
==== Front
Intern Med
Intern Med
Internal Medicine
0918-2918
1349-7235
The Japanese Society of Internal Medicine

38220187
10.2169/internalmedicine.2608-23
Case Report
Hot Water Eliminates the Bitter Taste of Oral Semaglutide: A Report of Four Cases
Okada Shuichi 1
Okada Junichi 2
Okada Kazuya 3
Yamada Eijiro 4
Saito Tsugumichi 4
Kikkawa Koji 1
Ando Tetsurou 1
Ohshima Kihachi 1
1 Diabetes Center, Hidaka Hospital, Japan
2 Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, USA
3 Department of Orthopedic Surgery, Tone Chuo Hospital, Japan
4 Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan
Correspondence to Dr.　Shuichi Okada, okadash1823@gmail.com

13 1 2024
15 8 2024
63 16 22972300
13 7 2023
23 11 2023
Copyright © 2024 by The Japanese Society of Internal Medicine
https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Semaglutide is a well-designed drug with a special coating that allows for oral administration to patients with type 2 diabetes mellitus. However, patients taking oral semaglutide complain of its bitter taste. We therefore considered suggesting that patients take oral semaglutide with hot water. When the hot water temperature was increased to above 46.0°C but below 52.0°C, no bitter taste was perceived, with the daily mean interstitial glucose level remaining at the target range. Taking oral semaglutide with hot water helps reduce its bitter taste.

type 2 diabetes mellitus
oral semaglutide
hot water
bitterness
==== Body
pmcIntroduction

Oral semaglutide is a glucagon-like peptide-1 receptor analog (GLP-1 RA) that increases insulin secretion from pancreatic β cells and reduces glucagon secretion from pancreatic cells, thereby helping control plasma glucose levels in patients with type 2 diabetes (T2D) (1). Oral semaglutide is a well-designed drug specially coated with salcaprozate sodium that allows its oral administration. However, patients taking oral semaglutide complain about an accompanying bitter taste, leading to discontinuation in some cases.

When oral semaglutide passes through the pharynx, the bitterness is strong until a few minutes after it has been completely swallowed with a glass of water. In our hospital, among 48 patients prescribed oral semaglutide, 4 complained of strong bitterness and were greatly stressed every morning. Nevertheless, these patients did not want to switch from oral semaglutide to intravenous administration of GLP-1 RA due to fear of pain and restrictions on their life and instead requested a solution to the bitterness.

We identified studies in PubMed that reported that the bitter taste of food is reduced when its temperature is above the body temperature (2). Thus, we instructed four patients to take oral semaglutide with hot water instead of regular water. This case report details the effects of hot water on the bitter taste of oral semaglutide in patients with T2D.

Case Reports

Case 1 was a 59-year-old Japanese woman taking metformin (1,500 mg/day), mitiglinide (30 mg/day), oral semaglutide (14 mg/day), and candesartan (12 mg/day) in the previous year. The patient had no history of smoking. Upon visiting the hospital for a regular checkup, her physical examination results were as follows: height, 160.0 cm; body weight, 70.0 kg; body mass index (BMI), 27.3 kg/m2, and blood pressure, 126/80 mmHg. No abnormalities or evidence of neuropathy, retinopathy, or nephropathy were noted. Her recent casual blood glucose and glycated hemoglobin levels were 169 mg/dL and 6.9%, respectively. Her peripheral blood laboratory findings were normal except for mild liver dysfunction due to mild fatty liver disease. The laboratory findings are summarized in Table 1.

Table 1. Peripheral Blood Laboratory Findings.

Inspection items	Measurement value	Normal range	
Case 1	Case 2	Case 3	Case 4	
Red blood cell count	446	440	462	413	376-516×104/mm3	
White blood cell count	5,520	6,670	4,952	7,300	3,500-9,700/mL	
Hematocrit	39.1	38.2	40.1	39.5	34.3-45.2 %	
Hemoglobin	13.6	14.3	14	13.9	11.2-15.2 g/dL	
Total bilirubin	0.9	0.6	0.8	0.7	0.3-1.2 mg/dL	
Aspartate aminotransferase	48	32	29	38	10-40 U/L	
Alanine aminotransferase	57	39	40	41	5-45 U/L	
Lactate dehydrogenase	164	184	193	201	124-222 U/L	
Blood urea nitrogen	12.8	19.8	20.1	18.6	8.0-22.0 mg/dL	
Creatinine	0.58	0.62	0.65	0.69	0.47-0.79 mg/dL	
Serum sodium	140	139	141	142	136-147 mEq/L	
Potassium	4.2	4.1	4.5	4	3.6-5.0 mEq/L	
Chloride	104	102	103	103	98-109 mEq/L	
Calcium	9.5	9.4	9.6	9.3	8.6-10.2 mg/dL	
Serum amylase	113	121	115	92	39-134 U/L	
C-reactive protein	0.06	0.01	0.03	0.01	<0.30 mg/dL	
Anti-glutamic acid decarboxylase antibody	<5.0	<5.0	<5.0	<5.0	<5.0 U/mL	
The patient's peripheral blood laboratory findings are presented. Those examinations were performed before oral semaglutide was started.

