The Effectiveness of Smoking Cessation in Prediabetic Smokers

Study Overview
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Brief Summary
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Existing literature investigating the impact of smoking cessation on new-onset diabetes mellitus (DM) risk is conflicting. Combing the need for smoking cessation and body weight self-management to prevent the progression of prediabetes stage into DM, with the public implementation of the second-generation cessation program, we aimed to study the effectiveness of the Fight Tobacco and Stay Fit (FIT2) program aiming at promoting smoking cessation and restricting post-cessation weight gain (PCWG) together in prediabetic smokers regarding long-term glycemic and DM-related health outcomes.

Detailed Description
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Participants: We expect to recruit study participants at National Taiwan University Hospital and its Yunlin branch, where a systematic identification system has been applied to classify the tobacco addiction status of every patient in outpatient clinics. This study invites identified current smokers to undergo screening tests between August 2013 to January 2017. All participants should give informed consent, with personal data protected. Only individuals aged 30 to 75 years are included. A history of diabetes, hypertension, Fagerström test for nicotine dependence, alcohol consumption, physical activity, depression, sleep quality, and current medications is collected through standardized personal interviews. Prediabetic participants are those who repeatedly have either of the following: 1) plasma glucose 100 to 125 mg/dL (5.6 to 6.9 mmol/L) in the fasting state; 2) plasma glucose 140 to 199 mg/dL (7.8 to 11.0 mmol/L) two hours after a 75-g oral glucose load; 3) glycosylated hemoglobin (A1C) 5.7% to 6.4%, in the absence of diabetic medications. Prediabetic participants who smoke ≥10 CPD for at least 6 months are classified as prediabetic smokers. Excluded are those with existing diagnosis of DM, thyroid diseases, acute cardiac conditions within 3 months, acute renal failure, chronic glomerulonephritis, polycystic kidney disease, mental health disorders ever diagnosed by psychiatrists, pregnancy, breast-feeding, malignancy; or current use of diabetic medications, smoking cessation medications, steroids, lithium or antipsychotics. Information about tobacco use, alcohol consumption, physical activity, depression, sleep quality, personal medical histories, and current medications is collected through standardized personal interviews and medical records. The study protocol was approved by the National Taiwan University Hospital Research Ethics Committee. Sample size estimation We estimate to recruit at least 596 prediabetic smokers, 33% (199) of whom decide to join the intervention, to reach 90% power and a two-sided 95% CI for the detection of a 50% risk reduction, assuming 30% as the risk of incident T2D during follow-up in the usual care group. Assignment, prospective follow-up, and analytic design The assignment of this trial is based on shared decision-making. At baseline, all eligible prediabetic smokers are asked if they would like to join the Fight Tobacco and Stay Fit (FIT2) program or just receive usual care. Beginning at enrollment, the smoking status, breath carbon monoxide levels, anthropometric indices, automated office and home blood pressures, and blood tests were recorded every six months. The intention-to-treat analysis is performed among all participants joining the FIT2 program and receiving usual care. The modified per-protocol analysis is adopted to compare participants with documented abstinence at prespecified study ends (e.g., 10 years) with the controls. The FIT2 program and post-program abstinence: The FIT2 program is a 16-week smoking cessation program that combines varenicline prescription with individualized counseling on not only smoking cessation but also weight control techniques. Participants in this group can receive their medications for up to 16 weeks within one year. Each participant also received counseling for individualized techniques for smoking cessation and body weight control at each visit. We do not prescribe nicotine replacement therapy (NRT) because it may induce insulin resistance and confound our study outcome. Bupropion is not available for smoking cessation in our institutions. Varenicline users are encouraged either to set their quit day 8 days after starting the medication; or to freely choose quit day at any time between Days 8 and 35 after starting treatment (i.e., following drug titration that took place within the first week). Varenicline users are also forbidden to use NRT during the study period. The varenicline prescription adheres to regulations by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan (www.hpa.gov.tw) and manufacturer's directions, usually initiated at 0.5 mg once daily for the first three days and then increased to 1 mg once daily. From day 8 to up to 16 weeks, the recommended dose is 1 mg varenicline twice daily. During the therapy course, physicians are allowed to adjust varenicline dosage according to tolerability. Drug adverse events, withdrawal symptoms, and perceived barriers to quitting should be recorded and addressed. Physicians should emphasize that if there are any uncontrolled depressed moods, suicidal thoughts, or attempts, they are to cease varenicline treatment and consult a psychiatrist immediately. Smoking status is assessed by self-reported 7-day point-prevalence abstinence, confirmed by a breath CO level. Cotinine is not used to assess abstinence because, when used with self-report to indicate whether a person has smoked, CO and cotinine levels show high agreement. We provide participants in the intervention group with individualized counseling to help minimize the relapse rate. In addition to varenicline prescription and smoking cessation counseling covered in conventional smoking cessation services, the FIT2 program also offers individualized weekly behavior coaching in diet and physical activity to restrict PCWG. The FIT2 participants are encouraged to do at least 150 minutes of moderate-intensity (3.0-6.0 metabolic equivalents) aerobic physical activity throughout the week. The counseling sessions allow opportunities to identify obstacles to lifestyle change and to discuss approaches with a professional panel of dietitians and certified personal trainers. The FIT2 participants are encouraged to do at least 150 minutes of moderate-intensity (3.0-6.0 metabolic equivalents) aerobic physical activity throughout the week. Emphasis is placed on checking the weekly diary for body weight, food, and physical activity through protected cellphone messages between participants and the assigned panel professionals. For those who gain weight, more intensive ways of calorie restriction and physical activity (at least 300 minutes of moderate-intensity aerobic physical activity per week) are instructed. Post-program smoking status is recorded weekly from 16 weeks to six months by self-reported 7-day point prevalence of abstinence and a breath carbon monoxide level of <6 ppm. Post-program quitters are those who quit successfully at 16 weeks after the FIT2 program and maintain their non-smoking status until the prespecified study ends (e.g., post-program abstinence at 10 years). For the modified per-protocol analysis, participants who fail to keep quit after the FIT2 program are reassigned to the control group. Usual care and control: Usual care is provided for prediabetic smokers who decide not to receive the FIT2 program. Usual care comprises encouragement to quit smoking and initiate a therapeutic lifestyle change at each visit. In the modified per-protocol analysis, the control group contains participants joining the FIT2 program who fail to achieve post-program abstinence and all participants receiving usual care, including those who quit smoking on their own.

