Excellent Blood Glucose Levels for 5 Years with Well Maintained Insulin Secretion by the Treatment Comprising a Once-Weekly Injection of Dulaglutide: GLP- 1RA Alone in a Patient with Type 2 Diabetes Mellitus

Case Report

Austin J Endocrinol Diabetes. 2023; 10(1): 1099.

Excellent Blood Glucose Levels for 5 Years with Well Maintained Insulin Secretion by the Treatment Comprising a Once-Weekly Injection of Dulaglutide: GLP- 1RA Alone in a Patient with Type 2 Diabetes Mellitus

Seiho Nagafuchi, MD, PhD1,2*#; Keiichiro Mine, PhD2#; Taizo Shiratsuchi, BA1; Erika Shibayama, RN1; Azusa Mitsueda, RN1; Hirokazu Takahashi, MD, PhD3; Keizo Anzai, MD, PhD2

1Department of Internal Medicine, Fukuoka Heartnet Hospital, Fukuoka, 819-0002, Japan

2Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan

3Liver Center, Faculty of Medicine, Saga University Hospital, Saga University, Saga 849-8501, Japan

*Corresponding author: Seiho Nagafuchi Department of Internal Medicine, Fukuoka Heartnet Hospital, Fukuoka, 819-0002, Japan. Email: [email protected]

#These authors contributed equally to the manuscript.

Received: June 15, 2023 Accepted: July 03, 2023 Published: July 10, 2023

Abstract

As a result of worsening of diabetes mellitus control to 9.1% hemoglobin A1c, a 61-year-old male Japanese patient began treatment with once-weekly subcutaneous injection of 0.75mg dulaglutide (a glucagon-like peptide-1 receptor agonist) alone. As a result, he demonstrated excellent diabetes mellitus control at an approximate 6.0% to 6.7% hemoglobin A1c level with this treatment alone for 5 years. The insulin secretion activity was well maintained as assessed by the HOMA-β score from 2.7 to 10.2. Interestingly, slight increase of insulin resistance, as assessed by the HOMA-IR was observed from 0.7 to 1.1. Taken together, the mild increase of insulin secretion may have been a positive reaction to keep good control of diabetes mellitus in response to slightly increased insulin resistance. Thus, a long-lasting favorable effect of treatment with dulaglutide alone, not only for diabetes mellitus control, but also for keeping insulin secretion, was demonstrated by this patient.

Keywords: β-cell; Dulaglutide; Glucagon-like peptide-1 receptor agonist (GLP-1RA); Insulin resistance; Type 2 diabetes mellitus

Introduction

A recent IDF report indicated that the number of patients with diabetes mellitus globally is now approximately 800 million, which will increase by 8 million annually [1]. Almost all patients are expected to have type 2 diabetes mellitus, and an appropriate prevention program and effective and safe treatment regimens are essential. Fortunately, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonist (GLP- 1RA) stimulate insulin secretion in response to diet-induced hyperglycemia, without the risk of hypoglycemia, which is in contrast to sulfonylureas (SUs) and/or insulin [2-4].

GLP-1 RA has been also reported to be useful not only to control diabetes, but also to reduce the risks of cardiovascular diseases, obesity and renal disorders [4]. The mechanisms of GLP-1RA-stimulated insulin release in pancreatic β-cells are displayed in Figure 1. Briefly, GLP-1RA stimulates pancreatic β-cells to increase the production and release of insulin through increasing Cyclic Adenosine Monophosphate (cAMP) production and calcium (Ca2+) elevation, followed by protein kinase A activation, leading to upregulation of proinsulin gene transcription and subsequent insulin secretion [3].

Figure 1: The mechanisms of GLP-1RA-stimulated insulin release in pancreatic β-cells. *ATP: adenosine triphosphate; GLUT2, glucose transporter 2; K, potassium; PRIG: promoter region of insulin gene.

    

    
    

    

    Figure 1: The mechanisms of GLP-1RA-stimulated insulin release in pancreatic β-cells.
*ATP: adenosine triphosphate; GLUT2, glucose transporter 2; K, potassium; PRIG: promoter region of insulin gene.

The SU group of drugs stimulate β-cells to secrete insulin, irrespective of the blood glucose concentration; thus, the risk of hypoglycemia is high. In addition, the accumulation of β-cell damage following long-term SU drug use frequently leads to the requirement for insulin treatment. By contrast, GLP-1RA drugs are believed to stimulate insulin secretion without damaging β-cells [2-4]. However, the long-term effects of GLP-1RA treatment on β-cell function and insulin secretion requires further investigation [4,5].

