Type 2 Diabetes Might Raise Risk of Liver Cancer
People with type 2 diabetes might be at somewhat higher risk of developing liver cancer, according to a large, long-term study.
The research suggests that those with type 2 diabetes have about two to three times greater risk of developing hepatocellular carcinoma (HCC) -- the most common type of liver cancer -- compared to those without diabetes.Still, the risk of developing liver cancer remains low, experts said.
Race and ethnicity might also play a role in increasing the odds of liver cancer, the researchers said.
An estimated 26 percent of liver cancer cases in Latino study participants and 20 percent of cases in Hawaiians were attributed to diabetes. Among blacks and Japanese-Americans, the researchers estimated 13 percent and 12 percent of cases, respectively, were attributed to diabetes. Among whites, the rate was 6 percent.
"In general, if you're a [type 2] diabetic, you're at greater risk of liver cancer," said lead author V. Wendy Setiawan, an assistant professor at the Keck School of Medicine at the University of Southern California.
Yet the actual risk of liver cancer -- even for those with type 2 diabetes -- is still extraordinarily low, said Dr. David Bernstein, chief of hepatology at North Shore University Hospital in Manhasset, N.Y.
Although liver cancer is relatively rare, it has been on the rise worldwide and often is associated with viral hepatitis infections and liver diseases, such as cirrhosis.
New cases of HCC in the United States have tripled in the past 30 years, with Latinos and blacks experiencing the largest increase, Setiawan said. During that time, type 2 diabetes also has become increasingly common.
What might the connection be?
It's possible that the increased risk of liver cancer could be associated with the medications people with diabetes take to control their blood sugar, said Dr. James D'Olimpio, an oncologist at Monter Cancer Center in Lake Success, N.Y. "Some medications are known to inhibit normal suppression of cancer," he said.
"Some of the drugs already have [U.S. Food and Drug Administration-ordered] black box warnings for bladder cancer," D'Olimpio said. "It's not a stretch to think there might be other relationships between diabetes drugs and pancreatic or liver cancer. Diabetes is already associated with a high risk of developing pancreatic cancer."
D'Olimpio said fatty liver disease is the No. 1 cause of HCC. "[Type 2] diabetics have twice the chance of having a fatty liver, at least," he said. "If you're an African-American or Latino, that may make you even more susceptible."
People with type 1 diabetes, however, do not have an increased risk of liver cancer, he said.
The new research is scheduled for presentation Sunday at an American Association for Cancer Research meeting in Atlanta. The data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.
The study analyzed data collected between 1993 and 1996 from nearly 170,000 black, Native Hawaiian, Japanese-American, Latino and white adults. Researchers followed up with the participants about 16 years after they had answered a comprehensive health questionnaire. Over that time, about 500 participants had developed liver cancer.
Information about risk factors -- such as age, whether they had type 2 diabetes, alcohol intake, body-mass index (a measure of body fat) and cigarette smoking -- was analyzed, and blood tests for hepatitis B and hepatitis C were performed on about 700 of the participants, with and without liver cancer.
Whether people smoked or drank alcohol did not appear to change the relationship between having diabetes and getting liver cancer, the researchers said.
Although the study found an association between having type 2 diabetes and developing liver cancer, it did not prove a cause-and-effect relationship.
North Shore's Bernstein urged caution in interpreting the results. "It's a single study that talks about a large number of people with a common disease like diabetes and links it to liver cancer," he said. "We have a lot more learning to do and more work is needed to prove an association and define what the risk really is."
The next step is to learn what role genetics may play in whether an individual with type 2 diabetes will develop liver cancer, study author Setiawan said.
A new study reveals links between BMI, diabetes, and liver cancer.
The American Cancer Society estimate that there will be 39,230 new cases of liver cancer and 27,170 deaths from the disease in America in 2016.
Globally, around 700,000 people are diagnosed each year.
Because symptoms do not become apparent until the disease has progressed substantially, cases of liver cancer are often caught relatively late.
Even if the cancer is diagnosed before it spreads to other organs, the 5-year survival rate is just 30.5 percent.
As Peter Campbell, author of the present study, says, "the prognosis for patients diagnosed with this type of cancer is especially grim."
The exact causes of liver cancer are not known, but most cases are associated with damage and scarring of the liver, referred to as cirrhosis. Known causes include alcohol abuse and hepatitis B and C infection.
Although liver cancer is fairly rare in America, since 1980, the incidence has more than tripled.
Why has liver cancer incidence increased?
It is well known that type 2 diabetes is on the rise in the United States, and this surge runs in parallel with a boom in average waist circumference and a sharp increase in obesity. As Campbell says: "All three relate to metabolic dysfunction."A team of researchers from the National Cancer Institute decided to investigate whether there could be links between these three obesity-related parameters and the rise in liver cancer.
Campbell and his team collated data from 1.57 million participants enrolled in 14 separate U.S.-based studies. In each study, questionnaire data was gathered at the start relating to weight, waist size, height, tobacco usage, alcohol intake, and other cancer-related risks.
Overall, type 2 diabetes occurred in 6.5 percent of study participants and 2,162 developed liver cancer.
Once the data had been analyzed, the team found that for every increase in body mass index (BMI) of 5 kilograms per meter squared, there was a parallel increase in liver cancer risk; this equated to a 38 percent increase in men and 25 percent in women.
As for waist circumference, every 5-centimeter extension increased the risk by 8 percent.
Once the findings had been adjusted for smoking, race, alcohol intake, and BMI, individuals with type 2 diabetes were 2.61 times more likely to develop liver cancer; this risk increased in line with BMI.
"The lifetime risk for liver cancer in the United States is about 1 percent; approximately eight adults per 100,000 will develop liver cancer in a given year. For adults with type 2 diabetes mellitus, their risk of developing liver cancer is more than doubled relative to those who do not have type 2 diabetes mellitus, according to this study."
Peter Campbell, Ph.D.
New risk factors for liver cancer
The results show that the three factors - BMI, waist circumference, and type 2 diabetes - all increased the risk of developing liver cancer.The list of obesity-related cancers already includes colorectal cancer, postmenopausal breast cancer, and cancers of the kidney, endometrium, thyroid, and gallbladder. As Campbell says, these results now give "substantial support to liver cancer being on the list of obesity-associated cancers."
Although this study does not prove that the rise of liver cancer is purely down to obesity, it demonstrates that it is more than likely involved. Liver cancer will no longer be considered the sole domain of alcohol abuse and hepatitis.
Senior investigator Katherine A. McGlynn drives home the importance of the study:
"From a public health perspective, these results are very important because obesity and diabetes, unfortunately, are common conditions in the population. While some other well-described risk factors, such as hepatitis B virus or hepatitis C virus, are associated with increased risks of liver cancer, these factors are much less common than are obesity and diabetes."
Learn how gut bacteria might affect obesity risk in youth.
Liver cancer risk factors
A risk factor is anything that affects your
chance of getting a disease, such as cancer. Different cancers have
different risk factors. Some risk factors, like smoking, can be changed.
Others, like a person's age or family history, can't be changed.
But risk factors don't tell us everything.
Having a risk factor, or even several risk factors, does not mean that
you will get the disease. And some people who get the disease may have
few or no known risk factors.
Scientists have found several risk factors that make a person more likely to develop hepatocellular carcinoma (HCC).
Gender
Hepatocellular carcinoma is much more common
in males than in females. Much of this is probably because of behaviors
affecting some of the risk factors described below. The fibrolamellar
subtype of HCC is more common in women.
