Benefits of icodec insulin in a patient with IgG4-related disease: the importance of therapeutic adherence to achieve the target

M. Faletto ¹, V. Faletto ², M.E. Malighetti ³

¹ Scuola di Specializzazione in Medicina Interna, IRCCS Istituto Clinico Humanitas, Rozzano, MI
² Medicina e Chirurgia Università degli Studi del Piemonte Orientale, sede di Alessandria
³ Ambulatorio di Diabetologia, Casa di Cura Ambrosiana, Cesano Boscone, Mi

Abstract

IgG4-related disease (IgG4-RD) is a rare, chronic, immunomediated fibro-inflammatory condition characterized by the development of pseudotumoral masses in various districts, composed of lymphoplasmacytic infiltrates, “storiform” fibrosis, and obliterative phlebitis, usually accompanied by increased serum IgG4 levels.

Aim of the study was to evaluate treatment efficacy and adherence in patient with IgG4-RD treated with Icodec insulin on chronic oral steroid therapy. In November 2024, multi-injective insulin therapy was initiated. In January 2025, because of poor therapeutic adherence and inadequate glycemic control, Lispro and Degludec insulins were discontinued and Icodec,  an ultra–long-acting basal insulin analogue that has proven effective in reducing HbA1c without increasing hypoglycemic events, was introduced to improve adherence and therapeutic efficacy. Excellent 24-hour glycemic coverage was observed, with a marked improvement in TIR and a low glucose variability coefficient, without an increase in the number of hypoglycemic episodes.
The advantage of reducing treatment burden, combined with improved glycemic control and a similar risk of hypoglycemia, significantly improved the patient’s compliance and quality of life.

Keywords: IgG4-related disease, Icodec, iCGM

Introduction

IgG4-Related Disease (IgG4-RD) is a rare chronic, fibro-inflammatory, immune-mediated condition characterized by the development of pseudotumoral masses in various anatomical regions. IgG4-RD (1) has a wide range of possible manifestations depending on the organs involved that are characterized by similar histopathological findings and responses to treatment. The disease can affect people of any age and gender, though it most commonly affects middle-aged and elderly males. For pancreatic involvement, the term IgG4-related pancreatitis type 1 (AIP) is recommended. The chronic nature of the disease and its favorable response to immunosuppressive therapy suggest an autoimmune pathogenesis (2).

Diagnosis requires a combination of clinical and laboratory findings, often confirmed by biopsy (3). The pancreas is the most frequently affected organ. Radiologically, it appears thickened with diffuse peripancreatic edema. Clinically, patients often present with jaundice, itching, abdominal pain, and ultimately both exocrine and endocrine gland insufficiency. Histological diagnosis is essential, with three key features: storiform fibrosis, a polyclonal lymphoplasmacytic infiltrate rich in IgG4+ cells and obliterative phlebitis. Blood tests show elevated serum IgG4 levels in about 70% of patients.

Treatment aims to reduce inflammation, induce remission, and preserve organ function. First-line therapy involves corticosteroids. Among immunosuppressive therapies, rituximab is the most effective in inducing and maintaining remission (4). Surgery is recommended for patients with obstructive, infiltrative, or compressive symptoms.

Basal insulin therapy still represents a therapeutic option for about 30% of the Italian diabetic population. To improve treatment adherence, in Italy it can be prescribed Icodec, a once-weekly insulin (Awiqli – Novo Nordisk) supported by evidence of efficacy (reduction of glycated hemoglobin and low hypoglycemia risk) and by a reduction of treatment burden in a frail patient (5, 6, 7).

Clinical case

The patient is male, born in 1949.
Medical history: appendicectomy, cholecystectomy, chronic atrial fibrillation with heart failure and preserved ejection fraction, arterial hypertension, benign prostatic hyperplasia, surgical removal of an angiosarcoma of the nasal pyramid .

In March 2024 he experienced a sudden onset of jaundice and was admitted to the emergency department. A contrast-enhanced total body CT scan showed heterogeneity in the head of the pancreas, dilatation of the Wirsung duct, portal vein branch thrombosis, intrahepatic bile duct dilatation, multiple mesenteric lymphadenopathies, minimal pleural effusion, and a nodular lesion in the apical segment of the right lung. Blood tests revealed elevated cholestasis markers (gamma-GT and bilirubin), while transaminases and tumor markers (CEA and CA 19-9) were within normal limits. Therefore, an endoscopic metallic stent was placed in the common bile duct.

In April 2024 a total body PET-CT scan confirmed the pancreatic head lesion with involvement of the portal vein and adjacent venous branches and lymph nodes. It also revealed a large right-sided pleural effusion that obscured the previously described lung nodule. Thus, an endoscopic ultrasound was performed for a fine-needle biopsy of the heterogeneous cephalopancreatic area. A suspicious peripancreatic lymph node (10×12 mm) was also biopsied, and part of the perihepatic ascitic fluid was aspirated (cytology negative for malignant cells).

He was hospitalized at another facility where a repeat total body CT and endoscopic ultrasound were performed with new biopsies. Histological exam showed squamous cells, columnar elements, granulocytes, lymphocytes mixed with some plasma cells with a significant number of IgG4+ cells, macrophages, epithelioid histiocytes, and occasional fibrous stroma (cytology again negative for malignancy). Blood tests showed elevated serum IgG4 levels.

In May 2024 he was admitted to a rheumatology department, where an MRI confirmed pathological tissue in the celiac/peripancreatic region and some lymphadenopathies. A diagnosis of IgG4-related disease with retroperitoneal involvement was made, and steroid therapy was initiated with IV methylprednisolone at 1 mg/kg.

In June 2024 he received his first infusion of rituximab while continuing oral steroid therapy with maintenance prednisone at 5 mg daily.

