Study Population and Study Oversight

We used data collected from three cohorts — the Nurses’ Health Study (NHS), the Nurses’ Health Study II (NHS II), and the Health Professionals Follow-up Study (HPFS) (Text 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) — with follow-up by means of questionnaires eliciting medical and lifestyle information that were mailed to participants every 2 years.12,13 The study baseline was set at 1984 for the NHS or the first follow-up cycle since recruitment for the NHS II (1991) and the HPFS (1988) for identifying participants who reported quitting smoking.

In analyses of the risk of type 2 diabetes, participants with prevalent diabetes, cardiovascular disease, or cancer at baseline were excluded; and in analyses of mortality, participants with prevalent cardiovascular disease and cancer at baseline were excluded. The exclusion of prevalent chronic diseases was critical for reducing the probability that participants had quit smoking owing to existing diseases. For all analyses, we also excluded participants with missing information on smoking status in two or more consecutive cycles and those who completed the baseline questionnaire only. In diabetes analyses, participants with a missing date of diagnosis were also excluded. After the exclusions, 162,807 participants were included in the diabetes analyses and 170,723 were included in the mortality analyses.

This study was approved by the institutional review board at Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health. The return of a completed questionnaire was considered to indicate informed consent. The last author had full access to all the data in the study and vouches for the completeness and accuracy of the data and data analysis.

Assessment of Smoking Status and Weight Change

In each 2-year survey cycle, we identified participants who had reported that they were smokers in the previous cycle but were past smokers in the current cycle, assuming the beginning of the previous cycle as the onset of quitting. We calculated the duration of smoking cessation from the onset of quitting to the relapse of smoking, occurrence of study outcomes, or the end of follow-up (Table S1 in the Supplementary Appendix). Quitters were mutually exclusively defined as transient quitters (participants who reported being past smokers in the current cycle but being current smokers in previous and next cycles), recent quitters (2 to 6 consecutive years since smoking cessation), and long-term quitters (>6 consecutive years since smoking cessation). We replaced missing information on smoking status with assessments in the previous cycle only (4.4% of participants for diabetes analyses and 4.6% for mortality analyses). In these cohorts, participant-reported smoking status and body weight have been shown to be highly accurate.14,15

Because the biennial weight-change trajectory overlapped with that of persons who had never smoked after 6 years of cessation (Text 2 in the Supplementary Appendix), we focused on weight change within the first 6 years after quitting, which was consistent with a previous study.16 Missing body-weight estimates were replaced with last available values (9.7% of participants for diabetes analyses and 9.6% for mortality analyses). We defined the “no weight gain” group as those who gained no weight or lost weight, and then we applied cutoff points of 0.1 to 5.0 kg, 5.1 to 10.0 kg, and more than 10.0 kg to define other groups.4 In a sensitivity analysis, we grouped participants according to quartiles of weight gain.

Assessment of Physical Activity and Diet

Physical activities were assessed with the use of a validated questionnaire regarding time spent on up to 10 recreational activities and were quantified as metabolic equivalent tasks (METs) in hours per week.17 In 1984, 1986, and every 4 years thereafter, a validated food-frequency questionnaire was administered in the NHS to assess diet. Diet has been assessed every 4 years in the NHS II and the HPFS with the use of similar food-frequency questionnaires since 1991 and 1986, respectively. Overall diet quality was assessed according to the Alternative Healthy Eating Index (AHEI) score (range, 0 to 110, with higher scores indicating a healthier diet).18

Assessment of Outcomes

Once participants reported a physician diagnosis of diabetes in questionnaires that were completed every 2 years, they were mailed a validated supplementary questionnaire19 to confirm the diagnosis (Text 3 in the Supplementary Appendix). We identified deaths through searches of the National Death Index, reports by the next of kin, or postal authorities.20 Deaths from cardiovascular disease were determined by study physicians’ review of medical records and death certificates with diagnostic codes of the International Classification of Diseases, 9th Revision.

Statistical Analysis

Because of the same study design and relatively homogenous populations in the cohorts, data from the three cohorts were pooled to maximize statistical power. Person-time for each participant was counted from the return of the baseline questionnaire to the occurrence of study outcomes, last return of a valid follow-up questionnaire, or the end of follow-up (June 2012 for the NHS, January 2012 for the HPFS, and June 2013 for the NHS II), whichever happened first. For the diabetes analyses, follow-up was further censored on the incidence of cancer or cardiovascular disease, including myocardial infarction, stroke, and coronary-artery bypass surgery, because these conditions are likely to lead to changes in both smoking status and body weight.

We used proportional-hazards regression to examine the association of smoking cessation with the incidence of type 2 diabetes, death from cardiovascular disease, and death from any cause. We used missing indicators for missing values of categorical variables, including physical activity, AHEI score, and intakes of total energy and alcohol (missing in 3.0 to 17.4% of participants). In a sensitivity analysis, we used a multiple-imputation procedure to impute values for missing data on these variables before making categories (Text 4 in the Supplementary Appendix). Participants with missing data on multivitamin use (15.2% of participants) were assumed to be nonusers. To minimize reverse-causation bias by the “ill quitter effect” in the mortality analyses, we stopped updating smoking status on the development of cancer, nonfatal vascular diseases, chronic obstructive pulmonary disease, or type 2 diabetes. We did not find evidence suggesting potential violation of the proportional-hazards assumption for any exposure–outcome associations (Text 5 in the Supplementary Appendix).

A cubic spline regression model was fitted to delineate the association with duration of smoking cessation. Interactions with weight change were tested by a likelihood-ratio test comparing models with and without product terms between duration-of-smoking-cessation spline variables and weight change. The estimated coefficients from the cubic spline regression were used to project the associations in three-dimensional figures (R rgl package).21 In secondary analyses among quitters, we modeled the association of diet-quality and physical-activity changes after quitting in relation to weight changes using a multivariable-adjusted, mixed-effects model (Text 6 in the Supplementary Appendix). In addition, by including persons who reported quitting since 1978 in the NHS, we modeled the long-term trajectory of the risk of type 2 diabetes among quitters who maintained cessation for up to 30 years. Lastly, to assess potential mediation effects of weight change, data were divided into 6-year intervals, and hazard ratios were compared in models with and without adjustment for weight change (Text 7 in the Supplementary Appendix).22

All P values presented were two-sided, with statistical significance determined by a false discovery rate of less than 0.05 (Text 8 in the Supplementary Appendix).23 Data were analyzed with the use of SAS software, version 9.4 (SAS Institute), and R software, version 3.3.2 (R Foundation).