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Active Smoking and the Risk of Type 2 Diabetes, Increased 44% Risk
 
 
  A Systematic Review and Meta-analysis
 
JAMA. Dec 12 2007;298(22):2654-2664.
 
Carole Willi, MD; Patrick Bodenmann, MD, MScPH; William A. Ghali, MD, MPH; Peter D. Faris, PhD; Jacques Cornuz, MD, MPH Department of Ambulatory Care and Community Medicine (Drs Willi, Bodenmann, and Cornuz), Institute of Social and Preventive Medicine (Drs Willi and Cornuz), University of Lausanne, Lausanne, Switzerland; and Departments of Medicine (Dr Ghali) and Community Health Sciences (Drs Ghali and Faris), University of Calgary, Calgary, Alberta, Canada.
 
Smoking is associated with a 44% increase in the risk of diabetes, a rise that appears greatest for heavy smokers....there is theoretical biological plausibility for causality in that smoking may lead to insulin resistance or inadequate compensatory insulin secretion responses according to several but not all studies. This could be due to a direct effect of nicotine or other components of cigarette smoke on beta cells of the pancreas, as suggested by the association of cigarette smoking with chronic pancreatitis and pancreatic cancer....
 
JAMA Editorial
(Eric L. Ding, ScD; Frank B. Hu, MD, PhD, Harvard School of Public Health, Boston, Massachusetts; Brigham and Women's Hospital and Harvard Medical School, Boston.): Given the increased incidence of type 2 diabetes associated with smoking, it is likely important and prudent for clinicians also to screen for and carefully monitor glucose levels among current and former smokers......the adverse effect of smoking on type 2 diabetes has been generally underrecognized.... Approximately 21 million persons in the United States currently have diabetes, with an additional 41 million with prediabetes.3 The American Diabetes Association estimates that diabetes costs US society $132 billion annually, with the economic burden expected to increase to $192 billion by 2020.4 Globally, more than 150 million people have diabetes, with international prevalence expected to double by 2025.... Even though smoking is known to decrease body weight, it is associated with an increase in central adiposity,7 an established marker of hyperglycemia and dyslipidemia. Smoking also is well recognized to increase inflammation and oxidative stress,10 to directly damage beta-cell function,11 and to impair endothelial function,12 each of which have been strongly implicated in insulin resistance13 and diabetes risk.14-15 Smoking has been shown to impair insulin sensitivity and glucose tolerance.16 Overall, multiple lines of evidence support a causal nature of the association17 between smoking and type 2 diabetes. See full Editorial below.
 
ABSTRACT
Context
Observational studies have suggested an association between active smoking and the incidence of type 2 diabetes.
 
Objective To conduct a systematic review with meta-analysis of studies assessing the association between active smoking and incidence of type 2 diabetes.
 
Data Sources A search of MEDLINE (1966 to May 2007) and EMBASE (1980 to May 2007) databases was supplemented by manual searches of bibliographies of key retrieved articles, reviews of abstracts from scientific meetings, and contact with experts.
 
Study Selection Studies were included if they reported risk of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes in relationship to smoking status at baseline; had a cohort design; and excluded persons with diabetes at baseline.
 
Data Extraction and Data Synthesis Two authors independently extracted the data, including the presence or absence of active smoking at baseline, the risk of diabetes, methods used to detect diabetes, and key criteria of study quality. Relative risks (RRs) were pooled using a random-effects model. Associations were tested in subgroups representing different patient characteristics and study quality criteria.
 
Results The search yielded 25 prospective cohort studies (N = 1.2 million participants) that reported 45 844 incident cases of diabetes during a study follow-up period ranging from 5 to 30 years. Of the 25 studies, 24 reported adjusted RRs greater than 1 (range for all studies, 0.82-3.74). The pooled adjusted RR was 1.44 (95% confidence interval [CI], 1.31-1.58). Results were consistent and statistically significant in all subgroups. The risk of diabetes was greater for heavy smokers (20 cigarettes/day; RR, 1.61; 95% CI, 1.43-1.80) than for lighter smokers (RR,1.29; 95% CI, 1.13-1.48) and lower for former smokers (RR, 1.23; 95% CI, 1.14-1.33) compared with active smokers, consistent with a dose-response phenomenon.
 
