The Importance of Glycemic Equipoise in NASH
Authors: Alina M. Allen, Brent A. Neuschwander‐Tetri
Journal: Hepatology (2021)

Potential conflict of interest: Dr. Neuschwander‐Tetri consults for and advises for Alimentiv, Allergan, Allysta, Alnylam, Amgen, Arrowhead, Axcella, Boehringer Ingelheim, Bristol‐Myers Squibb, Coherus, Cymabay, Enanta, Fortress, Genfit, Gilead, High Tide, HistoIndex, Innovo, Intercept, Ionis, LG Chem, Lipocine, Madrigal, Medimmune, Merck, Mirum, NGM, Novo Nordisk, Novus, pH‐Pharma, Sagimet, Target RWE, and 89Bio. He owns stock in HepGene. SEE ARTICLE ON PAGE XXXX Insulin resistance (IR) is a key pathogenic driver in NAFLD. Approximately one quarter of patients with NAFLD and 44% of those with NASH have type 2 diabetes mellitus (DM),(1) whereas an additional substantial proportion of those without DM have impaired fasting glucose. Guidance from major societies includes adequate glycemic control in those with DM, as part of the multidisciplinary management of NAFLD comorbidities, with the goal of reducing cardiovascular outcomes.(2) However, there is no established target of glycemic control that is shown to reduce NASH severity or liver‐related outcomes. In this issue, Alexopoulos et al.(3) aimed to examine the association between glycemic control and histological severity of NASH. In this retrospective analysis of 713 patients from the Duke NAFLD Clinical Database, they found that higher hemoglobin A1c (HbA1c) was associated with higher grades of steatosis, hepatocyte ballooning (HB), and fibrosis. Extrapolating from this cross‐sectional analysis, the researchers conclude that optimizing glycemic control might modify the risk of fibrosis progression in NASH. There are several important points worthy of elaboration. The primary outcome was an association between HbA1c and fibrosis stage. The exploration was done in two ways: ordinal logistic regression analysis, showing a statistically significant association (15% higher odds of increased fibrosis stage with each 1% increase in HbA1c; P value = 0.039); the second method was restricted cubic spline regression with three knots, with a spline that did not show a statistically significant association between the HbA1c and fibrosis stage. Because it is difficult to reconcile these two results, the conflicting statistical findings somewhat diminish the confidence in the strength of the association. Secondary outcomes included the association between HbA1c value and other histological features of NASH, such as steatosis, HB, and inflammation. There was a positive association between increasing HbA1c and each of these features. Interestingly, this was true for an HbA1c up to 7%, whereas no additionally increased risk was identified at HbA1c values above this cutoff. This might suggest a ceiling effect of glycemic control, such that once glycemic control is not optimal, the impact on NASH is not significant. This is somewhat counterintuitive, because a pathophysiological connection between glycemic control and NASH should be most pronounced at the extreme end of the severity spectrum if it is related to hyperglycemia. The researchers speculate that this lack of a continued linear relationship may be related to the burnt‐out NASH phenomenon. However, that concept is usually applied to the loss of typical histological features of NASH after fibrosis has progressed to cirrhosis rather than the relationship between metabolic abnormalities and histological features. Another explanation might be insufficient statistical power to estimate this effect at the extreme because of the small number of patients with poor glycemic control. A third possible explanation is that it is not hyperglycemia that impacts NASH severity, but that HbA1c and NASH have the same underlying determinant: IR. This latter argument is supported by previous studies,(4) which showed that hyperinsulinemia, but not hyperglycemia or HbA1c, were associated with histological severity of NASH. Our understanding of NASH has evolved from a focus on contributory events in the liver to the primary role of mechanistically upstream adipose‐tissue dysfunction that leads to IR in metabolic tissues throughout the body,(5,6) resulting in the manifestations of NASH, DM, hypertension, cardiovascular disease, and other manifestations (Fig. 1).FIG. 1: The hierarchy of metabolic abnormalities that lead to NASH and the other manifestations of metabolic disease. When the energy supply exceeds the capacity of adipose tissue to safely store it as triglyceride, adipocytes develop a stress response leading to inflammation, impaired insulin signaling, and inappropriate release of fatty acids into the circulation.( 5,6 ) Major factors that contribute to an excess energy supply include excessive calorie consumption and insufficient energy disposal through locomotion and thermogenesis to match intake. Storage capacity is highly variable among persons, such that the degree of obesity at which adipose tissue becomes dysfunctional varies widely. Complex relationships exist between the manifestations of metabolic disease, such that some may be causative (e.g., dyslipidemia and cardiovascular disease, IR, and NASH) and others may not have cause‐and‐effect relationships, but simply codevelop as a consequence of the same predisposing factors. Abbreviation: type 2 diabetes mellitus.The researchers should be congratulated for their work, which represents another chapter in the difficult quest to understand the role of glycemic control and underlying metabolic disease in NASH severity. Several strengths of this article need to be highlighted. The researchers approached the question methodically, with a robust cohort of well‐characterized patients, relevant outcomes of interest, and by considering several potential confounders for this association. They attempted to disentangle this further by examining the impact of long‐standing glycemic control on NASH in a subset of 298 patients with available serial HbA1c in the 5 years preceding the liver biopsy. In reference to good glycemic control (mean HbA1c of 6%), moderate glycemic control (mean HbA1c of 7.6%) was associated with higher odds of advanced fibrosis, HB, and NASH. Unfortunately, the impact of poor glycemic control was not clear because of the limited number of patients (n = 22) fitting this criterion. Although this work is an important addition to the field, it does not demonstrate a convincing causal relationship between glycemic control and NASH, because of the limitations mentioned above. The quest to disentangle this further may prove even more difficult with the newer NASH treatment candidates that address upstream events and thus have dual effects on glycemic control and histological features of NASH, such as glucagon‐like peptide 1 (GLP1) and sodium‐glucose cotransporter 2 receptor agonists. The use of these medications in this cohort was too sparse to assess medication effects and extend conclusions over these novel therapies, given that they were used by ≤3% of patients. Given that the benefits of GLP1 receptor agonists and other drugs that target metabolic disease extend beyond glycemic control, to reduction of liver fat, NASH resolution, and reduced cardiovascular risk, the association between HbA1c and NASH histology will be even more difficult to prove and perhaps less relevant. In a recent randomized controlled trial, a decrease in HbA1c by 1.15% in those treated with semaglutide versus 0.01% (placebo) was associated with NASH resolution and weight loss, but did not translate into differences in fibrosis regression.(7) Last, whether improved glycemic control to target an HbA1c lower than 7%, as the researchers concluded from this study, ultimately has any impact on liver‐related outcomes remains unclear. Given that longitudinal data are not available in the field of hepatology, one can extrapolate from the cardiovascular field, where poor glycemic control is associated with major cardiovascular events and heart failure. However, achieving normal HbA1c values is not effective in reversing myocardial dysfunction or improving survival in patients with type 2 DM. Moreover, in some studies, a U‐shaped association has been described between HbA1c levels and all‐cause mortality or hospitalization. Intensive glucose control (HbA1c below 6%) was associated with a higher mortality and hypoglycemia than standard therapy targeting a HbA1c level of 7.0%‐7.9%, without a reduction in major cardiovascular events.(8) Therefore, the harm of intensive glucose lowering described in patients with type 2 DM and cardiovascular events must be studied in the NAFLD patient population Clearly, more robust long‐term data are needed to disentangle the complex interplay between glycemic control and NASH to determine whether tight glycemic control has beneficial impact on disease management and outcomes. Nevertheless, the researchers should be commended on undertaking this difficult task in the largest cohort of patients to date.