Official Title
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The Effectiveness of Smoking Cessation in Prediabetic Smokers

Conditions
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Diabetes Mellitus, Cigarette Smoking, Prediabetes

Intervention / Treatment
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* Drug: Varenicline for tobacco smoking cessation
* Behavioral: Individualized counseling about both smoking cessation and weight control techniques


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals aged 30 to 75 years Prediabetic smokers Exclusion Criteria existing diagnosis of DM or current use of diabetic medications thyroid diseases acute cardiac conditions within 3 months acute renal failure, chronic glomerulonephritis, or polycystic kidney disease mental health disorders ever diagnosed by psychiatrists pregnancy or breast-feeding malignancy current use of smoking cessation medications, steroids, lithium, or antipsychotics.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>A 16-week FIT2 program that combines smoking cessation therapy with individualized behavior coaching in diet and physical activity for PCWG restriction. | Drug: Varenicline for tobacco smoking cessation<br>* The 16-week varenicline course conforms to real-practice government regulations in Taiwan.<br>* Other names: Varenicline (Champix);Behavioral: Individualized counseling about both smoking cessation and weight control techniques<br>* The FIT2 program also offers behavior coaching in diet and physical activity to restrict post-cessation weight gain, which is not covered in conventional smoking cessation services.<br>* Other names: Individualized behavior coaching;|
| No Intervention: Control<br>Usual care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With New-onset Type 2 Diabetes Mellitus (DM) | The primary outcome is type 2 DM, defined as having repeatedly at least one of the following criteria: 1) plasma glucose ≥126 mg/dL (7.0 mmol/L) in the fasting state; 2) plasma glucose ≥200 mg/dL (11.1 mmol/L) randomly with hyperglycemic symptoms or two hours after a 75-g oral glucose load; 3) A1C ≥6.5%;20 or under medications for physician-diagnosed type 2 DM. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Regression to Normoglycemia | Participants who regress to normoglycemia should met all the following conditions for more than six months and maintained such status until the study end: 1) plasma glucose <5.6 mmol/L (100 mg/dL) in the fasting state; 2) plasma glucose <7.8 mmol/L (140 mg/dL) two hours after a 75-g oral glucose load; or 3) HbA1c<39 mmol/mol (5.7%), in the absence of antidiabetic drugs. | Up to 5 years | 
| Major Adverse Cardiac Events | Cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke diagnosed by specialists according to medical records | At 10 years (between 2022 and 2026) | 
| Chronic Kidney Disease Progression | Each participant is evaluated for the renal outcome every six months and at 10 years. Defined as progression to macroalbuminuria [urinary albumin-to-creatinine ratio (UACR), >300 mg of albumin per gram of creatinine] for ≥ 3 months, or decrease in estimated glomerular filtration rate (eGFR) to <60mL/min/1.73 m2 for ≥ 3 months, as calculated by the four-variable Modification of Diet in Renal Disease (MDRD) formula, and incident albuminuria for ≥ 3 months. | Every 6 months and at 10 years (between 2022 and 2026) | 
| NAFLD Progression | Each participant is evaluated for the steatohepatitic outcome using FIB-4 scores, BARD scores, liver stiffness measurement (LSM) every six months and at 10 years. A FIB-4 score <1.45 means a low risk of advanced fibrosis, whereas patients with a score >3.25 are likely to have advanced fibrosis. A BARD score of 2-4 was associated with an OR for advanced fibrosis of 17 (CI 9.2-31.9) and a negative predictive value of 96%. LSM is useful to exclude advanced NASH fibrosis with a high negative predictive value (at a cutoff <7 kPa). Ref: FIB-4 scores (www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis); BARD scores (www.mdcalc.com/bard-score-nafld-fibrosis); | Every 6 months and at 10 years (between 2022 and 2026) | 
| Malignancy Incidence | Incident malignancies based on medical records are accessed at 10 years, confirmed by national cancer registry system. | At 10 years (between 2022 and 2026) | 
| All-Cause Mortality | Deaths are ascertained at 10 years by computer linkage to the national death registry (death certificates were created by the Ministry of Health and Welfare, Taiwan) using ID numbers and these death certificates have been validated. | At 10 years (between 2022 and 2026) | 
| HbA1c Change Between Baseline and 6 Months | The HbA1c change (in percentage of HbA1c) was calculated from values between baseline and 6 months. | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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community, preventive medicine, prediabetes, smoking cessation