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Effect of GLP-1 on Cardiovascular Risk Factors

Jul 6, 2011

Glucagon-like peptide-1 mimetics improve certain cardiovascular risk factors, although it is unclear if the observed benefits are direct effects or indirect effects due to weight loss.

Improvements in systolic blood pressure seen in exenatide and liraglutide trials are illustrated in Figure 3. The decreases in systolic blood pressure range from 2.3 to 5.6 mm Hg. Decreases also occurred in diastolic blood pressure, but were not statistically significant. In the LEAD studies with liraglutide, the decrease in blood pressure occurred within the first 2 weeks, before much weight loss had occurred.  Thus, it seems unlikely that these improvements in blood pressure can be completely ascribed to decreases in body weight that were progressive over the 26-week duration of each study. This suggests that the reduction in blood pressure could be a direct effect of the GLP-1 mimetic. Potential mechanisms for this include a natriuretic effect as well as a direct vasorelaxant effect on the vascular system of GLP-1.


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In 3-year data for exenatide, a significant decrease in triglycerides, low-density lipoprotein cholesterol and total cholesterol, and a significant increase in high-density lipoprotein cholesterol were observed.  A phase II study also demonstrated that liraglutide treatment was associated with improvements in triglycerides in addition to reductions in plasminogen activator inhibitor-1 (PAI-1).  PAI-1 is a prothrombotic peptide that circulates in higher levels in patients with diabetes. Because it may contribute to increased cardiovascular risk, a reduction in PAI-1 is likely to be beneficial.


 Glucagon-like peptide-1 may also have direct cardiac effects. In a clinical trial by Nickolaidis et al, 21 patients who experienced an acute myocardial infarction and received an angioplasty were randomized to either a GLP-1 infusion or a saline infusion for 72 hours. The patients who received the GLP-1 infusion had a significant improvement in their left ventricular ejection fraction (from 29+2% to 39+2%, P <.01) whereas the control group did not show improvement.  This could be due to improved perfusion, or it could be a direct inotropic effect of GLP-1.   Another study showed improvement in left ventricular ejection fraction and functional status in patients with chronic heart failure. Twelve patients meeting the New York Heart Association class III/IV heart failure classification were given a 5-week infusion of GLP-1 and the results were compared to 9 patients receiving standard therapy. The patients who received the GLP-1 infusion had a significant improvement in left ventricular ejection fraction, VO2 max, and 6-minute walking distance.

In summary, there appear to be beneficial effects of GLP-1 on cardiovascular disease risk factors, including blood pressure and lipids. Some of these beneficial effects are due to weight loss, but emerging data suggest that GLP-1 mimetics may have direct effects on the kidneys and vasculature. More research is needed, especially to explore direct cardioprotective effects of GLP-1.


Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care. 2008.

Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analog, added to a sulfonylurea (SU) offers significantly better glycemic control and favorable weight change compared with rosiglitazone and SU combination therapy in subjects with type 2 diabetes. Diabetes. 2008;57(suppl 1):A4 (abstract 13-OR).

Klonoff DC, Buse JB, Nielson LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated at least 3 years. Curr Med Res Opin. 2008;24:275-286.

Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 mono): a randomized, 52-week, phase III, double-blind, parallel treatment trial. Lancet. 2008.

Russel-Jones D, Vaag A, Schmitz O, et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes. Diabetes. 2008;57(suppl 1):A159 (abstract 536-P).

Schletter P, Beglinger C, Drewe J, et al. Glucagon-like peptide-1 receptor expression in primary porcine proximal tubular cells. Regul Pept. 2007;141:120-128

Nickolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-965.

Sokos, GG, Nickolaidis LA, Mankad S, et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Cardiac Fail. 2006;12:694-699.

Synopsis provided by Steve Freed, R.Ph., Diabetes Educator, Publisher