The effects of dietary instruction on cardiovascular risk markers after smoking cessation: study protocol for a multicenter randomized controlled trial in Japan

Smoking contributes to the development of fatal cardiovascular diseases and malignancies. Worldwide, approximately 5.4 million people die from preventable smoking-related diseases each year; this number corresponds to 10% of all adults [1]. According to the Ministry of Health, Labor, and Welfare, heart disease is the second-leading cause of death in Japan, accounting for approximately one sixth of Japanese deaths [2]. National medical expenditures have exceeded 38 trillion yen, accounting for more than 10% of the national income. The greatest portion (21%), 5.8 trillion yen, is spent on cardiovascular disease. The Japan Collaborative Cohort Study involved 95,000 Japanese, and it found that smoking increased the risk of death from cardiovascular disease 1.6–2.0-fold, resulting in exorbitant medical expenditures [3]. Nonetheless, 30% of male adults and 10% of female adults in Japan smoke [4]. Japan has one of the highest smoking rates among developed countries, and smoking cessation (SC) must be promoted further.

Efforts to curb smoking should significantly decrease the development of cardiovascular disease and sharply curtail medical expenditures. However, individuals are known to gain weight after SC, making obesity prevention and subsequent medical expenditures a concern [5, 6]. The extent of weight gain varies depending on the study, but men who quit smoking on their own gain 2.8 kg on average, whereas women gain an average of 3.8 kg; 20–40% of people gain 13 kg or more [6]. Weight gain after SC can cause individuals to resume smoking, which increases cardiovascular risk. SC aids, such as nicotine patches or varenicline, help minimize weight gain after SC; nevertheless, individuals can gain weight for several years after SC despite receiving treatment. Weight gain frequently results in poorer glucose tolerance and a resumption of smoking. We have reported a case in which glucose tolerance significantly decreased with weight gain after SC [7]. The current authors have previously examined predictors associated with weight gain during SC treatment. Smokers with a high Fagerström Test for Nicotine Dependence (FTND) score upon an initial visit to a SC clinic (smokers with a high level of nicotine dependence) were more likely to gain weight after quitting smoking [8]. The advantages of SC are intricately combined with the disadvantages of post-SC weight gain. α1-antitrypsin low-density lipoprotein (AT-LDL) complex is an oxidatively modified LDL that promotes atherosclerosis. We had previously found that the level of AT-LDL in the blood is closely related to smoking status, that AT-LDL levels improve (decrease) 3 months after SC [9], and that cardiovascular markers do not improve in individuals who gain a substantial amount of weight after quitting smoking [10]. These findings suggest that post-SC weight gain might increase the risk cardiovascular events even though the individual quits smoking. This hypothesis is compatible with a study reporting no clear advantages of SC in diabetics who gain 5 kg or more [11]. In other words, preventing weight gain after quitting smoking could further reduce cardiovascular risk. Smoking and obesity are closely related, and they synergistically increase cardiovascular risk factors such as cerebral infarction and myocardial infarction. Promptly addressing this problem is vital in terms of medical and social costs.

SC treatment will be conducted according to the Standard Procedures for Anti-Smoking Treatment (originally issued in March 2006 by the Japanese Circulation Society, the Japan Lung Cancer Society, and the Japanese Cancer Association) [12]. SC treatment consists of using SC aids, such as nicotine patches or varenicline, along with nondrug therapy such as counseling from a physician or nurse. Smokers may continue to gain weight for 2–3 years after SC. However, there are no specific practice guidelines regarding minimizing weight gain after completing the 12-week SC treatment covered by the National Health Insurance. The standard procedures for anti-smoking treatment list weight gain as a possibility despite the use of SC aids; however, it does not list specific methods to deal with problem.

Although diet is understood to affect obesity, appropriate dietary intake and a balanced diet for each individual are unclear, hampering obesity alleviation. Nutritional guidance allows a registered dietitian to review an individual’s diet in light of their energy expenditure and nutritional balance. It also helps the dietitian and individual to devise obesity prevention strategies and ameliorate illness, which has a substantial impact on medical economics. A study has reported that providing nutritional guidance to women who resume smoking due to fear of gaining weight helps inhibit post-SC obesity and increases the percentage of women who quit smoking for a prolonged period [13]. However, large-scale prospective, comparative trials have not yielded evidence for the effects of nutritional guidance on cardiovascular risk for every individual who is likely to gain weight after SC.

