Associations of Hyperglycemia and Insulin Usage With the Risk of Cancer in Type 2 Diabetes: The Hong Kong Diabetes Registry

Abstract

OBJECTIVEInsulin has mitogenic effects, although hyperglycemia may be a risk factor for cancer in type 2 diabetes. It remains uncertain whether use of insulin increases cancer risk because of its effect on cell growth and proliferation or decreases cancer risk because of its glucose-lowering effect.RESEARCH DESIGN AND METHODSA 1:2-matched new insulin user cohort on age (±3 years), smoking status, and likelihood of initiating insulin therapy (±0.05) was selected from a cohort of 4,623 Chinese patients with type 2 diabetes, free of cancer, and naive to insulin at enrollment. Stratified Cox regression analysis on the matched pairs was used to obtain hazard ratios (HRs) of insulin therapy and A1C for cancer risk. A structured adjustment scheme was used to adjust for covariates.RESULTSOf 973 new insulin users, 971 had matched nonusers (n = 1935). The cancer incidence in insulin nonusers was much higher than that in insulin users (49.2 vs. 10.2, per 1,000 person-years, P < 0.0001). After further adjustment for all other covariates with a P value less than 0.3 and nonlinear associations with cancer, A1C was associated with an increased cancer risk (HR per percentage 1.26, 95% CI 1.03–1.55), whereas use of insulin was associated with a decreased cancer risk (HR of insulin users vs. nonusers: 0.17, 0.09–0.32). Consistent results were found in analyses including all 973 insulin users and 3,650 nonusers.CONCLUSIONSIn Chinese patients with type 2 diabetes, hyperglycemia predicts cancer, whereas insulin usage was associated with a reduced cancer risk.

Insulin, glucose and the increased risk of cancer in patients with type 2 diabetes

“…Nonetheless, the consistency of the observed epidemiological association, including dose-risk gradient, across different studies, designs and populations is notable. In contrast to those previously consistent reports, one recent observational study reported a protective association of reduced risk of cancer with insulin therapy [22], although several methodological concerns limit the interpretation of those results [23,24].…”

Meta-analysis of trial data may support a causal role of hyperglycaemia in cancer. Reply to Yang XL, Ma RCW, Chan JCN [letter]

“…It appears, however, that these rates are similar to those reported in observational studies, such as the Hong Kong Diabetes Registry, where cancer incidence amongst a cohort of type 2 diabetes patients was reported to be 5.8-9.7 per 1,000 person-years [6]. Furthermore, while there may be a potential for limited follow-up, this would be a nondifferential bias, since it would be true for both the control and intensified treatment arms; thus the interpretation of the OR is not affected.…”

Enhancers and attenuators of risk associations of chronic hepatitis B virus infection with hepatocellular carcinoma in type 2 diabetes

“…These risk factors included LDLC-related risk indicators (LDLC !2.80 mmol/l plus TG !1.7 mmol/l, LDLC !2.80 mmol/l plus albuminuria, LDLC R3.80 mmol/l; Yang et al 2012b) and HDL-cholesterol-related risk indicators (HDLC !1.0 and R1.30 mmol/l; Yang et al 2011b). In addition, we adjusted for use of insulin (Yang et al 2010a), metformin (Yang et al 2011b), RAS inhibitors (Yang et al 2009b(Yang et al , 2010c, gliclazide/glibenclamide (Yang et al 2010d), and rosiglitazone/pioglitazone during follow-up (Yang et al 2012c), which was defined as use of the drug from enrollment to the earliest date of HCC, death, or 30 July 2005, whichever came first. In our review of major biases of pharmacoepidemiological analysis in nonclinical trial setting, we demonstrated that time-fixed Cox model analysis with exclusion of prevalent users and adjustment for drug use indication was free of major biases and could reproduce the effect of a drug as reported in clinical trials (Yang et al 2012d).…”

“…Diabetes is associated with increased risk of a spectrum of cancers (Yang et al 2012b) with a linear relationship between HbA1c and all-site cancer risk (Yang et al 2010a). In most surveys, among site-specific cancers, HCC ranks second in terms of strength of association with diabetes (El-Serag et al 2006), only preceded by pancreatic cancer (Everhart & Wright 1995).…”