One theory of increased colon cancer risk in Type 2 diabetes

Lack of association of colonic epithelium telomere length and oxidative DNA damage in Type 2 diabetes under good metabolic control
Original source: BMC Endocrine Disorders 2008, 8:12
Authors: Deepak Kejariwal (corresponding author), Karolina M Stepien, Tracy Smith, Hugh Kennedy, David A Hughes, and Mike J Sampson
Publication date: 10 October 2008
DOI (digital document ID): 10.1186/1472-6823-8-12
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
People with Type 2 diabetes are at greatly increased risk for developing colon cancer, but the reasons for this are not clear. One possible reason may be DNA damage and oxidative stress, which may or may not be related to high blood glucose levels. Telomeres are DNA repeat sequences at the ends of chomosomes that get shorter each time a cell divides. After a certain point, they become non-functional. This causes a chemical signal to go out to kill the cell, preventing the growth of tumors. If the chemical signal is missing, the cells will continue to divide and the chromosomes will become unstable. Eventually this instability and continued cell division can result in tumors. The loss of this signal is found in many cancers, including about half of all colorectal cancers.

Under oxidative stress, telomeres may shorten more quickly, and less accurately, than they might otherwise. The authors believed that the telomeres of people with Type 2 diabetes are more prone to the effects of oxidative stress than those without diabetes, and that the cells from their colons would show evidence of shorter telomeres, which would kick off a series of events leading to colorectal cancer.

People with lower-intestinal and colon disease were excluded from this study, as were those who took vitamins or fish oil. The patients controlled their diabetes by taking metformin, a sulfonylurea drug, both of those, or insulin. A total of 32 people were examined between the people with diabetes and the non-diabetic controls. None of the subjects were smokers. The diabetic subjects had A1c under 6.9% but were dealing with known complications of diabetes. Tissue samples were taken from the lower colon and examined for oxidative damage and telomere shortening.

There were no appreciable differences in telomere length between the two groups. However, the groups were small, and the greater number of people with diabetes taking aspirin, ACE inhibitors (anti-hypertension medication), and/or statins (to reduce high cholesterol levels) may have provided some level of protection. Other reasons a difference was not seen could be that the diabetic subjects were in good control of their blood glucose levels, and that 6.5 years may not be a long enough time with diabetes for the effects of oxidative stress and increased colon cancer risk to be measurable.

Reliability:
Two of the investigators associated with a University hospital. The research was published in a peer-reviewed journal. The sample size was extremely small, and though steps were taken to minimize its effects, this small a sample could cause a skewed set of results. The authors do suggest that further research is necessary to confirm or rule out their theory.

Practical Applications:
More research is needed to find out exactly why people with Type 2 diabetes are at higher risk of developing colon cancer, and ways of minimizing that additional risk.

This synopsis was based on the entire article.

Are adverse effects of some diabetes drugs related to their suppression of sex hormones?

Are the adverse effects of glitazones linked to induced testosterone deficiency?
Original source: Cardiovascular Diabetology 2008, 7:30
Authors: M. Carruthers (corresponding author), T. R. Trinick, E. Jankowska, and A.M. Traish
Publication date: 15 October 2008
DOI (digital document ID): 10.1186/1475-2840-7-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors pose a theory that the various adverse effects of diabetes drugs in the class called "glitazones" -- including rosiglitazone (RGZ -- brand name Avandia) and pioglitazone (PGZ -- brand name Actos) -- may be related to a separate known action of these drugs -- their suppression of sex hormones. These side effects include heart disease, swelling, weight gain, and anemia.

Glitazones act on sex hormones by reducing the levels to which they are released and by making the body less sensitive to them. These sex hormones are responsible for directing new cell growth to become blood vessels, skin, muscle, and other types of structural cells, rather than fat cells. This might give further weight to an existing theory of how obesity might cause diabetes (called "Ungar's theory of the 'Lipocentric Pathway to Hyperglycemia'"(1)). The authors note evidence that low testosterone levels in men can cause a number of the same side effects that are being observed in diabetes patients treated with glitazones; furthermore, that diabetes and/or cardiovascular disease are often seen to develop where testosterone production has been suppressed in order to treat prostate cancer. Much of this can be tied to the abdominal weight gain related to low testosterone levels. Treatment with testosterone in these cases has been shown to reduce the side effects and lower the statistical occurrence of cardiovascular disease among patients showing a number of these metabolic symptoms.

The authors note a number of known effects of rosiglitazone and troglitazone (Resulin, which has been removed from the US market) on sex hormones and on the development and maturation of new body tissues.

The authors suggest that this hypothesis might be tested by double-blind, placebo-controlled clinical studies examining the endocrine profiles, and levels of sex hormones, in people with Type 2 diabetes both before and while/after being treated with a glitazone. Additionally, studies on treating diabetic men with testosterone might show us whether this might counteract (or at least lessen) the adverse effects of glitazones. They also suggest further research into exactly how glitazones inhibit sex hormones.

