Mirabegron: Risks in Cardiovascular Disease

A first-in-class ?3-adrenoceptor agonist, mirabegron is used to treat symptoms associated with overactive bladder (OAB). These symptoms, such as urgency, increased micturition frequency or incontinence urgency, are the result of an overactive detrusor muscle due to an increased sensitivity to contraction-mediating neurotransmission. Approximately 20-30% of the population aged 75 and above is thought to suffer from this urological condition. Antimuscarinic drugs relieve OAB symptoms by inhibiting contractile activity of the detrusor muscle during urination, where it is under parasympathetic control (Wetter market al., 2007).

Whilst there is a lack of conclusive evidence explaining the exact cause of OAB, two hypotheses have been put forth thus far; the first involves injury to the central inhibitory neural pathway, either with or without deregulation of the afferent sensory bladder pathway; and the second implicates the injury to the myogenic component of the bladder. Mirabegron alleviates OAB symptoms via inhibition of involuntary contraction of the detrusor muscle and by increasing the bladder storage capacity of the bladder.

Mirabegron administration is associated with several side effects including cerebrovascular complications, hypersensitivity reactions and cancer. There are several factors that may contribute to the development cardiovascular complications during mirabegron use namely, the dose administered, genetics (host-specific factors), pre-existing cardiovascular complication(s), and drug metabolism (Altman, Granath, Mattiasson, & Falconer, 2009).

Cardiovascular Risk Factors Associated with Mirabegron Administration

Dosage and Concentration of Mirabegron

The recommended dose of mirabegron in humans is 50 mg daily. Animal studies have demonstrated an elevation of heart rate in rats exposed to two times the maximum recommended human dose (MRHD). Similar findings were observed in monkeys exposed to twelve times the MRHD. In dogs, intravenous administration of mirabegron was shown to lower left ventricular, systolic and mean blood pressures at systemic exposure levels less than 10% MRHD. The animals used in these studies, dogs, rats and monkeys, provide organ models biologically similar to humans. Conversely, exposure to 52 times the MRHD had no adverse effects in monkeys. A study reported that 200 mg mirabegron in females had a mean treatment difference of 15.05 msec when compared to placebo. The study was repeated using 352 human subjects that received therapeutic doses of mirabegron (50 mg), demonstrating a mean treatment difference below 5 msec. It was noted that at supra-therapeutic doses of Mirabegron (100 mg), the mean treatment difference was over 5 msec at 3.0 to 4.5 hour time points. At a higher dose (200 mg) the point estimate was over 5 msec at all evaluated time points and did not exceed 10 msec at any time points evaluated (Carroll et al., 2005; Astellas, 2014).

In another report, heart rate appeared to increase in a dose-dependent manner when examined via electrocardiogram. The average maximum difference after baseline adjustment from placebo was 6.7 (5.3, 8.1), 11 (9.4, 12.6) and 17 (15.3, 18.7) beats per minute (bpm) for 50, 100 and 200 mg mirabegron respectively. In female subjects, the mean maximum differences were 8.3 (6.0, 10.7), 13.6 (11.2, 16.0) and 20.0 (17.6, 22.3) bpm for 50, 100 and 200 mg mirabegron respectively (Barlow, Westergren, Holmberg, & Talbäck, 2009). In another study, systolic blood pressure (SBP) significantly increased with mirabegron plasma concentration in healthy individuals. The report showed a proportional increase in SBP at mirabegron doses of 50, 100, and 200 mg respectively. A 50 mg mirabegron dose increased SBP by approximately 4 mmHg 3 to 6 hours after administration in healthy subjects. A study observed an increase of 0.9, 1.0 and 1.9 bpm for doses of 25, 50 and 100 mg of Mirabegron respectively during morning hours (Bellamy, & Arya, 2008). An additional study demonstrated that peak plasma concentrations of mirabegron often coincided with maximal changes in blood pressure (Brostrøm, & Hallas, 2009). Other antimuscarinic drugs, telterodine and Trospium, also increase pulse rate in a dose-dependent fashion and are detailed in table 1.

