How Does Simultaneous Administration of Propranolol, Liraglutide Affect Patients With T2D and Cirrhosis?

In the first study of its kind, researchers reporting in Diabetologia conducted an observational case report evaluating reactions of 18 patients with type 2 diabetes (T2D) and cirrhosis who received both a non-cardioselective beta (b)-blocker (propranolol) and liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). According to authors, liraglutide seemed to hamper the pharmacological effects of beta-blockers.

Due to selective inclusion criteria, many individuals with alcoholism are often excluded from clinical trials assessing new treatments. This practice leads to diminished generalizability of trial findings. Thus, effects of even commonly used drugs can easily be overlooked in this cohort.

This oversight poses a significant problem as alcohol-related deaths in the United States more than doubled between 1999 and 2017, making alcohol the third leading cause of preventable death in the United States.

Glucagon-like peptide-1 (GLP-1), a naturally occurring incretin compound, acutely increases heart rate due to stimulation of the sympathetic nervous system. GLP-1RAs are commonly used to treat T2D as they lower blood glucose levels. Approved drugs in this class include Trulicity (dulaglutide), Ozempic (semaglutide), and Victoza (liraglutide), among others.

Contrarily, b-blockers are frequently prescribed to prevent bleeding from esophageal varices, in particular for patients with cirrhosis—a chronic liver disease often caused by alcohol consumption. However, b-blockers lower heart rate by blocking the effects of the hormone epinephrine (adrenaline). Clinicians often aim for a target of 55 to 65 beats/min in individuals receiving the medication, which is also used to treat high blood pressure and heart conditions.

Study participants received an initial dose of 20mg of propranolol/day orally. The amount was titrated upward until the patient could not tolerate a higher dose, target heartrate was achieved, or a maximum dose of 160 mg/day was administered. The starting dose of liraglutide was 1.2 mg/day, administered subcutaneously. Liraglutide was titrated to 1.8 mg/day in obese patients.

All patients achieved a target heart rate before starting liraglutide treatment with a median of 62 beats per minute.

Over the course of 18 months, researchers evaluated patient heart rates and responses to the treatments. “After 3 months of combined treatment, the median heart rate increased and then remained relatively stable despite increases in the propranolol dose,” authors said. In addition, no increase in bleeding rate was observed.

Throughout the course of the study, 2 patients required hospitalization, 1 patient exhibited acute variceal bleeding, 1 experienced persistent atrial fibrillation, and 1 had paroxysmal supraventricular tachycardia.

However, due to the small sample size, researchers note the findings do not resolve the question of whether patients with diabetes should receive alternative treatment to prevent variceal bleeding.

After researchers verified heartrates of the remaining 15 participants were out of the optimal range, despite up titration of b-blockers, all individuals underwent elective variceal endoscopic band ligation.

Although liraglutide provided optimal control of blood glucose, A1C, and body weight, researchers found b-blockers had suboptimal effects on patients’ heart rate after they began receiving GLP-1RAs. During the study, 4 patients were switched to a different b-blocker, which did not lead to achievement of target heart rate in patients.

The underlying mechanism of the complication is unknown, but researchers hypothesize, “the a subunit (G_as) of the intracellular signaling protein Gs decreases when propranolol inhibits b-adrenergic receptors and increases when liraglutide stimulates receptors for GLP-1.”

Investigators conclude they are not convinced individuals receiving propranolol and liraglutide have worse outcomes than individuals who do not take GLP-1RAs for diabetes management.

In addition, the case report did not offer information as to whether these effects are specific to propranolol and liraglutide or are common in other drugs in each class. However, researchers did add dulaglutide at a dose of 1.5 mg/day to the treatment regimen for a single patient with T2D who was receiving propranolol to prevent variceal bleeding. They found “dulaglutide lowered the patient's hemoglobin A1c level, but it also increased the heart rate above the target range.”

This finding, along with switching 4 patients to a different b-blocker, are consistent with class effects. Authors note, “a class effect is suggested by recent findings that the mechanism for the increase in heart rate associated with GLP-1RAs involves direct stimulation of the cells in the sinoatrial node.”

Since 2009, a growing number of Americans have died from liver disease caused by cirrhosis while prevalence was estimated to be at .27% (633,323 adults) in 2015. In 2018, diabetes prevalence was estimated at 10.5% or 34.2 million Americans and 1.5 million Americans are diagnosed with diabetes each year.

Future case studies using claims databases may offer insights into how often this mechanism occurs and provide real world evidence as to how best to handle the condition in patients with T2D and cirrhosis.

Reference:

Vukotic R, Raimondi F, Brodosi L, et al. The effect of liraglutide on b-blockade for preventing variceal bleeding: A case series [published online May 25, 2020]. Diabetologia. doi: 10.7326/L20-0041