Using a large cohort and multiple indicators for the occurrence of type 2 diabetes, we have shown that cigarette smoking is associated with incident diabetes and with mortality from diabetes. The effect was greater among current smokers than among former smokers. Among current smokers, the risk for incident diabetes increased slightly with amount smoked, but not with duration of smoking. The association of smoking with diabetes was robust to control for potential confounding factors including age, BMI, alcohol drinking, and exercise. The association was stronger in men and at younger ages and was not modified by alcohol consumption or BMI.
The association of smoking with type 2 diabetes has been examined previously in multiple studies. The 2007 meta-analysis by Willi et al. (2
) included 25 cohort studies with 45,844 cases of incident diabetes. All but one of the individual studies demonstrated a positive association with smoking. As observed in the KCPS cohort, there was evidence of a dose-response relationship among current smokers with amount smoked. Our confirmatory findings from a single cohort of 1.3 million are based on a far larger number of cases of incident diabetes than in the meta-analysis and add greatly to the evidence from Asian populations.
Type 2 diabetes is rapidly increasing in Asia, driven in part by increasing obesity (11
). Imaging studies suggest that Asians may have greater visceral adiposity at any particular BMI than Caucasians and hence a greater risk for type 2 diabetes (11
). To date there have been eight cohort studies of smoking and diabetes in Asian populations, involving diverse populations and various outcome measures (12
). Most show increased risk for type 2 diabetes in current smokers and the majority of the effect estimates indicate an approximate doubling of risk, somewhat higher than that observed in our study. The lower hazard rates among former smokers suggest that the acute effects of smoking on insulin resistance may play a role in the contribution of smoking to the onset of diabetes (4
We found that risk for incident diabetes increased with amount smoked; the magnitude of the increase was comparable to the estimate made by Willi et al. (2
) (relative risk 1.61 for smokers of ≥20 cigarettes/day vs. never smokers). Risk did not increase with duration of smoking in our study. We did not identify other reports providing similar estimates. Several found that risk increased with pack-years of smoking, but this cumulative measure combines amount smoked with duration of smoking (14
We found strong evidence for effect modification by age, with significantly lower risks at older ages, regardless of the outcome indicator. This pattern could reflect a depletion of susceptible individuals at older ages, lower amount smoked by older individuals, and possibly greater misclassification of exposures and outcomes in older participants. A similar pattern of effect modification has been observed for cigarette smoking and cardiovascular disease. For example, in the American Cancer Society's Cancer Prevention Study (CPS) I, risks for coronary heart disease and cerebrovascular disease declined progressively with increasing age, such that for individuals aged ≥80 years, risks were not increased among current smokers (20
). Our findings are in contrast to those presented in the meta-analysis by Willi et al. (2
). They found a higher pooled estimate in those aged ≥50 years compared with younger individuals. However, the comparison of relative risks by age was based on different sets of studies for the two age strata. With regard to BMI, Willi et al. (2
) also found significantly greater risk for individuals with BMI of ≥25 kg/m2
. In contrast, we found no evidence for greater risk in those with higher BMI. The lower risks in women are likely to reflect the lower number of cigarettes smoked per day by Korean women (10
Potential limitations of this study primarily reflect the need to rely on self-report for tobacco and alcohol use and on medical database information for establishing the diagnosis of diabetes, leading to concern for potential misclassification of exposures and outcomes. Smoking status was updated during the follow-up visit, however, and self-report of smoking in Korea has been shown to be valid when compared by use of cotinine (21
). Because the follow-up data collection on smoking occurred at various points after enrollment, we could not update duration of smoking for analytical purposes. Consequently, our analyses could not explore risk in relation to lengthening duration of exposure or cessation during follow-up.
For establishing the occurrence of incident diabetes, we used three different indicators based on outcomes unlikely to be subject to substantial misclassification and found similar results with each. Our definitions were intended to exclude individuals being evaluated for diabetes who did not actually have the disease. Consequently, for incident disease we required at least three outpatient visits or prescription of a therapeutic agent once or three times, the latter being less subject to misclassification. For establishing the diagnosis of prevalent disease, we relied in part on self-report, which may be subject to misclassification. We do not anticipate that misclassification of either smoking or the outcome variables would systematically induce a positive association of smoking with diabetes.
There are limitations to the generalizability of the findings. The age range of the population did not extend to adolescents and young adults, who are now experiencing type 2 diabetes because of extreme obesity. The majority of the study population were middle-class, employed individuals, who may be healthier than the general population in Korea. Although incidence rates of disease probably differ by socioeconomic status, there is little reason to suspect that the risk factor–disease relationship should markedly differ.
The mounting evidence on smoking and diabetes, particularly in Asians, suggests that smoking should be considered as a potentially reversible cause of diabetes. Our findings greatly strengthen the available evidence on smoking and diabetes and should be considered as a further basis for controlling tobacco use in Korea and throughout Asia.