Vonoprazan-Induced Hypomagnesemia Case Reports and Literature Review

Aiba M and Tsutsumi Y

Published on: 2022-02-26

Abstract

Proton pomp inhibitors (PPIs) are widely used in daily practice to improve symptoms associated with gastric acid secretion and to eradicate H. pylori. Hypomagnesemia is one of the side effects of PPIs and has been widely recognized as a complication of PPIs since the first case was reported in 2006. Vonoprazan is a drug with strong antacid action by a mechanism different from PPIs, and was introduced in Japan in 2015. There have been few reports of adverse events associated with vonoprazan, but considering the mechanism of action, adverse events similar to those associated with PPIs may occur. Although the number of cases of hypomagnesemia caused by vonoprazan is still small, it is possible that the number of similar cases will increase with the widespread use of vonoprazan. In this paper, we review 2 cases of vonoprazan-induced hypomagnesemia and discuss the mechanism about hypomagnesemia associated with antacids.

Keywords

Vonoprazan-Induced Hypomagnesemia

Introduction

Vonoprazan is an inhibitor of gastric acid secretion classified as a potassium-competitive acid blocker (P-CAB). It is a drug that suppresses gastric acid secretion by a mechanism different from that of conventional PPIs, and has been widely used for gastric ulcer and H. pylori eradication therapy since its launch in Japan in 2015 [1,2]. Although there have been few reports on side effects of vonoprazan, there is a possibility that adverse events associated with suppression of gastric acid secretion may occur, as with PPIs.

Hypomagnesemia is known to be one of the complications of PPIs. Since the first case was reported in 2006 (3), many similar cases have been reported, and the mechanism is thought to be a decrease in magnesium absorption from the intestinal tract due to suppression of gastric acid secretion [4,5]. On the other hand, there are only two cases of hypomagnesemia caused by vonoprazan, including our case [6,7]. As the use of vonoprazan increases in the future, the number of similar case reports is likely to increase. In this paper, we review 2 cases of vonoprazan-induced hypomagnesemia (Table 1) and discuss the mechanism about hypomagnesemia associated with antacids.

Table 1: 2 cases of vonoprazan-induced hypomagnesemia.

	Age, sex	Vonoprazan duration	Mg level at admission	Time from vonoprazan discontinuation to normal Mg level
Okamoto et al [6]	66yo. Male	2 year	0.2mg/dL	20 days
Aiba et al [7]	71yo. Felame	2 week	0.4mg/dL	4 days

(Case 1)(6)

A 66-year-old man with a history of old-onset cerebral infarction. A year and a half prior to this admission, the patient had been brought to the emergency room for a convulsive seizure, but the magnesium level at that time was unknown. One day, he was rushed to the hospital due to difficulty walking and disturbance of consciousness. The patient had been taking PPIs for a long time, but was switched to vonoprazan 2 years ago. Imaging and electroencephalographic examinations showed no obvious abnormality, and blood tests showed that his serum Mg level had dropped to 0.2 mg/dL, and he was diagnosed with consciousness disorder caused by hypomagnesemia. The urinary magnesium concentration decreased below the sensitive level. Suspecting magnesium malabsorption due to vonoprazan, it was interrupted and the magnesium level recovered to normal range 20 days after discontinuation.

(Case 2)(7)

A 71-year-old woman who underwent ileocecal resection for malignant lymphoma of the ileum. The patient had been taking PPIs for a long time, and had started taking vonoprazan 3 weeks prior to admission due to increased symptoms of reflux esophagitis. The patient had a convulsive seizure during a routine visit to hospital, and was hospitalized immediately. Head imaging showed no abnormality, and blood tests showed a decrease in serum Mg level to 0.4 mg/dL. The patient was diagnosed with consciousness disorder due to hypomagnesemia. Suspecting the involvement of vonoprazan, we discontinued vonoprazan.and the magnesium level recovered to normal range after 4 days.

Literature Review

In 4 meta-analyses of PPI and hypomagnesemia, all reported a correlation between PPI and hypomagnesemia (Table 2) [8-11]. Regarding the correlation between the strength of the inhibitory effect on gastric acid secretion and hypomagnesemia, Srinutta et al. reported that the probability of hypomagnesemia was higher with high-dose PPI medication compared with low-dose PPI medication; the median odds ratio for developing hypomagnesemia in patients taking high doses of PPIs was 2.13 compared with patients taking low doses [11]. Regarding the correlation between PPI duration and hypomagnesemia, Yoldemir et al. reported that the risk of hypomagnesemia increases with prolonged PPI use; the median PPI duration of use was 4.75 years for patients with hypomagnesemia vs 3.35 years for patients with normal magnesium level [12].

Table 2: Summary of findings from 4 meta-analysis about ppi-induced hypomagnesemia.

