Letter: Hepatoprotective Effects of Medications Used in Diabetes Mellitus—Optimal Glycaemic Control Is Just the Tip of the Iceberg

Abstract

We read with great interest and congratulate Mao et al. on their study entitled ‘Glycaemic control is a modifiable risk factor for hepatocellular carcinoma and liver-related mortality in patients with diabetes’ [1]. The results of this well-designed study revealed glycaemic control as an independent risk factor for hepatocellular carcinoma (HCC) and liver-related mortality.

HCC is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide [2]. Despite medical, interventional and surgical treatment options, HCC has a case-fatality rate of 85% [1, 3]. This unfavourable disease outcome mandates the identification of risk factors and underlying conditions related to HCC occurrence and prognosis, such as poor glycaemic control in patients with diabetes as defined by Mao and colleagues. However, we wish to emphasise the differences in medication use in two patient groups—with optimal and suboptimal glycaemic control—enrolled in the study which would be a confounding variable.

Patients enrolled in the study by Mao et al. were split into two groups in terms of glycaemic control: optimal glycaemic control group and suboptimal glycaemic control group. Rates of statin, aspirin, insulin, pioglitazone, dipeptidyl peptidase-4 inhibitor (DPP-4i), glucagon-like peptide-1 analogue (GLP-1a) and sodium-glucose transport protein 2 inhibitor (SGLT-2i) uses were all statistically significantly different between the two groups. Apart from their effect on glycaemic control, all the aforementioned medications affect the risk of development and/or prognosis of HCC, hence are potential factors that would alter data analysis and study results.

Use of aspirin has been shown to lower the risk of HCC in a meta-analysis including 18 studies [4]. Similarly, a meta-analysis involving 59,703 HCC patients has revealed the beneficial effect of statins on HCC development [5]. Increased insulin levels are associated with both increased risk of and poor outcome in HCC [6]. Pioglitazone has been associated with lower risk of HCC, and this protective effect was correlated with cumulative drug dosage and duration of use [7]. A study by Hsu et al. investigated the effect of DPP-4i on the risk of HCC in chronic hepatitis C patients with diabetes mellitus and found a lower risk of HCC in the study population using DPP-4i [8]. A recently published study by Wang and colleagues revealed that GLP-1a is associated with a lower risk of HCC incidence and hepatic decompensation [9]. SGLT-2i are also shown to be related to reduced risk of HCC [10].

In conclusion, this intriguing study highlights the importance of optimal glycaemic control in the prevention of liver-related mortality. Future studies taking into consideration both antiglycaemic and proposed hepatoprotective effects of various medications used in diabetes mellitus will shed more light on this tangled relationship between disease state, treatment modality used and liver-related morbidity and mortality.

Osman Cagin Buldukoglu: conceptualization, methodology, investigation, formal analysis, writing – original draft, writing – review and editing, resources, data curation, supervision. Serkan Ocal: conceptualization, methodology, writing – review and editing, formal analysis, investigation, supervision. Ayhan Hilmi Cekin: conceptualization, investigation, writing – review and editing, formal analysis, supervision, methodology.

The authors declare no conflicts of interest.

This article is linked to Mao et al paper. To view this article, visit https://doi.org/10.1111/apt.18254.