Relationship of cardiometabolic parameters in non-smokers, current smokers, and quitters in diabetes: a systematic review and meta-analysis

Despite an overwhelming body of evidence against smoking and all-out efforts to control tobacco-related harm, globally approximately 6 million deaths are attributed to use of tobacco every year [1]. If the current trend of smoking continues, the World Health Organisation (WHO) estimates that by 2030, the annual death toll will rise to over 10 million [2]. Smoking appears to positively contribute to glucolipotoxicity and insulin resistance, which are the hallmarks of diabetes. Nicotine and the free radicals in cigarettes have been linked to accelerated β-cell apoptosis and impedance of intracellular GLUT-4 mobilisation, which may feed into hyperglycaemia associated with diabetes [3‐5]. A number of studies have demonstrated that smoking is associated with increased cardiovascular mortality in people with diabetes [6, 7]. However, it is not entirely clear whether this increased mortality in smokers is due to atherogenic metabolic profile or due to the direct toxic effects of nicotine and other toxic substances in cigarettes on the cardiovascular milieu.

The European Association for Study of Diabetes (EASD) and the American Diabetes Association (ADA) recommend smoking cessation as an integral component of the management of diabetes [8]. Other international and national guidelines, including the World Health Organization (WHO), the National Institute for Health and Care Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) in the UK, have published similar recommendations [9, 10]. Despite multiple recommendations, the prevalence of smoking in people with and without diabetes remains comparable [11]. One of the commonest arguments against quitting in people with diabetes is the risk of weight gain and worsening glycaemic control after quitting [12, 13]. Some studies have demonstrated a positive correlation between weight gain and increased HbA1c after quitting [14, 15]. Interestingly, a number of studies also demonstrated a positive correlation between smoking cessation and developing diabetes suggesting that smoking cessation may have a detrimental impact on glucose metabolism [16‐18]. Due to the risk of weight gain and the potential risk of worsening glycaemic control, there is a significant anxiety about the benefit of smoking cessation in people with diabetes [19, 20]. The aim of this systematic review and meta-analysis was to explore the precise relationship of the cardiometabolic profiles in smokers, non-smokers, and quitters with diabetes.

In this systematic review, we conducted two types of analyses (narrative synthesis and meta-analysis), to compare two groups of populations (smoker vs. non-smokers and smokers vs. quitters), on three types of outcomes (HbA1c, lipid profiles and blood pressure). In addition, we also conducted meta-regression analysis to explore the association between study effect size and study level covariates such as age, gender, whether the participants were adults or adolescents, types of diabetes, study design and duration of smoking.

Using the agreed search terms, we identified 6866 articles on Medline, EMBASE, and CINAHL (Fig. 1). We reviewed 57 full-text articles, 16 of which met the inclusion criteria for the review and meta-analysis. Out of the 16 studies, 2 were excluded from the review; one of them was due to poor data quality [24] and the other one was because of participants’ resuming smoking within 12 months of quitting [25]. All the 14 studies were included for narrative synthesis. Out of the 14, 12 studies were cross-sectional while one study was a retrospective and another was a prospective cohort study. 10 studies were included for meta-analysis and the rest were excluded due to insufficient data. For smokers and non-smokers, we identified 10 studies for the outcome of HbA1c, 6 for lipid profile and 8 studies for blood pressure.

For smokers and quitters, only 4 out of 5 studies could be used for meta-analysis for the outcome of HbA1c. There was not enough data to pool the results for lipid profile and blood pressure for meta-analysis in this comparison groups. Full details of the study characteristics are summarised in Tables 1, 2, 3 and 4. Meta-regression data and results are shown in Tables 5, 6, 7, 8, 9, 10 and 11.