	Park et al [8].	Cheungpasitporn et al [9].	Liao et al [10].	Srinutta et al [11].
Year of publication	2014	2015	2019	2019
Total patients	115,455	109,798	129,347	131,507
Exposure variable	PPI user	PPI user	PPI user	PPI user
comparameter	PPI non user	PPI non user	PPI non user	PPI non user
Adjusted odds ratio(95% CI)	1.48(1.10-1.99)	1.43(1.08-1.88)	1.44(1.13-1.76)	1.71(1.33-2.19)

Discussion

Magnesium is the fourth-most abundant cation in the human body and is widely involved in the maintenance of human physiological and physical functions [13]. The balance of magnesium in the body is mainly regulated by absorption from the intestinal tract and excretion from the kidneys, and hypomagnesemia occurs when this balance is disrupted [4].

Drug-induced hypomagnesemia is thought to be caused by renal loss, whereas in the case of PPIs, it is thought to be caused by inhibition of intestinal absorption. Magnesium is passively absorbed into the blood through the concentration gradient between the lumen and the interstitium and is then actively absorbed into the intestinal cells via transient receptor potential melastin (TRPM) 6 and TRPM7, which are magnesium transporters in the intestinal mucosa [4]. TRPM has a high affinity for magnesium and plays an important role in the maintenance of magnesium concentrations in the body, and its activity increases as the surrounding environment becomes more acidic [5]. Therefore, one possible mechanism of PPI-induced hypomagnesemia is that PPIs inhibit gastric acid secretion, which raises the pH in the intestine, thereby decreasing the activity of TPRM6/7 and impairing the active absorption of magnesium [4,5].

PPI-induced hypomagnesemia was first reported by Epstein et al. in 2006, and many similar cases have been reported since then. Hypomagnesemia caused by PPIs has become known as a rare but serious adverse effect, but only two cases of hypomagnesemia caused by vonoprazan have been reported so far [6,7]. Vonoprazan is a novel oral inhibitor of gastric acid secretion with a different mechanism of action from conventional PPIs in that it inhibits H+/K+ ATPase in the gastric wall. Compared to conventional PPIs, vonoprazan does not require activation by gastric acid, is stable in an acidic environment, and has a shorter period of time to reach maximum blood concentration, and is considered to be more effective in gastric acid secretion than PPIs [14].

Srinutta et al. reported that the incidence of hypomagnesemia increased with high oral doses of PPIs [11]. Although the reason is not declared, it has been reported in another review that higher dose PPI administration causes an increase in intragastric pH [15], and that the activity of TRPM7 decreases as the pH of the surrounding environment increases [16]. Assuming that vonoprazan causes hypomagnesemia by the same mechanism as PPIs, vonoprazan may cause a higher increase in intestinal pH than PPIs and a decrease in magnesium absorption from the intestine.

Regarding the correlation between PPI duration and hypomagnesemia, Yoldemir et al. reported that the risk of hypomagnesemia increases with prolonged PPI use [12]. Similarly, Hess et al. reported that the time from the start of PPI use to the onset of hypomagnesemia ranged from 14 days to 13 years, with an average of 5.5 years [17], suggesting that long-term PPI use may be a risk. On the other hand, the onset of hypomagnesemia from the start of vonoprazan administration in these case reports was earlier than previously reported, 2 weeks and 2 years, respectively. Although further studies are needed to clarify the mechanism of the rapid onset of the disease, it is possible that the early antacid effect of vonoprazan caused an early decrease in TRPM activity. In comparison with these 2 cases, Aiba reported hypomagnesemia after 2 weeks of oral administration, but this patient had a history of ileal resection. Considering that 56% of magnesium absorbed in the gastrointestinal tract is absorbed in the ileum [18], it is possible that the patient's hypomagnesemia was brought about earlier because the total stored magnesium in the body was low due to malabsorption.

Hypomagnesemia is a common electrolyte abnormality occurring in as many as 11% of hospitalized patients [19]. However, the actual incidence of PPI-induced hypomagnesemia may be higher than previously reported, because it has been reported that 90% of hypomagnesemia is missed in actual clinical practice because serum magnesium level is not routinely collected [20]. Additionaly magnesium oxide is often prescribed as a laxative in Japan. Although magnesium oxide is known to cause hypermagnesemia in the elderly and in patients with impaired renal function, Wakai et al. reported that the incidence of hypermagnesemia was not increased in patients taking magnesium oxide together with PPIs [21], suggesting that when antacids and magnesium oxide are taken at the same time, it cannot be denied that hypomagnesemia caused by antacids may be masked.

We reported two cases of hypomagnesemia caused by vonoprazan and discussed the mechanism of the hypomagnesemia. The number of reports of hypomagnesemia is expected to increase as vonoprazan becomes more widely used. It is important to periodically measure blood magnesium levels in patients taking vonoprazan and to evaluate for complications of hypomagnesemia. The detailed mechanism by which vonoprazan causes hypomagnesemia is not clear, and further clarification is expected.

Journal of Biomedical Science and Research