Low LDLs Linked to Cancer Among Type 2 Diabetics

By Judith Groch
HONG KONG, 26 aug 2008-- Low levels of LDL cholesterol -- as well as high levels -- were associated with about a 50% greater cancer risk among patients with type 2 diabetes who did not use statins, a prospective cohort study found.
Explain that this study found an association but did not did not prove causation.
The risk for low and high LDL levels and cancer was V-shaped among 3,800 patients, Juliana C.N. Chan, M.D., of the Chinese University of Hong Kong, reported in the August 26 issue of the Canadian Medical Association Journal.
LDL levels below 2.80 mmol/L and levels of 3.90 mmol/L or more were both associated with a markedly elevated all-cancer risk, the researchers said.
Patients using statins were excluded from this calculation as statins obscured the association between LDL cholesterol and all-site cancer, they said.
Several prospective analyses have found an inverse relation between total cholesterol and cancer incidence and mortality in the general population.
However, recent studies have been controversial, and the independent associations between LDLs and cancer in both the general population and in patients with type 2 diabetes have not been explored, the researchers wrote.
So, in what they called a hypothesis-generating study, the researchers looked at the possible independent association between LDL cholesterol and cancer risk among 6,107 Chinese patients with type 2 diabetes.
During a median follow-up of 4.9 years, cancer developed in 270 (4.4%) of a total of 6,107 patients with complete data who were enrolled in the Hong Kong Diabetes Registry from 1995 through 2005.
Among 3,800 patients who did not receive statin therapy, the risk association between LDL cholesterol and cancer was represented by a V-shaped curve, with the lowest risk at an intermediate LDL level of ≥ 2.80 up to <3.80 mmol/L.
Compared with the patients at the intermediate level, the risk of cancer, death from any cause, or the composite outcome of cancer or death was greater among those with an LDL level of less than 2.80 mmol/L (hazard ratio for cancer 1.74, 95% confidence interval 1.20 to 2.52).
It was also greater for those with an LDL level of 3.80 mmol/L or greater (hazard ratio for cancer 1.87, CI 1.29 to 2.71).
About a 50% higher risk of cancer was observed among patients not using statins with an LDL level either above or below the middle range.
Using 3.8 mmol/L as a reference point, the hazard ratio for cancer for every millimole per liter absolute change in LDL cholesterol was 1.54 (95% CI 1.19 to 1.99) among patients not using statins.
For the entire study population -- statin users and those not using statins -- the hazard ratio was reduced to 1.24 (1.01 to 1.53).
These associations persisted after adjustment for covariates and exclusion of patients with fewer than 2.5 years of follow-up.
The elevated risk of cancer at any site among patients with LDLs of less than 2.80 mmol/L was driven mainly by cancers of the digestive organs and peritoneum, genitourinary organs, and lymphatic and hematopoietic tissues, the researchers said.
The cancer risk in patients with LDLs above 3.80 mmol/L was mainly for of the lips, oral cavity, and pharynx; the digestive organs and peritoneum; bone, connective tissue, skin, and breast; the genitourinary organs; and lymphatic and hematopoietic tissues, they noted.
The mechanisms for these links remain controversial, the researchers said. It is possible that the mevalonate pathway, which leads to cholesterol synthesis, can produce molecules, such as the isoprenoids and geranylgeraniol, important for a number of signaling proteins involved in cell proliferation, differentiation, and apoptosis.
Conversely, the underlying mechanisms for the risk of all-site cancer and low LDLs are not immediately obvious, but it could be that low LDLs may upregulate the mevalonate pathway in peripheral tissues.
The limitations of this observational study include the inability to evaluate the benefits of statin use and to control for other confounding factors such as inflammatory markers.
The cohort was primarily clinic-based, and given that clinical outcomes and cancer patterns may differ among populations, these cut-off values may not be applicable to other populations, the investigators wrote.
All told, the researchers called for reanalysis of available data from clinical trials to verify or refute the study's hypothesis.
In an accompanying editorial, Eric L. Ding, Sc.D., and Frank B. Hu, M.D., Ph.D., of the Harvard School of Public Health, wrote that what warrants careful consideration in this study is whether the association is biologically causal or merely confounded by other risk factors, including socioeconomic status.
A V-shaped association suggests that multiple mechanisms are involved, and LDL cholesterol is unlikely the sole or direct causal factor, according to Drs. Ding and Hu.
However, they said, because the study did not comprehensively adjust for many other major risk factors or conduct a risk-prediction analysis, the true clinical value of LDL cholesterol in risk stratification of a variety of cancers remains unclear.
For example, they said, low serum cholesterol is commonly observed in individuals who are in ill health, such those with cancer, and in those who engage in unhealthy behaviors, such as smoking and heavy drinking.
Further investigation is required, especially for clinical practice, they said, given that current recommendations assume that lower is always better and advocate interventions to push LDL target levels even lower.
More study is required about the implications for statin therapy and the ability of LDL cholesterol levels to predict specific cancers in the general population as well as in patients with diabetes, Drs. Ding and Hu wrote.
This study was supported by the Hong Kong Foundation for Research and Development in Diabetes, under the auspices of the Chinese University of Hong Kong.
No competing interests were declared.
Editorial writer Dr. Ding is supported by a postdoctoral fellowship from the American Diabetes Association.
Dr. Hu is supported by National Institutes of Heath grants.
The editorialists declared no competing interests.
Primary source: Canadian Medical Association JournalSource reference:Yang X, et al "Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus" CMAJ 2008; 179: 427-437. Additional source: Canadian Medical Association JournalSource reference: Ding EF, Hu FB "Cancer and cholesterol: understanding the V-shaped association in patients with diabetes" CMAJ 2008; 179: 403-404.