sulfonylureas and pioglitazone. Not only do these new drugs show promising efficacy, but the frequency of which they require injection is much less than other currently available injectable diabetic therapies, which may increase patient perception of QoL and improve long-term compliance. They can be administered in fixed doses, rather than requiring frequent titration as is necessary with insulin. Given all of the aforementioned advantages, it is possible that the LA GLP1-RAs could have an important place in a new algorithm for diabetes management in the near future. What is necessary to take GLP1 RAs to the next level is clear-cut documentation on the long-term safety of these agents and that the potential extra-glycemic effects translate to beneficial outcomes. Such information will depend on well-designed, long-term clinical trials, many of which are currently underway or about to begin.