Race/ethnicity
In the United States, Asian Americans and
Pacific Islanders have the highest rates of liver cancer, followed by
American Indians/Alaska Natives and Hispanics/Latinos, African
Americans, and whites.
Chronic viral hepatitis (Hep-B or Hep-C)
Worldwide, the most common risk factor for
liver cancer is chronic (long-term) infection with hepatitis B virus
(HBV) or hepatitis C virus (HCV). These infections lead to cirrhosis of
the liver (see above) and are responsible for making liver cancer the
most common cancer in many parts of the world.
In the United States, infection with
hepatitis C is the more common cause of HCC, while in Asia and
developing countries, hepatitis B is more common. People infected with
both viruses have a high risk of developing chronic hepatitis,
cirrhosis, and liver cancer. The risk is even higher if they are heavy
drinkers (at least 6 standard drinks a day).
HBV and HCV can spread from person to person
through sharing contaminated needles (such as in drug use), unprotected
sex, or childbirth. They can also be passed on through blood
transfusions, although this is very rare in the United States since the
start of blood product testing for these viruses. In developing
countries, children sometimes contract hepatitis B infection from
prolonged contact with family members who are infected.
HBV is more likely to cause symptoms, such
as a flu-like illness and a yellowing of the eyes and skin (jaundice).
But most people recover completely from HBV infection within a few
months. Only a very small percentage of adults become chronic carriers
(and have a higher risk for liver cancer). Infants and small children
who become infected have a higher risk of becoming chronic carriers.
HCV, on the other hand, is less likely to
cause symptoms. But most people with HCV develop chronic infections,
which are more likely to lead to liver damage or even cancer.
Other viruses, such as the hepatitis A virus
and hepatitis E virus, can also cause hepatitis. But people infected
with these viruses do not develop chronic hepatitis or cirrhosis, and do
not have an increased risk of liver cancer.
Cirrhosis
Cirrhosis is a disease in which liver cells
become damaged and are replaced by scar tissue. People with cirrhosis
have an increased risk of liver cancer. Most (but not all) people who
develop liver cancer already have some evidence of cirrhosis.
There are several possible causes of
cirrhosis. Most cases in the United States occur in people who abuse
alcohol or have chronic HBV or HCV infections.
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease, a
condition in which people who consume little or no alcohol develop a
fatty liver, is common in obese people. People with a type of this
disease known as non-alcoholic steatohepatitis (NASH) might go on to develop cirrhosis.
Primary biliary cirrhosis
Some types of autoimmune diseases that affect the liver can also cause cirrhosis. For example, there is also a disease called primary biliary cirrhosis (PBC).
In PBC, the bile ducts in the liver are damaged and even destroyed
which can lead to cirrhosis. People with advanced PBC have a high risk
of liver cancer.
Inherited metabolic diseases
Certain inherited metabolic diseases can lead to cirrhosis.
People with hereditary hemochromatosis
absorb too much iron from their food. The iron settles in tissues
throughout the body, including the liver. If enough iron builds up in
the liver, it can lead to cirrhosis and liver cancer.
Heavy alcohol use
Alcohol abuse is a leading cause of
cirrhosis in the United States, which in turn is linked with an
increased risk of liver cancer.
Obesity
Being obese (very overweight) increases the
risk of developing liver cancer. This is probably because it can result
in fatty liver disease and cirrhosis.
Type 2 diabetes
Type 2 diabetes has been linked with an
increased risk of liver cancer, usually in patients who also have other
risk factors such as heavy alcohol use and/or chronic viral hepatitis.
This risk may be increased because people with type 2 diabetes tend to
be overweight or obese, which in turn can cause liver problems.
Certain rare diseases
Diseases that increase the risk of liver cancer include:
Aflatoxins
These cancer-causing substances are made by a
fungus that contaminates peanuts, wheat, soybeans, ground nuts, corn,
and rice. Storage in a moist, warm environment can lead to the growth of
this fungus. Although this can occur almost anywhere in the world, it
is more common in warmer and tropical countries. Developed countries
such as the United States and those in Europe regulate the content of
aflatoxins in foods through testing.
Long-term exposure to these substances is a
major risk factor for liver cancer. The risk is increased even more in
people with hepatitis B or C infections.
Vinyl chloride and thorium dioxide (Thorotrast)
Exposure to these chemicals raises the risk of angiosarcoma of the liver (see What is liver cancer?).
It also increases the risk of developing cholangiocarcinoma and
hepatocellular cancer, but to a far lesser degree. Vinyl chloride is a
chemical used in making some kinds of plastics. Thorotrast is a chemical
that in the past was injected into some patients as part of certain
x-ray tests. When the cancer-causing properties of these chemicals were
recognized, steps were taken to eliminate them or minimize exposure to
them. Thorotrast is no longer used, and exposure of workers to vinyl
chloride is strictly regulated.
Anabolic steroids
Anabolic steroids are male hormones used by
some athletes to increase their strength and muscle mass. Long-term
anabolic steroid use can slightly increase the risk of hepatocellular
cancer. Cortisone-like steroids, such as hydrocortisone, prednisone, and
dexamethasone, do not carry this same risk.
Arsenic
Drinking water contaminated with naturally
occurring arsenic, such as that from some wells, over a long period of
time increases the risk of some types of liver cancer. This is more
common in parts of East Asia, but it might also be a concern in some
areas of the United States.
Infection with parasites
Infection with the parasite that causes
schistosomiasis can cause liver damage and is linked to liver cancer.
This parasite is not found in the US, but infection can occur in Asia,
Africa, and South America.
Tobacco use
Smoking increases the risk of liver cancer.
Former smokers have a lower risk than current smokers, but both groups
have a higher risk than those who never smoked.
Factors with unclear effects on liver cancer risk
Birth control pills
In rare cases, birth control pills, also known as oral contraceptives, can cause benign tumors called hepatic adenomas.
But it is not known if they increase the risk of hepatocellular cancer.
Some of the studies that have looked at this issue have suggested there
may be a link, but most of the studies were not of high quality and
looked at types of pills that are no longer used. Current birth control
pills use different types of estrogens, different estrogen doses, and
different combinations of estrogens with other hormones. It is not known
if the newer pills increase liver cancer risk.
Cases of liver cancer in the UK are far and few between but certain people, including those diagnosed with diabetes, face a higher risk of developing the cancer than the general population.
As with other forms of cancer, however, many cases of liver cancer can be prevented by keeping healthy lifestyle habits such as eating healthily, keeping fit and quitting or avoiding smoking.
What is liver cancer?
Liver cancer is a general term that refers to either:- Primary liver cancer - cancer that originates in the liver
- Secondary liver cancer - cancer that spreads to the liver from another part of the body, such as the bowel
Damage to the liver, which is a common problem for people with diabetes, can disrupt these functions and cause them to fail altogether (liver failure) if left untreated.
How common is liver cancer?
In the UK, nearly 4,000 people are diagnosed with a form of liver cancer each year. The majority of these are secondary liver cancer - primary liver cancer is rare in the UK, but a common problem in other parts of the world.More men are affected than women (60% versus 40%) and cases tend to develop in older adults over the age of 65.
What causes liver cancer?
The exact cause of liver cancer is unclear, but the disease is strongly linked to damage, inflammation and scarring of the liver, a condition known as cirrhosis.Common causes of cirrhosis include alcohol misuse, viral infections such as hepatitis B or hepatitis C, and non-fatty alcoholic liver disease (NAFLD).
Can diabetes increase my risk?
