The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis

AimTo evaluate the effect of diabetes mellitus type 2 (T2DM) on the outcomes after treatment of hepatocellular carcinoma (HCC).MethodsPubMed and Cochrane Central Register of Controlled Trials Databases were systematically searched. Three HCC clinical outcomes were explored: death, progressive disease after locoregional therapies, and recurrence. Sub-analysis was performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between T2DM and non-T2DM groups.ResultsA total of 27 studies were analyzed. Overall, 85.2% of articles were from Asia. T2MD was associated with an increased risk of death (OR 3.60; 95%CI 2.18-5.95; P < 0.001), irrespective of the treatment approach: curative (OR 1.30 95%CI 1.09-1.54; P = 0.003) or non-curative (OR 1.05; 95%CI 1.00-1.10; P = 0.045), increased HCC recurrence (OR 1.30; 95%CI 1.03-1.63; P = 0.03), and increased disease progressiveness (OR 1.24; 95%CI 1.09-1.41; P = 0.001).ConclusionsCurrent data provide strong evidence that T2DM unfavorably affects HCC progression and recurrence, and patients'' survival after treatment, irrespective of the approach used.

The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is increasing (1,2) as the result of the globally increased prevalence of NALFD, which is estimated to be about 25% (3). NAFLD patients have a two- to three-fold increase in the risk of developing diabetes mellitus type 2 (T2DM), and the risk is even higher in those with more severe hepatic disease and fibrosis (4-6). On the other hand, patients with T2DM have a higher prevalence of non-alcoholic steatohepatitis (NASH), liver fibrosis, and end-stage liver disease (7).Several studies have documented the relation between T2DM and the incidence of different cancer types, while the data on the relationship between T2DM and increased risk of incident HCC seem especially robust and clinically reliable (8-10). Observational studies suggest higher mortality of patients developing HCC in the presence of T2DM (11,12). On the other hand, data from meta-analyses suggest that both the risk and prognosis of patients with HCC and diabetes might be influenced by the type of anti-diabetic treatment, where metformin, unlike sulphonylurea, potentially protects against cancer and leads to better prognosis in case of cancer development (13,14).The underlying mechanisms linking T2DM and HCC are still under scientific scrutiny. However, the interconnections between metabolic derangements characteristic for T2DM, obesity, and NAFLD suggest that insulin resistance on the hepatic and systemic level and the release of pro-inflammatory cytokines, vasoactive factors, and pro-oxidant molecules are potentially implicated in the development and progression of HCC.With the intent to gain a better insight into this issue, we performed a meta-analysis to evaluate the effect of T2DM on poor outcomes after HCC treatment. To explore several different clinical settings, three outcomes of interest were investigated: death, progressive disease after locoregional therapies, and recurrence. Moreover, sub-analyses were performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies.