Nonalcoholic fatty liver disease (NAFLD), particularly its severe form [nonalcoholic steatohepatitis (NASH) with advanced fibrosis], is the second leading indication for liver transplant. More than a third of all patients with type 2 diabetes mellitus (T2DM) have this silent and severe disease [1,2]. NASH is often overlooked as many consider it a non-serious disease that has no available pharmacotherapy; however, its pathophysiology has many of the elements present in both T2DM and cardiovascular disease (CVD), such as oxidative stress, endothelial dysfunction, chronic inflammation, etc. In addition, there is current evidence that certain drugs intended to treat T2DM and CVD have also a positive or negative impact on the liver biology, such as steatosis, inflammation (NASH), and fibrosis [i.e., glucagon-like peptide-1 agonists (GLP-1 agonists), sodium-glucose cotransporter 2 (SGLT-2) inhibitors and beta-blockers] [3–6]. Endocrinologists and cardiologists often surprise when patients under their watch have advanced forms of this silent disease when screened using current noninvasive methods to assess liver fibrosis, such as transient elastography, FIB-4, AST to platelet ratio index (APRI), etc. Patients with advanced liver fibrosis are at the highest risk to present not just cardiovascular events but also liver-related complications. Therefore, it is important to identify patients at high risk for a close clinical monitoring or for enrollment into a clinical trial, so the patient can have access to NASH pharmacotherapy.
Nonalcoholic fatty liver disease in type 2 diabetes mellitus and cardiovascular disease
NAFLD is commonly present in populations that have T2DM and CVD and affects approximately 25% of the worldwide population . The severe or inflammatory version of NAFLD is called NASH, which leads to subsequent liver fibrosis and its associated cardiovascular and liver-related mortality . Globally, the prevalence of NASH in patients with T2DM has been estimated to be approximately 37.3%, resulting in millions of affected patients across the globe . Liver biopsy studies have shown that the more fibrosis, the higher the mortality due to cardiovascular and liver-related complications (stage 3 and 4 by CRN scoring) . The relative risk of all-cause mortality is almost a 2-fold increase and 5-fold increase in liver-related mortality/transplantation in advanced liver fibrosis (stages 3 and 4) compared to milder stages of NASH-related liver fibrosis (stages 1 and 2) [8,9]. T2DM is the main driver of fibrosis in the liver and other vital organs according to the National Health and Nutrition Examination Survey and other registries. This favors internal endocrine dysregulation and its associated end-organ complications, such as nonalcoholic cirrhosis, renal insufficiency, retinopathy, etc .
In this regard, there is evidence that glucose toxicity at cellular and epigenetic levels induce oxidative stress in multiple cells and organs . Oxidative stress is also present in CVD and in NASH and its believed to be an important therapeutic target. Antioxidants (vitamin E), polyphenol-like, and other pharmacotherapies are currently under development to tackle this important node avoiding the domino effect of inflammation and subsequent organ fibrosis [10,12] (Table 1).
Another important element for endocrinologists and cardiologists is glucagon. Patients with T2DM display fasting and postprandial hyperglucagonemia as the alpha-beta cell ratio may be favoring a higher density of alpha cells due to an increase in the apoptosis rate in beta cell and dedifferentiation of beta cells into alpha cells which are more resistant to cellular stress than beta cells. GLP-1 agonists decrease fasting and postprandial hyperglucagonemia, therefore, resulting in better glycemic control particularly when combined with an SGLT-2 inhibitor. This effect certainly may have an impact on the body weight and Acetyl Co-A availability for de novo lipogenesis in the liver and other organs (Fig. 1) [17–19].
Nonalcoholic steatohepatitis with advanced fibrosis in patients with type 2 diabetes mellitus and cardiovascular disease
The current guidelines from the American Association of the Study of the Liver Disease and European Association of the Study of the Liver encourage the use and development of noninvasive tests (NITs) that can inform clinicians the risk for advanced liver fibrosis in patients. Among those NITs, FIB-4, NAFLD fibrosis score (NFS), and APRI are widely used to identify subjects at risk . FIB-4 and NFS have high negative predictive values (NPV) to rule out advanced fibrosis (88 and 95%, respectively) but also high positive predictive values (PPV) to rule in advanced fibrosis (93 and 95%, respectively) [20,21]. These NITs should be used first when risk stratifying patients. However, caution may be needed when using NFS in patients with T2DM as several analyses have reported low performance in such population . Instead, APRI can be used as it performs well in both diabetic and nondiabetic populations (NPV 65% and PPV 91%) . Additionally, APRI can be used in the clinic as reference for interpretation of FIB-4 in diabetic populations, increasing the confidence of the clinician to proceed with the next steps of the patient’s care (Table 2).
In certain clinics or hospitals, transient elastography (Fibroscan) and Magnetic Resonance Elastography (MRE) may be available. These diagnostic modalities constitute a second step for risk stratification of patients that have high scores by FIB-4, APRI, or NFS. However, Fibroscan is not part of the standard of care in many clinics, even for hepatologists, and reimbursement issues make it difficult to deploy it at the bedside. The cost of transient elastography is moderate compared with MRE. MRE is one of the most expensive testings of the liver at this point in time but has excellent NPV and PPV (94 and 95%) for the identification of advanced fibrosis (≥stage 3 or ‘F3 and above’) .