Case 2 was a 64-year-old Japanese woman taking metformin (1,500 mg/day), oral semaglutide (14 mg/day), valsartan (40 mg/day), amlodipine besilate (5 mg/day), and rosvastatin (2.5 mg/day) in the previous year. The patient had no history of smoking. Upon visiting the hospital for a regular checkup, her physical examination results were as follows: height, 148.0 cm; body weight, 64.0 kg; BMI, 29.2 kg/m2; and blood pressure, 136/84 mmHg. No abnormalities or evidence of neuropathy, retinopathy, or nephropathy was observed. Her recent casual blood glucose and glycated hemoglobin levels were 133 mg/dL and 6.8%, respectively. The peripheral blood laboratory findings were normal. The laboratory findings are summarized in Table 1.

Case 3 was a 74-year-old Japanese man taking gliclazide (20 mg/day), dapagliflozin (5 mg/day), and oral semaglutide (14 mg/day) who had not taken any other medication in the previous year. The patient had no history of smoking. Upon visiting the hospital for a regular checkup, his physical examination results were as follows: height, 166.0 cm; body weight, 82.5 kg; BMI, 29.9 kg/m2, and blood pressure, 143/81 mmHg. No abnormalities or evidence of neuropathy, retinopathy, or nephropathy was observed. His recent casual blood glucose and glycated hemoglobin levels were 298 mg/dL and 7.2%, respectively. The peripheral blood laboratory findings were normal. The laboratory findings are summarized in Table 1.

Case 4 was a 75-year-old Japanese man taking oral semaglutide (14 mg/day); similar to Case 3, he had not taken any other medication in the previous year. The patient had no history of smoking. Upon visiting the hospital for a regular checkup, his physical examination results were as follows: height, 150.0 cm; body weight, 70.2 kg; BMI, 31.2 kg/m2, and blood pressure, 118/71 mmHg. No abnormalities or evidence of neuropathy, retinopathy, or nephropathy was observed. His recent casual blood glucose and glycated hemoglobin levels were 195 mg/dL and 6.7%, respectively. The peripheral blood laboratory findings were normal. The laboratory findings are summarized in Table 1.

All four patients had been taking oral semaglutide with water before breakfast and other medications at least 30 min earlier. Before taking oral semaglutide, they first held a small amount of water (calories: 0 CaL/100 mL; protein: 0 g/100 mL; lipids: 0 g/100 mL; carbohydrates: 0 g/100 mL; sodium: 0.0 g/100 mL; potassium: 0.04 mg/100 mL; calcium, 0.31 mg/100 mL; and magnesium: 0.2 mg/100 mL) in their mouths and then drank more water afterward. All participants consistently perceived a strong bitter taste every morning, which caused considerable annoyance.

Based on the information from the literature (2), we suggested that they take oral semaglutide with hot water to reduce their bitter taste. To determine an appropriate hot water temperature, we asked them to test the effect of various temperatures of water on the bitterness of oral semaglutide. We found that hot water (46°C) clearly reduced the bitterness of oral semaglutide. The upper temperature limit was set at 52°C, as this was the upper temperature limit of easily available hot water.

To test the effect of hot water on bitterness, we initially proposed that they take oral semaglutide with normal-temperature water as usual for 20 days (days 1 through 20). We monitored interstitial glucose levels using a FreeStyle Libre (Abbott Diabetes Care, Alameda, USA) for 20 days. We asked them to record the temperature of the water (in °C) and grade the taste based on how bitter they perceived it to be: “-3: Almost no bitterness,” “-2: Bitterness been clearly reduced,” “-1: Bitterness seems to have decreased slightly,” “0: No change,” “1: Bitterness has become a little stronger,” “2: Bitterness has become obviously stronger,” and “3: Bitterness has become so strong that it is difficult to consume” (Table 2) (3).

Table 2. Estimation of Bitterness.