Type 2 diabetes, the most common form of diabetes mellitus, is considered a risk factor for liver cancer due to its strong association with obesity.Obesity can lead to the build-up of excess fat inside the tissue of your liver (NAFLD), which not only raises the risk of cirrhosis but also heart disease and type 2 diabetes.
But as well as being a type 2 diabetes risk factor, non-alcoholic fatty liver disease is also one of the many health conditions (or complications) that can develop as a result of long-term type 2 diabetes, due largely to the fact that type 2 diabetes tends to develop in people who are overweight or obese.
Latest research
In December 2013, scientists from the University of Southern California found an association between type 2 diabetes and increased risk of hepatocelluar carcinoma or HCC - a rare form of liver cancer linked with having fatty liver disease.Analysis of more than 150,000 medical records revealed that the liklihood of developing HCC was 2 to 3 times higher in patients diagnosed with type 2 diabetes compared to patients without diabetes
- Type 2 diabetes linked with up to 3 times increased liver cancer risk
Screening and diagnosis
For people deemed to be at high risk for developing liver cancer, such as those who have had cirrhosis, regular check-ups are important for identifying any early signs of cancer. Screening tests are usually carried out every six months and involve a blood test followed by an ultrasound examination.If you show any of the signs of liver cancer, your GP may use one of the following tests to confirm a diagnosis of liver cancer:
- CT (computerised tomography) scan
- MRI (magnetic resonance imaging) scan
- Bopsy - a small sample of liver tissue is removed and tested for cancerous cells
- Laparoscopy - a small, flexible camera is slipped into your abdomen and used to examine your liver
Treatment
If diagnosed early, there are a number of ways in which liver cancer can be treated, including:- Resection - surgery to remove a section of liver where the cancer is contained
- Liver transplant - replacing the liver with a healthy, donor liver
- Radiofrequency ablation - using heat in the form of an electric charge to destroy the cancerous cells or tumour
However, in most cases the cancer has advanced too far to be controlled or cured by the time a diagnosis is made. At this stage, the only option doctors have is to relieve pain and any other symptoms of liver cancer the patient may be experiencing.
Will my diabetes affect my treatment?
If you have diabetes, your multidisciplinary team (MDT) of cancer specialists will consult with your diabetes care team to determine the most suitable course of treatment.They will take into account how well controlled your diabetes is and the stage your liver cancer is at.
Treating diabetes in a patients who also have cancer is often complicated by the cancer, cancer therapies such as chemotherapy, and the adverse effects of these treatments.
Chemotherapy, for example, can destabilise blood glucose control which will need to be closely monitored by your diabetes care team.
In addition, cancer treatment can be delayed by the development of any short-term diabetes complications, such as severe hypoglycemia.
Diabetes
and cancer are common diseases with tremendous impact on health
worldwide. Epidemiologic evidence suggests that people with diabetes are
at significantly higher risk for many forms of cancer. Type 2 diabetes
and cancer share many risk factors, but potential biologic links between
the two diseases are incompletely understood. Moreover, evidence from
observational studies suggests that some medications used to treat
hyperglycemia are associated with either increased or reduced risk of
cancer. Against this backdrop, the American Diabetes Association and the
American Cancer Society convened a consensus development conference in
December 2009. Following a series of scientific presentations by experts
in the field, the writing group independently developed this consensus
report to address the following questions:
- Is there a meaningful association between diabetes and cancer incidence or prognosis?
- What risk factors are common to both diabetes and cancer?
- What are possible biologic links between diabetes and cancer risk?
- Do diabetes treatments influence risk of cancer or cancer prognosis?
For
each area, the authors were asked to address the current gaps in
evidence and potential research and epidemiologic strategies for
developing more definitive evidence in the future. Table 1
includes a summary of findings and recommendations. Recommendations in
this report are solely the opinions of the authors and do not represent
official position of the American Diabetes Association or the American
Cancer Society.
Table 1
Summary and recommendations
1. Is there a meaningful association between diabetes and cancer incidence or prognosis?
Both
diabetes and cancer are prevalent diseases whose incidence is
increasing globally. Worldwide, the prevalence of cancer has been
difficult to establish because many areas do not have cancer registries,
but in 2008 there were an estimated 12.4 million new cancer cases
diagnosed. The most commonly diagnosed cancers are lung/bronchus,
breast, and colorectal, whereas the most common causes of cancer deaths
are lung, stomach, and liver cancer (1).
In the U.S., the most commonly diagnosed cancers are prostate,
lung/bronchus, and colon/rectum in men and breast, lung/bronchus, and
colon/rectum in women. Of the world population between the ages of 20
and 79 years, an estimated 285 million people, or 6.6%, have diabetes (2).
In 2007, diabetes prevalence in the U.S. was 10.7% of persons aged 20
years and older (23.6 million individuals), with an estimated 1.6
million new cases per year. Type 2 diabetes is the most common form,
accounting for ∼95% of prevalent cases (3). Worldwide, cancer is the 2nd and diabetes is the 12th leading cause of death (4).
In the U.S., cancer is the 2nd and diabetes is the 7th leading cause of
death; the latter is likely an underestimate, since diabetes is
underreported on death certificates as both a cause and comorbid
condition (3).
Cancer
and diabetes are diagnosed within the same individual more frequently
than would be expected by chance, even after adjusting for age. Both
diseases are complex with multiple subtypes. Diabetes is typically
divided into two major subtypes, type 1 and type 2 diabetes, along with
less common types, while cancer is typically classified by its anatomic
origin (of which there are over 50, e.g., lymphoma, leukemia, lung, and
breast cancer) and within which there may be multiple subtypes (e.g.,
leukemia). Further, the pathophysiologies underlying both cancer and
diabetes are (with rare exceptions) incompletely understood.
For
more than 50 years, clinicians have reported the occurrence of patients
with concurrent diabetes and cancer. However, as early as 1959, Joslin
et al. (5)
stated, “Studies of the association of diabetes and cancer have been
conducted over a period of years, but evidence of a positive association
remains inconclusive.” Subsequently, an association between the two
diseases was identified in the 1960s in population-based studies. More
recently, the results of several studies have been combined for
meta-analytic study (6),
indicating that some cancers develop more commonly in patients with
diabetes (predominantly type 2), while prostate cancer occurs less often
in men with diabetes. The relative risks imparted by diabetes are
greatest (about twofold or higher) for cancers of the liver, pancreas,
and endometrium, and lesser (about 1.2–1.5 fold) for cancers of the
colon and rectum, breast, and bladder. Other cancers (e.g., lung) do not
appear to be associated with an increased risk in diabetes, and the
evidence for others (e.g., kidney, non-Hodgkin lymphoma) is
inconclusive. Few studies have explored links with type 1 diabetes.
Since
insulin is produced by pancreatic β-cells and then transported via the
portal vein to the liver, both the liver and the pancreas are exposed to
high concentrations of endogenously produced insulin. Diabetes-related
factors including steatosis, nonalcoholic fatty liver disease, and
cirrhosis may also enhance susceptibility to liver cancer. With regard
to pancreatic cancer, interpretation of the causal nature of the
association is complicated by the fact that abnormal glucose metabolism
may be a consequence of pancreatic cancer (so-called “reverse
causality”). However, a positive association between diabetes and
pancreatic cancer risk has been found when restricted to diabetes that
precedes the diagnosis of pancreatic cancer by at least 5 years, so
reverse causation does not likely account for the entirety of the
association.
