Influence of quitting smoking on diabetes-related complications: A scoping review with a systematic search strategy

DSX 18 (2024) 103044 Available online 22 May 2024 1871-4021/© 2024 The Authors. Published by Elsevier Ltd on behalf of Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Influence of quitting smoking on diabetes-related complications: A scoping review with a systematic search strategy Magdalena Walicka a , b , * , Arkadiusz Krysi´ nski a , b , Giusy Rita Maria La Rosa c , Ang Sun d , Davide Campagna c , Agostino Di Ciaula e , Tabinda Dugal f , Andre Kengne g , h , Phuong Le Dinh i , Anoop Misra j , k , l , Riccardo Polosa m , n , c , Syed Abbas Raza o , Cristina Russo p , Roberta Sammut q , Noel Somasundaram r , the DiaSmokeFree Working Group a Department of Human Epigenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland b Department of Internal Diseases, Endocrinology and Diabetology, National Medical Institute of the Ministry of the Interior and Administration, Warsaw, Poland c Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy d Department of Biology, and Center for Biotechnology/Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, USA e Clinica Medica “A. Murri” Department of Precision and Regenerative Medicine and Ionian Area [DiMePre-J], University “Aldo Moro” Medical School, Bari, Italy f Department of Endocrinology College of Physicians and Surgeons, Royal Cornwall Hospital NHS Trust, Truro, UK g Non-Communicable Diseases Research Unit, South African Medical Research Council and University of Cape Town, Cape Town, South Africa h Department of Biological and Environmental Science, Faculty of Science, Walter Sisulu University, Mthatha, South Africa i General Practice, Family Medicine and Check-up Department, FV Hospital Ho Chi Minh City, Viet Nam j Diabetes Foundation [India], New Delhi, India k National Diabetes, Obesity and Cholesterol Foundation [N-DOC], New Delhi, India l Fortis C-DOC Centre for Excellence for Diabetes, Metabolic Disease, and Endocrinology, New Delhi, India m Center of Excellence for the acceleration of Harm Reduction [CoEHAR], University of Catania, Vietnam, Italy n Centre for the Prevention and Treatment of Tobacco Addiction (CPCT), University Teaching Hospital “Policlinico-Vittorio Emanuele”, University of Catania, Catania, Italy o Shaukat Khanum Cancer Hospital and Research Center, Peshawar, Pakistan p Ashford and Saint Peter’s Hospitals NHS Foundation Trust, Chertsey, UK q Department of Nursing, Faculty of Health Sciences, University of Malta, Msida, Malta r Diabetes and Hormone Center, Colombo, Sri Lanka ARTICLE INFO Keywords: Smoking Smoking cessation Diabetes Cardiovascular disease Nephropathy Retinopathy Neuropathy Diabetic foot Erectile dysfunction ABSTRACT Introduction: Smoking in people with diabetes markedly elevates their risk of developing complications and increases the likelihood of cardiovascular mortality. This review is the first to specifically provide evidence-based analysis about the influence of quitting smoking on diabetes-related complications in people with type 2 diabetes. Method: The present review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews. All human clinical studies assessing the effects of stopping smoking cessation on diabetes-related complications were included. PubMed and Embase were screened until January 2024. References of primary studies and principal peer-reviewed scientific journals in the field were manually screened. Results: We identified a total of 1023 studies. Only 26 met the criteria for eligibility. In general quitting smoking is associated with decreased risks of myocardial infarction and ischemic stroke. Regarding microvascular complications, the strongest evidence for the beneficial effects of smoking cessation is observed in diabetic nephropathy. However, the relationship between smoking cessation and retinopathy, neuropathy, diabetic foot complications and diabetic-related