Early action required for prevention, management of fatty liver in type 2 diabetes
Nonalcoholic fatty liver disease, or NAFLD, a condition traditionally treated by hepatologists, is widespread and frequently associated with obesity, insulin resistance, diabetes and other metabolic risk factors. Type 2 diabetes appears to worsen the course of NAFLD and promote development of nonalcoholic steatohepatitis, or NASH, the more severe form of the disease, as well as increase risks for cirrhosis and hepatocellular carcinoma. Liver disease similarly makes diabetes management more challenging. At least half of all individuals with type 2 diabetes also have NAFLD, setting the stage for a worse metabolic profile and greater cardiovascular risks. Currently, there are no drugs approved to treat NAFLD.
“Most people with type 2 diabetes are going to have varying degrees of NAFLD and NASH, and the presence of these conditions is significant for several reasons,” W. Timothy Garvey, MD, FACE, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham, told Endocrine Today. “NAFLD tends to be associated with worse lipid profile and worse glycemia. It tends to be associated with worse cardiovascular risk. It is a sign that we need to be more aggressive with CV risk management, with glycemic management and with weight-loss therapy.”
In a recent “call to action” on the management of NAFLD in type 2 diabetes published in Diabetes Care, Kenneth Cusi, MD, FACP, FACE, chief of the division of endocrinology, diabetes and metabolism at University of Florida, and Fernando Bril, MD, a researcher with Malcom Randall Veterans Affairs Medical Center in Gainesville, Florida, wrote that a better understanding of the natural history of the disease, novel diagnostic tools and recent evidence of safe and effective treatment modalities have led to a “major paradigm shift” in the management of NAFLD in diabetes and prediabetes.
“The message for the clinician is now loud and clear: There is an urgent need to screen for liver fibrosis in patients with obesity or type 2 diabetes with NAFLD,” Cusi, also an Endocrine Today Editorial Board Member, said in an interview. “A call for action has been in the making for some time now, as these patients have the greatest risk for NASH and progressive liver damage. Although it appears to be an indolent condition, more than 40 studies associate NAFLD with an increased risk for CVD and a twofold greater risk for developing type 2 diabetes.”
NAFLD as risk factor
Progression across stages of fibrosis takes a long time — on average, progressing one stage every 7 years, according to Samuel Klein, MD, the William H. Danforth professor of medicine and nutritional science and director of the Center for Human Nutrition at Washington University School of Medicine in St. Louis. A subgroup of people with NAFLD are what he called “rapid progressors.”
The more liver fibrosis a patient has, the greater the mortality risk, Klein said.
“The main cause of death is CVD, not liver disease,” Klein told Endocrine Today. “Only when you get to cirrhosis do you see a big spike in death from liver disease. When you have cirrhosis, about 50% of the deaths are attributed to liver disease, so half die from nonliver disease causes.”
Klein said NAFLD is “clearly a risk factor” for developing cardiometabolic abnormalities, noting that one-third of people with NAFLD have metabolic syndrome, and 90% have at least one component of metabolic syndrome criteria. In a Mayo Clinic study that investigated the incidence of cardiometabolic disease over 5 to 7 years among people with NAFLD, 25% died from CVD and similar percentages developed type 2 diabetes, dyslipidemia and hypertension, Klein said.
“NAFLD tracks with cardiometabolic abnormalities,” Klein said. “The more inflammation and fibrosis, the more severe the atherosclerosis.”
One major risk factor for CVD that is associated with fatty liver is an increase in serum triglyceride concentration, which Klein called an important marker for increased fat in the liver.
“We know that VLDL triglyceride, which is made by the liver and is a major source of triglyceride in the bloodstream, is an important risk factor for heart disease,” Klein said. Among people with obesity, those with NAFLD have hepatic VLDL triglyceride secretion rates that are twice as high as those with normal liver fat content, he said.
Increased fat in the liver is associated with insulin resistance in adipose and muscle tissues and the liver and also with multiorgan systemic insulin resistance, Klein said.
The critical issue is that often NAFLD is overlooked, Cusi said.
“Unfortunately, NAFLD is still widely unrecognized by most primary care physicians and endocrinologists or dismissed as the hepatic manifestation of metabolic syndrome,” Cusi said. “This leads to inertia and to overlooking that NAFLD is a leading cause of cirrhosis, liver transplantation and hepatocellular carcinoma. Of note, NAFLD may also affect nonobese individuals, or patients without metabolic syndrome, because NAFLD is a mirror of metabolic health and reflects, above all, insulin resistance, even in the absence of typical metabolic syndrome clinical features.”