Table 1: Impact of antimuscarinic drugs on pulse rate in OAB Patients

Adapted from (Astrella’s Advisory Committee Briefing Document April 5, 2012)

History

A patient’s cardiovascular history contributes to the development of adverse cardiovascular effects with mirabegron use. Studies show that patients with history of cardiovascular complications are more likely to develop cardiovascular complications when taking mirabegron (Brostrøm, & Hallas, 2009). Patients at high risk include those with higher baseline systolic blood pressure (median: 141 mmHg), have an increased prevalence of diabetes (22–23%), require treatment for hypertension (67–68%) and have a higher baseline 10?year cardiovascular disease risk (median: 30.6%). Alarmingly, global projections indicate that treatment of high-risk patients with 50 mg mirabegron daily for one year could result in an additional 556 cardiovascular disease events per million patients (Graham et al., 2010).

Further, one study stated that a 62-year-old woman given 50 mg mirabegron daily was hospitalized for a hypertensive crisis on the thirteenth day of treatment. Diagnosis revealed that the woman had a long-standing history of hypertension with 170/90 mmHg blood pressure at admission. Researchers classified the event as severe and concluded it was related to the mirabegron administration. The patient was withdrawn from treatment on the 24^th day. In another study, a 72-year-old woman receiving a 50 mg mirabegron daily who had a long history of hypertension, suffered fatal cardiac failure at 190^th day of treatment (Altman, Granath, Mattiasson, & Falconer, 2009; Astrellas, 2012). Similar side effects are observed in response to other antimuscarinic drugs. Table 2, shows that tolterodine increases cardiovascular complications similarly to mirabegron in patients with a history of cardiovascular complications according to a report by Astrellas (2012).

Table 2: The effects of antimuscarinic medication on patients with a history of cardiovascular complications

Adapted from (Astrella’s Advisory Committee Briefing Document April 5, 2012)

Age and Host-Specific Factors

Age or host-specific factors may also contribute to mirabegron’s association with adverse cardiovascular complications in high-risk patients (Linnér, Schiöler, Samuelsson, Milsom, & Nilsson, 2011).

 A study reported that patients aged 65 years and above experience more cardiovascular problems than patients less than 65 years of age when administered mirabegron and tolterodine (Table 3). Elsewhere, several inconsistencies were noted in the heart rates of individual animals, and similar studies failed to produce the same effects in the same or different animals at different time points. Thus, it can be concluded that the effect of mirabegron on heart rate varies by species or individual, and that oral administration of mirabegron is associated with increases in heart rate at supra-therapeutic doses (Nomiya, & Yamaguchi, 2003).

Table 3: Effect of age on cardiovascular events upon antimuscarinic administration

Adapted from (Astrella’s Advisory Committee Briefing Document April 5, 2012)

Metabolism of Mirabegron

The metabolic pathways involved in mirabegron metabolism include; oxidation (N-dealkylation) of the secondary amine; amide hydrolysis; acetyl conjugation; glucuronidation of the hydroxyl group or the primary amine on the thiazole ring, or carbamoyl glucuronidation of the secondary amine; oxidation of the hydroxyl group to a carbonoyl group; or a combination of these four metabolic pathways. Mirabegron is hydrolysed in human plasma by the enzymes such as CYP2D6, CYP3A4, and plasma butyrylcholinesterase. In healthy people who are inherently poor metabolisers of CYP2D6 substrates, the mean plasma levels following a single 160 mg mirabegron dose were 14% and 19% higher than in extensive metabolisers, indicating that CYP2D6 genetic polymorphism has an impact on the mean plasma exposure of mirabegron (Andersson, & Wein, 2004). It has also been shown that mirabegron promotes lipolysis, increases metabolism and improves glucose tolerance in animal models (Furuet al., 2010; Ludvigssonet al., 2011). Rats demonstrated small gains in body weight and triglyceride levels. Lipolysis effect was not replicated in humans inferring mirabegron could cause coronary problems (Altman, Granath, Mattiasson, & Falconer, 2009).

Conclusion

Several factors increase the risk of cardiovascular complications associated with mirabegron administration. These factors include dosage, host-specific factors, a history of cardiovascular disease and the patient’s metabolism. Mirabegron showed a dose-dependent increase in both pulse rate and SBP in both humans and animal trials. Overall increased blood pressure is associated with near maximal plasma concentrations of the drug potentially predisposing mirabegron users, especially those with an existing history of cardiovascular disease, to increased risks of cardiac events. Further, patients found to be poor metabolisers of mirabegron have higher plasma concentrations of mirabegron compared to those who extensively metabolise the drug. Overall, mirabegron could cause cardiovascular complications but the benefit it offers overrides the risks. More importantly, the cardiovascular complications are less compared to other antimuscarinic agents. 

References

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