erectile dysfunction, is poorly investigated. Conclusion: Quitting smoking offers significant advantages in managing diabetes-related complications, significantly lowering the risks of myocardial infarction, ischemic stroke, and diabetic nephropathy. This underscores the importance of cessation. Providing evidence-based information on the benefits of stopping smoking for * Corresponding author. , Mossakowski Medical Research Institute, Polish Academy of Sciences, ul. Adolfa Pawi´ nskiego 5, 02-106, Warszaw, Poland. E-mail address: [email protected] (M. Walicka). Contents lists available at ScienceDirect Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx https://doi.org/10.1016/j.dsx.2024.103044 Received 21 March 2024; Received in revised form 13 May 2024; Accepted 17 May 2024 Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 2 people with type 2 diabetes who smoke, can bolster smoking cessation efforts in the context of diabetes management. 1. Introduction Diabetes mellitus encompasses metabolic disorders marked by high blood glucose resulting from defects in insulin secretion, action, or both [1]. It’s a global public health crisis, with 537 million adults affected in 2021 and an anticipated 46 % rise in cases by 2045, according to the International Diabetes Federation [2]. Type 2 diabetes (T2D) the most prevalent form of the disease, stems from insulin resistance coupled with a progressive decline in β-cell insulin secretion [3]. It is most often the result of obesity and is accompanied by dyslipidemia and hypertension, creating a metabolic syndrome. Persistent hyperglycemia in T2D can progressively damage the vascular network in the human body leading to macrovascular and microvascular complications. Remarkably, up to 50 % of people with newly diagnosed T2D exhibit chronic complications [4]. Microvascular complications associated with diabetes include diabetic nephropathy, the primary cause of kidney function deterioration [5], diabetic retinopathy, the leading contributor to vision loss in developed countries [6], and diabetic neuropathy, the most widespread form of autonomic neuropathy [7]. Prevalent macrovascular complications include coronary heart disease, stroke, and peripheral artery disease. Cardiovascular disease stands as the most substantial contributor to morbidity and heightened mortality risk among individuals with T2D. Affecting roughly 32.2 % of all those with T2D, it leads to fatalities in at least 50 % of this demographic [8]. Lifestyle modification plays an important element in preventing vascular complications [9] and reducing cardiovascular risks in individuals with T2D [10]. A key component of this modification is smoking cessation. Exposure to cigarette smoke and its combustion by-products can activate numerous pathways associated with the development and acceleration of diabetes complications [11–13]. This is also the mechanism by which smoking amplifies the probability of cardiovascular mortality in individuals with T2D [14–16]. Despite a notable decrease of 29.6 % in age-adjusted smoking rates among the general population from 1990 to 2019 [17], the prevalence of smoking among individuals diagnosed with T2D remains persistently high. This pattern shows variations across different time frames, countries, and regions [18,19]. A systematic review, covering 74 studies conducted between 1990 and 2017 across 33 countries, revealed that the global average prevalence of tobacco smoking in individuals with T2D stood at 20.8 %. Notably, the highest rates were observed in the WHO East Asia and Pacific regions (28.0 %) and South Asia (25.96 %) [19]. The problem of smoking among individuals with type 2 diabetes is both critical and urgent, requiring targeted efforts to enhance education for people with diabetes and aid healthcare professionals in adapting effective smoking cessation strategies. This scoping review aims to deliver a thorough examination of the existing evidence