Related Experiment Video
Updated: Jul 31, 2025
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer
Alessio Cortellini1,2, Antonio D'Alessio2,3, Siobhan Cleary2
1Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy.
Purpose:
No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors.
Experimental Design:
In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes.
Results:
A total of 1,395 patients were included. Primary tumors included non-small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07-1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03-1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16-2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04-1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM.
Conclusions:
In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population.
Insights
Patients with type 2 diabetes mellitus (T2DM) on glucose-lowering medications (GLM) experienced worse outcomes with immune checkpoint inhibitors (ICI). Metformin use was specifically associated with increased mortality and disease progression in solid tumor patients receiving immunotherapy.
Area of Science:
- Oncology
- Immunotherapy
- Endocrinology
Background:
- Type 2 diabetes mellitus (T2DM) is a common comorbidity in cancer patients.
- The impact of T2DM and its treatments on the efficacy of immune checkpoint inhibitors (ICI) remains unclear.
- Understanding these interactions is crucial for optimizing cancer immunotherapy outcomes.
Purpose of the Study:
- To investigate whether T2DM, particularly glucose-lowering medication (GLM) use, affects clinical outcomes in patients with solid tumors treated with ICI.
- To explore the association between specific GLMs, such as metformin, and patient survival.
- To examine potential immunomodulatory effects of T2DM in the tumor microenvironment.
Main Methods:
- Retrospective analysis of a large cohort (n=1,395) of ICI-treated patients across 21 institutions (June 2014-June 2020).
- Multivariable analysis to assess the association between GLM use and overall survival (OS) and progression-free survival (PFS).
- Matched-pair analyses comparing metformin users, other GLM users, and controls; targeted transcriptomics of tumor samples from a subset of patients.
Main Results:
- Patients on GLM (n=226) showed a significantly increased risk of death (HR, 1.29) and disease progression/death (HR, 1.21) compared to those without T2DM.
- Metformin exposure was independently associated with a higher risk of death (HR, 1.53) and disease progression/death (HR, 1.34).
- Higher pretreatment glycemia correlated with increased neutrophil-to-lymphocyte ratio; transcriptomic analysis indicated differential immune pathway regulation in T2DM patients.
Conclusions:
- GLM use in patients with T2DM is associated with poorer outcomes from immunotherapy, irrespective of baseline characteristics.
- Metformin, specifically, appears to be linked to worse survival and progression in this population.
- Further prospective studies are needed to elucidate the precise role of metformin and T2DM in modulating immunotherapy response.
Related Concept Videos
01:27Tumor Immunotherapy
01:22Diabetes Mellitus: Type 2 and Gestational
01:19Psychoneuroimmunology: Diabetes and Cancer
01:22Diabetes Mellitus: Overview and Type I Subtype
Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. As a result, the body is unable to produce sufficient insulin, and individuals with...
01:36Carbohydrate Metabolism
Starch accounts for approximately 60% of the carbohydrates consumed by humans. Since amylase enzymes cannot function in the stomach's acidic environment, starch can only be digested in the mouth and small intestine. Simple sugars are found naturally in milk and fruits in...
01:15Diabetes: Management and Pharmacotherapy
Insulin remains the cornerstone of treatment for most patients with type 1 and many...