| BackgroundsSmoking is one of the major risk factors for many diseases,and quitting smoking is the only way to reduce the harm of smoking.However,despite 70%of smokers expressing a desire to quit,the current cessation rate remains low,nicotine withdrawal symptoms are the reason most people have difficulty quitting,and withdrawal related anxiety symptoms contribute to the relapse of smoking behavior.A 2018 study published in the Proceedings of the National Academy of Sciences of the United States of America(PNAS)found that the mouse exposed to metformin showed a significant decrease in anxiety-like behavior after nicotine withdrawal.Mechanism studies have exposed that the AMP activated protein kinase(AMPK)pathway is closely related to anxiety-like behavior induced by nicotine withdrawal.Long-term nicotine use causes the activation of the AMPK pathway,which is rapidly suppressed after nicotine withdrawal.Metformin,as an activator of the AMPK pathway,alleviates nicotine withdrawal symptoms by activating the AMPK pathway in the hippocampus.As a safe and well-tolerated drug commonly used in the treatment of type 2 diabetes,metformin may have the potential to enhance the effectiveness of smoking cessation interventions.However,few population-based studies have been conducted to evaluate the effect of metformin on smoking cessation interventions.This study aims to explore at the population level whether metformin can reduce nicotine dependence among smokers and thus reduce the number of daily smokers,and provide a new approach for the effective implementation of smoking cessation in diabetic and pre-diabetic population.MethodsIn this study,based on the Chronic Disease Follow-up Management Project of Pingyi Center for Disease Control and Prevention in Shandong Province,type 2 diabetes patients aged over 30 who smoked were followed up for two years(from January 1,2019 to December 30,2020).A cohort was constructed among those who had been followed up twice or more and had no history of major disease or surgery.Taking metformin as exposure and daily smoking amount as outcome,the generalized estimation equation(GEE)model was used to explore the influence of metformin on daily smoking amount.Then,the quantitative relationship between metformin dose and daily smoking was analyzed in patients who continued to take metformin alone,and the external data were used to verify the main analysis results in the diabetes follow-up cohort in Jiaonan,Shandong Province.In addition,this study also used the two-sample Mendelian Randomization(TSMR)method to examine whether there is a causal association between metformin and daily smoking and the time from waking to smoking the first cigarette at the genetic level,using the reduction of HbA1c caused by the activation of AMPK pathway,the target of metformin,as a substitute for metformin.At the same time,HbA1c was used as a negative control to investigate whether changes in the AMPK pathway after the use of metformin were responsible for the response variables,rather than changes in blood glucose levels.Results1.In the cohort study,a total of 2678 smokers with diabetes were followed up with a mean follow-up of 4.9 times.The association analysis showed that patients taking metformin smoked 1.201(0.358～2.045)fewer cigarettes per day than non-users,while there was no statistically significant difference in alcohol consumption among those taking metformin or not.2.Subgroup analysis showed that the inverse association between metformin use and daily smoking was more significant in individuals younger than 60 years,male,without hypertension,with a history of CVD,alcohol consumption,and overweight but not obese.3.At the same time,the study results showed that the daily smoking amount of patients taking metformin alone was 0.629(95%CI 0.356 to 0.902)less than that of patients taking no antidiabetic drugs,3.819(95%CI 2.481 to 5.156)less than that of patients taking other antidiabetic drugs,and 5.988(95%CI 4.961 to 7.015)less than that of patients taking sulfonylureas antidiabetic drugs.4.For smokers with diabetes who took metformin alone,the study found that the dose of metformin was also significantly associated with the daily smoking amount.For each additional 500 mg of metformin daily dose,the daily smoking amount was 0.729 less.Similarly,there was no significant association between metformin dose and daily alcohol consumption as a control.In the segmented regression,the estimated breakpoint of the cumulative dose of metformin was 2410(/500mg).After reaching the breakpoint,with the increase of the cumulative dose of metformin,the reduction rate of the daily smoking volume of patients increased significantly.5.In the validation data,patients taking metformin smoked 0.404(95%CI 0.297 to 0.511)fewer cigarettes per day compared with non-users.Mixed-effect model analysis showed that there was no significant difference in baseline daily smoking among metformin users,but there was a significant decrease in daily smoking among metformin users over time(P=0.004).6.In the Mendelian randomization study,inverse-variance weighted(IVW)analysis results showed that the reduction of HbA1c through AMPK activation was associated with lower daily smoking[-0.425(95%CI-0.701 to-0.149)],and a longer time from waking to smoking the first cigarette[0.507(95%CI 0.050 to 0.964)].There was no statistically significant causal association between the genetic prediction of HbAlc and the daily smoking and the time from waking to smoking the first cigarette.There was no statistically significant causal association between the genetic prediction of HbA1c and the amount of daily smoking or the time from waking to smoking the first cigarette.Conclusion1.The results of the cohort study showed that smoking diabetics taking metformin were significantly less likely to smoke daily than non-users,and this difference may not be due to changes in psychosocial factors associated with taking metformin.The effect of metformin on daily smoking is related to the intensity and duration of metformin exposure,that is,the observable effect of metformin on daily smoking may require a certain dose and a comparable duration of use.2.Results of the Mendelian randomized study showed that metformin was associated with a causal association with a decrease in daily smoking and an increase in the time from waking to smoking the first cigarette,and that this causal association may not be due to a decrease in HbA 1 c levels associated with metformin administration. |
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