on the impact of smoking cessation on diabetes-related complications in people with T2D. It seeks to highlight the significant effects that quitting smoking can have on mitigating cardiovascular disease, peripheral arterial disease, diabetic nephropathy, retinopathy and neuropathy, erectile dysfunction, and diabetic foot. The authors present for first time a detailed analysis specifically focusing on the influence that quitting smoking can have on these diabetes-related complications in people with T2D. Additionally, by synthesizing current research findings, this review also intends to identify and elucidate knowledge gaps, thereby guiding future research directions. 2. Methods This scoping review adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews [20]. The primary focus was determining the impact of stopping smoking on chronic diabetes complications, including cardiovascular disease, diabetic nephropathy, retinopathy, neuropathy, diabetic foot, and erectile dysfunction in people with type 2 diabetes. 2.1. Inclusion criteria Human studies (i.e., systematic reviews, observational studies, randomized and non-randomized clinical trials) that contained data on the influence of smoking abstinence on diabetes-related complications (i.e., cardiovascular disease, diabetic nephropathy, retinopathy, neuropathy, diabetic foot and erectile dysfunction) were included. For completeness, we also expanded our discussion to include key studies on the impact of smoking and smoking cessation on liver disease and bone health in individuals with diabetes. Only papers available in English were selected. 2.2. Exclusion criteria Studies focusing on pre-gestational and gestational diabetes were not included. Investigations involving patients with type 1 diabetes mellitus were selectively considered, depending on the limited availability of relevant data. In vitro, ex vivo, and animal research, along with case reports, review article, short communications, and editorials were also excluded. 2.3. Search strategy A comprehensive review of the literature was carried out in January 2024. The search was conducted across PubMed and Embase databases. Search queries were formulated by experts from the DiaSmokeFree Working Group. Tailored search strings were created and utilized to find pertinent studies. Search strings details for each outcome and database are reported in Table 1. The references of the included articles and review papers underwent additional screening to identify any potentially relevant articles. 2.4. Studies’ selection Experts from DiaSmokeFree Working Group screened each title and abstract to select studies for full-text review. Studies that either seemed appropriate for inclusion or those that could not clearly be excluded on title and abstract alone were carried forward for further evaluation. The software EndNote (EndNote X9; Thomson Reuters, New York, NY, USA) was used to manage the records and duplicates. Then, two authors (MW and AK) independently assessed each remaining full-text article to determine its eligibility. Disagreement was resolved by discussion and consensus with Experts from DiaSmokeFree Working Group. Articles meeting the specified inclusion criteria were chosen for inclusion in the qualitative synthesis. 2.5. Data extraction and findings’ synthesis The extraction of relevant data was performed by using a standardized data extraction form designed explicitly for this purpose. The extracted information, including author, study population, study design, definition of smoking status, median duration of follow up, and results, M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 3 Table 1 Search strategy adopted for each database. Outcome Database Pubmed Embase Cardiovascular disease (“diabetes mellitus, type 2"[MeSH Terms] OR “type 2 diabetes mellitus"[Title] OR “T2DM"[Title] OR “Type 2 Diabetes"[Title] OR “diabetes*"[Title] OR “diabetic*"[Title]) AND (“smoking"[MeSH Terms] OR “smoking"[Title/Abstract] OR “smok*"[Title/Abstract] OR “cigarette"[Title/Abstract]) AND (“cessation"[Title/Abstract] OR “quit*"[Title/Abstract] OR “abstinence"[Title/Abstract] OR “stop*"[Title/Abstract]) AND (“coronary disease” [MeSH Terms] OR “coronary disease"[Title/Abstract] OR “heart diseases” [MeSH Terms] OR “heart diseases"[Title/ Abstract] OR “Myocardial Ischemia”[MeSH Terms] OR “Myocardial Ischemia"[Title/ Abstract] OR “coronary artery disease”[MeSH Terms] OR “coronary artery disease"[Title/ Abstract] OR “myocardial infarction”[MeSH Terms] OR “myocardial infarction"[Title/ Abstract] OR “ischemic stroke”[MeSH Terms] OR “ischemic stroke"[Title/Abstract] OR “stroke”[MeSH Terms] OR “stroke"[Title/Abstract] OR haemorrhagic stroke[MeSH Terms] OR haemorrhagic stroke [Title/Abstract] OR “cardiovascular diseases”[MeSH Terms] OR “cardiovascular diseases"[Title/Abstract] OR “coronary heart disease"[Title/ Abstract] OR “ischemic heart disease"[Title/Abstract] OR “cardio*"[Title/Abstract]) #1 ‘Type 2 Diabetes ’/exp OR ’ Type 2 Diabetes Mellitus’/exp #2 ‘smoke’/exp OR ‘smoking’/exp OR ’smokers’/exp OR ‘tobacco’/exp OR ‘cigarette’/exp #3 ‘cessation’/exp OR ‘quit’/exp OR ‘abstinence’/ exp OR ‘stop’/exp OR ‘withdraw’/exp #4 ‘cardiovascular diseases’/exp OR ‘coronary heart disease’/exp OR ‘ischemic heart disease’/ exp OR ‘Myocardial Ischemia’/exp OR ‘myocardial infarction’/ exp OR ‘ischemic stroke’/ exp OR ‘stroke’/exp #1 AND #2 AND #3 AND #4 Diabetic nephropathy (“diabetes mellitus, type 2"[MeSH Terms] OR “type 2 diabetes mellitus"[Title] OR “T2DM"[Title] OR “Type 2 Diabetes"[Title] OR “diabetes*"[Title] OR “diabetic*"[Title]) AND (“smoking"[MeSH Terms] OR “smoking"[Title/Abstract] OR “smok*"[Title/Abstract] OR “cigarette"[Title/Abstract]) AND (“cessation"[Title/Abstract] OR “quit*"[Title/Abstract] OR “abstinence"[Title/Abstract] OR “stop*"[Title/Abstract]) AND (“Diabetic Nephropathies"[MeSH Terms] OR “Diabetic Nephropathies"[Title/Abstract] OR “microalbuminuria” [Title/ Abstract] OR “glomerular filtration rate"[MeSH Terms] OR “glomerular filtration rate"[Title/ Abstract] OR proteinuria[MeSH Terms] OR proteinuria[Title/ Abstract] OR “renal insufficiency"[MeSH Terms] OR “renal failure"[Title/Abstract] OR “creatinine clearance” [Title/ Abstract] OR “kidney failure, #1 ‘Type 2 Diabetes ’/exp OR ’ Type 2 Diabetes Mellitus’/exp #2 ‘smoke’/exp OR ‘smoking’/exp OR ’smokers’/exp OR ‘tobacco’/exp OR ‘cigarette’/exp #3 ‘cessation’/exp OR ‘quit’/exp OR ‘abstinence’/ exp OR ‘stop’/exp OR ‘withdraw’/exp #4 ‘Diabetic Nephropathies’/exp OR ‘Diabetic Nephropathy’/ exp OR ‘microalbuminuria’/exp OR ‘glomerular filtration rate’/exp OR ‘proteinuria’/ exp OR ‘renal insufficiency’/exp OR ‘renal failure’/exp OR ‘creatinine clearance’/exp OR ‘renal insufficiency, chronic’/exp OR ‘chronic kidney failure’/exp OR Table 1 (continued) Outcome Database Pubmed Embase chronic"[MeSH Terms] OR “kidney failure"[Title/Abstract] OR “end stage renal disease"[Title/Abstract] OR “renal insufficiency"[Title/ Abstract] OR “chronic kidney disease"[Title/Abstract]) ‘end stage renal disease’/ exp #1 AND #2 AND #3 AND #4 Diabetic retinopathy (“diabetes mellitus, type 2"[MeSH Terms] OR “type 2 diabetes mellitus"[Title] OR “T2DM"[Title] OR “Type 2 Diabetes"[Title] OR “diabetes*"[Title] OR “diabetic*"[Title]) AND (“smoking"[MeSH Terms] OR “smoking"[Title/Abstract] OR “smok*"[Title/Abstract] OR “cigarette"[Title/Abstract]) AND (“cessation"[Title/Abstract] OR “quit*"[Title/Abstract] OR “abstinence"[Title/Abstract] OR “stop*"[Title/Abstract]) AND (“retinopathy”[Title/Abstract] OR “macular edema”[MeSH Terms] OR “macular edema”[Title/Abstract] OR “diabetic retinopathy"[MeSH Terms] OR “diabetic retinopathy"[Title/Abstract] OR “proliferative diabetic retinopathy"[Title/Abstract] OR “ocular manifestations"[Title/ Abstract] OR “ocular complications"[Title/Abstract] OR “macular degeneration"[MeSH Terms] OR “macular degeneration"[Title/ Abstract]) #1 ‘Type 2 