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Long-Term, Poorly Controlled Diabetes May Impair Efficacy of Immune Checkpoint Inhibitors

Findings from a large, multicentre, retrospective cohort of patients with advanced cancer
16 Sep 2021
Immunotherapy;  Cancer Treatment in Patients with Comorbidities

How diabetes mellitus affects the efficacy of immune checkpoint inhibitors (ICIs) is yet to be defined. It prompted the investigators from 21 Italian and 1 UK institutions to evaluate the impact of diabetes mellitus in a retrospective cohort of patients with advanced cancer treated with a single-agent ICI. Dr. Alessio Cortellini from the Department of Surgery and Cancer, Imperial College London in London, UK and the Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila in L’Aquila, Italy and colleagues reported that long-term or poorly controlled diabetes may impair ICIs efficacy in a poster during the ESMO Congress 2021 (16-21 September).

The authors explained in the study background that it is known that chronic hyperglycaemia induces immune dysfunctions. Furthermore, multiple studies have identified resistance or adherence to insulin therapy as barriers to achieving an optimal glycaemic control in patients with diabetes mellitus after front line metformin failure.

In this study, the researchers evaluated the impact of diabetes mellitus in patients with advanced cancer treated with ICI. They used diabetes medication burden at initiation of treatment with ICI as a proxy of long-term or poorly controlled diabetes mellitus. Patients with a high diabetes medication burden were on high dose metformin, more than 1000 mg, either alone or in combination with insulin therapy and/or other oral antidiabetics. Patients with low diabetes medication burden were on oral antidiabetics or insulin with or without low dose metformin.

In a subgroup of 133 patients the inter-relationships between the median baseline glycaemia computed upon up to 3 random blood glucose tests within 3 months of ICI initiation and the neutrophil-to-lymphocyte ratio were assessed.

The study team included in the analysis 1395 patients who were treated treated with CTLA-4 (2.5%) and PD-(L)1 (97.5%) inhibitors from June 2014 to November 2020. Median age was 68 years with male/female ratio 888/507. Primary tumours were non-small cell lung cancer in 54.7% patients, melanoma in 24.7% patients, renal cell carcinoma in 15.0% and other types in 5.6% of patients.

In total, 148 patients (10.6%) were on low diabetes medication burden and 78 patients (5.6%) were on high diabetes medication burden. Diabetes medication burden was proportionally associated to both an increasing median baseline glycaemia (5.6, 7.5 and 9.5 mmol/L) and median neutrophil-to-lymphocyte (3.8, 4.1 and 5.6).

After adjusting for gender, age, body mass index, primary tumour, treatment line, burden of disease, performance status and corticosteroids, patients on high diabetes medication burden had shorter progression-free survival (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.09-1.78; p = 0.0075) and overall survival (HR 1.44, 95% CI 1.09-1.90; p = 0.0087) as compared to non-diabetes.

Median baseline glycaemia significantly predicted for the neutrophil-to-lymphocyte (F [1,131] 4.09, p = 0.04), R2 of 0.030, and was associated to a high neutrophil-to-lymphocyte even after adjusting for corticosteroids (odds ratio 1.68, 95% CI 1.23 – 2.29; p = 0.0011).


Kaplan-Meier univariable survival estimates according to diabetes medication burden for A) overall survival, and B) progression-free survival. C) Linear regression plot for the association between the median baseline glycaemia and the neutrophil-to-lymphocyte ratio.

© Alessio Cortellini.

The authors stated that strategies should be pursued to improve glycaemic control in patients who need to start the treatment with ICI.

This was an academic analysis with no receipt of external funding. 


966P – Cortellini A, Mallardo D, Cleary S, et al. Diabetes therapy burden as proxy of impairment of immune checkpoint inhibitors efficacy. ESMO Congress 2021 (16-21 September).

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