Conclusion Active smoking is associated with an increased risk of type 2 diabetes. Future research should attempt to establish whether this association is causal and to clarify its mechanisms.
 
A number of primary studies have assessed the association between smoking and incidence of glucose abnormalities, suggesting that active smoking could be independently associated with glucose intolerance, impaired fasting glucose, and type 2 diabetes; smoking may therefore be a modifiable risk factor for type 2 diabetes. Some of these studies have been summarized in qualitative reviews.6-8 However, to our knowledge, the quality of existing studies has not been systematically assessed and the clinical features of these studies have not been fully assessed to further characterize this potential association and its determinants.
 
We therefore conducted a systematic review and meta-analysis of prospective cohort studies describing the association between active smoking and the incidence of diabetes or other glucose metabolism irregularities.
 
COMMENT
There is an extensive body of literature reporting on the association between active cigarette smoking and the incidence of diabetes. The 25 studies that we identified report RRs that, while somewhat variable in magnitude, indicate a positive association in all but 1 study. Furthermore, the association persists and remains statistically significant across a number of stratified analyses exploring clinical and study quality factors, and also persists in sensitivity analyses performed to assess the potential effect of varying diabetes outcome definitions and hypothetical unpublished studies. Given this consistency, we conclude that the relevant question should no longer be whether this association exists, but rather whether this established association is causal.
 
Observational primary studies cannot prove causality. However, the studies in this review do meet several of the Hill criteria55 for causation. First, there is an appropriate temporal relationship: the cigarette smoking preceded diabetes incidence in all studies. Second, the findings are consistent with a dose-response relationship, with stronger associations for heavy smokers relative to lighter smokers and for active smokers relative to former smokers. However, an observed dose-response relationship can arise from the intensity of clustering with other diabetes risk factors such as lack of physical activity and unhealthy diet. Third, there is theoretical biological plausibility for causality in that smoking may lead to insulin resistance or inadequate compensatory insulin secretion responses according to several56-61 but not all62 studies. Smoking also has a clinically significant effect on both oral and intravenous glucose tolerance tests that could influence diabetes detection.60, 63-65 This could be due to a direct effect of nicotine or other components of cigarette smoke on beta cells of the pancreas, as suggested by the association of cigarette smoking with chronic pancreatitis and pancreatic cancer.66 Fourth, there is consistency of this association across 24 studies, as shown by the forest plot (Figure 2). Fifth, the strength of the association with diabetes is not negligible in the context of tobacco research.
 
Conversely, there are also possible noncausal explanations for this association. Smoking is often associated with other unhealthy behaviors that favor weight gain and/or diabetes, such as lack of physical activity, poor fruit and vegetable intake, and high alcohol intake.67-68 Furthermore, this clustering of behaviors is more prevalent in individuals of lower socioeconomic status.69-70 Some of these factors were considered and adjusted for in the studies included in our review, but the extent to which these potential intervening factors were controlled for in the individual studies was generally limited. The lack of adjustment for socioeconomic status (only 6 studies adjusted for socioeconomic status or education), diet (only 2 studies), physical activity (only 13 studies), and alcohol consumption (only 14 studies) could contribute to a noncausal association between smoking and diabetes.
 
Smokers tend to be thinner than nonsmokers or former smokers, and several studies have shown that smokers' BMI is lower.71-73 However, there is evidence that smokers (especially heavy smokers) tend to have higher BMIs than lighter smokers and even some nonsmokers.74 In addition to a clustering of risky behaviors, this finding could be due to the weight cycling phenomenon. Smokers tend to gain weight when they quit smoking; the stronger the dependence, the greater the risk of relapse.75-76 Therefore, heavy smokers may need several attempts before they definitively quit smoking, and they gain weight during these attempts that they never completely manage to lose when they relapse. Furthermore, with a normal BMI, smokers tend to have a greater risk of abdominal fat accumulation compared with nonsmokers.62, 77-79 The mechanism is not well elucidated but because smoking has an anti-estrogenic effect,80-81 it could be related to a hormonal imbalance that could lead to central obesity. Obesity and weight gain are strong risk factors for developing type 2 diabetes82-83 and several studies also show that abdominal obesity is associated with the development of type 2 diabetes.84-85
 
