Article Type : Research Article
Authors : Bando H, Yamashita H, Kato Y, Kato Y, Ogura K and Kawata T
Keywords : Glucagon-like peptide 1 receptor agonist (GLP-1RA); Oral semaglutide (Rybelsus); Oral hypoglycemic agents (OHAs); Sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC); Japan LCD promotion association (JLCDPA)
Background: Authors and researchers have
continued clinical practice and research of diabetes and endocrinology for
long. As a glucagon-like peptide 1 receptor agonist (GLP-1RA), oral semaglutide
(Rybelsus) was applied to patient with type 2 diabetes (T2D) and investigated.
Case Presentation: Case is 51-year-old
male patient with T2D for 8 years. His diabetic control was exacerbated to
HbA1c 8.5% in autumn 2021, and then Rybelsus was administered for increasing
doses of 3mg, 7mg, and 14mg per day. The results showed improvement of HbA1c
8.5% to 7.1% and weight 96kg to 91kg for 3 months.
Discussion and conclusion: Current
remarkable effect may be from the characteristic benefit of Rybelsus. It is
provided per os with 50-120 ml of water in the early morning, and after that at
least 30 min of fasting time period is required. As fasting time is longer, the
Rybelsus concentration in the blood and clinical efficacy become higher. The
case has daily habit of no breakfast for long, and fasting time was about 3-4
hours. This situation may be one of the main reasons for remarkable efficacy.
Current case will become an impressive reference for clinical effect of
Rybelsus in patient with T2D.
For practical guideline, Standards of Medical Care in
Diabetes-2022 was recently presented from American Diabetes Association (ADA)
[1]. Latest diabetic situation has been regularly announced from World Health
Organization (WHO) including international situation [2]. Patients with type 2
diabetes (T2D) have been graudually increasing for developed and developing
countries [3]. The fundamental methods for diabetic therapy include diet,
exercise and medication [4]. Regarding pharmacological treatment, oral
hypoglycemic agents (OHAs), insulin and other injectable agents have been used.
Authors and researchers have continued clinical reports in the field of
diabetes and endocrinology [5]. Among them, our group has proposed low
carbohydrate diet (LCD) and developed Japan LCD promotion association (JLCDPA)
for decades [6]. We have also investigated detail situation of continuous
glucose monitoring (CGM), meal tolerance test (MTT), analysis for insulin and
C-peptide secretory response to carbohydrate intake and others [7]. Moreover,
case reports were published including recent anti-diabetic agents of
sodium-glucose transporter 2 inhibitor (SGLT2i) and also glucagon-like peptide
1 receptor agonist (GLP-1RA) [8,9]. In the area of diabetes and endocrinology,
impressive topic includes clinical application of novel GLP-1RA [10]. It is
oral semaglutide with brand name Rybelsus, which has been reported to show
clinical usefulness and efficacy [11]. Furthermore, semaglutide has presented
clinical effect of reducing body weight for a series of trials [12]. Authors
have treated various situation of T2D patients. Recently, we have experienced a
case who was provided Rybelsus, leading to remarkable improvement of blood
glucose control and reduction of body weight. The general progress and some
discussion will be described in this article.
History
& Physical
The patient is a 51-year-old male patient with T2D. In 2013, he was diagnosed to have T2D and he has been treated by some kinds of OHAs. The OHAs included metformin 1000mg and Ipragliflozin L-proline 50mg. In autumn 2020, his diabetic control was exacerbated to HbA1c 8.5%. Then, he was started to given dugulatide (Trulicity) 0.75 mg/week. Due to one-week injection, his HbA1c was decreased to 7.2%. However, glucose control became gradually worse (Figure 1).
Figure 1: Clinical progress with changes in HbA1c, weight and treatments.