Only for prostate cancer is diabetes
associated with a lower risk. This association has been observed both
before and after the advent of screening with prostate-specific antigen
(PSA), so detection bias due to differential PSA utilization does not
account for this finding. Some metabolic factors associated with
diabetes, such as reduced testosterone levels, may be involved (although
circulating testosterone levels have not been consistently associated
with prostate cancer incidence). While obesity has not been associated,
and in some studies is even inversely associated, with prostate cancer
incidence, obese men with prostate cancer have higher cancer mortality
rates than those of normal weight (7).
In addition to metabolic factors such as hyperinsulinemia, obesity may
be associated with clinical factors (such as delayed diagnosis, poorer
treatment) that may underlie the worsened prostate cancer prognosis.
Results
of some, but not all, epidemiological studies suggest that diabetes may
significantly increase mortality in patients with cancer (8).
For example, in one study, 5-year mortality rates were significantly
higher (hazard ratio 1.39) in patients diagnosed with both breast cancer
and diabetes than in comparable breast cancer patients without diabetes
(9).
Since diabetes is associated with excess age-adjusted mortality,
whether the apparent excess mortality associated with diabetes in cancer
patients is any greater than the excess mortality observed among
diabetic patients without cancer is unclear. Of note, higher
pre-diagnosis C-peptide levels (an indirect marker of insulin
resistance) have been associated with a poorer disease-specific survival
for prostate cancer (7) and colorectal cancer (10).
Go to:
Unanswered questions
Diabetes
has been consistently associated with increased risk of several of the
more common cancers, but for many, especially the less common cancers,
data are limited or absent (6)
and more research is needed. Uncertainty is even greater for the issue
of diabetes and cancer prognosis or cancer-specific mortality. It
remains unclear whether the association between diabetes and cancer is
direct (e.g., due to hyperglycemia), whether diabetes is a marker of
underlying biologic factors that alter cancer risk (e.g., insulin
resistance and hyperinsulinemia), or whether the cancer-diabetes
association is indirect and due to common risk factors such as obesity.
Whether cancer risk is influenced by duration of diabetes is a critical
and complex issue and may be further complicated by the multidrug
therapy often necessary for diabetes treatment (as discussed in question
4). What is also required is a better understanding of whether diabetes
influences cancer prognosis above and beyond the prognosis conferred by
each disease state independently.
To
adequately address these questions, prospective population-based studies
with high-quality databases are needed to compare incidence of specific
cancers between individuals with high circulating insulin levels with
or without diabetes and nondiabetic individuals with normal insulin
sensitivity (and therefore low insulin levels). Examining other
diabetes-related biomarkers (e.g., adiponectin, hyperglycemia) is also
critical. Importantly, common confounders (such as body weight and
physical activity) must also be more readily available and assessed.
Better characterization of aspects of diabetes (diabetes duration,
therapy, degree of glycemic control) in relation to cancer risk is
needed. In view of the variable associations between diabetes and cancer
risk at specific sites, the authors discourage studies exploring links
between diabetes and risk of all cancers combined. For example, since
lung cancer does not appear to be meaningfully linked with diabetes,
including this common cancer in studies will dilute observed
associations, should they exist.
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2. What risk factors are common to both cancer and diabetes?
Potential
risk factors (modifiable and nonmodifiable) common to both cancer and
diabetes include aging, sex, obesity, physical activity, diet, alcohol,
and smoking.
Go to:
Nonmodifiable risk factors
Age.
Although
the incidence of some cancers peaks in childhood or in young adults,
the incidence of most cancers increases with age. In economically
developed countries, 78% of all newly diagnosed cancer occurs among
individuals aged 55 years and older (11).
Diabetes also becomes increasingly common with age: Prevalence is 2.6%
in U.S. adults 20–39 years of age, 10.8% in those 40–59 years of age,
and increases to 23.8% in those 60 years of age or older (3). In parallel with the obesity epidemic, type 2 diabetes is becoming more frequent among adolescents and young adults (12,13), potentially adding years of additional risk from diabetes to the population.
Sex.
While
certain cancers are sex-specific (e.g., cervix, uterine, testicular,
prostate), or nearly so (breast), overall cancer occurs more frequently
in men. Men have slightly higher age-adjusted risk of diabetes than
women (3).
Race/ethnicity.
The
age-standardized incidence of cancer and diabetes varies significantly
among different populations. Factors that may contribute to this
variability include differences in the prevalence of major risk factors,
genetic factors, medical practices such as screening, and completeness
of reporting. In the U.S., African Americans are more likely to develop
and die from cancer than other race or ethnic groups. Following African
Americans are non-Hispanic whites, with Hispanics, Native Americans, and
Asian Americans/Pacific Islanders having lower cancer incidence and
mortality (14).
As with the worldwide situation, the U.S. race/ethnic variability in
cancer incidence is attributed, at least in part, to socioeconomic and
other disparities, but biological factors, such as levels of hormones
that vary by race (15), may also play a role.
In
the U.S., type 2 diabetes and its complications disproportionately
affect a number of specific populations, including African Americans,
Native Americans, Hispanics, and Asian Americans/Pacific Islanders
compared with non-Hispanic whites (3).
While incompletely understood, genetic, socioeconomic, lifestyle, and
other environmental factors are thought to contribute to these
disparities.
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Modifiable risk factors
Overweight, obesity, and weight change.
Overweight (BMI ≥25 and <30 kg/m2) or obese (BMI ≥30 kg/m2)
individuals have a higher risk for many types of cancer compared with
individuals whose BMI is considered within the normal range (18.5 to
<25 kg/m2) (16,17).
The cancers most consistently associated with overweight and obesity
are breast (in postmenopausal women), colon/rectum, endometrium,
pancreas, adenocarcinoma of the esophagus, kidney, gallbladder, and
liver. Obesity may also increase risk of mortality from some cancers,
such as prostate (7).
A growing body of evidence suggests that weight gain is associated with
an increased risk of some cancers, breast cancer in particular (17).
Increases in body weight during adulthood largely reflect increases in
adipose tissue rather than lean mass, so total body fat may be a better
measure of the risk for cancer than BMI.
Studies over
decades have consistently shown a strong association between obesity and
both insulin resistance and type 2 diabetes incidence (18), with risk of diabetes and earlier age at onset directly linked to obesity severity (19). For type 2 diabetes (20) as well as certain cancers (e.g., colon) (21),
some studies suggest that waist circumference, waist-to-hip ratio, or
direct measures of visceral adiposity are associated with risk
independently of BMI.
The case for a causal
relationship between obesity and disease is strengthened by evidence
that weight loss lowers disease risk. In the case of diabetes, numerous
studies have shown that weight loss decreases diabetes incidence and
restores euglycemia in a significant fraction of individuals with type 2
diabetes. In the randomized, prospective, multicenter Diabetes
Prevention Program trial, an intensive lifestyle intervention of diet
(targeting 5–7% weight loss) and physical activity was associated with a
58% reduction in diabetes incidence in high-risk individuals (22), and weight loss accounted for most of the effect (23). In addition, weight loss may also limit the risk of developing gestational diabetes (24).
The
association between weight loss and subsequent cancer risk is less
clear. Most evidence has been derived from breast cancer studies, where
weak or null associations were observed. Since the weight loss
definition and the referent groups differed across studies, these
studies are difficult to compare. Weight loss categories tend to have
small numbers, and many women who do lose weight do not maintain their
weight loss beyond 1 year. In the Nurses' Health Study, a statistically
significant inverse association between adult weight loss and
postmenopausal breast cancer was found only when the weight loss had
been maintained for two survey cycles, or 4 years (25).
