Authors’ reply

We appreciate comments of Dr Patoulias et al1 about the results of our study on pentraxin 3 (PTX3) in patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). The authors of the comment suggest that PTX3 could be a novel treatment target for glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with T2D and NAFLD. Nonalcoholic fatty liver disease is believed to independently increase risk of macro- as well as microvascular complications. NAFLD can progress to nonalcoholic steatohepatitis and other serious hepatic diseases; however, the majority of deaths among patients with NAFLD is attributable to cardiovascular diseases.2 In our study, we demonstrated a strong correlation between PTX3 and lipids as well as apolipoprotein cardiovascular markers such as total and low-density lipoprotein cholesterol, triglycerides, apolipoprotein C3, and apolipoprotein B100. Pentraxin 3, an endothelial stress and inflammation marker, was earlier described as a predictor of cardiovascular events.

Our study group consisted of consecutive patients with T2D who were referred to the Department of Metabolic Disease, University Hospital, Kraków, Poland due to poor glycemic control. This group was characterized by high prevalence of not only central obesity, arterial hypertension, and dyslipidemia but also hepatic steatosis. In general, they represented typical patients with T2D in real clinical practice.

In recent years, several cardiovascular outcome trials (CVOTs) in patients with T2D that examined novel hypoglycemic therapies produced positive results. The use of these new drugs, as compared with standard diabetes care aiming at similar glycemic control, resulted in a decrease of cardiovascular risk, including a reduction of 3-point major adverse cardiovascular events and cardiovascular deaths.3 This was rather unexpected to the majority of diabetes experts as a generation of CVOTs in patients with T2D performed in the previous decade, such as ADVANCE (Action in Diabetes and Vascular Disease), VA-HIT (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial), and ACCORD (Action to Control Cardiovascular Risk in Diabetes), failed to prove possible cardiovascular benefits for intensive hypoglycemic therapy in those patients. Two types of hypoglycemic drugs contributed to the recent landmark findings, namely, sodium-glucose co­transporter­ 2 (SGLT-2) inhibitors and GLP-1RAs. The publication of the positive results of CVOTs3 involving medications from both groups sparked a discussion on possible mechanisms other than just hypoglycemic action of the described beneficial cardiovascular effects. Evidence points to improvement in classical cardiovascular risk factors, such as obesity, dyslipidemia, or arterial hypertension. However, there is also confidence that they do not fully explain the advantageous action of either SGLT-2 inhibitors or GLP-1RAs. Therefore, there is a belief that some other, nonclassical cardiovascular risk factors could have been involved.3

As correctly pointed out by Dr Patoulias et al,1 an effect of GLP-1RAs on PTX3 was observed in humans and in vitro studies. Thus, PTX3 and related metabolic pathways could be perceived as candidates for such nontraditional, rarely considered action of injectable incretins. Moreover, PTX3, an inflammation marker correlating with the decrease of cardiovascular risk factors in patients with NAFLD and T2D, may constitute an interesting treatment target. Interestingly, in the LEAN (Liraglutide Efficacy and Ac­tion in Nonalcoholic Steatohepatitis) study4 the GLP-1RA treatment also demonstrated a positive effect on NAFLD, which was documented by liver biopsy. The Lira-NAFLD (Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes) study5 confirmed the efficacy of liraglutide in reducing liver fat content also in patients with NAFLD and T2D. In this study, 6 months of treatment with liraglutide at a dose of 1.2 mg/d significantly reduced liver fat content in patients with inadequately controlled T2D, which was accompanied by body weight reduction.

Of note, SGLT-2 inhibitors also seem to possess some immunomodulatory and antioxidant properties. However, their effect on PTX3 has never been examined, while data on NAFLD in humans are limited. In the EFFECT-II study,6 the authors compared the effect of monotherapy with dapagliflozin, omega-3 carboxylic acids, combined treatment, or placebo, on liver fat content assessed with magnetic resonance imaging in patients with T2D and NAFLD. The results indicated that only combined treatment with an SGLT-2 inhibitor, dapagliflozin, and omega-3 carboxylic acids significantly reduced liver fat content in comparison with placebo. Monotherapy with dapagliflozin in these patients reduced all measured biomarkers of hepatocyte injury and fibroblast growth factor 2, suggesting a disease-modifying effect in NAFLD.6

Summarizing, we fully support the hypothesis presented by Dr Patoulis et al1 that GLP-1RAs are a class of drugs that not only prevent cardiovascular events in patients with T2D but also promise to act on other related comorbidities, such as NAFLD, that are common in those patients. This could constitute an important element of individualized therapy in patients with T2D, NAFLD, or cardiovascular disease with the aim to improve their prognosis. In this context, PTX3 could be a valuable biomarker and possible treatment target for GLP-1RAs.