Case Report

We report a patient who achieved a significant long-term effect with GLP-1RA treatment alone. A 42-year-old man (height: 163cm; weight: 55.0kg; body mass index: 20.7kg/m2) was diagnosed with type 2 diabetes mellitus in 1998. Until 2016, his diabetes mellitus was well controlled by diet, exercise, and daily 40mg oral gliclazide: SU treatment. From 2016 to 2017, his diabetes mellitus control worsened (>8.0% hemoglobin A1c (HbA1c) (Figure 2A) without any sign of improvement, suggesting that the gliclazide treatment had lost its effectiveness. The patient did not have obesity or anti-glutamic acid decarboxylase antibody [6]. During worsening, he did not experience flu-like syndrome, and he was negative for the virus-induced diabetes susceptibility gene, Tyrosine kinase 2 promoter variant [7,8], suggesting that autoimmunity or viral infection did not contribute to the deterioration in his condition. In July 2017, dulaglutide injection therapy was suggested. However, because his brother who also had type 2 diabetes mellitus and had received multiple daily insulin injections for 10 years, suddenly died in the bathroom of an unknown cause, he first refused the therapy. Three months later, his diabetes mellitus control deteriorated to a HbA1c level of 9.1%. His insulin secretion activity decreased, as assessed by a fasting C-peptide concentration of 0.8ng/ml, an insulin concentration of 1.4μU/ml, and a homeostatic model assessment of β-cell function (HOMA-β) [9] score of 2.7. Fortunately, he understood the difference between daily insulin therapy and once-weekly subcutaneous injection of 0.75mg dulaglutide. Since he did not like to be given drugs, he accepted dulaglutide alone treatment. This treatment enabled him to obtain excellent control of diabetes mellitus with a 6.0%–6.7% HbA1c level for 5 years (Figure 2A). Throughout the observation period, he had kept body weight around 55.5kg and good exercise every day. His clinical data regarding liver, kidney, electrolyte, and uric acid all showed normal without hyperlipidemia. In addition, he had no diabetic retinopathy nor microalbuminuria. His insulin secretion was well maintained, and the fasting insulin concentration moderately increased to 2.8μU/ml, with a HOMA-β score of 10.2 (Figure 2B), which was consistent with the mild elevation in the fasting C-peptide concentration from 0.8 to 1.1ng/ml. Interestingly, slight increase of insulin resistance, as assessed by the HOMA-IR [10], was observed from 0.7 to 1.1 (Figure 2B). Taken together, the mild increase of insulin secretion may have been a positive reaction to keep good control of diabetes mellitus in response to slightly increased insulin resistance.

Figure 2: Clinical time course of the patient. A: Profile of fasting blood glucose and hemoglobin A1c (HbA1c). B: Profile levels of homeostasis model assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR). Gliclazide (Gli): 40mg/day; Dulaglutide: 0.75mg subcutaneous injection/week

    

    
    

    

    Figure 2: Clinical time course of the patient.
A: Profile of fasting blood glucose and hemoglobin A1c (HbA1c).
B: Profile levels of homeostasis model assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR).
Gliclazide (Gli): 40mg/day; Dulaglutide: 0.75mg subcutaneous injection/week

Thus, a long-lasting favorable effect with dulaglutide treatment alone on diabetes mellitus control and insulin secretion was evident in this case. Because aging is an important factor associated with impaired β-cell function and increased insulin resistance [11], the mild increase in insulin secretion in this patient may play a role against the worsening of insulin resistance.

Discussion

We report that dulaglutide, a GLP-1RA, provided excellent control of blood glucose concentration for 5 years in a 66-year-old Japanese man with type 2 diabetes mellitus, with well maintained insulin secretion. Although the long-term favorable effect of GLP- 1RA treatment has been reported, the significant improvement was not maintained for more than 12 months [5]. Actually, its effectiveness reduced year on year over a 72-month observation period [5]. By contrast, as shown in the present case study, dulaglutide: GLP-1RA therapy alone provided excellent blood glucose control for 5 years without losing its effectiveness. In a previous study, all patients received combinations of other anti-diabetic drugs. Most importantly, 45.9% of the patients received SUs [5], suggesting that long-term SU drug combination therapy may reduce the long-term effectiveness of GLP-1RA.

Control of diabetes mellitus is influenced by many factors, including body weight, age, sex, duration, exercise, race [11,12], and combinations of other anti-diabetic drugs.