Observational studies of weight loss and cancer risk require extremely
large sample sizes with long-term follow-up and careful monitoring of
weight change. One concern of all observational studies of weight loss
and subsequent cancer risk is that weight loss may be a sign of
undiagnosed cancer. As a practical matter, a randomized clinical trial
to study the effect of weight loss on cancer risk is unlikely to be
feasible; such a study would have to be very large and would likely be
stopped early due to a protective effect on diabetes and heart disease
before enough cancer end points would accumulate.
The significant amount of weight lost with bariatric surgery may also provide clarity to this issue. However, a recent summary (26)
noted the limited evidence of the effects of bariatric surgery on
cancer incidence. Among the studies published to date, three found that
obese women who underwent bariatric surgery were at lower risk of cancer
(relative risks ranging from 0.58 to 0.62) compared with untreated
obese women. The inverse associations appeared to be due in large part
to a protective effect on breast and endometrial cancer. In the two
studies that included men, no association between bariatric surgery and
cancer risk was observed.
Bariatric
surgery is a very effective treatment for type 2 diabetes, with a
meta-analysis showing that type 2 diabetes resolved in 78% and resolved
or improved in 87% of patients after bariatric surgery (27).
In contrast to the known effects of bariatric surgery on treating
diabetes, the therapy's role in preventing diabetes would seem likely
but has not been established through prospective trials.
Diet.
A
majority of studies (despite different study designs and differing
study populations) suggest that diets low in red and processed meats and
higher in vegetables, fruits, and whole grains are associated with a
lower risk of many types of cancer (17,28,29).
Diets that are low in red and processed meat but high in
monounsaturated fatty acids, fruits, vegetables, whole grain cereals,
and dietary fiber may protect against type 2 diabetes, possibly through
improving insulin sensitivity (30,31).
Low-carbohydrate diets (which often include greater consumption of red
meats and fat) have also been associated with weight loss and
improvements in insulin sensitivity and glycemic control. However,
randomized controlled trial evidence of dietary interventions and
diabetes prevention only exists for low-fat, low-calorie, plus/minus
high-fiber diets (22,32).
Several
studies suggest that diets high in foods with a high glycemic index or
load are associated with an increased risk of type 2 diabetes (28,33). However, evidence of their associations with cancer risk is mixed (28,34,35).
Regardless, to the extent that energy-dense and sugary foods contribute
to overweight and obesity, the American Cancer Society, the World
Cancer Research Fund, and the American Institute for Cancer Research
recommend limiting consumption of these foods (17,29).
Physical activity.
Evidence
from observational epidemiologic studies consistently shows that higher
levels of physical activity are associated with a lower risk of colon,
postmenopausal breast, and endometrial cancer (17,36,37).
Physical activity may also help prevent other cancers, including lung
and aggressive prostate cancer, but a clear link has not been
established. Some evidence also suggests that physical activity
postdiagnosis may improve cancer survival for some cancers, including
breast (38) and colorectal (39).
A
protective role for increased physical activity in diabetes metabolism
and outcomes has been demonstrated. Data from observational and
randomized trials suggest that ∼30 min of moderate-intensity exercise,
such as walking, at least 5 days per week substantially reduces (25–36%)
the risk of developing type 2 diabetes (40).
Analyses of the effects of different components of the intensive
lifestyle intervention in the Diabetes Prevention Program suggested that
those who did not reach weight loss goals still significantly reduced
their risk of diabetes if they reached the exercise goals, although
weight loss was the only component independently associated with
diabetes prevention in multivariate analyses (23).
Tobacco smoking.
It is estimated that worldwide, tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths (41).
Other cancers strongly associated with smoking are larynx, upper
digestive, bladder, kidney, pancreas, leukemia, liver, stomach, and
uterine cervix. Studies suggest that smoking is also an independent risk
factor for the development of diabetes (42,43).
In addition, because of the effect of smoking on increasing risk of
cardiovascular disease, retinopathy, and other complications of
diabetes, smoking has an adverse effect on diabetes-related health
outcomes (44).
Alcohol.
Alcoholic
beverage consumption, even in moderate amounts, increases the risk of
many types of cancer including those of the oral cavity, pharynx,
larynx, esophagus, liver, colon/rectum, and female breast (45).
While excess alcohol consumption is also a risk factor for diabetes,
moderate alcohol consumption has been associated with reduced diabetes
incidence in both men and women (46,47).
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Unanswered questions
A
critical question is whether the associations between diabetes and risk
of certain cancers is largely due to shared risk factors (obesity, poor
diet, physical inactivity, and aging), or whether diabetes itself, and
the specific metabolic derangements typical of diabetes (e.g.,
hyperglycemia, insulin resistance, hyperinsulinemia), increase the risk
for some types of cancer. While it is clear that lower levels of
adiposity, healthy diets, and regular physical activity are associated
with reduced risk for type 2 diabetes and for several common types of
cancer, these factors are generally interrelated, making the
contribution of each factor difficult to assess. More research is needed
to understand the role of specific components of healthy lifestyles
independent of others (e.g., diet quality independent of body weight).
In addition, further study of those who are of normal body weight but
have hyperinsulinemia or are sedentary, and of those who are obese but
have normal metabolic parameters, is necessary to better understand the
relationship between diabetes and cancer risk. Little is known about how
modifiable lifestyle factors influence prognosis in cancer patients.
How genetic variants that influence diverse aspects of diabetes (e.g.,
insulin resistance, β-cell depletion) influence cancer risk may provide
insights into the nature of the diabetes-cancer relationship. Addressing
these questions will require large, long-term observational studies,
with their inherent limitations. Although not powered for cancer
outcomes, long-term trials such as the Look AHEAD trial of the effects
of weight loss on cardiovascular outcomes in patients with diabetes (48),
and follow-up of cohorts in lifestyle studies such as the Diabetes
Prevention Program, may provide further evidence for the impact of
lifestyle improvements on cancer incidence.
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3. What are possible biologic links between diabetes and cancer risk?
Carcinogenesis
is a complex process. Normal cells must undergo multiple genetic “hits”
before the full neoplastic phenotype of growth, invasion, and
metastasis occurs. This process of malignant transformation can be
divided into multiple steps: initiation (irreversible first step toward
cancer), promotion (stimulation of the growth of initiated cells), and
progression (development of a more aggressive phenotype of promoted
cells). Factors that affect one or more steps of this pathway could be
associated with cancer incidence or mortality. Diabetes may influence
the neoplastic process by several mechanisms, including hyperinsulinemia
(either endogenous due to insulin resistance or exogenous due to
administered insulin or insulin secretogogues), hyperglycemia, or
chronic inflammation.
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The insulin/IGF axis
Insulin
and insulin-like growth factor (IGF) receptors form a complex network
of cell surface receptors; homodimers and heterodimers have been
described, and all function to mediate insulin and IGF responses (49).
Most cancer cells express insulin and IGF-I receptors; the A isoform of
the insulin receptor is commonly expressed. The A receptor isoform can
stimulate insulin-mediated mitogenesis, even in cells deficient in IGF-I
receptors (50).
In addition to its metabolic functions, the insulin receptor is also
capable of stimulating cancer cell proliferation and metastasis. Because
most glucose uptake in cancer cells is constitutively high and
independent of insulin binding to its receptor (51),
the effects of insulin receptor activation on neoplastic cells may
relate more to cell survival and mitogenesis than to enhanced glucose
uptake.