Limitations of this meta-analysis must be considered. First, the quality of individual studies was not always optimal, as shown by the general lack of information on blinding and recruiting of consecutive patients for all studies. Second, conversion of ORs to RRs15 could have underestimated the variance of the RRs derived from ORs. However, a sensitivity analysis that excluded the affected studies and use of the Miettinen test-based approach to calculate variance of the lnRR had only an extremely small effect on the results. Third, there is heterogeneity of RRs across studies, corresponding in part to heterogeneity in study definitions. However, stratified analyses showed pooled RRs consistently greater than 1 across a number of clinical factors. Fourth, the funnel plot analysis showed some asymmetry suggesting the possibility of publication bias. The trim and fill sensitivity analysis did not change the general result (although the strength of the association was slightly attenuated), suggesting that the association is not an artifact of unpublished negative studies. Nevertheless, that possibility is not fully excluded by this method.
 
Considering the consistent finding of increased diabetes incidence associated with active cigarette smoking across a large number of studies, we believe that there is no need for further cohort studies to test this hypothesis. However, there is a need for studies that include detailed measurement and adjustment for potential confounding factors such as socioeconomic status, education, and exercise with a goal of establishing whether the association with smoking is causal. We recommend that future studies focus on plausible causal mechanisms or mediating factors such as obesity, lack of physical activity, dietary habits, and stress levels.
 
Editorial
 
Smoking and Type 2 Diabetes
 
Underrecognized Risks and Disease Burden

 
Eric L. Ding, ScD; Frank B. Hu, MD, PhD Departments of Nutrition and Epidemiology (Drs Ding and Hu), Harvard School of Public Health, Boston, Massachusetts; Division of Preventive Medicine (Dr Ding) and Channing Laboratory (Dr Hu), Department of Medicine (Drs Ding and Hu), Brigham and Women's Hospital and Harvard Medical School, Boston.
 
JAMA. 2007;298(22):2675-2676.
 
Although smoking has long been acknowledged as a major contributor to the global burden of cardiovascular disease and cancer, the adverse effect of smoking on type 2 diabetes has been generally underrecognized. Indeed, the most recent Centers for Disease Control and Prevention estimates of smoking-attributable mortality do not incorporate the impact of smoking on diabetes.1
 
Diabetes exerts a considerable national and global disease burden. For US residents born in 2000, an estimated 1 in 3 will develop diabetes during their lifetime.2 Approximately 21 million persons in the United States currently have diabetes, with an additional 41 million with prediabetes.3 The American Diabetes Association estimates that diabetes costs US society $132 billion annually, with the economic burden expected to increase to $192 billion by 2020.4 Globally, more than 150 million people have diabetes, with international prevalence expected to double by 2025.5
 
In this issue of JAMA, Willi and colleagues6 present the results of a systematic review and meta-analysis of 25 prospective cohort studies, comprising 1.2 million participants and 45 844 cases of diabetes, and report that both active and past smoking are significantly associated with increased risk of type 2 diabetes. Although the study is not able to analyze exact differences in diabetes risk associated with different smoking pack-years, duration, and cessation patterns, the findings demonstrate strong consistency of the association. Despite some evidence for heterogeneity, the association was overall robust and consistent across a range and variety of smoking patterns, demographics, and study characteristics. Although there is potential for residual confounding by factors such as body mass index and alcohol use, the results were similar if not stronger among studies included in the meta-analysis that used substantial multivariable adjustment for such confounders. Furthermore, because smoking is inversely related to body weight,7 and alcohol is associated with lower glucose levels and diabetes risk in a randomized controlled trial8 and prospective cohort studies,9 residual confounding by relative weight and alcohol would be expected to attenuate the association between smoking and diabetes. Therefore, the findings in the study by Willi et al6 likely reflect a conservative underestimate of the true association between smoking and type 2 diabetes.
 