Because the patient rejected being prescribed other drugs, he had been taking only dulaglutide, which was not combined with other drugs. Although the contribution of these factors remains to be clarified, this case demonstrated the effectiveness of long- term dulaglutide treatment alone, not only for the control of diabetes mellitus, but also for maintaining good insulin secretion in a patient with type 2 diabetes mellitus. Thus, dulaglutide treatment alone is a good choice for the treatment of type 2 diabetes mellitus. This case report not only promotes the use of GLP-1RA alone therapy for the treatment of diabetes mellitus, but it also enhances clinical research to assess the significance of GLP-1RA application and to find combined appropriate anti-diabetes drug(s) not to reduce the long-term effectiveness of GLP-1RA for the treatment of type 2 diabetes mellitus.

Author Statements

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Fukuoka Heartnet Hospital.

Informed Consent Statement

Written informed consent was obtained from the patient to publish this paper.

Data Availability Statement

All of the data described in this case report are available freely.

Conflict of Interest

SN, KM, TS, ES, and AM have no conflicts of interest. HT received grants from Astellas Pharma Inc. and AbbVie Inc. KA received grants from Sumitomo Pharma, Mitsubishi Tanabe Pharma, and Novo Nordisk Pharma.

Acknowledgments

The financial assistance from Japan IDDM network to cover the cost of the genetic analysis of the TYK2 gene is greatly appreciated. The authors thank Ai Miyashita, Miyuki Fujino, Nami Kitahara, Miho Nakamura, Yuki Nakashima, Mari Oda, Narumi Furuie, and Keiko Watanabe as RNs for their significant clinical care contributions. We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Contribution of Each Author

SN took clinical care of the patient, collected the clinical data, and wrote the report. KM assessed the laboratory data, performed genetic analysis of the TYK2 gene, drew the figure, and co-wrote the report.

TS contributed to patient care and clinical data collection. ES took clinical care of the patient.

AM took clinical care of the patient.

HT contributed to the analysis of the clinical data.

KA contributed to the analysis of the clinical data and co-wrote the manuscript.

References

  1. IDF Diabetes Atlas. 10th ed. 20: 1-142.
  2. Gilbert MP, Pratley RE. GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: review of head-to-head clinical trials. Front Endocrinol. 2020; 11: 178.
  3. Bain EK, Bain SC. Recent developments in GLP-1RA therapy: A review of the latest evidence of efficacy and safety and differences within the class. Diabetes Obes Metab. 2021; 23: 30-39.
  4. Mayendraraj A, Osenkilde MM, Sasbjerg L. GLP-1 and GIP receptor signaling in beta cells- A review of receptor interactions and co-stimulation. Peptides. 2022: 151: 70749.
  5. Kwan AYK, Gerstein HC, Basile J, Xavier D, Maldonado JM, et al. HbA1c reduction in dulaglutide-treated patients irrespective of duration of diabetes, microvascular disease, and BMI: A post hoc analysis from the REWIND trial. Diabetes Care. 2022: 45: 547-554.
  6. Lundgren VM, Isomaa B, Lyssenko V, Laurila E, Korhonen P, et al. GAD antibody positivity predicts type 2 diabetes in an adult population. Diabetes. 2010: 59: 416-422.
  7. Nagafuchi S, Kamada Y, Hirakawa K, Tsutsu N, Minami M, et al. TYK2 promoter variant and diabetes mellitus in the Japanese. EBioMedicine. 2015; 2: 744-749.
  8. Mori H, Takahashi H, Mine K, Higashimoto K, Inoue K, et al. TYK2 promoter variant is associated with impaired insulin secretion and lower insulin resistance in Japanese type 2 diabetes patients. Genes. 2021; 12: 400.
  9. Cersosimo EM, Solis-Herrera C, Trautmann ME, Malloy J. Triplitte CL. Assessment of pancreatic ☐-cell function: review of methods and clinical applications. Curr Diabetes Rev. 2014; 10: 2-42.
  10. Zhang W, Tang Y, Huang J, Yang Y, Yang Q, et al. Efficacy of insulin supplementation in improving insulin control, HbA1c and HOMA-IR inpatients with type 2 diabetes: a systemic review and meta-analysis of randomized controlled trials. J Clin Biochem Nutr. 2020; 66: 176-183.
  11. Chang AM, Halter JB. Aging and insulin secretion. Am J Physiol Endocrinol Metab. 2003; 284: E7-12.
  12. Kolb H, Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med. 2017; 15: 131.

Citation: Nagafuchi S, Mine K, Shiratsuchi T, Shibayama E, Mitsueda A, et al. Excellent Blood Glucose Levels for 5 Years with Well Maintained Insulin Secretion by the Treatment Comprising a Once-Weekly Injection of Dulaglutide: GPL- 1RA Alone in a Patient with Type 2 Diabetes Mellitus. Austin J Endocrinol Diabetes. 2023; 10(1): 1099.