The aim of this trial is to determine and compare the effectiveness with which nutritional guidance prevents obesity after SC, the effects of nutritional guidance on cardiovascular, glucose, and lipid metabolism biomarkers, and the effects of nutritional guidance on individuals who quit smoking for a prolonged period. This trial will involve individuals who successfully quit smoking with the help of a SC clinic and gained weight.

Inhibiting weight gain after SC will help maintain glucose tolerance and prevent new-onset diabetes mellitus. An altered body composition with increased visceral fat reduces glucose tolerance while promoting oxidative stress and inflammation. However, a previous study reported that weight gain due to SC increases not only fat but also bone and muscle tissues [14]. Adiponectin levels are closely and inversely correlated with the amount of visceral fat, and numerous studies have reported that decreased adiponectin levels are associated with decreased glucose tolerance. Furthermore, adiponectin levels decrease even when weight gain is inhibited by resuming smoking. Among the numerous markers and items studied, blood adiponectin levels are particularly closely associated with abdominal obesity, smoking, oxidative stress, and obesity- and smoking-associated inflammation. Thus, adiponectin is an optimal marker for use in our study, and we have selected it as the primary endpoint.

This trial will be a multicenter, prospective, parallel-group randomized controlled trial. Participants will be assigned either to a group receiving nutritional guidance (once every 3 months) or to a group not receiving nutritional guidance. We chose 3-monthly visits because nutritional guidance typically continues for about 6 months. In addition, a previous study reported that frequent visits have a greater effect on weight gain and that follow-up is needed at least once every 3 months [15]. Participants will be enrolled for 3 years after the trial is approved by the Central Ethics Review Committee. The total duration of the trial will be 6 years (scheduled duration: April 2016 to March 2022).

Our target enrollment is 250 participants (125 individuals in the control group, 125 individuals in the intervention group). No similar clinical studies exist to serve as a reference. Although the exact sample size cannot be calculated, it has been estimated as follows:

In previous studies by our group, changes in adiponectin levels had served as the primary endpoint, and the standard deviation (SD) for changes in adiponectin levels (defined as the percentage of change in adiponectin levels before and after treatment, with the adiponectin level prior to treatment representing 100%) was 20%. We envision a similar approach for the current trial, and the SD is set at 20% to compare the percentage of change in adiponectin levels in the two groups (individuals who do not receive nutritional guidance vs. individuals who do). In order to detect a 10% difference between the assigned groups (effect size: 0.5) at a two-tailed alpha level of 5%, with a power of 80% and an adjustment for multiple primary endpoints, each group will need to consist of 82 individuals. Assuming a 25% drop-out rate during follow-up, based on data amassed from the SC clinic, 110 participants would need to be enrolled in each group. In light of the aforementioned estimates and other factors for error, the required enrollment would ultimately be a total of 250 individuals who visit the SC clinic, or approximately 125 individuals in each group.

The study’s inclusion and exclusion criteria are outlined in Table 1. The participants must meet all of the inclusion criteria and none of the exclusion criteria.

The trial treatment will be discontinued for participants in any of the following situations:

(1) a participant asks to withdraw their consent; (2) a participant has asked to stop receiving the trial treatment; (3) a participant’s underlying illness is exacerbated or recurs; (4) a participant’s underlying illness recurs or new cancerous lesions are noted; (5) a participant fails to make a visit as a result of a change in address or similar; (6) a participant dies; or (7) a participant is deemed ineligible for enrollment.

Participants who cease receiving the trial treatment will be followed and will receive routine care as drop-outs.

All procedures will be performed in accordance with the ethical standards of the Institutional and National Research Committees as well as the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

An overview of the proposed study protocol can be found in Fig. 1. The schedule of enrollment, interventions, and assessments is shown in Fig. 2. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist is provided in Additional file 1.