The need for clinicians to replace inaction with screening patients with steatosis or elevated alanine aminotransferase (ALT) and prediabetes or type 2 diabetes became clear this year in an update to the 2019 American Diabetes Association’s Standards of Medical Care in Diabetes, Cusi said. The updated position statement now recommends that patients with type 2 diabetes or prediabetes and elevated liver enzymes or fatty liver on ultrasound be evaluated for presence of nonalcoholic steatohepatitis and liver fibrosis. Noninvasive tests, such as elastography or fibrosis biomarkers (ie, FIB-4), can be used to assess risk of fibrosis, but referral to a liver specialist and liver biopsy may be required for definitive diagnosis, according to the statement.
In the clinic, the nonhepatologist should measure levels of plasma aspartate aminotransferase (AST) or ALT for any person with obesity, prediabetes or metabolic syndrome, according to Peter Goulden, MD, FRCP, PGCE, senior faculty and medical director of the division of endocrinology, diabetes and bone diseases at Mount Sinai St. Luke’s in New York.
“We see that when there is inflammation in the liver, the levels of those enzymes can rise,” Goulden told Endocrine Today. “It is a basic screening test, and it’s easy for anyone with type 2 diabetes to have those blood tests done. Given the prevalence of this process, NASH and the potential risks for progression, screening is critical. It is something that can be addressed if picked up early, and we can actually tackle it and stop it from progressing.”
Diagnostic panels, such as the Fibrosis-4 calculator or NAFLD fibrosis score, help to rule out severe disease, Cusi said. The validated panels are available free online. In addition, a liver ultrasound may help to detect steatosis, Cusi said.
“Fibrosis can be measured by elastography, often as a point-of-care test in liver clinics by FibroScan (Echosens) or by radiology, where magnetic resonance techniques are also available,” Cusi said. “If advanced fibrosis/cirrhosis is suspected, definite disease stratification requires a liver biopsy. Taken together, while the cost-effectiveness of screening awaits long-term outcomes, incorporating NAFLD and NASH-fibrosis early screening into the management of type 2 diabetes will likely help identify patients at the highest risk of severe liver and cardiovascular disease.”
Garvey, who noted the updated ADA standards are worded “very carefully,” said clinicians may need to be more aggressive about diagnostics with respect to NAFLD in diabetes.
“We should not be waiting for ALTs and ultrasounds,” Garvey said. “We know it’s there. When you have a condition that is there up to 70% of the time, like NAFLD, it is almost like, do you even need to do the test? We are really in a conundrum, because we don’t have a good way to assess the level of NASH noninvasively, and we don’t know how to identity those people who are at more risk of progressing to cirrhosis and liver failure.”
Several drugs are in development for NAFLD, and the first available therapy for people with fibrosis due to NASH may soon become reality. On Nov. 26, the FDA accepted a new drug application for obeticholic acid, or OCA (Ocaliva, Intervcept), a semi-synthetic bile acid analogue primarily used to treat biliary cholangitis, for the treatment of liver fibrosis due to NASH. The therapy first received breakthrough designation from the FDA for this treatment in 2015, and interim results from the phase 3 REGENERATE study were presented at the International Liver Congress in April 2019 in what the presenter called a ‘watershed moment.’
The REGENERATE study, which focused on prespecified endpoints of NASH treatment with OCA, included 931 participants with biopsy-confirmed NASH and stage F2 or F3 fibrosis. Investigators randomly assigned patients to receive either placebo (n = 311), OCA 10 mg (n = 312) or OCA 25 mg (n = 308).
In assessing the primary endpoints of either fibrosis improvement (1 stage) with no worsening of NASH or NASH resolution with no worsening of liver fibrosis on liver biopsy, there was dose-dependent response. Daily OCA of 25 mg met the primary endpoint of fibrosis improvement without worsening of NASH in 23.1% of patients (P = .0002 vs. placebo). The 10-mg group showed a 17.6% improvement (P = .04 vs. placebo).
Recent data on drugs to treat type 2 diabetes, such as liraglutide (Victoza, Novo Nordisk) and semaglutide (Ozempic, Novo Nordisk), have shown promise for NAFLD/NASH as well, Garvey said.
In a phase 2 study, Matthew J. Armstrong, PhD, MSc, MBChB, MRCP, a consultant in hepatology and transplant medicine at University Hospital Birmingham, U.K., and colleagues analyzed data from 52 adults with overweight with or without diabetes and clinical evidence of NASH who were randomly assigned 1.8 mg daily liraglutide (n = 26) or placebo (n = 26) for 48 weeks. The primary outcome was resolution of NASH with no worsening in fibrosis from baseline to end of study.
