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

CV Effects of GLP1-RA

Another aspect of heightened interest surrounding GLP1-RA is the evidence of their direct and indirect effects on the CV system. Several animal studies and analyses in humans have demonstrated a potential cardioprotective effect of GLP-1 RAs.[43,44] A therapy with these additional benefits would be invaluable in the treatment of T2D, as many patients with diabetes are also ultimately found to have significant CV disease and are at increased risk of CV events and myocardial infarction (MI).[45,46] There is evidence that the GLP-1 protective effect on myocardium may be particularly important in ischemic conditions[47] and may also attenuate other factors causing premature atherosclerosis.[48]

GLP-1 receptors in mice have been located on endocardium, cardiomyocytes and microvascular endothelium.[48] While the exact location of these receptors in humans is slightly more elusive, evidence suggests that the same tissues in humans are responsive to GLP-1 effects. For example, it has been shown that GLP-1 directly affects factors of endothelial dysfunction in human diabetics and may function as a vasorelaxant. A study by Nyström et al. evaluated the effects of GLP-1 on endothelial function in patients with T2D and coronary artery disease compared with healthy controls by infusing native GLP-1 with an insulin pump.[49] GLP-1 infusion significantly increased flow-mediated vasodilation in diabetics with coronary artery disease, but had no effects in healthy subjects, thus demonstrating improved perfusion in compromised tissues in diabetic subjects by increasing endothelial-dependent vasodilation.[49] A subsequent study by Nyström et al. showed that GLP-1 also relaxes arteries in a rat organ model. Circular sections of rats' femoral artery were dissected and mounted in an organ bath. Addition of GLP-1 to these baths during phenylephrine-induced contractile tone resulted in dose-dependent vascular relaxation.[50]

Further studies in animals have demonstrated that GLP-1 may also protect cardiomyocytes from damage during ischemia and reperfusion.[51] In mice pretreated with liraglutide for 7 days prior to induction of MI, there was a significant increase in post-MI survival, significant improvement in cardiac output and significant decrease in infarct size 28 days postischemia in those animals treated with liraglutide compared with saline infusion.[52] Bose et al. also reported that infusion of GLP-1 prior to induction of ischemia and reperfusion significantly reduced infarction size compared with saline in both isolated rat hearts and whole animal models.[47] Similar findings were published by a study completed in human subjects by Nikolaidis et al.; ten post acute MI patients with left ventricular ejection fraction (LVEF) <40% were treated with a 72-h GLP-1 infusion after successful angioplasty and compared with 11 control patients who received standard therapy postangioplasty. Those subjects treated with GLP-1 showed significantly improved LVEF and wall motion scores compared with placebo.[53] This evidence suggests that GLP-1 RAs could aid in reducing infarct size and enhancing recovery and LVEF in diabetic patients who suffer an ischemic cardiac event.

In addition to protecting against ischemic injury, GLP-1 may also be of benefit to subjects with congestive heart failure (CHF). Studies by Nikolaidis et al. demonstrated that dogs with dilated cardiomyopathy treated with GLP-1 infusion showed an increase in myocardial glucose uptake and improved left ventricular performance.[54] A pilot study in humans was then published in 2004 reporting a trend towards improved myocardial function in subjects with T2D and New York Heart Association class II and III CHF treated with a 3-day infusion of GLP-1.[55] A later, more extensive study by Sokos et al. compared New York Heart Association class III and IV heart failure patients, giving them either 5 weeks of GLP-1 infusion versus placebo.[56] Results showed improved left ventricular contractile function with LVEF improved from 21 to 27% (p < 0.001) in GLP-1-treated patients but remained unchanged in the control group (21–22%). It also showed significant improvement in exercise tolerance (as measured by 6-min walk test and VO2 max), and improved QoL scores in subjects treated with GLP-1 infusion compared with controls (p < 0.001).[56] These benefits were seen in both diabetic and nondiabetic patients, again suggesting that the effect of GLP-1 is independent of changes in glucose control.