Prior to beginning this trial, the University Hospital Medical Information Network’s Internet Data and Information Center for Medical Research will be asked to create a central assignment system using the Electronic Data Capture (EDC) system. Once written consent is obtained from an individual who meets the inclusion criteria, and a lead investigator has verified that the individual meets all of the eligibility criteria and none of the exclusion criteria, the participant’s information will be registered in the EDC system. After registration, the EDC system will assign patient numbers that do not include the participant’s personal information. Immediately after entry, the EDC system will randomly assign the participants to one of two groups (the group receiving nutritional guidance or the group not receiving nutritional guidance) via dynamic allocation. A lead investigator (or study chair) and the study office of the Kyoto Medical Center will be notified of the patient numbers and the group assignments. Based on the EDC system assignment, a lead investigator will schedule nutritional guidance for individuals receiving nutritional guidance and a visit 9 months later for individuals not receiving nutritional guidance. Registration in the EDC system allows adjustments for confounding factors (age, sex, the FTND score, weight gain (kg) before and after SC, and the fear of gaining weight according to a survey) between groups. The participants will be randomized by minimization (a method of dynamic allocation).

The individuals in the experimental group will receive nutritional guidance from a registered dietitian at 1, 4, and 7 months after enrollment. A study has reported that nutritional guidance for 6 months or longer, or in numerous sessions, is effective for preventing weight gain and for discouraging former smokers from resuming smoking [15]. An investigator or associate will explain the significance of the nutritional guidance in this trial (preventing weight gain after SC) to a registered dietitian at each study site. Typically, food intake and the number of meals increase in response to oral cravings and increased appetite after quitting smoking. During nutritional guidance, participants will be educated on the significance of actively managing nutrition while quitting smoking. Participants’ height and weight will be determined, and they will be informed of their optimal weight based on a reasonable Body Mass Index (BMI) (22). An instructional plan to meet an individual’s estimated energy requirements and nutrient intake will be formulated based on the Dietary Reference Intake for Japanese (2015) as stipulated by the Ministry of Health, Labor, and Welfare [16]. In principle, the estimated energy requirement and nutrient intake are based on Article 20, Point 2 of the Health Promotion Act (Act No. 103 of 2002) [16]. The Dietary Reference Intakes help calculate the estimated energy requirement based on basal metabolism, physical activity level, sex, age, height, and weight. It also assesses the status of food intake, whereby changes in weight are used to assess whether the actual energy requirement is lower or higher than the estimated value. If a participant has an illness, such as diabetes, hypertension, dyslipidemia, atherosclerotic disease, or chronic kidney disease, an instructional plan will be devised based on management guidelines for that particular illness. For this, an individual’s energy needs will be determined and their dietary intake assessed so that the individual can be instructed on how to improve their diet.

During follow-up, the participants will log their dietary intake, activity level, and weight to the greatest extent possible. During follow-up, an excess or lack of energy will be assessed in light of weight changes. Targets will be reset while referring to individual logs as needed, and the participants will be encouraged to appropriately manage their energy and nutrient intake and weight. Individuals who resume smoking while receiving nutritional guidance will not be prompted to quit smoking. Items covered and materials used in nutritional guidance will be standardized among the study sites.

Individuals not receiving nutritional guidance will have a follow-up visit 9 months after enrollment.

Studies have reported that oral antidiabetic, antihypertensive, antidyslipidemic, antipsychotic, and antiepileptic drugs, and other medications can affect weight and adiponectin levels (the primary endpoint of this trial). Thus, the baseline dosage and concomitant medications will, in principle, not be modified, nor will new medications be added during the follow-up of either group. If the baseline dosage or concomitant medications must be modified, or a new medication must be added, the reason for the change, the name of the medication, the dosage, and the duration of administration will be described in detail on the questionnaire. If a participant fails to make a scheduled visit, the individual will be contacted by telephone to ascertain the reason. Upon the conclusion of the trial treatment period, routine treatment covered by National Health Insurance will be provided as needed at the physician’s discretion.

The following items will be assessed during the fifth visit to the SC clinic (upon enrollment) and at 9 months after enrollment:

At the time of manuscript submission, recruitment for this study is ongoing.