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Update: GLP-1 Analogs and Cardiovascular Health

May 26, 2014

The cardiovascular morbidity and mortality associated with diabetes are well established, so much so that type 2 diabetes has been described as a cardiovascular disease presenting as a metabolic disorder. Patients with type 2 diabetes are particularly at risk for atherosclerosis; so medications with ancillary vascular benefits are particularly useful, and the effects of glucose-lowering medications are of interest with regards to their effects on markers of cardiovascular health. Glucagon-like peptide-1 (GLP-1) receptors are widely expressed in a number of tissues including the myocardium and cardiovasculature, and GLP-1 appears to have a range of neurotrophic, neuroprotective and cardioprotective effects. As a consequence, there seems to be potential therapeutic benefit from these drugs….

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Initial animal studies of GLP-1 agonist therapy suggested varying effects on blood pressure. In humans, GLP-1 and GLP-1 agonists tend to cause a small reduction in blood pressure, although it remains to be seen whether this will be of clinical significance. The Liraglutide Effect and Action in Diabetes (LEAD) trial reported reductions of 3.6 mmHg to 6.7 mmHg in systolic blood pressure in the liraglutide-treated group compared with those treated with other agents or placebo1. Interestingly, these blood pressure reductions were observed prior to weight loss, suggesting that the effects on blood pressure are independent of weight reduction. Exenatide treatment has also been shown to be associated with beneficial effects on systolic blood pressure2. The mechanisms by which GLP-1 agonist therapy may reduce blood pressure remain unclear. Postulated theories include improvements in endothelial function leading to improved vasodilatory capacity and enhanced urinary sodium excretion3.

GLP-1 receptor agonists have been shown to modify some inflammatory mediators and markers of vascular risk, although larger trials of longer duration will be required to confirm these preliminary findings. Significant reductions in high-sensitivity C-reactive protein (hsCRP) and improved insulin sensitivity have been reported in human subjects with type 2 diabetes treated with exenatide compared with treatment with glibenclamide, despite similar effects on HbA1c4. In addition, a meta-analysis of six phase III trials of liraglutide reported a significant 23.1% reduction in hsCRP following treatment5. Other small studies have observed beneficial effects of GLP-1 infusions on other markers such as tumour necrosis factor alpha (TNFα)6 and venous occlusion plethysmography7.

Both liraglutide and exenatide have been shown to have a beneficial effect on both fasting and post-prandial lipid profiles in type 2 diabetes. One of the largest recent studies randomized 533 subjects to liraglutide or placebo (in combination with metformin and rosiglitazone), and demonstrated significant reductions in serum low-density lipoprotein (LDL)-cholesterol, free fatty acids and triglycerides in the treatment group when compared with placebo8 These findings have been replicated in other smaller studies. Infusions of GLP-1 have also been shown to improve post-prandial lipaemic excursions9, an independent risk factor in the development of atherosclerotic cardiovascular disease.

GLP-1 receptors are expressed on cardiac tissue, therefore, it is possible that the hormone, or its synthetic analogues, may directly mediate a range of cardiac functions. Current areas of research include the investigation of GLP-1 involvement in myocardial metabolism, coronary blood flow, pre-/post-ischemic conditioning, left ventricular (LV) remodelling and LV performance. Both animal and human studies have suggested that GLP-1 agonists may have effects on myocardial metabolism, and this may be translated into possible therapeutic benefit on cardiac function. Animal studies have demonstrated improved glucose utilization and reduced accumulation of lactate in the myocardium following infusions of GLP-1 agonist10. Improvements in LV function have been demonstrated in animal studies11,12 but results from a few small studies in humans have shown conflicting results.

In addition, an animal study suggested that GLP-1 may have effects on coronary blood flow and protect against ischemia and reperfusion injury13. These findings in rodents require further work before conclusions can be drawn.

If an individual with type 2 diabetes is able to tolerate GLP-1 receptor agonist therapy then the early clinical beneficial effects on HbA1c, weight and blood pressure may be substantial. The possible direct benefits on the heart and vascular system in animals and humans require further study and investigation.

There is recent information from a large database containing 39,275 patients treated with exenatide, that exenatide was associated with a significant reduction in cardiovascular events and hospitalizations, despite the fact that patients treated with exenatide were more likely to have prior coronary heart disease or other co-morbidities14. There are large ongoing cardiovascular safety trials with liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – LEADER) and the once-weekly formulation of exenatide (Exenatide Study of Cardiovascular Event Lowering – EXSCEL).

Several animal studies and analyses in humans have demonstrated a potential cardioprotective effect of GLP-1 RAs15,16. 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)17,18. There is evidence that the GLP-1 protective effect on myocardium may be particularly important in ischemic conditions19and may also attenuate other factors causing premature atherosclerosis20.

GLP-1 receptors in mice have been located on endocardium, cardiomyocytes and microvascular endothelium21. 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 pump22. 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 vasodilation23. 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 relaxation24.

Further studies in animals have demonstrated that GLP-1 may also protect cardiomyocytes from damage during ischemia and reperfusion25. 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 infusion26. 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 models27. 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 placebo28. 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 performance29. 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-155. 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 placebo30. 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)31. 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 therapy32.

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 diabetics33. 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 groups34. 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 profiles35. 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 control36. 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 compounds37.

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. group11. 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 pioglitazone13. In the DURATION 3 trial EQW-treated patients showed a significant change from baseline in SBP and total cholesterol parameters only15. 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 trials11-17,24.

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 control38. 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 T2D36,37.

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-RA, and I am sure that the future will show the value of this class to be more than just glucose lowering.

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  35. Singh S, Chang HY, Richards MS, et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in Type 2 diabetes mellitus. JAMA Intern. Med. 25, 1–6 (2013).
  36. Bjerre Knudsen L, Madsen LW, Andersen S et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid c-cells causing calcitonin release and c-cell proliferation. Endocrinology 151(4), 1473–1486 (2010).
  37. Guillermin AL, Lloyd A, Best JH, DeYoung MB, Samyshkin Y, Gaebler JA. Long-term cost-consequence analysis of exenatide once weekly vs sitagliptin or pioglitazone for the treatment of Type 2 diabetes patients in the United States. J. Med. Econ. 15(4), 654–663 (2012).
  38. Gaebler JA, Soto-Campos G, Alperin P et al. Health and economic outcomes for exenatide once weekly, insulin, and pioglitazone therapies in the treatment of Type 2 diabetes: a simulation analysis. Vasc. Health Risk Manag. 8, 255–264 (2012).