Is there any evidence for using GLP-1s or SGLT-2s in patients with type 2 diabetes who have undergone partial pancreatectomy with preserved islet cells?

Is there any evidence for using GLP-1s or SGLT-2s in patients with type 2 diabetes who have undergone partial pancreatectomy with preserved islet cells?

Comment by InpharmD Researcher

A paucity of clinical data has demonstrated glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes after partial pancreatectomy. One small (N= 10 patients), severely limited study of combination therapy with insulin glargine and the short-acting GLP-1 receptor agonist, lixisenatide, in patients with diabetes after partial pancreatectomy to achieve glycemic control (See Table 1). Of note, while lixisenatide is no longer available in the U.S. market as of January 2023, Soliqua (insulin glargine & lixisenatide injection) is an alternative product containing lixisenatide. A comprehensive literature search found no clinical evidence utilizing SGLT-2 inhibitors after pancreatectomy. Available data mainly emphasized the importance of preoperative cessation of these agents to prevent euglycemic diabetic ketoacidosis.

Background

Euglycemic diabetic ketoacidosis (euDKA), a potential side effect associated with sodium-glucose cotransporter 2 (SGLT-2) inhibitors, is often recognized in patients who undergo surgery, and there are multiple published case reports in patients with type 2 diabetes mellitus (T2DM) who underwent pancreatectomy and were diagnosed with euDKA postoperatively. One study reported two cases, with canagliflozin and dapagliflozin use, undergoing pancreatectomy with euDKA despite withholding SGLT-2 inhibitor 24 hours before surgery. Another case report presented a T2DM patient who underwent distal pancreatectomy and developed euDKA even though she didn’t receive her empagliflozin for five days before the surgery. While these studies emphasized the importance of preoperative cessation of SGLT-2 inhibitors to avoid this complication, none of these reports discussed the optimal timing of when the SGLT-2 inhibitor agents were re-initiated or continued postoperatively and whether these medications were tolerated in this specific population. [1], [2]

Relevant Prescribing Information

Canagliflozin tablet:
Ketoacidosis: In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. [1]

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is there any evidence for using GLP-1s or SGLT-2s in patients with type 2 diabetes who have undergone partial pancreatectomy with preserved islet cells?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Table 1 for your response.

Combination therapy of glucagon‐like peptide‐1 receptor agonists and insulin for patients who developed diabetes after partial pancreatectomy
Design	Prospective, single-center, single-arm, non-controlled trial N= 10
Objective	To evaluate the efficacy and safety of combination therapy with long‐acting insulin glargine and the glucagon‐like peptide‐1 (GLP-1) receptor agonist lixisenatide in patients who developed diabetes after pancreatectomy
Study Groups	All subjects (n= 10)
Inclusion Criteria	Japanese patients who underwent pancreatectomy and developed diabetes
Exclusion Criteria	Type 1 diabetes patients who had an absolute indication of insulin therapy and those who had undergone total pancreatectomy
Methods	Participants were treated with a combination therapy of glargine and lixisenatide. Glargine administration was started upon admission. The glargine dose was adjusted to achieve the target fasting plasma glucose (FPG) levels of 100-130 mg/dL, and lixisenatide was added when the target FPG levels were achieved and continued for 12 weeks. Glargine was administered at bedtime.
Duration	12 weeks
Outcome Measures	Primary: changes in glycated hemoglobin (HbA1c), FPG, 1‐h postprandial plasma glucose (PPG) and 2‐h PPG after breakfast, and C‐peptide immunoreactivity (CPR) levels from baseline to the end of the 12‐week combination therapy Secondary: frequency of hypoglycemia (serious and non‐serious), frequency of gastrointestinal disorders, and changes in body weight
Baseline Characteristics		All subjects (n= 10)
	Age, years	70.2 ± 6.6
	Female	20%
	Primary disease Pancreas cancer Duodenal tumor	80% 20%
	Areas of resection Pancreatic tail Pancreatic head	60% 40%
	Body mass index, kg/m²	20.53 ± 3.21
	Glargine dose unit	6.7 ± 3.6 (range: 3–14)
	Time from pancreatectomy to lixisenatide administration, days	470.3 ± 483.1
Results	Endpoint	All subjects (n= 10)	p-value
	Changes in HbA1c, % Baseline End of the 12‐week combination therapy Patients who achieved HbA1c levels of <7.0%	8.46 ± 1.64 6.81 ± 1.15 80%	< 0.001
	Changes in 1‐h PPG levels, mg/dL Baseline End of the 12‐week combination therapy	222.9 ± 56.2 125.1 ± 37.5	< 0.001
	Changes in 2‐h PPG levels, mg/dL Baseline End of the 12‐week combination therapy	247.5 ± 56.8 115.1 ± 29.0	< 0.001
	Changes in CPR levels, ng/mL Fasting CPR Post‐breakfast 1‐h CPR Post‐breakfast 2‐h CPR	0.44 ± 0.31 1.37 ± 0.69 1.89 ± 1.16	--
	Changes in body weight, kg Baseline End of the 12‐week combination therapy	54.0 ± 9.0 49.9 ± 9.1	0.013
Adverse Events	Neither hypoglycemia nor clinically relevant adverse events, including gastrointestinal disorders (nausea) uniquely caused by GLP‐1 receptor agonists, were observed during this study.
Study Author Conclusions	The present study shows that combination therapy with basal insulin and glucagon‐like peptide‐1 receptor agonists after partial pancreatectomy can be a useful therapeutic option for providing effective glycemic control with a reduced risk of hypoglycemia.
InpharmD Researcher Critique	The findings of this study are limited by its small sample size, single-arm, and single-center design. As only Japanese patients were enrolled in the study, the application of results is limited to this patient population. The focus of the study was on short-acting GLP-1 agonists and, therefore, the effect of administering long-acting GLP-1 agonists to patients with partial pancreatectomy remains unknown. Of note, as of January 2023, lixisenatide was no longer available in the U.S. market. However, Soliqua (insulin glargine & lixisenatide injection) is considered an alternate treatment option containing lixisenatide.

References:

Kitazawa T, Yokoyama K, Kubota K. Combination therapy of glucagon-like peptide-1 receptor agonists and insulin for patients who developed diabetes after partial pancreatectomy. J Diabetes Investig. 2016;7(3):381-385. doi:10.1111/jdi.12423