Diabetes and HCV: Unraveling a Complicated Relationship

The relationship between diabetes and hepatitis C virus is a complicated one. Despite years of research involving a host of studies and meta-analyses, the clinical community has failed to reach a consensus on the nature of the association between diabetes and the hepatitis C virus.

Some research suggests that curing HCV would reduce the likelihood of developing diabetes, that controlling diabetes would improve HCV outcomes, and that adequately treating one condition would allow the other to be more manageable. In conflict with those studies, recent study data published in Hepatology suggested no association between HCV and diabetes.

“The link between HCV and diabetes is multifactorial and not completely understood,” Salvatore Petta, MD, PhD, specialist and lecturer in gastroenterology at the University of Palermo, Italy, said in an interview.

Uncertainty aside, HCV Next interviewed leading experts about the link between HCV and diabetes, the current evidence base, treatment options and what is needed in the future to fully understand this association.

Early Research Provides Clues

“We have had literature demonstrating a link between diabetes and HCV for some years now,” HCV Next Co-Chief Medical Editor Ira M. Jacobson, MD, said.

Perhaps the most compelling early data on HCV and diabetes came from an analysis of the Third National Health and Nutrition Examination Survey (1988-1994) published in Annals of Internal Medicine in 2000. Among 9,841 participants studied, 1,242 had type 2 diabetes and 230 had HCV. In this seminal paper, researchers reported that patients with HCV were approximately three times more likely to develop type 2 diabetes than patients without HCV.

“In the NHANES study, we demonstrated a strong association between HCV and prevalent diabetes among persons 40 years of age and older after consideration of other risk factors for diabetes that were also associated with HCV infection,” lead investigator Shruti H. Mehta, PhD, MPH, professor in the department of epidemiology at the Bloomberg School of Public Health, told HCV Next. “This study was the first to demonstrate a link in a general-population sample, which was important because prior studies had been conducted in clinic-based populations that would have been expected to have more severe liver disease than the general population.” However, she said the NHANES study was limited in its ability to establish a temporal link due to its cross-sectional nature.

Thereafter, additional community-based studies along with some prospective studies suggested HCV was associated with new onset of type 2 diabetes, whereas others found no risk or greater risk only in specific subgroups, further clouding the issue. Evidence also emerged indicating that patients with HCV and diabetes have more aggressive liver disease. Study data published in the October issue of Hepatology by Elkrief and colleagues concluded that diabetes is an independent prognostic factor in patients with chronic HCV and cirrhosis, and improving diabetes control might improve outcomes of cirrhosis.

These existing studies give many cause to believe there is a true association between these two chronic diseases.

“The amount of evidence is huge. So much has been done,” Francesco Negro, MD, of the divisions of gastroenterology and hepatology and of clinical pathology at the University Hospitals of Geneva in Switzerland, told HCV Next. “You cannot ignore what has been done up until now.”

Prevalence of HCV, Diabetes

The increased prevalence of both HCV and diabetes may be a big piece of this puzzle, experts told HCV Next.

Although this association was strong using the earlier cycle of NHANES (1988-1994), an analysis of the more recent NHANES cycle (1998-2008) no longer confirmed this association, according to Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for Research at Inova Health System in Falls Church, Va. “It is possible that [this relationship] may have become diluted by the rapid rise of other risks for diabetes, specifically, the prevalence of obesity.”

Negro pointed to the obesity epidemic as hindering research on HCV and diabetes.

“There is a metabolic syndrome epidemic in the States and things have changed. The metabolic syndrome is causing a transaminase elevation,” he said. “At the end of the day, it’s becoming extremely difficult to see whether there is any difference of the HCV effect between infected cases and uninfected controls because the prevalence of the metabolic syndrome in controls is so high.”