Several
exams
The biochemical results of Oct 2021 were summarized in the following: GOT 22 U/L,GPT 34 U/L, GGT 16 U/L, ChE 277 U/L (213-501), LDL-C 67 mg/dL, TG 211 mg/dL, HDL-C 51 mg/dL, BUN 12 mg/dL, Cr 0.96 mg/dL, eGFR 66 mL/min/1.73m2, UA 5.2 mg/dL, RBC 5.34 x 106 /?L, Hb 13.2 g/dL, Ht 43.5 %, MCV 81.5 fL, MCH 25.4 pg, MCHC 30.3 g/dL, WBC 5100 /?L, Plt 17.5 x 104 /?L, serum Fe 29 mcg/dL, TIBC 377 mcg/dL, UIBC 348 mcg/dL, ferritin 13 ng/mL. For several tests for DM, HbA1c 7.5 %, post-prandial blood glucose 225 mg/dL, Urinalysis data were presented as protein (-), glucose (++), urobilinogen (+/-). Chest X-P was negative for lung and heart, and ECG showed unremarkable. Occult blood in stool was negative twice, and no remarkable findings were observed in colonofiberscopic examination.
Clinical
progress
He developed increasing HbA1c and occasional nausea from autumn 2021. He received the examination of abdominal CT scan and gastrofiberscopic examination (Figure 1). The results showed fatty liver, cholecystolithiasis (galls stones), right renal cyst, delayed gastric emptying (DGE), acute gastritis (C-3) with redness (Figure 2a,2b).
Figure 2: Abdominal CT scan.
2a: Fatty liver and slight delayed gastric emptying (DGE).
2b: cholecystolithiasis (gall stones).
Histological study of gastric mucosa showed the
presence of Helicobacter pylori (H.Pylori). Then, he was given 7 days of
medication for H. Pylori, including Vonoprazan, Amoxicillin and Clarithromycin.
His HbA1c increased to 8.5% in Dec 2021. Consequently, he was changed the
diabetic therapy, which was from Trulicity to Rybelsus. The dose of Rybelsus
was increased as 3 mg, 7mg and 14 mg for every 4 weeks. HbA1c values decreased
from 8.5% to 7.1% for 3 months, associated with weight reduction from 96kg to
91kg. Concerning his symptom, he has noticed nausea in early Oct, mid Nov and
early Feb associated with each improvement of 1-2 days.
Medical
problems
From general history, examinations and clinical
progress, medical problems can be summarized in the following. They are #1 T2D
with successful control by Rybelsus, #2 fatty liver, #3 delayed gastric
emptying (DGE), #4 gall stones, #5 Gastro Esophageal Reflux Disease (GERD) with
treatment for H.Pylori, #6 dyslipidemia for taking medicine rosuvastatin 2.5mg
for years, #7 arteriosclerosis for taking medicine of acetylsalicylic acid
(Byaspirin) 100mg.
Current investigation has been basically conducted
along with the ethical principles of the Declaration of Helsinki. Further,
partial commentary was according to the Ethical Guidelines for Research for
Humans. It has been associated with Good Clinical Practice (GCP). Authors and
collaborators related to this report have established an ethical committee for
ethical considerations. It exists in the hospital including several
professionals. They are the director, surgeon, physician, head nurse,
pharmacist, dietician and legal specialty. We have discussed enough for
adequate way, and the agreements were obtained for this study protocol. The
informed consent associated with written agreement document were given from the
patient.
As to recent pharmacological therapy for T2D, several
types of GLP-1Ras have been introduced so far [13]. These agents have different
properties of duration of effect and molecular weight. There are also
differences for providing methods and characteristics [14]. Some categories are
present as follows. There are a) liraglutide and lixisenatide injection
subcutaneous injection once daily, b) exenatide subcutaneous injection twice
daily, c) duraglutide, exenatide and semaglutide subcutaneous injection once
weekly, and d) oral semaglutide form that is investigated from the PIONEER
studies (Peptide InnOvatioN for Early diabEtes tReatment). Concerning clinical
efficacy of semaglutide, systematic review was found for 9890 patients in
11RCTs [15]. In comparison with liraglutide, empagliflozin and sitagliptin,
semaglutide showed the priority of HbA1c decrease for 0.35% and weight decrease
for 1.48kg. Moreover, it showed superiority of all-cause mortality as odds
ratio (OR) 0.58 and cardiovascular (CV) mortality as OR 0.55. For
cardiovascular outcome trials (CVOTs) with 56004 cases, semaglutide had
decreased OR of CV death than 4 GLP-1Ras, including lixisenatide (0.43),
albiglutide (0.45), dulaglutide (0.46) and exenatide (0.47) [16].