Diabetes ’/exp OR ’ Type 2 Diabetes Mellitus’/exp #2 ‘smoke’/exp OR ‘smoking’/exp OR ’smokers’/exp OR ‘tobacco’/exp OR ‘cigarette’/exp #3 ‘cessation’/exp OR ‘quit’/exp OR ‘abstinence’/ exp OR ‘stop’/exp OR ‘withdraw’/exp #4 ‘retinopathy’/exp OR ‘macular edema’/exp OR ‘diabetic retinopathy’/exp OR ‘diabetic macular edema’/exp OR ‘ocular complications’ OR ‘macular degeneration’/ exp #1 AND #2 AND #3 AND #4 Diabetic neuropathy (“diabetes mellitus, type 2"[MeSH Terms] OR “type 2 diabetes mellitus"[Title] OR “T2DM"[Title] OR “Type 2 Diabetes"[Title] OR “diabetes*"[Title] OR “diabetic*"[Title]) AND (“smoking"[MeSH Terms] OR “smoking"[Title/Abstract] OR “smok*"[Title/Abstract] OR “cigarette"[Title/Abstract]) AND (“cessation"[Title/Abstract] OR “quit*"[Title/Abstract] OR “abstinence"[Title/Abstract] OR “stop*"[Title/Abstract]) AND (polyneuropath*[Title/Abstract] OR neuropath*[Title/Abstract] OR “Peripheral Nervous System Diseases"[Mesh] OR “Peripheral Nervous System Diseases"[Title/ Abstract] OR “Diabetic Neuropathies"[Mesh] OR “Diabetic Neuropathies"[Title/ Abstract] OR “Polyneuropathies"[Mesh] OR “Polyneuropathies"[Title/ Abstract]) #1 ‘Type 2 Diabetes ’/exp OR ’ Type 2 Diabetes Mellitus’/exp #2 ‘smoke’/exp OR ‘smoking’/exp OR ’smokers’/exp OR ‘tobacco’/exp OR ‘cigarette’/exp #3 ‘cessation’/exp OR ‘quit’/exp OR ‘abstinence’/ exp OR ‘stop’/exp OR ‘withdraw’/exp #4 ‘diabetic neuropathy’/ exp OR ‘peripheral neuropathy’/exp OR ‘polyneuropathy’/exp #1 AND #2 AND #3 AND #4 Diabetic foot (“diabetes mellitus, type 2"[MeSH Terms] OR “type 2 diabetes mellitus"[Title] OR “T2DM"[Title] OR “Type 2 Diabetes"[Title] OR “diabetes*"[Title] OR “diabetes"[All fields]) AND (“smoking"[MeSH Terms] OR “smoking"[Title/Abstract] OR #1 ‘Type 2 Diabetes ’/exp OR ’ Type 2 Diabetes Mellitus’/exp #2 ‘smoke’/exp OR ‘smoking’/exp OR ’smokers’/exp OR ‘tobacco’/exp OR ‘cigarette’/exp (continued on next page) M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 4 was systematically recorded and organized in a tabular format. In the qualitative synthesis, emphasis was placed on the clinical impact of smoking abstinence on diabetes-related complications. 3. Results The search process is illustrated in Fig. 1, according to PRISMA 2020 for scoping reviews. A total of 1060 potentially relevant studies were retrieved. Duplicates (n =37) and articles not meeting the inclusion criteria (n =997) were removed. Finally, 26 studies were included for the qualitative synthesis. The main characteristics of the included studies are reported in Tables 1–3. A total of 16 studies was identified for cardiovascular outcomes, 6 for nephropathy, 2 for retinopathy, 2 for neuropathy and 3 for diabetic foot and erectile dysfunction. 3.1. Impact of smoking cessation on cardiovascular events in people with diabetes Smoking and diabetes are interlinked, significantly increasing the risk of cardiovascular events [21]. The mechanisms by which smoking escalates cardiovascular disease risk are complex, exhibiting variability among individuals due to genetic and environmental influences. It is postulated that the most critical impact of smoking in this context is endothelial damage caused by chemicals found in cigarette smoke [11], [21–23]. Smoking is also known to induce chronic, low-intensity inflammation in the body and activate thrombotic processes [11], [22, 23] potentially exacerbating glycemic control [24,25] and leading to less favorable lipid profiles [25–27]. Consequently, stopping smoking should yield health benefits by mitigating the risk of cardiovascular complications among individuals with diabetes. Nilsson et al. [28] estimated that cessation of smoking in patients with type 2 DM under 60 could prevent 24 % (95 % CI: 15–33 %) of cases of fatal/nonfatal myocardial infarctions. A detailed examination of coronary heart disease (CHD) risk among current and former smokers with T2D in Spain revealed that former smokers had a roughly 20 % lower risk of CHD over 