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Association between smoking, microvascular complications mediated by HbA1c in type 1 diabetes
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Among adults with type 1 diabetes, a relationship between smoking status and diabetes-related complications is predominantly mediated by differences in HbA1c observed between current vs. never smokers, according to findings published in PLOS ONE.
“Previous studies have also shown that smoking is associated with poor metabolic control and through this mechanism may play a part in accelerating the development of diabetic complications,” Barbara H. Braffett, PhD, assistant research professor in the department of epidemiology and biostatistics at George Washington University in Washington, D.C., and colleagues wrote in the study background. “However, most of these studies have not utilized longitudinal measurements of both glycemic control and smoking history in a large cohort of subjects with type 1 diabetes. Additionally, conflicting results have been reported on the risks associated with smoking on both nephropathy and retinopathy.”
Braffett and colleagues analyzed data from adults with type 1 diabetes without advanced diabetes-related complications participating in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial designed to investigate whether intensive therapy could prevent the development and/or progression of diabetes-related complications. Within the cohort, 711 participants were assigned to intensive therapy and 730 participants were assigned to conventional therapy. Participants self-reported smoking status annually; if current smokers, participants reported the average daily number of cigarettes smoked. Information on age at which participants became daily smokers was collected at baseline, as was the number of years since first quitting smoking, if applicable. Researchers characterized participants as never, former or current smokers.
Researchers used generalized linear mixed models to test differences between smoking groups in annual HbA1c values during the study period and separate Cox proportional hazard models to examine the effect of time-dependent smoking status on time to retinopathy and time to nephropathy after adjustment for DCCT treatment group. Additionally, mediation analyses were conducted to explore HbA1c as a mechanism that underlies the relationship between smoking and complications.
“Specifically, we sought to identify whether the association of smoking and complications is explained by the difference in HbA1c between smokers and nonsmokers,” the researchers wrote. “It was hypothesized that, after controlling for HbA1c, any previously significant effect of smoking on complications would either be diluted or no longer significant.”
Smoking effects on HbA1c
At baseline, 294 (20%) of participants were current smokers and 221 (15%) were former smokers. Among never smokers at baseline, 100 reported smoking during the course of the trial, increasing the frequency of ever smokers from 35% at baseline to 43% by the end of follow-up. The percentage of former smokers increased from 15% at baseline to 21% at the end of the study.
Researchers found that mean levels of HbA1c averaged across all of the repeated measures were different by smoking status. Current smokers had the highest mean levels, with an average differences of 0.34% from never smokers (P < .01) and an average difference of 0.31% from former smokers (P < .01). Mean HbA1c levels of former smokers were similar to those of never smokers. After collapsing current and former smokers into one category, mean HbA1c levels remained higher for ever smokers compared with never smokers (0.16%; P < .01).
Smoking effects on comorbidities
During an average 6.5 years of follow-up, 271 participants developed retinopathy and 276 participants developed nephropathy. Compared with never smokers, current smokers had a 43% increased risk for developing retinopathy during follow-up (HR = 1.43; 95% CI, 1.08-1.89) and a 36% increased risk for developing nephropathy (HR = 1.36; 95% CI, 1.03-1.8). There were no between-group differences when comparing former smokers and never smokers, according to researchers; however, after collapsing all current and former smokers into one category, ever smokers were at higher risk for retinopathy compared with never smokers (HR = 1.26; 95% CI, 1-1.61).
After including HbA1c as a time-dependent covariate in models, increased risks for retinopathy and nephropathy no longer rose to significance for current smokers, with the HR decreasing from 1.43 to 1.18 in the retinopathy model and from 1.36 to 1.21 in the nephropathy model. The changes represented 54% and 39%, respectively, of the total effect between smoking and complications explained by HbA1c values alone, according to researchers. After further adjustments for baseline covariates, the HR was further reduced in the retinopathy model, with HbA1c representing 78% of the total effect observed.
“Elevated blood glucose levels, caused by the negative effects of smoking, account for most of the significant association between smoking and complications,” the researchers wrote. “Individuals with type 1 diabetes who smoke have significantly worse metabolic control and are therefore at a greater risk of developing complications. This work highlights the importance of smoking as a major modifiable risk factor in the development of microvascular complications in type 1 diabetes and reinforces the importance of smoking cessation.” – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.
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