A final line of evidence supporting this association between HCV and diabetes comes from the Scientific Registry of Transplant Recipients (2003-2012). In this study, 17,121 patients with HCV and 1,450 patients with hepatitis B virus were included. At 5 years after transplantation, both the relative risk for diabetes (RR=1.18; 95% CI, 1.08-1.29) and the hazard ratio for time to developing diabetes (HR=1.27; 95% CI, 1.15-1.41) were significantly higher in patients with HCV vs. those with HBV. In a multivariate analysis, after adjustment for confounders including the use of immunosuppressants, HCV infection was independently associated with developing post-transplant diabetes (adjusted HR=1.55; 95% CI, 1.34-1.79).

“It is possible to speculate that HCV, via indirect mechanisms, affects insulin signaling, leading over time to diabetes development. This is not, however, a linear and perfect way. The link between HCV and diabetes is perhaps modulated by the interaction with primitive metabolic disorders and genetic background that likely play a relevant role,” Petta said.

The Role of Insulin Resistance

Negro explained that chronic infections like HCV induce insulin resistance, perpetuating the theory that improving insulin sensitivity may aid responses to antiviral therapy and prevent complications of insulin resistance, including diabetes and vascular diseases. Clinical trials of metformin and peroxisome proliferator-activated receptor (PPAR)-gamma agonists have thus far yielded inconclusive results.

“Hepatitis C is extremely efficient in [inducing insulin resistance],” Negro said. “After many years, you end up with type 2 diabetes because you essentially exhausted the beta cells.”

Results from the HALT-C trial demonstrated that insulin resistance is ameliorated in patients with sustained virologic response after HCV treatment. Other research has shown that patients with SVR after interferon-based therapy had a lower incidence of diabetes in later years compared with patients who were nonresponders. Romero-Gomez and colleagues reported in a study published in the Journal of Hepatology in 2008 that type 2 diabetes incidence rates and impaired fasting glucose were cut in half when SVR was achieved in patients with chronic HCV.

Similarly, Arase and colleagues followed more than 2,800 patients in Japan for 6 years and found that SVR reduced type 2 diabetes risk by more than 60%, independent of prediabetes, cirrhosis and age.

“So, if you take hepatitis C away from these key groups of patients, you still reduce considerably the risk of diabetes. This is nice evidence that hepatitis C is causing diabetes in some cases,” he said of this study. “It’s not explaining the whole story, of course, since if you are at risk of developing diabetes, you will get it anyway. But if you have hepatitis C, you might get it 10 years earlier.”

In a recent Hepatology study, Hsu and colleagues investigated the role of HCV antiviral therapy as an approach to improve clinical outcomes associated with diabetes, showing that treatment in patients with HCV and diabetes lowered their risk of developing end-stage renal disease, ischemic stroke and acute coronary syndrome (see Table).

 

“Previous research has suggested that if we can cure a patient’s HCV, that patient will be less likely to [develop] diabetes. Now there is some indication that if a patient has diabetes already and is cured of his HCV, he is less likely to develop diabetic complications, which is intriguing,” said Jacobson, chief of the division of gastroenterology and hepatology and Vincent Astor distinguished professor of medicine at the Joan Sanford I. Weill Cornell Medical College, attending physician at New York-Presbyterian Hospital Cornell Campus and medical director of The Center for the Study of Hepatitis C.

Conflicting Data

Despite a broad range of evidence, there is still speculation about why the link exists.

“In terms of controversy, the majority of studies have demonstrated a link between HCV and diabetes, but a few studies have failed to observe an association,” Mehta said.

One such study was published in the October issue of Hepatology. Ruhl and colleagues analyzed population-based data on 15,128 individuals from NHANES 1999-2010. Serum HCV antibodies were reported in 1.7% of the cohort while HCV RNA was reported in 1.1%.

The prevalence of diabetes was 10.5% and the prevalence of prediabetes was 32.8%. Multivariate analysis indicated no association between diabetes and anti-HCV antibodies (HR=1; 95% CI, 0.6-1.7) or HCV RNA (OR=1.1; 95% CI, 0.6-1.9). Elevated alanine aminotransferase and gamma-glutamyl transferase (GGT) activities demonstrated associations with diabetes regardless of HCV status, according to the results.

