Efficacy And Safety Of Smoking Cessation With Varenicline Tartrate In Diabetic Smokers: A Double-Blind, Placebo-Controlled, Randomized, Trial

INTRODUCTION

Cigarette smoking harms nearly every system of the human body, thus causing a broad range of diseases, many of which are fatal. In particular, cardiovascular disease (CVD) is the most important cause of death in those who smoke (1). Both diabetes mellitus and cigarette smoking are well-known risk factors for the development of CVD and atherothrombosis (2,3). It is now acknowledged that endothelial cell dysfunction and clotting activation are not exclusive of diabetes. Cigarette smoking is also associated with functional changes of the endothelium and with an hypercoagulability state (4). It is likely that the combined injurious effects of high blood glucose together with cigarette smoke may be responsible for the observed accelerated course of vascular complications in diabetic patients who smoke.

Findings from both cross-sectional and prospective studies appear to support this notion by consistently showing a heightened risk of morbidity and premature death associated with the development of micro- and macro-vascular disease from the combination of smoking and diabetes. There is evidence that smoking increases the risk of coronary artery disease in type 2 diabetes (5,6). For example, in a prospective cohort of 7,401 female nurses with type 2 diabetes, cigarette smoking was found to be strongly associated with the risk of coronary heart disease (CHD) and this risk increased with the number of cigarettes smoked per day (7). Based on data from 4,540 patients with type 2 diabetes followed in the UK Prospective Diabetes Study (UKPDS), smoking was shown to increase the risk of coronary heart disease in both males and females with type 2 diabetes. The estimated Risk Rate (RR) occurrence of a fatal or non-fatal MI or sudden death attributable to smoking was 1.35 (8). Smoking also increases the risk of stroke (9). Based on patients with type 2 diabetes enrolled in the UKPDS, mathematical models including major confounding variables (including age, sex, atrial fibrillation, etc) estimated that a non-smoking male with a current age of 67 years would have a 6.9% probability of a stroke within 5 years compared with a 10.5% probability for a smoking male of the same age (10). Moreover, several studies have shown that smoking promotes the onset and progression of nephropathy in type 2 diabetes (11-13). In a logistic regression analysis examining associations between gender, age, stage of nephropathy, smoking status, cigarette pack-years, hypertension, total cholesterol, triglycerides, Glycated hemoglobin (HbA1c), and Blood pressure (BP), current and former smoking (P = 0.0012) and number of pack-years (P = 0.011) were shown to be the greatest predictors of the progression of nephropathy (12). Smoking has also been shown to exacerbate markers of kidney failure in this population, such as microalbuminuria (14). In addition, stopping smoking has been shown to reduce the progressive damage to the kidneys in comparison with continued smoking in type 2 diabetes (14).

Because the prevalence of smoking among people with diabetes remains elevated (15), decreasing the exposure to tobacco products is a public health imperative also for subjects with diabetes. Moreover, the most recent US Clinical Guidelines for Treatment of Tobacco Dependence (2008) list diabetes, along with other comorbid medical conditions, as a target group for smoking cessation treatment, due to the increased health risks associated with this disease and smoking (16). It must be also noted that along all known modifiable cardiovascular risk factor (e.g. raised glycemic levels, elevated cholesterol levels, high Body Mass Index) smoking appears to be the most relevant for the reduction of morbidity and mortality in this patient population. Risk management parameters of CVD that include smoking cessation may reduce morbidity and mortality more than tightening glycemic control (17,18).

Surprisingly, there are little data available in the literature on smoking cessation intervention for this specific disease group. Also, no specific information on the efficacy and safety of new pharmacological support for smokers with diabetes can be found. Varenicline is a partial agonist of the α4β2 nicotinic acetylcholine receptor that causes partial stimulation while it competitively inhibits nicotine binding. Recently, randomized, controlled clinical trials have shown that varenicline at a dose of 1 mg twice a day is superior to placebo for smoking cessation (19-21). Varenicline appears to be also more effective than sustained-release bupropion (19). Data from these trials indicate that the most common adverse event attributed to varenicline at a dose of 1 mg twice daily is nausea (19,20). However, the efficacy and safety of varenicline has never been tested in diabetic smokers.