Multiple signaling pathways are activated after
insulin receptors or IGF-I receptors interact with their ligands. By
phosphorylating adaptor proteins, most notably the insulin receptor
substrate (IRS) family, the initial kinase event is linked to downstream
signaling pathways (52).
Once activated, these signaling pathways may stimulate multiple cancer
phenotypes including proliferation, protection from apoptotic stimuli,
invasion, and metastasis, potentially enhancing promotion and
progression of many types of cancer cells. It is also clear that
insulin/IGF may stimulate normal cells that are involved in cancer
progression. For example, hyperglycemia allows IGF-I to stimulate
vascular smooth muscle cell proliferation and migration (53).
While this process has been linked to the pathophysiology of
atherosclerosis, abnormal vasculature growth is also a hallmark of
cancer.
Apart from direct effects of insulin on cancer
cells, it is possible that hyperinsulinemia could promote carcinogenesis
indirectly through its effects on IGF-I (54). Insulin reduces the hepatic production of IGF binding protein (IGFBP)-1 (55,56) and possibly IGFBP-2 (57)
with resultant increases in the levels of circulating free, bioactive
IGF-I. IGF-I has more potent mitogenic and anti-apoptotic activities
than insulin (58) and could act as a growth stimulus in preneoplastic and neoplastic cells that express insulin, IGF-I, and hybrid receptors (49).
Human tumors commonly over-express these receptors, and many cancer
cell lines have been shown to be responsive to the mitogenic action of
physiological concentrations of IGF-I.
As has been found in other cancers, insulin receptors are frequently expressed by breast cancer cells (59).
Compared with the ligand (i.e., insulin), higher levels of insulin
receptor have been associated with favorable breast cancer prognosis in
some studies (60,61).
While these findings may seem to be contradictory, they are consistent
with other hormone-dependent pathways in breast cancer. Elevated serum
levels of estradiol are weakly associated with increased breast cancer
risk (62), while expression of estrogen receptor (ER)-α is a favorable prognostic factor (63).
Just like ER, insulin receptor may be a marker of breast cancer cell
differentiation and identify cells with a potentially less aggressive
phenotype. On the other hand, a recent larger study (64)
concluded that high insulin receptor levels are related to adverse
prognosis; further research is needed. Moreover, the relationship
between serum levels of insulin and regulation of insulin receptor
levels in neoplastic tissues has never been established. Since growth
factors may downregulate the expression of their cognate receptors, it
is possible that tumors with low insulin receptor levels are the most
insulin-stimulated. Thus, there are biologically plausible models and
correlative human clinical studies suggesting that insulin acting
through insulin receptors might affect breast cancer risk and
progression.
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Effect of hyperinsulinemia on other hormones
Increased
circulating insulin has a number of indirect effects including a
reduction in the hepatic synthesis and blood levels of sex hormone
binding globulin, leading to increases in bioavailable estrogen in both
men and women and increased levels of bioavailable testosterone in women
but not in men (65).
Androgen synthesis in the ovaries and possibly the adrenals is
increased by hyperinsulinemia in premenopausal women. Elevated
endogenous sex steroid levels are associated with a higher risk of
postmenopausal breast, endometrial, and possibly other cancers.
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Hyperglycemia and cancer
In
considering the complexity of interactions between diabetes, diabetes
treatments, and cancer, it is important to not overlook glucose as a
potentially relevant mediator. The recent resurgence of interest in the
Warburg hypothesis and cancer energetics (66)
emphasizes the dependence of many cancers on glycolysis for energy,
creating a high requirement for glucose (or even “glucose addiction”),
since ATP generation by glycolysis requires far more glucose than
oxidative phosphorylation. Indeed, this forms the basis for FDG-PET
imaging of cancers, which detects tissues with high rates of glucose
uptake. The possibility that untreated hyperglycemia facilitates
neoplastic proliferation therefore deserves consideration. Direct data
concerning dose-response characteristics of cancers to glucose are
sparse, but it is relevant that most cancers have highly effective
upregulated, insulin-independent glucose uptake mechanisms (67) and therefore may not derive a further growth advantage from hyperglycemia.
In vivo models showing reduced tumor growth in the setting of type 1 diabetes (68)
suggest that hyperglycemia does not lead to increased neoplastic
growth, at least in the setting of insulin deficiency. Studies relating
hyperglycemia to cancer do not necessarily indicate that glucose
mediates the relationship; rather, hyperglycemia may serve as a
surrogate for a causative factor such as hyperinsulinemia. Given the
molecular heterogeneity of cancers, one cannot at this point exclude the
possibility that there exists a subset of tumors for which
hyperglycemia confers a growth advantage and appropriate therapy for
diabetes therefore limits tumor growth, but the aggregate data suggest
that insulin receptor activation may be a more important variable than
hyperglycemia in determining tumor growth.
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Inflammatory cytokines, diabetes, and cancer risk
In
addition to the direct effects of insulin, type 2 diabetes and/or the
related obesity might enhance other pathways resulting in malignant
progression. As recently reviewed, adipose tissue is an active endocrine
organ producing free fatty acids, interleukin-6 (IL-6), monocyte
chemoattractant protein, plasminogen activator inhibitor-1 (PAI-1),
adiponectin, leptin, and tumor necrosis factor-α (69).
Each of these factors might play an etiologic role in regulating
malignant transformation or cancer progression. In some cases, the role
for these molecules is well known. For example, the plasminogen system
has been linked to cancer with expression of PAI-1 linked to poor
outcome in breast cancer (70).
Activation of signal transducer and activator of transcription protein
(STAT) signaling, via cytokines such as IL-6, is known to enhance cancer
cell proliferation, survival, and invasion while also suppressing host
anti-tumor immunity (71).
Similarly,
animal studies of energy balance support epidemiologic results relating
obesity with cancer mortality. Certain experimental cancers tend to
behave more aggressively when animals overeat and less aggressively when
animals are calorically restricted (72–74).
These studies provide evidence that diet-induced changes in IL-6 and/or
insulin may mediate the effect of diet on neoplasia and indicate that
differences between tumors with respect to specific signaling pathways
determine the extent to which diet influences tumor behavior (75).
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Major unanswered questions
As
previously outlined, there is a growing body of epidemiologic evidence
supporting a link between diabetes and the incidence and/or prognosis of
some cancers. It is recognized the association may not be causal;
diabetes and cancer may be associated simply because they share common
predisposing risk factors such as obesity. However, a number of
plausible biologic mechanisms have been described that may account for
this link, including effects of hyperglycemia, hyperinsulinemia, and
inflammation on cancer etiology and progression. Mechanisms by which
these factors interact with cancer risk require further study. Another
important area for investigation concerns the issue of insulin
resistance in type 2 diabetes in cells of non-classic insulin target
organs, such as the breast, colon, or prostate. The assumption that in
the setting of insulin resistance of classic insulin target organs
(liver, muscle, adipose tissue) at least a subset of cancers remain
insulin-sensitive, or that insulin insensitivity to metabolic pathways
does not extend to resistance to growth-promoting properties, needs to
be more closely examined. How common is this? And what are the
dose-response characteristics of insulin stimulation of such cancers?
Research
is ongoing to provide a clearer understanding of these possible links,
and this information may be relevant for prevention and optimal patient
management. Most of the supporting evidence on biologic mechanisms comes
from in vivo and in vitro studies. Since multiple prediagnostic
biospecimens are rarely available on cohorts large enough for studies of
cancer, many epidemiologic studies are only able to evaluate a single
time point when measuring levels of insulin, glucose, or other analytes.