“In the US population, HCV was not associated with diabetes or with insulin resistance among persons with normal glucose,” Ruhl and colleagues concluded. “Previously reported relationships of HCV with diabetes were possibly attributable to the effect of elevated liver enzymes.”

These findings are in “contrast” to the prior study published in 2000 that used an earlier version of the NHANES data and demonstrated “a strong association” between HCV and diabetes among adults aged 40 years and older at the population level, Mehta said. She noted that key differences between the two studies included different definitions of diabetes; lack of age stratification in the study by Ruhl and colleagues, including the inclusion of participants younger than 40 years; and adjustment for liver enzymes, which may be in the causal pathway.

Negro said the aforementioned metabolic syndrome epidemic made the distinction difficult to see in this new cohort of patients.

“The fraction of diabetes attributable to HCV is low, especially now. It was not so low 30 years ago. Now it is very low because things have changed,” he said. Additionally, he said adjusting for liver enzymes would affect the appearance of an association.

“In most cases, patients with hepatitis C don’t have elevated liver enzymes for reasons other than hepatitis C,” he said. “The adjustment does not prove anything. What really proves the association is when you cure hepatitis C” and therefore lower risk of diabetes.

In a related editorial published in the same issue of Hepatology, Kenneth Cusi, MD, chief of the division of endocrinology, diabetes and metabolism at University of Florida, said these data confirm “quite conclusively the lack of a clear association between HCV infection and diabetes.”

During an interview with HCV Next, Cusi said, “There is a tangled web of factors relating to advanced liver disease. But the findings from Ruhl and colleagues are quite solid in that we need to rethink the paradigm of diabetes and HCV.

“Health care professionals who manage patients with HCV should start thinking that HCV will be defeated in the near future, but type 2 diabetes will create longstanding complications that will need to be treated aggressively,” he said. For example, “most of these patients will have nonalcoholic steatohepatitis, which will impact outcomes in diabetes.”

Cusi also raised the question of whether type 2 diabetes is actually a consequence of HCV infection or whether it is actually an “innocent bystander.” He discussed the answer in terms of obesity: “Evidence may show that once you are obese and diabetic, HCV most likely will not make outcomes any worse.”

According to Cusi, there will never be a simple answer to any of these intertwining complications. “Insulin resistance varies in patients with diabetes whether or not they are obese. Different HCV genotypes provide different complications. When you put all that together, the impact of these factors will vary individually,” he said.

Negro said this interpretation of data falls under the “exception fallacy” and discounts the long-standing research showing an association between these chronic diseases.

“If you look at one single piece of evidence and are totally oblivious to everything else, which goes in favor [of the association], that from the epidemiological standpoint is unacceptable,” he said. “Data is data, but the interpretation must be taken with a grain of salt.”

Diabetes Treatments’ Impact on HCV

Treatment options for patients with HCV and diabetes also are under investigation.

Metformin, a commonly used oral diabetes medication to control blood glucose levels, may be a useful therapy in patients with HCV.

In vitro data indicated that metformin may suppress replication of HCV, as demonstrated in a study published in Microbiology and Immunology in 2011. In the randomized controlled, double blind TRIC-1 study, metformin added to standard therapy for treatment of HCV was associated with a greater decrease in viral load during the first 12 weeks and a doubled SVR in women with HCV genotype 1 infection and insulin resistance compared with women who received placebo.

Other studies also have reported improved SVR among patients with HCV and insulin resistance who received metformin in addition to standard therapy. A 2009 Hepatology study by Romero-Gómez and colleagues found that metformin added to pegylated interferon and ribavirin was safe and improved insulin sensitivity, with a particularly improved SVR observed in women.