Grade of bitterness	Score	
1. Almost no bitterness	-3	
2. Bitterness has been clearly reduced	-2	
3. Bitterness seems to have decreased a little	-1	
4. No change	0	
5. Bitterness has become a little stronger	1	
6. Bitterness has become obviously stronger	2	
7. Bitterness has become so strong that it is difficult to use	3	
The way how the bitterness of oral semaglutide was estimated is shown in this table before and after warm water was tested. We referred to the literature as cited #3 in the reference list.

Next, we proposed that they take their oral semaglutide with hot water for the next 20 days (days 21 through 40) above 46.0°C but below 52.0°C. We again monitored interstitial glucose levels using a FreeStyle Libre (Abbott Diabetes Care, Alameda, USA) throughout this period, considering the potential for hot water to decrease the therapeutic effects of oral semaglutide on interstitial glucose levels. As the half-life of oral semaglutide is 7 days, we considered 20 days of observation to be sufficient to estimate the effect of hot water on the bitterness of oral semaglutide (4). We also asked the patients to record the temperature of the water (in °C) and grade the taste, as described above.

From days 1 through 20, the mean (range) temperature of the water (°C) was 25.1±2.7 (20.1-28.2), 25.3±2.6 (20.2-27.9), 25.4±3.6 (20.5-27.4), and 25.0±3.3 (20.7-28.4) in Cases 1, 2, 3, and 4, respectively (Table 3), while the mean daily interstitial glucose levels (mg/dL) were 143.8±13.7, 199.3±18.4, 186.8±18.4, and 172.8±15.9, respectively (Table 4).

Table 3. Estimation of Bitterness Either with Water or with Hot Water.

Temperature (°C)	Recorded days	Bitterness score	
Case 1			
25.1±2.7 (20.1-28.2)	20	2±0	
49.6±3.9 (45.4-51.8)	20	-3±0	
Case 2			
25.3±2.6 (20.2-27.9)	20	2±0	
49.0±5.4 (45.0-51.5)	20	-3±0	
Case 3			
25.4±3.6 (20.5-27.4)	20	2±0	
49.5±2.5 (45.2-51.7)	20	-3±0	
Case 4			
25.0±3.3 (20.7-28.4)	20	2±0	
49.4±4.4 (46.0-52.0)	20	-3±0	
The left-most column represents the water temperature indicated in Celsius. The temperature is represented as mean±standard deviation. In brackets, the lowest and highest temperature is presented. The column in the middle represents the recorded days. The right-most column represents the results of estimated bitterness score in cases 1-4. When the water temperature was 25.1±2.7°C (mean±standard deviation), the patient felt same grade of strong bitterness consistently every morning as presented 2±0 (mean±standard deviation). When the water temperature was 49.6±3.9°C, the patient changed to feel almost no bitterness consistently every morning as scored -3±0 (case 1). When the water temperature was 25.3±2.6°C, the patient felt same grade of strong bitterness consistently every morning as presented 2±0. When the water temperature was 49.0±5.4°C, the patient changed to feel almost no bitterness consistently every morning as scored -3±0 (case 2). When the water temperature was 25.4±3.6°C, the patient felt same grade of strong bitterness consistently every morning as presented 2±0. When the water temperature was 49.5±2.5°C, the patient changed to feel almost no bitterness consistently every morning as scored -3±0 (case 3). When the water temperature was 25.0±3.3°C, the patient felt same grade of strong bitterness consistently every morning as presented 2±0. When the water temperature was 49.4±4.4°C, the patient changed to feel almost no bitterness consistently every morning as scored -3±0 (case 4).

Table 4. Results of FreeStyle Libre.

	Case 1		Case 2		Case 3		Case 4	
Water	Hot water	t	Water	Hot water	t	Water	Hot water	t	Water	Hot water	t	
Days	20	22			20	22			20	22			20	22		
eHbA1c (%)	6.6	6.9			7.5	7.0			7.2	6.8			7.0	6.5		
Average (mg/dL)	143.8±13.7	150.4±16.3	0.23		199.3±18.4	170.5±16.9	0.14		186.8±18.4	156.4±15.8	0.12		172.8±15.9	169.6±20.3	0.19	
TAR (%)	11	12			36	20			32	11			24	10		
TIR (%)	89	88			64	80			68	89			76	90		
TBR (%)	0	0			0	0			0	0			0	0		
This table represents the results of FreeStyle Libre to exam the potential for hot water to decrease the therapeutic effects of oral semaglutide on interstitial glucose levels.