The risk of long-term exposure to high levels of insulin is relatively
underexplored and has direct relevance to the cancer risk associated
with diabetes duration and use of exogenous insulin. In addition, most
of the large studies have only fasting levels; postprandial (area under
the curve) insulin levels have not been adequately examined.
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4. Do diabetes treatments influence cancer risk or cancer prognosis?
Improved
glucose control remains one of the central goals of effective diabetes
management, which strives to minimize morbidity and mortality by
reducing the risk of diabetes-associated complications. Several factors
are considered by clinicians and patients when selecting pharmacologic
diabetes therapies. These include the type of diabetes being treated,
the glucose-lowering potential of a given agent, known acute and chronic
adverse effects of treatment (such as weight gain, hypoglycemia, fluid
retention, gastrointestinal intolerance), treatment costs, and patient
comorbidities and characteristics. Only recently has the issue of cancer
risk with diabetes treatments been considered.
Individuals
with type 1 diabetes represent ∼5% of the diabetes population
worldwide. The autoimmune destruction of the pancreatic β-cells results
in the loss of insulin production and the need for immediate and
lifelong insulin therapy. In contrast, type 2 diabetes is much more
common and accounts for ∼95% of the diabetes population. Type 2 diabetes
is generally associated with overweight and obesity (in an estimated
80% of cases) and commonly advances from a pre-diabetic state
characterized by insulin resistance (hyperinsulinemia) to frank diabetes
with sustained insulin resistance accompanied by a progressive
reduction in insulin secretion. The resulting relative insulin
deficiency gives rise to both fasting and postmeal hyperglycemia.
Ongoing loss of insulin secretory capacity, along with a diminished
incretin effect and several other pathophysiologic defects (76),
makes the hyperglycemia of type 2 diabetes progressive. This results in
increasing use of pharmacologic agents over time and the eventual need
for insulin therapy in approximately half of all patients (77).
The selection of the most appropriate pharmacologic agent(s) for each
patient involves clinical decision-making process that includes an
ongoing risk/benefit analysis (78).
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Metformin
The
biguanide metformin is the most commonly used therapy in patients with
type 2 diabetes, often prescribed as initial or combination therapy (79).
While the mechanism of action of metformin in diabetes is only
partially understood, metformin treatment generally reduces levels of
both circulating glucose and insulin in patients with insulin resistance
and hyperinsulinemia. The primary mode of action is through reduced
hepatic glucose output (80).
In
laboratory studies, metformin has been shown to inhibit cell
proliferation, reduce colony formation, and cause partial cell cycle
arrest in cancer cell lines (81–83).
These studies suggest that metformin-induced activation of
AMP-activated protein kinase (AMPK) in tumor cells may lead to growth
inhibition, at least in part by inhibiting protein synthesis (84).
Interestingly, in vivo studies show that metformin has less
antineoplastic activity in mice on a control diet than it does in mice
on a high-energy diet associated with hyperinsulinemia and accelerated
tumor growth (74).
This suggests that the insulin-lowering action of metformin may
contribute to its anti-neoplastic activity, and that it may have less
impact on cancers in less hyperinsulinemic patients. Other in vitro
studies suggest that metformin may selectively kill cancer stem cells
and enhance effectiveness of breast cancer treatment regimens (85–87). Metformin has also been shown to reduce mammary tumor growth in rodent models (88).
Results
of a growing number of observational human studies suggest that
treatment with metformin (relative to other glucose-lowering therapies)
is associated with reduced risk of cancer (89–93) or cancer mortality (94).
However, these studies have generally been limited in their ability to
assess association with specific cancer types. Confounding by indication
may limit the interpretation of results from observational studies, as
metformin is most typically prescribed to those with short duration of
diabetes and without contraindicating factors (advanced age, liver, or
kidney disease) that also might impact risk of some cancers.
Additional
observational data suggest that metformin might improve cancer
prognosis. Metformin treatment was associated with higher pathologic
complete response among early-stage breast cancer patients receiving
neoadjuvant therapy (95).
The potential effect of metformin on breast cancer cell proliferation
(as measured by Ki67 index) is currently being evaluated in a clinical
trial with a small number of subjects (96), and other trials of metformin therapy in patients with breast cancer are planned.
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Thiazolidinediones
Thiazolidinediones
(TZDs) are insulin-sensitizing peroxisome proliferator–activated
receptor (PPAR)γ agonists that do not increase insulin secretion
directly or cause hypoglycemia when used alone. Two drugs in this class,
pioglitazone and rosiglitazone, are currently available. Unlike
metformin, TZDs may be used in patients with renal insufficiency,
although fluid retention is a potential adverse effect. TZDs are
contraindicated in selected patients, most notably those with liver
disease or with active untreated or unstable congestive heart failure.
In
vitro studies indicate that PPARγ agonists have several anti-cancer
activities, such as inhibiting growth and inducing apoptosis and cell
differentiation (97),
and PPARγ is currently considered a potential target for both
chemoprevention and cancer therapy based on other preclinical studies (98,99).
However, since recent in vitro studies indicate that the effects of
PPARγ agonists on cell growth are often independent of the presence of
PPARγ (100–102),
the clinical relevance of findings of in vitro studies is unclear.
Rodent studies also indicate that PPAR agonists can potentiate
tumorigenesis, and they have been considered by some to be
multi-species, multi-sex carcinogens (103).
Therefore, it is possible that TZDs may increase, decrease, or have a
neutral effect on the risk of cancer or cancer progression in humans.
Definitive
human data on cancer risk associated with TZDs are not available. Three
epidemiologic studies conducted among patients with diabetes focused on
all cancers combined or only on a limited number of cancer sites, and
results were inconsistent (104–106).
Results of a recent meta-analysis of clinical trials of rosiglitazone
showed no statistically significant increase or decrease in the risk of
cancer at all sites combined or at the more common sites, although the
numbers of cancer cases at these specific sites were small (107).
The epidemiologic studies and the meta-analysis of trials were able to
examine only short-term exposure, largely due to the relatively recent
introduction of these medications and the shorter duration of many
clinical efficacy trials.
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Insulin secretagogues
Secretagogues,
including sulfonylureas and the rapid-acting glinides, stimulate
β-cells to release insulin by binding to specific cell receptors,
resulting in β-cell depolarization and release of insulin stores.
Sulfonylureas (e.g., glyburide, glipizide, glimepiride) have been used
to treat type 2 diabetes for more than 50 years. While this class of
agents is one of the more effective in lowering A1C, these drugs can
cause hypoglycemia and weight gain. A small number of observational
studies found a higher risk of cancer or cancer death among individuals
with diabetes treated with sulfonylureas compared with those treated
with metformin or other diabetes medications (90–92,110).
However, most of these studies had very few cancer cases among users of
sulfonylureas, and therefore power was limited to examine associations
with specific cancer sites (91,111). Studies regarding dose, duration, recency, and persistence of use are limited.
While
it is possible that the association of sulfonylureas and cancer risk is
genuine, it is difficult to determine whether the findings reflect
excess cancer among users of the secretagogues or reduced risk in those
using comparator drugs, which often include metformin therapy.
Furthermore, if the association were to be confirmed, it remains to be
determined if the mechanism involves direct actions of the agents on
transformed cells or cells at risk for carcinogenesis, as compared with
indirect effects mediated by increased insulin levels. There are no
published data that support an association between the glinide
secretagogues and cancer risk, perhaps because they are newer and use of
these agents is less common.