10 years compared to current smokers [29]. The Finnish prospective study by Barengo et al. [30], involving 28,712 men and 30,700 women, found that smokers with T2D had a 3.27-fold higher risk of CHD in men (95 % CI 2.45–2.40) and 4.55-fold in women (95 % CI 2.48–8.33), compared to non-diabetic, non-smokers, after adjusting for various factors. Although T2D patients who had ceased smoking showed a lower CHD incidence than those who continued to smoke, this was still higher than non-smoking, non-diabetic individuals. In addition to demonstrating that quitters significantly reduced their risk of myocardial infarction (HR 0.80), with an absolute risk difference of −0.38 (−0.49, −0.27), Jeong SM [31] also observed a significant decrease in ischemic stroke risk (HR 0.80). Similarly, Kim MK [32] found that smoking cessation post-T2D diagnosis improved MI or stroke risks, with no increased CVD risk among quitters with <10 pack-years of smoking history compared to non-smokers in a large Korean study of 181,591 participants. Using the Nurses’ Health Study cohort, Al-Delaimy et al. [33] showed that women with T2D who quit smoking and remained abstinent for over 10 years significantly reduced their CHD risk. The inverse relationship between duration of smoking abstinence lower CVD incidence was also confirmed by Liu et al. [34], but this was clear only in T2D patients who quit smoking without gaining weight. The observed patterns of associations observed with CHD and stroke were noted in other studies, but some did not reach statistical significance, possibly due to the limited power of the studies. The ADVANCE study [35] found no significant impact of smoking cessation versus continuous smoking on major cardiovascular events, including death from CVD, non-fatal stroke, and non-fatal myocardial infarction, as well as on major coronary and cerebrovascular events. This lack of effect was attributed to the relatively brief follow-up period. Similarly, in a study by Clair et al. [36], involving 370 diabetes patients (99 % with T2D), no significant CVD risk reduction was associated with quitting smoking. This result was possibly influenced by the small number of cardiovascular cases, wide confidence intervals, and weight gain after cessation. Furthermore, the research conducted by Cho et al. [37], analyzing data from the Korean National Sample Cohort that included 17,204 males recently diagnosed with T2D, revealed that cessation of smoking did not significantly affect the risk of CVD, such as strokes and myocardial infarction. This study highlighted that the potential benefits of quitting smoking could be diminished by changes in BMI following smoking cessation. Numerous studies have reported a decrease in the risk of overall mortality among individuals with T2D who have quit smoking, suggesting similar benefits for cardiovascular mortality [31], [34,35], [38]. For instance, the Finnish study by Barengo et al. [30] mentioned earlier showed that, compared to non-diabetic non-smokers, the risk of CHD mortality was significantly higher in both men and women with T2D who smoked (HR 6.15 for men and 6.92 for women). However, this risk was reduced in those who had quit smoking, though it remained higher than in non-smoking, non-diabetic individuals (HR 4.30 for men and 5.00 for women). Similarly, the Nurses’ Health Study cohort [39], found a graded increase in the risk of cardiovascular mortality with higher smoking intensities compared to non-smokers. The relative risks (RRs) were 1.30 for past smokers, 1.58 for current smokers of 1–14 cigarettes/day, 2.56 for 15–34 cigarettes/day, and 1.85 for ≥35 cigarettes/day, indicating a strong dose-response relationship (P for trend <0.0005). A nationwide study involving 349,137 Korean patients with T2D who smoked showed that smoking cessation was associated with a Table 1 (continued) Outcome Database Pubmed Embase “smok*"[Title/Abstract] OR “cigarette"[Title/Abstract]) AND (“cessation"[Title/Abstract] OR “quit*"[Title/Abstract] OR “abstinence"[Title/Abstract] OR “stop*"[Title/Abstract]) AND (foot [MeSH Terms] OR foot [Title/Abstract] OR amputation [Title/Abstract] OR “foot ulcer” [Title/Abstract] OR “lower limb"[Title/Abstract] OR “peripheral arterial disease"[MeSH Terms] OR “peripheral arterial disease"[Title/Abstract]) #3 ‘cessation’/exp OR ‘quit’/exp OR ‘abstinence’/ exp OR ‘stop’/exp OR ‘withdraw’/exp #4 ‘diabetic foot’/exp OR ‘amputation’/exp OR ‘foot ulcer’/exp OR ‘peripheral arterial disease’/exp #1 AND #2 AND #3 AND #4 Erectile dysfunction (“diabetes mellitus, type 2"[MeSH Terms] OR “type 2 diabetes mellitus"[Title] OR “T2DM"[Title] OR “Type 2 Diabetes"[Title] OR “diabetes*"[Title] OR “diabetes"[All fields]) AND (“smoking"[MeSH Terms] OR “smoking"[Title/Abstract] OR “smok*"[Title/Abstract] OR “cigarette"[Title/Abstract]) AND (“cessation"[Title/Abstract] OR “quit*"[Title/Abstract] OR “abstinence"[Title/Abstract] OR “stop*"[Title/Abstract]) AND (“erectile dysfunction"[MeSH Terms] OR “erectile dysfunction”[Title/Abstract] OR “sexual dysfunction*“[Title/ Abstract] OR “sexual dysfunction, physiological” [MeSH Terms] OR ejaculation [MeSH Terms] OR ejaculation [Title/Abstract]) #1 ‘Type 2 Diabetes ’/exp OR ’ Type 2 Diabetes Mellitus’/exp #2 ‘smoke’/exp OR ‘smoking’/exp OR ’smokers’/exp OR ‘tobacco’/exp OR ‘cigarette’/exp #3 ‘cessation’/exp OR ‘quit’/exp OR ‘abstinence’/ exp OR ‘stop’/exp OR ‘withdraw’/exp #4 ‘erectile dysfunction’/ exp OR ‘sexual dysfunction’/exp OR ‘ejaculation’/exp #1 AND #2 AND #3 AND #4 M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 5 significant reduction in mortality from myocardial infarction (21 %) and ischemic stroke (34 %) compared to those who continued smoking [31]. Furthermore, the population-based cohort study of Liu et al. [34] reported that, within 6 years after quitting, long-term quitters had a significantly reduced mortality from CVD compared to ongoing smokers, regardless of any weight gain experienced within the first six years post-cessation. Notably, those who gained more than 5 kg after quitting smoking had lower mortality rates compared to those with minimal weight gain (0.1–5 kg) or no weight gain at all. However, this observation requires careful interpretation, as it could partially be influenced by reverse causality. In contrast, a study by Choi et al. [38], which included 13,377 Korean men aged ≥40 years with new-onset type 2 diabetes, observed no significant effect of smoking cessation on CVD mortality, highlighting the variability in outcomes across studies and populations. It is also worth mentioning the findings from key, large-scale studies and meta-analyses conducted on mixed populations of patients with type 1 diabetes (T1D) and type 2 diabetes. One international cohort study by Chaturvedi et al. [40], which included 4427 individuals with diabetes, found that the prevalence of probable CHD was highest among individuals who had quit smoking for 1–9 years. This prevalence decreased in the years following cessation when compared to never smokers. Similarly, compared to nonsmokers, quitters for 1–9 years had the highest risk of circulatory death which fell as the years since quitting increased. The greatest fall of risk was from those who quit 1–9 years ago to those who had quit 20–29 years ago. Thereafter, risk ratios raised but statistically not significantly. In the Women’s Health Initiative (WHI) study [41], which followed Fig. 1. The process of selecting the studies used in this work. M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 6 Table 2 Studies assessing the impact of smoking cessation in people with type 2 diabetes on cardiovascular events. Reference, year Study design Study population Median duration of follow-up Outcome Reference group Outcome in quitters Outcome in continuing smokers Summary of effects Nilsson et al. [28], 2009 Prospective, longitudinal study. The partial PARp estimating the percentage cases of assessed outcomes. In the cohort that may have been prevented with cessation of smoking was calculated 13,087 female and male patients with T2D with no previous MI or stroke at baseline, aged 30–74 years. 