Observation period with water was 20 days and observation period wiht hot water was 20 days.

eHbA1c: estimated glycated hemoglobin, Average: average of interstitial glucose levels, TAR: time above range, TIR: time in range, TBR: time below range

During the same period, the estimated glycated hemoglobin (eHbA1c; %) was 6.6, time above range (TAR; %) was 11, time in range (TIR; %) was 89, time below range (TBR; %) was 0, and the grade of the bitter taste remained 2 in case 1; eHbA1c was 7.5, TAR was 36, TIR was 64, TBR was 0, and the grade of the bitter taste remained 2 in case 2; eHbA1c was 7.2, TAR was 32, TIR was 68, TBR was 0, and the grade of the bitter taste remained 2 in case 3; eHbA1c was 7.0, TAR was 24, TIR was 76, TBR was 0, and the grade of the bitter taste remained 2 in case 4 (Table 4).

From days 21 through 40, the mean (range) temperature of the water (°C) was increased compared with the previous period, at 49.6±3.9 (45.4-51.8) in case 1, 49.0±5.4 (45.0-51.5) in case 2, 49.5±2.5 (45.2-51.7) in case 3, and 49.4±4.4 (46.0-52.0) in case 4 (Table 3), while the mean daily interstitial glucose levels (mg/dL) were 150.4±16.3, 170.5±16.9, 156.4±15.8, and 169.6±20.3, respectively (Table 4). Daily interstitial glucose levels were not significantly different between using normal-temperature and hot water (Table 4; p=0.23; case 1, p=0.14; case 2, p=0.12; case 3, p=0.19; case 4).

During the same period, however, the eHbA1c was 6.9, TAR was 12, TIR was 88, TBR was 0 in case 1; eHbA1c was 7.0, TAR was 20, TIR was 80, TBR was 0 in case 2; eHbA1c was 6.8, TAR was 11, TIR was 89, TBR was 0 in case 3; and eHbA1c was 6.5, TAR was 10, TIR was 90, and TBR was 0 in case 4. During the same period, the grade of the bitter taste remained -3 in all four cases (Table 3).

Thus, taking oral semaglutide with hot water did not diminish its therapeutic effects on interstitial glucose levels despite significantly ameliorating its bitterness.

Discussion

Among antidiabetic drugs, acarbose, voglibose, nateglinide, and metformin are associated with dysgeusia. According to an interview form for oral semaglutide, oral paresthesia occurs, but its frequency is below 1%; thus, it is a rare adverse effect. Details on the bitter taste of oral semaglutide have not yet been reported, so the mechanism underlying the bitter taste produced by it is unclear. We therefore report four patients with T2D who complained of bitterness.

Despite its bitter taste, it is recommended that oral semaglutide be taken with water, usually below body temperature. However, patients often become irritated with the bitter taste, with some even discontinuing the medication altogether; further complicating matters is the fact that the level of bitterness also varies.

Although the precise mechanisms have not yet been elucidated, the intensity of bitterness is greater in cold than in warm conditions, and the thresholds of bitterness are positively correlated with temperature, suggesting that sensitivity decreases with increasing temperature (2). In the present case series, hot water was helpful in reducing the bitter taste, which is consistent with the literature (2). Furthermore, the optimal hot water temperature range was above 46.0°C but below 52.0°C, conditions that allowed the patient to swallow the drug without any difficulty. We confirmed that such conditions had no adverse effects on the therapeutic effects of oral semaglutide on interstitial glucose levels.

In four patients, the bitterness was dramatically reduced (score 2 to -3), and hot water did not appear to interfere with the therapeutic effects of semaglutide. The differences in the improvement in HbA1c levels between cases 1 and 2 to 4 may have been due to differences already present at the start of oral semaglutide.

Thus, based on these findings, taking oral semaglutide with hot water (above 46.0°C but below 52.0°C) can help reduce its bitter taste. Based on our literature search of PubMed, this is the first study to describe an approach to reduce the bitter taste caused by oral semaglutide. This clinical case report will contribute to improving adherence to oral semaglutide in T2D patients.

However, given that this was only a case series of four patients with T2D with no marked differences in ethnicity, age, or weight, our findings cannot be completely generalized. Therefore, to verify our results, future studies should include larger cohorts with a wider range of demographics.

Nevertheless, given the relative simplicity of this approach, it is worth taking oral semaglutide in hot water (between 46.0 and 52.0°C), and if side effects appear, it can be stopped immediately.

Written informed consent was obtained from the patient for the publication of this manuscript and any accompanying images.

The authors state that they have no Conflict of Interest (COI).
==== Refs
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