An abdominal CT scan in July 2024 showed reduced hypodensity near the hepatic artery in the peripancreatic area and persistent poor differentiation of peripancreatic fat planes. The previously noted heterogeneous tissue in the isthmic region near the thrombosed portal segment was no longer visible. A decrease in size and number of perilesional lymph nodes, reduced thickening of the mesenteric fold and reactive lymph nodes, multiple ill-defined hepatic intraparenchymal areas, likely related to recent inflammatory activity from cholangitis, complete recanalization of the previously thrombosed porto-mesenteric axis and chronic thrombosis of the proximal splenic vein were also noted.

In September 2024 a clinical diagnosis of large fiber sensory polyneuropathy was made (EMG pending), causing postural instability. Thus, the dosage of pregabalin was increased.

The chest and abdominal CT scan in December 2024 showed: decreased lymph nodes size in the thorax, the retroperitoneal peripancreatic mass remaining stable, persistent lymphadenopathy in front of the pancreas and along the lesser curvature of the stomach, resolution of mesenteric edema and normalization of mesenteric lymph nodes.

The patient was referred to our clinic in November 2024 due to elevated glycated hemoglobin levels found in blood tests. The ongoing therapy at the time included: prednisone 5 mg, pantoprazole 40 mg, bisoprolol 2.5 mg twice daily, dutasteride 0.5 mg, tamsulosin 0.4 mg, canrenone 50 mg, empagliflozin 10 mg, calcium carbonate, cholecalciferol 600 mg/400 IU, pregabalin 75 mg twice daily, alendronate 70 mg, ursodeoxycholic acid 450 mg, dabigatran 150 mg twice daily, pancrelipase 35,000 IU (5 tablets per day).

He reported fatigue and weight loss and brought in vision blood tests from early October showing (Table 1).

Legend: BMI=body mass index, HbA1c=glycate haemoglobin (v.n. <53 mmol/mol), crea=creatinine (v.n. 0,7-1,3 mg/dl), AST=aspartato aminotransferasi (v.n. 8-48 U/L), ALT=alanina aminotransferasi (v.n. 7-55 U/L), lip=lipasi (v.n. 140-200 U/l), amil=amilasi (v.n. 17-115 U/l), c pep=c peptide (v.n. 0,5-2 ng/ml), TIR=time in range (glicemia 70-180 mg/dl, ideale superiore a 70%), TBR=time below range (glicemia<70 mg/dl, ideale inferiore a 5%), TAR=time above range (glicemia >180 mg/dl, ideale inferiore a 30%), CV glucose variability (v.n. < 36%)

Insulin therapy was initiated using a multi-injection regimen. The patient was invited to use the Dosecheck App to properly titrate the basal insulin. A continuous glucose monitoring (iCGM) sensor was also used to monitor glucose levels.

On January 2025, after the second infusion of rituximab, the patient presented new blood tests (Table 1). Data from the sensor showed Time in Range (TIR) 90%, Time Above Range (TAR) 7%, and Time Below Range (TBR) 3%.  The patient reported poor adherence to the diet and often skipped the mealtime insulin, especially at lunch. He asked for alternative therapies, but several drug classes were excluded: incretins due to AIP (Autoimmune Pancreatitis), pioglitazone due to concurrent heart failure, sulfonylureas as they are not recommended by guidelines and metformin due to repeated episodes of diarrhea, particularly when took rituximab.

Therefore, to improve adherence and therapeutic persistence, we advised discontinuing prandial insulin and switching to Icodec insulin, an ultra-long-acting basal insulin analog (5, 6, 7). An initial dose of 270UI was prescribed, to be reduced to 180UI per week. On Aprile 9, 2025 the patient presented with recent blood tests (Table 1). The profile recorded by the sensor is shown in Figure 1.

On Aprile 9, 2025 the patient presented with recent blood tests (Table 1). The profile recorded by the sensor confirmed a TIR of 98% with TBR 2%, estimated HbA1c 43 mmol/mol, CV 21% (Figure 1).

Figura 1. Profilo registrato tramite iCGM tra il 27 marzo e il 9 aprile 2025

Discussion

The patient described has a rare condition, IgG4-related disease (IgG4-RD), which has led to impaired exocrine function of the pancreas without affecting endocrine function, as demonstrated by the C-peptide levels.

The pancreatic disease and steroid therapy initially led to the choice of a multi-injection insulin regimen. Given the patient’s poor adherence to both diet and therapy and considering the inability to prescribe other drug classes as previously explained, a treatment option ischosen that would be more manageable, with proven safety and efficacy, and a low risk of hypoglycemia.

As noted in the literature (6), in patients with type 2 diabetes treated with basal insulin, once-weekly Icodec  demonstrates non-inferiority, and statistical superiority, in reducing HbA1c compared to once-daily Degludec after 26 weeks, although associated with a modest weight gain. Overall hypoglycemia rates arelow, with rates of level 2 or 3 hypoglycemic events being numerically but not statistically significantly higher with Icodec than with Degludec.

In this clinical case, Icodec provides excellent 24-hour coverage, achieving an optimal glucose profile throughout the day, despite the discontinuation of mealtime insulins and continued poor dietary adherence (Figure 1).

The patient himself, a retired physician, isinformed of the rationale behind the therapeutic decision and expresse a desire to continue with the current treatment, considering the once-weekly administration an optimal solution for both his lifestyle and clinical condition.

Conclusion

The advantage of reduced treatment burden, combined with better glycemic control and a lower risk of hypoglycemia thanks to the use of once-weekly Icodec insulin, has significantly improved the patient’s compliance and quality of life, especially considering the multiple and significant comorbidities already being treated.

Bibliografia

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