Among several GLP-1RAs, semaglutide (Rybelsus) has
been developed as the first oral agent. Its characteristics is the
co-formulation of semaglutide peptide with the novel caprylate of the
absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) [17,18].
It can overcome the difficult situation for the absorption of the peptide in
the acidic circumstance of the stomach. Concerning clinical efficacy of
Rybelsus, CV safety was found to be non-inferiority to placebo group, and CV
effect for Rybelsus seems to have similarity to that of subcutaneous injection
of semaglutide [19]. Such evolution of GLP-1RA for oral intake will bring
beneficial treatment for earlier management for many diabetic patients.
Oral semaglutide was applied to current patient with
T2D. Clinical efficacy showed decreased HbA1c -1.4% and body weight -5kg for 3
months, which was satisfactory results. Some factors may contribute this
improved situation. One is taking Rybelsus situation, when the patient wakes up
in the morning [20]. The patient has regular daily life style with no breakfast
for years. That is one of the reasons why we decided to give him Rybelsus. As a
matter of fact, he has kept fasting about 3-4 hours after intake of Rybelsus
every day [20]. Comparison study was conducted for food influence test. Area
under the curve (AUC) and maximum concentration (Cmax) were compared between
fasting and fed pre-med situation. As a result, AUC and Cmax were about 40%
greater in fasting than fed pre-med situation, where P values were 0.082 and
0.080, respectively [21]. Consequently, intake of oral semaglutide in fasting with
water 50-120cc and more than 30 minutes post-dose fasting seemed to be relevant
in the clinical practice. These conditions for adequate amount were shown in
the phase 3 trials. Furthermore, pharmacokinetics of oral semaglutide was
investigated for fasting time period. As a result, the ratio AUC was 1.00,
1.98, 2.48, 3.33, and the ratio of Cmax was 1.00, 1.87, 2.30, 3.05,
respectively, for 15, 30, 60 and 120 minutes [21].
From mentioned above, current case has longer fasting
period after intaking of Rybelsus. Then, remarkable improvement of glucose
variability and weight reduction may be found [22]. On the other hand, he
showed nausea three times for 1-2 days during the clinical progress. Some
adverse effects are reported so far [23]. The first episode of nausea may be
from GERD with H. Pylori and/or gall stones. The second nausea may be from
combined oral antibiotics treatment for a week. The third nausea was observed
on the first day of 14mg of Rybelsus. Then, it may be from the adverse effect.
However, the symptom was disappeared only 1 day. Authors asked the patient
three possible management including i) discontinue Rybelsus, ii) decrease the
dose from 14 to 7 mg, iii) continue 14mg associated with anti-nausea agent, iv)
continue 14 mg without other med. He decided IV) option, because he felts
nausea only 1 day, and wants to intake Rybelsus with remarkable effect of -1.4%
of HbA1c for 3 months. This case was provided injectable GLP-1RA (Dulaglutide),
which showed insufficient clinical effect. Successively, oral GLP-1RA
(semaglutide) was started, which showed sufficient efficacy. Thus, several
hours fasting time period after intake of Rybelsus may be involved.
Consequently, fasting time would be one of the factors that anticipates
clinical improvement [24].
Some limitation exists in this report. The patient
with T2D is 51 years old and only one case presented. His characteristics
include i) usual habit of no breakfast, ii) longer fasting time period after
intaking Rybelsus, iii) three times of nausea from possible three reasons, iv)
delayed gastric emptying (DGE), v) satisfactory results of decreased HbA1c and
weight and vi) no special adverse effect. Future follow up the detail clinical
progress will be observed. In summary, T2D patient showed satisfactory clinical
efficacy for Rybelsus. Some discussion and perspectives were presented from
several points of view. This report will hopefully become a reference data for
future practice and research in the diabetology.
The authors declare no
conflict of interest.
There was no funding received for this paper.