The liver forum and other international consortia recognize the value of the deployment of NITs to identify severe NASH patients, and there are ongoing efforts by NIMBLE (Foundation of NIH) and LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) in the USA and EU, respectively, to establish more advanced NITs. Nonetheless, currently available NITs are valuable low-cost risk stratification tools for clinicians, utilizing commonly used biomarkers in most clinics including endocrinology and cardiology practices at no additional cost for patients and healthcare systems.
Clinical implications for endocrinologist, cardiologists, and hepatologists
Patients with high NIT scores should be monitored closely and referred to a hepatologist for further confirmation of liver fibrosis staging. Once the staging is confirmed, hepatologists, endocrinologists, and cardiologists should work together to discuss long-term management plans. Many hospitals and clinics in the USA, Europe, and Canada have established clinical protocols for NASH patients with advanced fibrosis or cirrhosis. T2DM is not just a risk factor but a strong predictor of fibrosis progression. Therefore, endocrinologists and cardiologists, who are the gatekeepers of such patient population, need to implement similar programs. Such programs could include a continuous care done by the endocrinologist and cardiologist in their monthly or bimonthly standard of care patient office visits but including a 6 or 12 months additional visit to the hepatologist for any change on the treatment plan. Approval of NASH pharmacotherapy is underway, potentially starting this year 2020 with obeticholic acid (Ocaliva), followed by peroxisome proliferator-activated receptors (Elafibranor), CCR2-5 antifibrotic agents (Cenicriviroc), thyroid hormone receptor agonists (Resmetirom), etc in the following immediate years.
Therefore, physicians currently overseeing patients with T2DM need to be aware of the following:
- 1. Patients at high risk for complications or death related to NASH-related advanced fibrosis (Table 2).
- 2. Current antidiabetic and cardiovascular medications that have positive and negative effects in NASH patients with advanced liver fibrosis (Table 3).
- 3. Upcoming NASH pharmacotherapy, including their potential clinical challenges and adverse effects (see above and Fig. 1).
Antidiabetic drugs with cardiovascular benefits in nonalcoholic steatohepatitis
Several GLP-1 single, dual, or triple agonist with glugose dependent insulinotropic polypeptide and glucagon have shown benefits for not only HbA1c control but also for reduction of liver fat content with potential additional cardiovascular benefits in patients with T2DM and NASH. The recently Food and Drug Administration approved oral semaglutide has shown dose-dependent HbA1c and body weight benefits in patients with T2DM. Semaglutide and other GLP-1 agonist are currently under development for the indication of NASH due to its body weight reduction profiles. Tirzepatide is another example of dual agonist with impact on liver enzymes, CK-18, and adiponectin (2019 ADA and EASD scientific sessions) [31,32]. SGLT-2 inhibitors have shown dramatic improvement in HbA1c, body weight, and hemodynamics in patients with preexisting CVD due to their glucoretic effects . Combination therapy with GLP-1a and SLGLT-2i maximize glycemic control, body weight loss, and potential suppression of hyperglucagonemia in patients with T2DM .
Endocrinologists have started to work together with hepatologists in this effort, which translates into an increasing volume and quality of relevant research presented at the ADA and EASD forums as well as the American Association of the Study of the Liver Disease and European Association of the Study of the Liver symposia. Cardiology practice is a logical and organic addition to this ongoing effort as patients with T2DM and NASH with advanced fibrosis are at even higher risk for cardiovascular complications, including myocardial infarction, stroke, and lower extremity amputation [33,34].
Cardiovascular drugs with potential impact on liver
Beta-blockers, such as propranolol, have being studied for the NASH indication but some reports have shown that this drug class may induce drug-induced liver injury . In contrast, interleukin-1-beta mAb therapy (canakinumab) has shown reduction of residual cardiovascular risk independently of statin use in the CANTOS trial . Similarly, NXY-059 has been studied as free radical trapping agent in stroke with promising results in the SAINT-1 trial . This could potentially have a systemic impact on oxidative stress not only in the CNS but also in other vital organs such as liver and pancreas in those cardiovascular patients. Statins and antiplatelets have also anti-inflammatory properties via NLR family pyrin domain containing 3 attenuation or reduction of C-reactive protein that could potentially improve systemic chronic inflammation, such as in diabetes, obesity, and NASH [36–39]. Further studies are granted on those exploratory efforts to expand on safety and efficacy for diabetes and NASH endpoints in patients with CVD; however, clinicians should be aware of these potential positive and negative effects of cardiovascular drugs in patients with T2DM and NASH (Table 1).
Discussion and conclusion
There are still many missing gaps in our current understanding of NASH and its complications but as the field evolves, literature will be updated and both endocrinologists and cardiologists need to update their knowledge and clinical protocols as well to provide a truly state of the art-patient care for patients with T2DM with CVD that are at risk for severe forms of NASH. For example, to date, there is no literature about the NITs cutoff values in T2DM only. As T2DM is very symptomatic and involves many systems and organs, it would be recommended to validate such values and scoring performances to increase precision on the clinical decisions in such patient population.
Current medications have shown potential benefits for patients with T2DM and NASH. More phase 2b and 3 studies are currently underway to expand on efficacy not only just for T2DM or obesity endpoints but also for NASH endpoints as well. In addition, new therapies for NASH are just around the corner and endocrinologist and cardiologist need to familiarize themselves with those new drugs as they directly relate to their patients.
Establishing solid purposed multidisciplinary protocols in clinics and hospitals across the globe could represent an improvement in the overall patient’s quality of care and most importantly, patient’s quality of life, reducing the tremendous cost to the society of NASH complications in patients with T2DM, dyslipidemia, or obesity.
Conflicts of interest
There are no conflicts of interest.
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