Even though smoking is known to decrease body weight, it is associated with an increase in central adiposity,7 an established marker of hyperglycemia and dyslipidemia. Smoking also is well recognized to increase inflammation and oxidative stress,10 to directly damage beta-cell function,11 and to impair endothelial function,12 each of which have been strongly implicated in insulin resistance13 and diabetes risk.14-15 Smoking has been shown to impair insulin sensitivity and glucose tolerance.16 Overall, multiple lines of evidence support a causal nature of the association17 between smoking and type 2 diabetes.
 
Given the strong evidence of causality, it is important to try to quantify the burden of diabetes attributable to smoking. Using the most recent US statistics of current and former smoking prevalence,18 the estimates from the study by Willi et al,6 and the conventional population-attributable risk formula,19 an estimated 12% of all type 2 diabetes in the United States may be attributable to smoking. This percentage would be expected to be much higher in populations with higher smoking rates. Additionally, with type 2 diabetes accounting for 95% of the 20.6 million adults with diabetes,3 an estimated 2.3 million cases of diabetes in the United States and a corresponding $14.9 billion of the annual US $132 billion diabetes cost burden may be attributable to smoking.
 
Diabetes also is recognized to be a strong causal contributor to other leading causes of death, notably cardiovascular disease mortality.20 A large international review indicates that 21% of all coronary heart disease deaths and 13% of all stroke deaths are attributable to high blood glucose levels.21 Diabetes and elevated glucose levels also are suspected as a contributor to the disease burden of cancer, associated with a 20% to 30% relative increase in overall cancer risk22 and even stronger associations for several common types of cancer. To date, such major contributions to the mortality burden have not been assigned to diabetes in tabulation of conventional cause-of-death statistics and analyses of attributable mortality. Thus, although the Centers for Disease Control and Prevention listed diabetes as the sixth leading cause of death in the United States with 74 000 deaths in 2003,23 the total attributable national and global mortality burden is likely underestimated for diabetes, and thus the impact of smoking as well.
 
Given the substantial influence of smoking on diabetes risk, consideration should be given to clinical screening. Because diabetes is currently highly underdiagnosed, with an estimated 30% to 50% of all diabetes cases clinically unrecognized,3 the American Diabetes Association recommends general screening for undiagnosed diabetes every 3 years among men and women aged 45 years or older.24 However, as recently as 2003, the US Preventive Services Task Force had not endorsed universal clinical screening for glucose abnormalities, with current recommendations suggesting screening only among adults with hypertension and hyperlipidemia,25 although updated recommendations are pending. Given the increased incidence of type 2 diabetes associated with smoking, it is likely important and prudent for clinicians also to screen for and carefully monitor glucose levels among current and former smokers.
 
Furthermore, along with clinical screening, recommendations for type 2 diabetes prevention should incorporate smoking avoidance accompanied by lifestyle modification. Although a frequent concern of smoking cessation is subsequent weight gain, moderately increasing exercise can largely minimize the approximately 2 kg weight gain associated with stopping smoking,26 indicating that the public health issues of smoking, exercise, and obesity are inextricably intertwined. Major population prevention of type 2 diabetes is achievable via avoidance of smoking and modification of lifestyle factors through a combination of healthy weight control, regular physical activity, moderate alcohol intake, and proper diet. An estimated 91% of all type 2 diabetes is preventable by smoking prevention and lifestyle modification.27
 
Although global smoking-attributable mortality is expected to decline 9% between 2002 and 2030 among high-income countries, the disease burden of tobacco is expected to at least double from 3.4 million to 6.8 million in low- and middle-income countries,28 exclusive of the effect of smoking on type 2 diabetes risk. The synergy between recent increasing obesity and smoking prevalence in developing nations bodes ominously for further escalation of the global burden of diabetes and other chronic diseases. In the United States, smoking tends to cluster in the low socioeconomic stratum of society and in minority groups.18 Moreover, while obesity prevalence continues to increase, the decline in smoking rates in the United States has stalled in the past several years.18
 
Therefore, further focus on public health and clinical interventions is needed to prevent tobacco use and promote smoking cessation. As jointly recognized and highlighted by the American Diabetes Association, the American Heart Association, and the American Cancer Society,29 prevention of diabetes, cardiovascular disease, and cancer share many common agendas-a central focus of which is the avoidance of cigarette smoking.
 
 
 
 
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