The key findings of the review were non-smokers with diabetes had a lower level of HbA1c −0.61 (95% CI −0.88 to −0.33; p < 0.001), a higher level of HDL cholesterol 0.12 (95% CI 0.08 to 0.15; p < 0.001) and lower level of LDL cholesterol −0.11 (95% CI −0.21 to −0.01; p = 0.03), compared to smokers. However, there was no statistically significant difference in either SBP or DBP between non-smokers and smokers −0.34 (95% CI −2.54 to 1.87; p = 0.77) and −0.21 (95% CI −1.10 to 0.68; p = 0.64), respectively. Univariate adjusted meta-regression analyses revealed that for HbA1c, the difference is significantly associated with the mean age of the study population, whereby studies with an older population resulted in a larger difference in HbA1c between smokers and non-smokers 0.02 (95% CI 0.01, 0.02; p < 0.001). The study effect size was also significantly associated with the duration of smoking 0.021 (95% CI 0.004 to 0.038; p = 0.034) and whether the subjects were adults or adolescents 0.36 (95% CI −0.16 to 0.89; p = 0.016). Univariate adjusted meta-regression analyses revealed that the relationship observed in HDL and LDL cholesterol in non-smokers and smokers was not significantly associated with any of the study level covariates assessed. Whilst meta-regression analysis did not show any significant association between SBP and study level covariates, but difference in DBP was significantly associated with the age of the study participants.

This review did not identify any statistically significant difference in HbA1c between smokers and quitters. The precise effect-size of quitting on lipid profiles and blood pressure could not be accurately delineated, as it was not possible to carry out the meta-analysis due to inadequate number of studies with available data. Conversely, this review did not show the expected reduction in HbA1c after smoking cessation despite overwhelming evidence that the insulin resistance improves after smoking cessation [28, 29].

The major weakness of this review is that it is carried out on observational studies and no temporal relationship can be established. Due to the heterogeneity of study populations, the findings cannot be generalised. The outcome of quitting for less than 12-months is unknown, as this study did not include quitters of less than 12-month duration of abstinence. Despite the outlined weaknesses, this is the first systematic review on this subject, which can be used as a useful tool to raise awareness about the current evidence on this topic of immense public health importance.

The detrimental effects of smoking in diabetes are well documented. It is estimated that cigarettes contain around 4000 chemicals of which, approximately 400 are considered to be harmful [30]. Inhalation is a very efficient method of nicotine delivery, the compound gaining access to the key organs within seconds of administration [31]. After distribution in the circulation, nicotine triggers a cascade of biochemical, hormonal, and metabolic disarray, which appears to be much more pronounced in people with diabetes [32, 33]. A recent study demonstrated that nicotine infusion acutely impairs insulin sensitivity in people with T2DM, but not in healthy subjects suggesting that smoking might affect people with diabetes differently compared to people who do not have diabetes [34]. Several studies have confirmed that smokers with diabetes have a higher HbA1c and atherogenic lipid profiles compared to non-smokers [35, 36]. The relationship of HbA1c and lipid profiles in this study can explain to a large extent the reason why smokers with diabetes have a worse cardiovascular outcome compared to non-smokers.

A number of possible mechanisms, including metabolic deregulation, endothelial dysfunction, and alteration of plasma viscosity by interfering with the coagulation cascade are suggested to explain the association between smoking and diabetes. Nicotine directly inhibits the binding of insulin receptor substrate (IRS) and prevents the activation of intracellular GLUT4, which in turn impedes intracellular glucose transport [37]. This action is followed by a compensatory rise in β-cell insulin secretion as reflected by a higher circulating concentration of c-peptide in smokers, compared to non-smokers [38]. The findings of this review are complementary to the existing knowledge that smokers with diabetes have poorer cardiometabolic profile compared to non-smokers.

However, our current understanding of the impact of quitting on cardiometabolic profile is vague. There are some anecdotal evidence suggesting that a transient rise in HbA1c takes place after smoking cessation [38, 39], while some other studies indicate improved insulin sensitivity as early as 2 weeks after smoking cessation [29]. One of the possible explanations for this paradoxical relationship between the improved insulin sensitivity and a rise in HbA1c, could be a direct blunting effect of smoking on glycosylation of haemoglobin. In a study, researchers measured HbA1c in people without diabetes from the original cohort of Framingham Heart Study and demonstrated that with increasing age and BMI, the HbA1c gradually increased over a period of 4–6 years. On the contrary, smokers did not show any such rise in HbA1c, suggesting that smoking might have a blunting effect on the glycosylation of haemoglobin [40]. It is, therefore, a possibility that after smoking cessation the blunting effect disappears and HbA1c value rises, without any actual deterioration of glycaemic control. Although this study did not show any statistically significant change in HbA1c following quitting for the first 3-years, but it found that if the abstinence continued for 10 years, the HbA1c in quitters was comparable to never smokers. A WHO study showed there was an increase in mortality risk lasting for up to 10 years following quitting, which gradually declined to the level of non-smoker around 10 years after abstinence [30]. This increase in mortality rate may or may not be associated with a transient rise in HbA1c following quitting. As this systematic review showed there was a potential risk of worsening glycaemic control soon after quitting, we recommend that patients should be closely monitored for cardiovascular risk factors following smoking cessation.

