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Roles of GLP-1 RAs

CE / CME

The Many Roles of GLP-1 Receptor Agonists

Nurses: 0.25 Nursing contact hour

Physicians: maximum of 0.25 AMA PRA Category 1 Credit

Released: December 18, 2020

Expiration: December 17, 2021

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Our understanding of the mechanisms underlying the development of type 2 diabetes has expanded during the years, and we now know that the disease leads to physiologic changes in many different tissues. As a result, we now also have medications that act on these different tissues to alleviate hyperglycemia.

Glucagon like peptide-1 (GLP-1) receptor agonists are one such class of medications and one that has probably the most far-reaching effects, including the potential to restore the physiology of almost all the affected tissues.

My Practice
In my practice, I have pivoted to adding a GLP-1 receptor agonist for any patient with type 2 diabetes who is overweight, has established atherosclerotic cardiovascular disease, or has hyperglycemia and is not yet receiving insulin therapy.

I also prescribe them for patients who are referred to me who are on multiple daily injections of insulin but who have never tried GLP-1 receptor agonists, and I favor their use in patients with nonalcoholic fatty liver disease or persistent albuminuria, despite being on or unable to tolerate sodium glucose cotransporter-2 inhibitors.

My broad use of GLP-1 receptor agonists stems from their numerous benefits that include both glycemic and nonglycemic outcomes.

Metabolic Effects
The most prominent actions of GLP-1 receptor agonists are those that occur in response to food consumption. Similar to the gut peptides such as GLP-1 and gastric inhibitory polypeptide that are released by the body, GLP-1 receptor agonists stimulate insulin secretion from β-cells of the pancreas in response to food and suppress the release of glucagon from α-cells, thereby reducing hepatic glucose release. This “incretin effect” is key in lowering plasma glucose.

Other key actions of GLP-1 receptor agonists include reducing gastric motility and acting on the appetite center in the brain to suppress food intake. These mechanisms further aid in lowering plasma glucose and are key drivers of weight loss, and both are well-documented effects of GLP-1 receptor agonist therapy.

Additional metabolic effects of these agents are also under investigation, including improvement in hepatic steatosis and dyslipidemia.

Cardioprotective Effects
The close interplay among diabetes mellitus, obesity, and cardiovascular disease has long been evident, so the natural consequence of improvements in glycemia and weight would be reduction of long-term cardiovascular events. However, unlike previous medications used to manage type 2 diabetes, GLP-1 receptor agonists offer cardiovascular disease risk mitigation even in the short term and by mechanisms that extend beyond the glycemic and weight-loss benefits.

Data from preclinical and clinical studies have shown that these agents reduce heart rate and blood pressure, improve endothelial function, improve left ventricular function, have favorable effects on lipid and cardiac metabolism, and reduce atherosclerosis. The cardiovascular outcome trials have borne out that the concerted effort of all these mechanisms results in reduction in major adverse cardiovascular events with agents like liraglutide, semaglutide, and dulaglutide. As a result, GLP-1 receptor agonists have become the preferred glucose-lowering agents in patients with diabetes and atherosclerotic cardiovascular disease.

Renoprotective Effects
GLP-1 receptors are expressed in various cells in the kidneys, including endothelial cells and proximal tubular cells. Preclinical studies have shown that GLP-1 receptor agonists can reduce oxidative stress, counteract angiotensin II, inhibit effects of advanced glycation end products, and counteract fibrosis in the kidneys.

In fact, the cardiovascular outcome trials also looked at reduction in microvascular diabetic complications as secondary outcomes. These data revealed that liraglutide, semaglutide, and dulaglutide could potentially reduce progression of diabetic kidney disease, as they showed fewer “nephropathy events” vs placebo. Trials designed to look at diabetic kidney disease progression as the primary outcome are currently underway.

Summary
GLP-1 receptor agonists have become a vital tool in the armamentarium of antidiabetic agents. Given their many extraglycemic benefits, I am excited to see what the future holds in terms of their role in patients without diabetes as well, as our focus moves from treatment of diabetes and its complications to prevention of these ailments.

Your Thoughts?
How do you use GLP-1 receptor agonists in your practice? Answer the polling question and join the conversation by posting a comment below.

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When managing patients with type 2 diabetes and the following comorbidities, for which patient(s) would you consider a GLP-1 receptor agonist? Check all that apply.
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