While the aforementioned studies suggest exciting and important potential for GLP-1-related therapy, most of the studies utilized a continuous GLP-1 infusion, which is not practical in day-to-day practice. Few studies on LA GLP1-RAs have been published examining CV outcomes, but results appear similar to those mentioned earlier. In 2011, Bao et al. showed that rats treated with albiglutide and then subjected to 30 min of myocardial ischemia had reduced myocardial infarct size and improved cardiac function post-MI compared with those not receiving albiglutide therapy.[57] A large retrospective analysis by Best et al. used the LifeLink database of insurance claims from 2005 to 2009 to assess the effects of exenatide therapy on risk of CV events. The analysis compared patients with T2D started on new therapy with either exenatide (n = 39,275) or treated with other glucose-lowering therapies (n = 381,218) during this time frame. It found the exenatide group to be significantly less likely to have a CV-related event (MI, ischemic stroke or coronary revascularization procedure; p = 0.01) or a CV disease-related hospitalization (p = 0.02) than nonGLP1-treated diabetics.[58] A second meta-analysis of 20 randomized controlled trials assessed incidence of major adverse CV events in GLP-1-treated subjects. This analysis found the total number of events as well as all-cause mortality in GLP-1 patients versus active comparator therapy groups was similar. However, there was a significant reduction of events in GLP-1-treated patients compared with placebo groups.[59] Further long-term prospective trials are needed to confirm whether beneficial effects result from LA GLP-1 RA therapy.

Additional CV-related outcomes include effects on blood pressure, heart rate and lipid profiles.[60] A recent meta-analysis of 32 trials reviewed the current GLP-1RA (including exenatide b.i.d., liraglutide and EQW) and their effects on blood pressure and heart rate. Reduction in systolic blood pressure (SBP) was -0.79 mmHg (-2.94 to -0.64), while reductions in diastolic blood pressure did not reach statistical significance when compared with placebo or active control.[61] The LEAD-6 trial was a 26-week, open-label, randomized study comparing once-daily liraglutide to exenatide b.i.d. and showed no difference in blood pressure reductions between the two compounds.[62]

Publications examining these risk factors in the DURATION trials have shown mixed results. In the DURATION-1 study, patients in the EQW therapy arm showed a significantly greater reduction in total cholesterol and LDL-cholesterol than the exenatide b.i.d. group. Subjects treated with EQW also showed a significant reduction from baseline in SBP and triglycerides, similar to but not superior to that seen in the exenatide b.i.d. group.[11] In the DURATION-2 trial comparing EQW with pioglitazone and sitagliptin, all three treatment arms showed a significant improvement in SBP and HDL-cholesterol from baseline. All three arms also showed a statistically significant reduction in C-reactive protein and adiponectin levels compared with baseline. EQW was associated with a significantly greater reduction in B-type natriuretic peptide than sitagliptin or pioglitazone.[13] In the DURATION 3 trial EQW-treated patients showed a significant change from baseline in SBP and total cholesterol parameters only.[15] In all DURATION trials, groups treated with EQW showed significant reductions from baseline weight, and there were no episodes of severe hypoglycemia reports in any subjects in any of the published trials.[11–17,24]

Some data have shown GLP1-RAs to be associated with a small increase in heart rate of 1–2 beats per minute (bpm). In a meta-analysis of 22 studies that included data on heart rate, GLP-1 RA were associated with a weighted mean difference in heart rate of 1.86 bpm (0.85–2.87) compared with placebo and 1.90 bpm (1.30–2.50) compared with active control. Evaluation of individual agents showed larger changes in heart rates with liraglutide than exenatide b.i.d., 2.71 versus 0.88 bpm compared with placebo (although exenatide b.i.d. did not reach statistical significance) and 2.49 vs 0.82 bpm compared with active control. Minimal data available for EQW showed a more significant change of 2.14 bpm compared with active control.[61] Larger increases in heart rate were seen with dulaglutide in Phase II studies in a dose-dependent manner and by an average of 1.3–4.3 bpm in the EGO study in T2D.[36,37]

It is unclear to what degree these specific changes in CV parameters and risk factors play in overall clinical outcomes. As earlier outlined, short-term studies in animals and humans have shown GLP-1 to have some direct vasorelaxation action, cardioprotective effects in models of ischemia-reperfusion injury, and may augment myocardial contractility in subjects with heart failure. Further studies are required to confirm whether these promising initial findings yield demonstrable and clinically significant long-term CV benefits. Reduction in weight, blood pressure, lipid profiles, as well as the lower risk of severe hypoglycemia are also likely to be important factors that may contribute to improved cardiac outcomes in patients receiving GLP1-RA therapy. There are no published studies on long-term CV outcomes in patients receiving any of these LA GLP1-RAs. However, there are several ongoing trials looking specifically at CV events as the primary outcomes in therapy with GLP1-RAs including the EXSCEL trial (EQW), REWIND trial (dulaglutide), LEADER trial (liraglutide) and ELIXA trial (lixisinitide), which are summarized in Table 3.