It must be emphasized that the harmful effects of smoking are not limited to insulin resistance and poor glycaemic control. It is evident that cigarettes smoking, in addition to metabolic deregulations, plays a crucial role in endothelial dysfunction that contribute to increased cardiovascular mortality in smokers with diabetes. Cigarettes release free radicals into the circulation, which triggers a chronic inflammatory response [31]. Over and above, nicotine and the free radicals alter plasma viscosity by their action on circulating plasminogen activator and natural endothelial vasodilator nitric oxide [32, 33]. The collective outcome is atherosclerosis and a heightened sensitivity of the intrinsic coagulation cascade, which can lead to spontaneous thromboembolism [34]. It is, therefore, not inconceivable that smoking enhances vascular complications in diabetes not only by impaired glucose metabolism but also by several other concomitant vascular perturbations.

Irrespective of the value of HbA1c, the cardiovascular mortality seems to improve after smoking cessation. ADVANCE (action in diabetes and vascular disease: preterax and diamicron modified release controlled evaluation) study has shown, despite moderate weight gain and transient rise in HbA1c, there was a 30% reduction in mortality after smoking cessation [35]. In Nurse’s Health study, the relative risk (RR) of coronary heart disease (CHD) in nurses with type 2 diabetes who had stopped smoking and remained abstinent for 10 years or over was similar to those who never smoked (RR 1.01; 95% CI 0.73–1.38) [6]. After 10 years of abstinence, their HbA1c also dropped at the level of non-smokers.

Dyslipidemia is often associated with diabetes, which seems to be aggravated by smoking. Raised LDL cholesterol is highly atherogenic, particularly with a low level of HDL cholesterol. Nicotine impairs the function of hepatic lipase, which in turns leads to atherogenic dyslipidemia [36]. Several studies have shown marked improvement in lipid profiles following quitting [37, 38]. The HDL cholesterol starts rising as early as within 17 days after quitting [21] and by 48 days there is up to about 15% increase in HDL cholesterol [39]. In this review, we have demonstrated that there was a rise in HDL cholesterol following smoking cessation, consistent with the current evidence.

The influence of smoking and quitting on blood pressure in people with diabetes is not very well studied. Researchers using data from the Health Survey for England for 3 years (1994–1996) examined the relationship between blood pressure and smoking status in people without diabetes [41]. This study was conducted on randomly selected adults (n = 33,860; 47% male) with BP measurements and smoking status (never, current and quitters) and was stratified into younger (age 16–44) and older (>45 years) age groups. After adjusting for age, BMI, social class and alcohol intake older male smokers had higher SBP compared to non-smokers. No such difference was observed (Additional file 3) in SBP in younger group and in DBP in either group. There was no statistically significant difference observed between smokers and quitters for either SBP or DBP. This review did not find any statistically significant difference in blood pressure between smokers, non-smokers and quitters suggesting that the influence of smoking is similar on BP in people with and without diabetes. However, the older smokers may be at a higher risk of vascular complications compared to younger smokers, as their SBP seems to be higher.

In conclusion, this review demonstrated that smoking negatively impacts upon the cardiometabolic parameters in people with diabetes, which might have a significant detrimental influence on cardiovascular complications. Smoking cessation, on the other hand, improves the cardiometabolic profile particularly by raising cardioprotective HDL cholesterol. However, the benefit of smoking cessation may not be immediately reflected on the HbA1c. The effects of nicotine should be viewed in the bigger context of overall cardiovascular milieu rather than HbA1c alone. Smoking cessation, on the other hand, can cause weight gain and transient rise in HbA1c. Therefore people with diabetes, when they stop smoking, should be followed up very closely and their weight and HbA1c monitored. In addition, at the time of smoking cessation, the healthcare professionals should offer appropriate support to modify lifestyles and consider intensifying pharmacotherapy to address the transient rise of HbA1c.