“Resolution of nonalcoholic steatohepatitis was selected as the primary endpoint instead of changes in NAFLD activity score, in keeping with guidance from an expert consortium,” the researchers wrote. “Notably, the NAFLD activity score does not predict liver-related morbidity or mortality, whereas the presence of nonalcoholic steatohepatitis (as opposed to simple NAFLD) is associated with a significant increase in liver-related outcomes and all-cause mortality.”
Among participants who underwent end-of-treatment liver biopsy, nine who received liraglutide and two in the placebo group had resolution of NASH (RR = 4.3; 95% CI, 1-17.7). Two participants in the liraglutide group, compared with eight in the placebo group, experienced progression of fibrosis at 48 weeks.
“Moreover, improvements in weight and glycemic control with liraglutide might have a favorable effect on the future risk of cardiovascular disease and premature death in patients with nonalcoholic steatohepatitis, although longer-term outcome studies are needed to confirm this hypothesis,” the researchers wrote.
Goulden, who said The Lancet findings are interesting, said a GLP-1 receptor agonist could be an attractive option for a person with type 2 diabetes and NAFLD due to the drug’s ability to improve glycemic response and reduce body weight.
“With liraglutide and pioglitazone, there appears to be evidence for their use in helping reduce the risk for progression,” Goulden said. “In the pipeline, there is a lot of research in this area, so in the next few years, there may be even more options.”
Guidelines on the treatment of NAFLD published by the American Association for the Study of Liver Diseases, American College of Gastroenterology and the American Gastroenterological Association do not recommend metformin as a specific treatment for liver disease for adults with NASH because the agent has no significant effect on liver histology. The guidelines do support use of pioglitazone to treat steatohepatitis for patients with biopsy-proven NASH, but long-term safety and efficacy of the drug have not been established in this setting. Vitamin E at a dose of 800 IU per day could be used as a therapy for adults without diabetes with biopsy-proven NASH, although vitamin E is not recommended for patients with NASH who have diabetes.
“The ongoing controversy is whether vitamin E may increase the risk for CVD or prostate cancer,” Cusi said. “For patients with prediabetes or type 2 diabetes, the guidelines say that you may use pioglitazone. There are now five randomized controlled trials of between 6 months and 3 years in duration in patients with prediabetes or type 2 diabetes that have shown a resolution of NASH of about 50% or 60%, or about a 40% improvement over placebo. However, the most recent trial adding vitamin E to pioglitazone did not show an added benefit when compared with past studies of pioglitazone alone.”
To reduce the heightened CV risk for a person with NAFLD and type 2 diabetes, more aggressive disease management may be in order, Garvey said.
“You may want to prescribe ezetimibe plus a statin, instead of just a statin, to get a decrease in LDL, just as an example,” Garvey said. “Or you may want tighter control of blood pressure. You have to individualize care, but these are examples of some things you might want to do for a person with NAFLD and type 2 diabetes that you might not do for a person without the NAFLD. I would stress weight-loss therapy in this whole paradigm.”
Garvey said more options for the treatment of NAFLD in diabetes are urgently needed.
“People tend to rely on pioglitazone, and that has some efficacy, but it is only effective in less than half of patients, and there are side effects,” Garvey said. “We need better treatments. We have to go with the best we’ve got, which is weight loss, and maybe pioglitazone. We need not only better diagnostics, but better medications as well.”
Importance of weight loss
Weight loss reduces liver fat content and has been shown to improve CV structure and function, including early diastolic and systolic myocardial velocity, left ventricular mass and carotid intima-media thickness, Klein said.
“Fatty liver disease, chronic kidney disease, cardiovascular disease and diabetes are all organ damages responding to a systemic metabolic insult,” Klein said. “A lot of investigators look at these different organ systems independently and forget to consider the simultaneous biological dysfunction of multiple organs, which are caused by obesity.”
Cusi said weight loss is the best option for both the prevention and treatment of NAFLD in the setting of diabetes.
“A lot of doctors say, ‘Well, we don’t have any FDA-approved drugs, so there’s nothing to do. Why would I do a biopsy? Why would I do anything?’” Cusi said. “That is the most significant error an endocrinologist, primary care doctor or related health care provider can make, because a weight loss of 7% causes significant reduction in liver fat and even inflammation 70% of the time. With at least 10% weight loss, you can reverse inflammation and fibrosis 80% to 90% of the time. In addition, pioglitazone and liraglutide improve steatohepatitis in patients with or without diabetes.”
Garvey, too, noted that at least 10% weight loss has been shown in lifestyle intervention studies and bariatric surgery studies to reduce liver fibrosis and inflammation.
