Summary | GLP-1 receptor agonists: The cardiovascular benefits beyond glucose control

Dr. Knop first wanted to refresh everybody’s knowledge on the glucose-dependent pancreatic effects of glucagon-like peptide 1 (GLP-1) on both insulin and glucagon secretion. In healthy subjects, ingesting 25 mg glucose will lead to a glucose excursion as a result of small-intestinal glucose absorption. The resulting elevated plasma glucose level is the major signal to the pancreatic beta cells to secrete insulin. Insulin then facilitates glucose uptake by tissues, thus lowering plasma glucose levels. In healthy persons, a higher glucose load gives rise to the exact same glucose excursion as was seen upon ingestion of 25 mg [16]. This is the result of a bigger insulin response. But, contrary to what we were taught, this means that elevated plasma glucose is in fact not the major determinant of insulin secretion, as different insulin responses are seen after identical glucose excursions. This can be explained by the incretin hormones that are secreted from the enteroendocrine cells in our gut. Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the proximal part of the intestine, while GLP-1 is secreted from the small intestine, more distally. The level of both hormones is very low in the fasting state, and it rises several-folds in response to ingestion of a meal. GIP and GLP-1 control post-prandial glucose excursions. One of their many functions is to stimulate insulin secretion from the pancreatic beta cells upon oral glucose ingestion. Thus, in healthy persons, this incretin effect helps control the plasma glucose excursion, irrespective of the amount of glucose ingested.

In T2DM patients, however, plasma glucose levels remain higher after oral glucose ingestion, and the incretin effect is significantly reduced [17]. Infusing GLP-1 intravenously can normalize the hyperglycemic state of T2DM patients, via increased insulin secretion and lower glucagon secretion from the pancreatic islets. Interestingly, the effects on insulin and glucagon secretion cease to exist upon normalization of glucose levels, indicating that GLP-1 only affects pancreatic islet hormones when glucose levels are high [18].

That means that the risk of inducing hypoglycemia is low with GLP-1RA treatment, as shown in the LEADER CV outcomes trial evaluating liraglutide (HR: 0.80, 95%CI: 0.74-0.88 for confirmed hypoglycemia, HR: 0.69, 95%CI: 0.51-0.93 for severe hypoglycemia) [13]. In a study that measured glucose levels over a 19-hour period, T2DM patients showed a characteristic hyperglycemic state both during fasting and after a meal, as compared to healthy subjects. After GLP-1 infusion, glucose levels of the T2DM patients completely normalized to levels seen in healthy subjects [19].

GLP-1 has effects beyond glucose metabolism, as GLP-1 receptors (GLP-1R) are also present in other organs [20]. For instance, in the rodent and monkey brain, GLP-1R is abundantly expressed in many regions, including areas of importance for appetite control [21]. An experiment in which labelled liraglutide was infused in peripheral veins, demonstrated that GLP-1RA indeed bound to GLP-1R in the brain [22].

Secondly, GLP-1 also affects the heart. In Apo-E knock-out mice with early, low-burden atherosclerotic lesions, liraglutide reduced lipid deposition and lowered the intima media ratio. Giving also a GLP-1 receptor antagonist (Ex-939) counteracted the effect of liraglutide, suggesting that the GLP-1RA has a direct effect on plaque formation [23]. Another GLP-1RA, semaglutide, was tested in LDL receptor knock-out mice, which are prone to develop atherosclerotic lesions in response to a Western diet. With increasing doses of semaglutide, the mice lost more body weight. Moreover, the semaglutide-treated mice showed lower aortic plaque lesion area size, as compared with vehicle-treated mice. This suggests that the GLP-1RA has a direct effect on plaque lesion formation, independent of the body weight reducing effect of semaglutide [24].

Lastly, GLP-1RA may affect macrophage phenotype. Macrophages play a role in formation of atherosclerotic plaque lesions. The precursors of macrophages can be directed towards pro-atherogenic macrophages, or toward a pro-resolving state that has beneficial effects on atherosclerotic lesions. It has been shown that liraglutide can drive the macrophage cell fate towards pro-resolving macrophages [25]. This might be important in the atherosclerotic lesion reduction as induced by GLP-1RA.

In addition to its effects on insulin and glucagon, the reduction of appetite via GLP-1R activation in the brain, GLP-1 also lowers gastric emptying. Thus, via these indirect effects, and its direct effects on arteries in the heart, GLP-1 affects several markers of CVD, namely glucose, BP, lipids, and also overweight. CV outcome studies have investigated whether these effects actually translate into a hard endpoint such as major adverse cardiovascular events. The ELIXA [lixisenatide, 26], LEADER [liraglutide, 13], SUSTAIN 6 [semaglutide, 27] and EXSCEL [exenatide, 28] trials, have now been completed. Liraglutide and semaglutide showed a positive effect on outcomes, suggesting that GLP-1RA treatment reduces CV risk in patients with T2DM and at high risk of CVD.

To finish off, Knop gave some suggestions on how to benefit from GLP-1RA in these patients. A GLP1RA with proven benefits in terms of CVD should be used. It is important to realize that GLP-1 lowers blood glucose via different mechanisms, including strictly glucose-dependent effects on pancreatic islets, which minimizes the risk of hypoglycemia. The effect of GLP-1 on the brain results in body weight loss. Also of interest is the fact that GLP-1 seems to reduce systolic blood pressure, most likely through a natriuretic effect in the kidneys. The reduction in BP is accompanied by a small but significant increase in heart rate, with unknown implications to date. The most frequent side effects of GLP-1RA are mild gastrointestinal side effects with nausea being the most predominant. Most GLP-1RAs can be used in patients with chronic kidney disease with EGFR down to 30 mL/min/1.73m2. GLP-1RAs have few interactions with other glucose-lowering drugs, and can for instance be combined with SGLT2 inhibitors without any problems. There are only very few contraindications to GLP-1RA use and most of these are due to lack of knowledge.

References

Educational information

This is a summary of the presentation given by dr. Knop, during the PACE symposium entitled 'Outcomes of GLP-1 RA in Diabetes & CVD: What are the key opportunities for cardiology practice?', held during ESC in Munich, Germany, on August 27, 2018.