Metformin also has been linked to better prognosis in patients with diabetes who also have HCV and cirrhosis. In a 2011 Journal of Clinical Endocrinology & Metabolism study, the 5-year occurrence of hepatocellular carcinoma (HCC) was 9.5% in metformin-treated patients and 31.2% in those not treated with metformin (P=.001). At the same time point, incidence of liver-related death or liver transplantation was 5.9% and 17.4% (P=.013), respectively, in patients who received metformin and in those who did not. Adverse events with metformin were limited.

“Metformin is not associated with liver toxicity,” Petta told HCV Next.

HCV Therapies’ Impact on Diabetes

Current HCV therapies also have been studied in this patient population, such as in the study by Hsu and colleagues.

This represents just one study on the link, but “the quoted data are in line with other recent studies in diabetic and nondiabetic subjects showing a link between HCV infection and cardiovascular risk, as well as between HCV eradication and reduced cardiovascular risk,” Petta said. “All of these data are fascinating and add new evidence on HCV infection as a systemic disease. But, further data are necessary to conclusively attribute to HCV the ability to increase cardiovascular risk.”

Additionally, since diabetes has been linked to increased prevalence of cancers, Negro said curing a patient’s HCV in the light of having diabetes will further lower the risks of cancer.

In 2013, Arase and colleagues showed that type 2 diabetes was linked to nearly twice as many HCC cases as well as other malignancies and that maintaining an HbA1c measurement less than 7.0% reduced that development.

“If you control diabetes also, you reduce the risk of cancer eminently,” Negro said. “If you have HCV and you have diabetes, you have three times higher risk of developing cancer than if you don’t have diabetes. To have the two conditions is a time bomb.”

The new direct-acting antiviral therapies for HCV appear to be highly effective in patients with diabetes, according to Jacobson.

“Although there is ongoing research in this area, these drugs don’t seem to worsen glucose abnormalities during treatment. Whether successful treatment and achieving SVR will lead to improvement of insulin resistance and diabetes is a subject of investigation and must be proven,” Younossi said.

Given the cost associated with current therapies, a key challenge with their study in this patient population is access, according to Mehta. “Persons who will get access first will be those with more severe disease. The potential risk of diabetes and other nonhepatic complications among patients with HCV may provide further rationale for treating people earlier before they develop these other complications,” Mehta said.

The potential impact of treating HCV on cardiovascular outcomes makes this a public health question, Negro said.

“To recognize this link has a lot of consequences for public health,” he said. “If you do a cost-effectiveness analysis and you evaluate the effect of treatment in terms of health gains, you have to consider not only the fact you prevent cancer, you prevent liver transplant, but also that you may prevent some of the consequences of diabetes, such as ischemic stroke. That has never been done because the data started coming out only now.”

Further Evidence, Future Research

With conflicting data and more research underway, physicians interviewed by HCV Next said more data are needed to provide a definitive answer on the link between HCV and diabetes.

“From a practical and clinical point of view, the available evidence is sufficient to consider that patients with diabetes and HCV are not only at high risk for severe liver damage, but also at high risk for liver disease progression and complications such as hepatocellular carcinoma,” Petta said.

On a fundamental level, a definitive study might require the ability to measure insulin resistance in a more sophisticated way, according to Cusi. “Future work will need to assess the role of [insulin resistance] and hepatic steatosis more in depth to understand the association between HCV infection and diabetes,” he wrote in Hepatology.

This might include a longitudinal study involving patients with and without diabetes who have similar levels of insulin resistance, and studies that include large groups of patients with and without HCV who are followed for 10 or 20 years, he told HCV Next. “I just don’t see that happening.”

“Until then, it appears that this relationship may be going separate ways and ‘talk of a divorce is in the air,” he wrote in his editorial.

In the meantime, “clinicians should be aware of the potential extrahepatic manifestations and how they can impact clinical outcomes for patients,” Jacobson said. “Once we accept these associations, it is difficult to conceive of the denial of currently anticipated, highly effective new therapies to patients with HCV.”

Despite new clinical data, the pathogenic basis for these changes must be supported by further evidence and future research.

Still, Negro said, “If you start saying diabetes has nothing to do with hepatitis C, we are probably going to miss the train.”