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Incretin-based therapies
Two
recently developed classes of drugs either enhance or mimic the effect
of gut-derived incretin hormones that improve glucose-dependent insulin
secretion, suppress postprandial glucagon levels, and delay gastric
emptying. The first of the incretin-based therapies introduced,
exenatide, has ∼50% homology with the incretin hormone glucagon-like
peptide 1 (GLP-1), while the more recently approved liraglutide is an
analog of human GLP-1. Both compounds bind to the GLP-1 receptor to
exert agonist activity. The oral dipeptidyl peptidase-4 (DPP-4)
inhibitors inhibit the action of the ubiquitous enzyme that rapidly
degrades many peptides including endogenous GLP-1.
Liraglutide
increased risk of medullary thyroid cancer in rats and mice in
preclinical tests and was associated with slight increases in serum
calcitonin in human trials (U.S. Food and Drug Administration).
Exenatide, liraglutide, and DPP-4 inhibitors increased β-cell
proliferation in animal studies, and in one small study of a transgenic
rodent model, the DPP-4 inhibitor sitagliptin was demonstrated to
increase pancreatic ductal hyperplasia (112).
No impact of incretin-based agents on human cancer incidence has been
reported, likely due to the fact that these newer drugs have not been
used in sufficient numbers of patients or for long enough periods of
time to fully assess any possible effects on cancer risk.
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Insulin and insulin analogs
Insulin
is required for all patients with type 1 diabetes. It is also necessary
for many patients with type 2 diabetes to treat hyperglycemia, in part
due to the progressive loss of β-cell function over time. Between 40–80%
of individuals with type 2 diabetes will ultimately be considered for
insulin therapy in an effort to achieve glycemic targets (77).
Several formulations of insulin exist: short-acting human regular
insulin, intermediate-acting human NPH insulin, and both rapid- and
long-acting analogs of human insulin. Subcutaneous injection of insulin
results in significantly higher levels of circulating insulin in the
systemic circulation than endogenous insulin secretion, thereby possibly
amplifying links between hyperinsulinemia and cancer risk.
Recently,
a series of widely publicized epidemiologic analyses examined a
possible association between insulin use and/or use of the long-acting
insulin analog glargine (91,110,113,114)
and an increase in risk of cancer. As noted below, insulin glargine may
have a disparate impact on cancer risk through its binding to IGF-1
receptors. The potential strengths and weaknesses of these studies have
been broadly debated and well detailed (115–117).
For example, one concern is that insulin is more commonly prescribed in
patients with longer duration of type 2 diabetes and is used more often
in those with one or more comorbid conditions that preclude use of
comparator medications. Rarely have these or other potential confounders
(body mass, actual insulin dose, degree of glucose control, glucose
variability, other patient characteristics) been fully accounted for in
the study designs or analyses.
Randomized
clinical trial data from an open-label 5-year trial of insulin glargine
versus NPH insulin did not find evidence of excess cancer risk (all
sites combined) in the insulin glargine arm (118),
although among the ∼1,000 subjects randomized, there was a very small
number of cancer end points (57 cancer cases in the glargine arm and 62
cases in the NPH arm). The ongoing randomized ORIGIN trial (glargine
versus placebo in patients with impaired fasting glucose or newly
diagnosed type 2 diabetes) is much larger (∼12,000 patients randomized
and followed for 6–7 years) (119).
Importantly, this trial was powered for cardiovascular outcomes and may
still not provide definitive evidence regarding cancer incidence,
especially for specific cancers.
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Possible mechanisms for the link between exogenous insulin, insulin analogs, and cancer
Potential
mechanisms by which administration of insulin or insulin analogs might
influence neoplastic disease include both direct and indirect actions.
Direct actions have received the most attention and involve interactions
of the administered ligands (or their metabolites) with cancer cells,
partially transformed cells, or cells at risk for transformation.
Indirect mechanisms have been less well studied but would involve
interactions of signaling molecules whose levels (e.g., glucagon,
adiponectin, or IGFBPs) or activity are influenced by administered
insulin on these target cells.
With respect to direct
actions, one must consider not only the affinity of the administered
agents for the various receptors involved, but also pharmacokinetic
aspects. Substantial prior research has emphasized differences between
human insulin and analog insulins with respect to binding affinity to
the IGF-I receptor, including evidence that insulin glargine has much
higher affinity, and higher mitogenic potency, than human insulin or
other analogs (120–122).
The affinity of particular analog insulins for the IGF-I receptor is an
important issue, in view of evidence that knockdown of the IGF-1
receptor, but not the insulin receptor, abolished proliferation of
malignant cell lines in response to insulin glargine (120).
However, the implicit assumption that an insulin or analog that retains
specificity for the insulin receptor over the IGF-I receptor is
unlikely to have important mitogenic effects or effects on neoplasia may
be simplistic in the light of recent research results (64,123)
that show that the insulin receptor is present on neoplastic cells and
may itself influence neoplastic behavior in certain contexts.
Other
pharmacokinetic issues must also be considered. It is not clear if
there is a biologic difference between exposure of neoplastic cells to
fluctuating levels of endogenous insulin seen under normal physiologic
conditions, as compared with the levels of endogenous insulin in
obesity, type 2 diabetes, and/or after administration of exogenous human
or synthetic insulins. Classic subcutaneous therapy with subcutaneous
human insulin involves transient exposures to very high insulin levels,
while subcutaneous administration of some synthetic insulins results (by
design) in longer-term exposure to higher insulin concentrations. As
such, simple pharmacokinetics may not fully explain observed changes in
the behavior of neoplastic tissues. It also is critical to recognize
that cancer cells in type 2 diabetic patients may be exposed to
abnormally high levels of endogenous insulin for many years prior to
administration of exogenous insulin.
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Unanswered questions
There
are several important limitations in human studies of diabetes
treatment and cancer risk that require careful consideration. First,
most studies have had limited power to detect modest associations,
particularly for site-specific cancers. Conducting studies with all
sites combined might attenuate or even mask important associations with
only specific cancer sites. Another limitation of observational studies
is that most diabetic patients are treated with one or more
anti-hyperglycemic medications. Indeed, the progressive nature of type 2
diabetes, requiring changes in pharmacotherapy over time, adds
complexity to studies of a long-term outcome such as cancer incidence.
Therefore, it is extremely difficult to assess the independent
association of a specific medication on cancer risk relative to no
medication. For example, if some medications increase risk, while other
decrease or have no effect on risk, different comparator drugs will
likely lead to different associations and may explain some of the
observed inconsistencies across studies.
Because
specific anti-hyperglycemic medications are associated with cancer risk
factors, confounding by unmeasured or incompletely measured risk factors
may at least in part explain the previously reported drug-cancer
associations. Few studies examined risk associated with dose, duration,
or recency of medication use, which might inform the biologic
plausibility of observed associations. Many agents that affect
carcinogenesis have long latencies or require a minimum exposure level,
and risk associated with some agents may return to baseline after the
exposure has been terminated for a period of time. Some diabetes
medications have only recently come on the market (e.g., TZDs, insulin
analogs, incretin-based therapies). Therefore, studies of these agents
will only assess cancer risk associated with relatively short-term use.
It
is unlikely that the effect of diabetes therapies on cancer risk and
progression—particularly at specific cancer sites—will be fully
addressed with randomized controlled clinical trials, due to both cost-
and follow-up time limitations. Such trials would also be confounded by
the natural crossover and treatment escalation required to appropriately
treat progressive hyperglycemia. Given these limitations, multiple
well-conducted and appropriately designed prospective observational
studies are needed. Results of in vitro and preclinical studies should
inform design considerations for observational studies but by themselves
cannot be considered conclusive.
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