TY - JOUR

T1 - Treatment of type 2 diabetes by targeting interleukin-1

T2 - a meta-analysis of 2921 patients

AU - Kataria, Yachana

AU - Ellervik, Christina

AU - Mandrup-Poulsen, Thomas

PY - 2019

Y1 - 2019

N2 - With obesity and type 2 diabetes prevalence steadily increasing and no effective means in sight to support the population in obtaining and maintaining stable weight loss, there is an imminent need for pharmacological therapy to treat and prevent type 2 diabetes. Current anti-diabetic treatment is symptomatic, and very few drugs have both a strong preclinical rationale and clinical proof-of-principle as therapies targeting pathogenic processes in type 2 diabetes. The emerging appreciation of low-grade inflammation as a significant cause of insulin resistance and beta cell failure warrants exploring anti-inflammatory compounds as drug candidates. Since recent studies have demonstrated considerable phenotypic heterogeneity in the type 2 diabetic syndrome, the concept of one drug fits all is naïve, and biomarkers for the selection of type 2 diabetes subtypes for differentiated treatment based on genetic and pathogenic stratification are urgently needed. Biologics antagonizing the master pro-inflammatory cytokine interleukin-1 is one of the few principles specifically targeting low-grade inflammation in type 2 diabetes. Although early phase II studies were encouraging, subsequent underpowered studies and phase III studies designed primarily with cardiovascular endpoints have discredited the potential of anti-interleukin-1 approaches to treat the subgroup of patients that may benefit from this treatment. In this meta-analysis of 2921 individuals from eight phase I–IV studies, we demonstrate a significant overall HbA1c-lowering effect of interleukin-1 antagonism. Meta-regression analyses demonstrated a significant correlation between baseline C-reactive protein and C-peptide, and HbA1c outcome. The identification of further biomarkers for future clinical trials to define the potential of anti-interleukin-1 therapies in type 2 diabetes is urgently needed.

AB - With obesity and type 2 diabetes prevalence steadily increasing and no effective means in sight to support the population in obtaining and maintaining stable weight loss, there is an imminent need for pharmacological therapy to treat and prevent type 2 diabetes. Current anti-diabetic treatment is symptomatic, and very few drugs have both a strong preclinical rationale and clinical proof-of-principle as therapies targeting pathogenic processes in type 2 diabetes. The emerging appreciation of low-grade inflammation as a significant cause of insulin resistance and beta cell failure warrants exploring anti-inflammatory compounds as drug candidates. Since recent studies have demonstrated considerable phenotypic heterogeneity in the type 2 diabetic syndrome, the concept of one drug fits all is naïve, and biomarkers for the selection of type 2 diabetes subtypes for differentiated treatment based on genetic and pathogenic stratification are urgently needed. Biologics antagonizing the master pro-inflammatory cytokine interleukin-1 is one of the few principles specifically targeting low-grade inflammation in type 2 diabetes. Although early phase II studies were encouraging, subsequent underpowered studies and phase III studies designed primarily with cardiovascular endpoints have discredited the potential of anti-interleukin-1 approaches to treat the subgroup of patients that may benefit from this treatment. In this meta-analysis of 2921 individuals from eight phase I–IV studies, we demonstrate a significant overall HbA1c-lowering effect of interleukin-1 antagonism. Meta-regression analyses demonstrated a significant correlation between baseline C-reactive protein and C-peptide, and HbA1c outcome. The identification of further biomarkers for future clinical trials to define the potential of anti-interleukin-1 therapies in type 2 diabetes is urgently needed.

KW - Anti-cytokine biologics

KW - Immunometabolism

KW - Inflammation

KW - Innate immunity

KW - Meta-regression

U2 - 10.1007/s00281-019-00743-6

DO - 10.1007/s00281-019-00743-6

M3 - Review

C2 - 31025084

AN - SCOPUS:85065184117

VL - 41

SP - 413

EP - 425

JO - Seminars in Immunopathology

JF - Seminars in Immunopathology

SN - 1863-2297

IS - 4

ER -