Reliability:
The authors are associated with a number of universities and medical research institutes throughout the world. The hypothesis was published in a peer-reviewed journal. The authors are posing a theory, rather than a statement of fact, and suggesting ways that others could determine whether or not their theory is correct.

Practical Applications:
If the theory is correct, and if administering testosterone to men can completely counteract the adverse effects of Avandia and similar medications, that would make Avandia a relatively safer choice to treat Type 2 diabetes than it is now.

For further reading:
(1) Roger H. Unger, MD Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. Journal of the American Medical Association (JAMA), 2008;299(10):1185-1187.
Full text requires paide subscription.
First 150 words available free.

"Evidence-Based Medicine", Patient Pages, Journal of the American Medical Association (JAMA)

This synopsis was based on the entire article.

Merck analyzes Januvia safety studies

Safety and tolerability of sitagliptin
Original source: BMC Endocrine Disorders 2008, 8:14
Authors: Debora Williams-Herman, Elizabeth Round, Arlene S. Swern, Bret Musser, Michael J. Davies, Peter P. Stein, Keith D. Kaufman and John M. Amatruda
Publication date: 27 October 2008
DOI (digital document ID): 10.1186/1472-6823-8-14
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors are trying to assess the safety and of sitagliptin (Januvia) by combining the results of 12 separate double-blind human trials of up to 2 years in duration. (Double-blind trials are ones in which neither the investigators nor the patients know who is getting the drug under test and who is getting an alternate therapy or no drug therapy. This helps keep the results unbiased.)

A total of 6139 patients were involved in the studies; 3415 were either given 100 mg Januvia per day or the equivalent dose of another oral anti-diabetic pill; 2724 were given a placebo (a pill that has no drug action to it). The shortest study ran 18 weeks (about 4 months) and the longest ran 2 years. The patients were either given sitagliptin (Januvia) alone, or with metformin (similar to Janumet), or as addition to other antidiabetic drugs such as metformin (Glucophage), sulfonylurea, pioglitazone (Actos), and/or rosiglitazone (Avandia). The patients not getting the Januvia were getting either a placebo or one or more of the above antidiabetic drugs.

A number of known adverse reactions and side effects were examined in both the sitagliptin groups and the various control groups. According to the abstract, the only significant side effect was an increase in patient-reported hypoglycemic events among those patients who were also taking sulfonylurea drugs. The definition of "hypoglycemia" was somewhat loose, not requiring the patient to test his blood glucose and add it to the report. The authors do examine the frequency of reports of nausea and stomach pain, pancreatitis, immune system suppression, nose and throat discomfort, skin reactions (hives, discoloration, redness, etc.), and swelling in the heart and chest. These adverse reactions were considered to be similar in frequency between those taking Januvia and those who were not. The reasons for other studies reporting different results were discussed and discounted. (In at least one case, it was one of the longer-term studies that was looking specifically for adverse effects.)

The authors conclude that Under most circumstances, sitagliptin is safe and effective compared to other oral antidiabetic medications.

Reliability: The research was published in a peer-reviewed journal. One of the authors is a medical doctor.

All of the authors work for Merck, or worked for Merck during the period the research was being done. Merck manufactures Januvia, so the authors have a bias towards proving this medication safe and effective.

While a large number of patient experiences were collated into this analysis, most of the component studies were very small in scale.

Since most of the studies aggregated in this analysis only went on for four to six months, it is easy to misinterpret the data as indicating the drug is as safe over two years as it is over four months. People taking drugs to manage Type 2 diabetes are likely to stay on the same drug for much longer than the two-year longest studies examined -- so there is a possibility that there will be side effects from long-term use that have not yet shown up in laboratory and clinical studies.


Practical Applications:
Based on the authors' analysis, Januvia -- for the short-term and intermediate term -- is as safe as other drugs used to manage Type 2 diabetes.

However, because the severe reactions and deaths that have been tied to other new drugs* didn't start showing up in the media until the drugs were out in the marketplace for more than five years, and being taken by tens of thousands of patients, it is probably premature to say that Januvia is safe to be taken by the everyone covered by the prescribing instructions for the entire length of time one might expect it to be used. As with any medication, discuss the pros and cons with your doctor, as well as any additional concerns and risk factors you might have. Untreated Type 2 diabetes can cause serious complications up to and including death.

*Avandia (rosiglitazone), made by Glaxo Smith Kline, is the most recent drug with this sort of safety issue.

For further reading:
Januvia prescription information for doctors: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf
Januvia site for consumers: http://www.januvia.com/sitagliptin/januvia/consumer/index.jsp
Merck website: http://www.merck.com/
Drugs.com consumer information for Januvia: http://www.drugs.com/cdi/januvia.html
Drugs.com professional information for Januvia: http://www.drugs.com/pro/januvia.html

This synopsis was based on the provisional (online preprint) article.