“How long you maintain that improved picture, I don’t think we know,” Garvey said. “I would assume that if you maintain the weight loss, your liver picture is going to stabilize, but we need more data to prove that.”
“A lot of biotech is out there, pharma out there trying to develop drugs to treat this,” Garvey said. “In the end, we have weight loss, and people forget that. These are the diseases where we need to bring all of the tools of obesity medicine to the table to treat these patients. Our goal is 10% weight loss or more. People often leave that out, but that is the evidence. That is the best treatment we have.”
Prevention of liver disease
Experts agree that insulin resistance is key to NAFLD, NASH and the development of type 2 diabetes, making early intervention an important strategy in preventing the development of fatty liver and its consequences.
“A lot of this predates the onset of diabetes,” Garvey said. “NAFLD is something we need to think about in metabolic syndrome and in prediabetes as well. We know diabetes is associated with worse outcomes and a worse histological picture, so the thinking is the diabetic milieu does make things worse. We want to improve the glycemic and lipid aspects of diabetes as best we can, because if a person has NASH, outcomes are worse.”
Goulden said any treatment plan should begin with lifestyle, aiming for a target of 7% to 10% weight loss while setting smaller goals that are more achievable for the patient.
“The most important thing is not just telling the patient, ‘This is what you need to do.’ It is giving them the how,” Goulden said. “There is a lot to be said for programs that have a coach. Weight loss is not easy. What I will sometimes do is make a clear connection, set some goals, starting with 5% weight loss. Even 5 to 10 pounds is going to be a great start. It is important to set goals that are not impossible to achieve, while rooting that in the evidence-based recommendations.”
The “how,” Goulden said, also means clearly explaining to patients how NAFLD develops in with type 2 diabetes, outlining the risk picture and stressing the importance of screening.
“The most important thing is raising awareness,” Goulden said. “When we talk about diabetes complications, we often talk about obesity, or eye, kidney and nerve complications. The more people are aware of NAFLD, the more people can take action to prevent it from progressing or even reverse it. That is the key.” – by Regina Schaffer
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- American Diabetes Association. Standards of Medical Care in Diabetes. Available at: www.care.diabetesjournals.org/content/42/Supplement_1/S34.full-text.pdf. Accessed Sept. 26, 2019.
- Armstrong MJ, et al. Lancet. 2016;doi:10.1016/s0140-6736(15)00803-x.
- Bril F, Cusi K. Diabetes Care. 2017;doi:10.2337/dc16-1787.
- Portillo-Sanchez P, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc..2015-1966.
- Younossi Z. GS-06. Presented at: International Liver Congress; April 10-14, 2019; Vienna, Austria.
- For more information:
- Kenneth Cusi, MD, FACP, FACE, can be reached at the University of Florida, Division of Endocrinology, Diabetes and Metabolism, 1600 SW Archer Road, M509, Gainesville, FL 32610; email: Kenneth.firstname.lastname@example.org.
- W. Timothy Garvey, MD, FACE, can be reached at the University of Alabama at Birmingham, 1675 University Blvd., Birmingham, AL 35294; email: email@example.com.
- Peter Goulden, MD, FRCP, PGCE, can be reached at Mount Sinai St. Luke’s, Division of Endocrinology, Diabetes and Bone Diseases, 1111 Amsterdam Ave., Babcock 10th Floor, Suite 1027, New York, NY 10025; email: firstname.lastname@example.org.
- Samuel Klein, MD, can be reached at the Center for Human Nutrition, Washington University School of Medicine, Campus Box 8031, 660 S. Euclid Ave., St. Louis, MO 63110; email: email@example.com.
Disclosures: Cusi reports he is a consultant for Allergan, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Coherus, Deuterex, Genentech, Gilead, Merck, Novo Nordisk, Pfizer, Poxel SA and ProSciento, and receives research support from Cirius Therapeutics, Echosens, Eli Lilly, Inventiva Pharma, Janssen, Novartis, Novo Nordisk and Poxel SA. Klein reports he holds stock in Aspire Bariatrics and has received research support from Centene, Janssen and Pershing Square Foundation, consultant fees from Dannon-Yakult, Lobesity, Merck, Novo Nordisk and Pfizer and endowments from the Atkins Philanthropic Trust and the Kilo Foundation. Garvey reports he serves on advisory boards for Amgen, BOYDSense, Boehringer Ingelheim, Gilead, Novo Nordisk and Sanofi and has receive research grants paid to his institution from Novo Nordisk, Pfizer and Sanofi. Goulden reports no relevant financial disclosures.