The Association of High-Density Lipoprotein Cholesterol with Cancer Incidence in Type II Diabetes: A Case of Reverse Causality?

Jamie Morton,Martin K.C Ng,Giuseppe Mancia,Michel Marre,Mark Woodward,Sophia Zoungas,Neil R Poulter,Mark E Cooper,John Chalmers

doi:10.1158/1055-9965.epi-13-0149

Abstract

Low high-density lipoprotein cholesterol (HDL-C) and type II diabetes are associated with an increased risk for cancer. Patients with type II diabetes typically have low HDL-C; however, the association between HDL-C and cancer has not been examined in this population. A total of 11,140 patients with type II diabetes were followed for a median of 5 years. Cox proportional hazard models were used to assess the association between baseline HDL-C and risk of cancer incidence and cancer death, with adjustments made for potential confounders. To explore the possibility of reverse causation, analyses were repeated for the cancers occurring in the first and second halves of follow-up. Six hundred and ninety-nine patients developed cancer, with 48% occurring within the first half of follow-up. For every 0.4 mmol/L lower baseline HDL-C, there was a 16% higher risk of cancer [HR 1.16; 95% confidence interval (CI), 1.06-1.28; P = 0.0008] and cancer death (HR 1.16; 95% CI, 1.01-1.32; P = 0.03). After adjustment for confounding, the higher risk remained significant for cancer (adjusted HR 1.10; 95% CI, 1.00-1.22; P = 0.05) but not for cancer death (adjusted HR 1.08; 95% CI, 0.93-1.25; P = 0.31). The association was driven by cancers occurring within the first half of follow-up (adjusted HR 1.22; 95% CI, 1.05-1.41; P = 0.008) as no significant association was found between HDL-C and cancer in the second half of follow-up. Low HDL-C is associated with cancer risk in patients with type II diabetes. However, this association may be explained by confounding and reverse causation. HDL-C is not a risk factor for cancer in type II diabetes.

Highlights

There is a well-recognized relationship between low total cholesterol levels and higher rates of cancer [1]
We explore the association between baseline high-density lipoprotein cholesterol (HDL-C) level and cancer incidence in ADVANCE [12, 13], a large contemporary diabetes population drawn from 20 countries, with special consideration of the possibility of reverse causation
Higher HDL-C was associated with lower triglycerides and higher total cholesterol and low-density lipoprotein cholesterol (LDL-C)

Summary

Introduction

There is a well-recognized relationship between low total cholesterol levels and higher rates of cancer [1] This has been attributed to reverse causation whereby preclinical cancers lower the cholesterol either through increased metabolism or reduced catabolism [2]. Studies examining the relationship between high-density lipoprotein cholesterol (HDL-C) and cancer have suggested an inverse association. Several of these studies have considered the possibility of reverse causation, but have presented limited sexor cancer-specific data [3,4,5]. Low high-density lipoprotein cholesterol (HDL-C) and type II diabetes are associated with an increased risk for cancer. Patients with type II diabetes typically have low HDL-C; the association between HDL-C and cancer has not been examined in this population

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Conclusion