5.7 years fatal/nonfatal MI and stroke Non-smokers In the entire study population PARp for MI 9.0 (5.8–12.2)for stroke 3.9 (0.1–7.2)In middle-aged patients (age 30–59 years) who smoked more frequently than older patients PARp for MI 24.0 (15.1–32.6) for stroke 2.3 (– 6.7 to 11.2) HR for firstincident fatal/ nonfatal MI and stroke 1.7 (CI 1.4–2.0), and 1.3 (CI 1.1–1.6) respectively Smoking cessation would strongly affect fatal/ nonfatal MI and stroke risk reduction Smoker was defined as a patient smoking one or more cigarettes per day, or using a pipe, or who had stopped smoking within the past 3 months LuqueRamírez et al. [29], 2018 A cross-sectional, observational, epidemiological multicenter nationwide study. 890 patients with T2D (444 smokers and 446 formersmokers). n/a The estimated likelihood of coronary heart disease risk at 10 years n/a The likelihood of CHD at 10 years according to the UKPDS risk engine 20.8 % (CI 19.3–22.4) The likelihood of CHD at 10 years according to the UKPDS risk engine 25.4 % (CI 23.6–27.2) Quitting smoke in patients with T2D is accompanied by a significant decrease in the estimated risk of coronary events as assessed by UKPDS. Current smokers daily consumed at least 1 cigarette for the last month, former smokers quit at least 10 years ago Barengo et al. [30], 2017 A large Finnish population, cohort follow-up study. 59,412 men and women aged 25–64 years, with or without T2D. n/a a. CHD Non-diabetic non-smokers a. HR 3.00 (CI 2.33–3.85) in men and 2.80 (CI 1.48–5.30) in women b. HR 4.30 (CI 3.04–6.08) in men and 5.00 (CI 2.15–11.64) in women a. HR 3.27 (CI 2.45–2.40) in men and 4.55 (CI 2.48–8.33) in women b. HR 6.15 (CI 4.22–8.96) in men and 6.92 (CI 2.79–17.19) in women T2D patients who were not smoking or who had quit had an increased risk of CHD incidence and CHDrelated mortality, however, the increase seemed to be lower than the one observed in continuing smokers Quitters had stopped smoking at least six months before the survey. b. CHD-related mortality Jeong et al. [31], 2023 The prospective study, using nationwide data from the Korean National Health Insurance System. 349,137 people with T2D. Continuing smokers - the participants who answered that they have smoked ≥100 cigarettes in his or her lifetime and currently smoke. 5.1 years a. MI Continuing smokers a. HR 0.80 (CI 0.75–0.86) a. HR 1.0 Decreased risk of MI, ischemic stroke, and mortality related to MI and ischemic stroke for quitters vs. continuing smokers b. Ischemic stroke b. HR 0.80 (CI 0.75–0.85) b. HR 1.0 c. MI-related mortality c. HR 0.79 (CI 0.64–0.98) d. Ischemic strokerelated mortality d. HR 0.67 (CI 0.47–0.95) Kim et al. [32], 2022 The prospective study, using nationwide data from the Korean National Health Insurance Service (NHIS) database. 181,591 people with newly diagnosed T2D including continuing smokers, quitters (after their T2D diagnosis) and nonsmokers (including quitters before T2D diagnosis) 6.07 (5.09–7.02) years MI or stroke Nonsmokers (including exsmokers who had stopped smoking at any time point before their T2D diagnosis) HR 1.33 (CI 1.08–1.63) for 10–20 packyears HR 1.66 (CI 1.48–1.87) for 10–20 packyears Although quitters had a higher risk of MI, and stroke than nonsmokers, their risk was much lower than that of continuous smokers HR 1.39 (CI 1.14–1.70) for 20–30 packyears HR 1.86 (CI 1.68–2.07) for 20–30 packyears HR 1.36 (CI 1.15–1.60) for ≥30 pack-years HR 1.82 (CI 1.67–1.98) for ≥30 packyears Blomster et al. [35], 2016 Analysis of patients enrolled to the ADVANCE study - a randomized, factorial, controlled trial 11,140 people with T2D aged ≥55 years and at increased cardiovascular risk 5 years a. Major coronary event Continuing smokers a. HR 0.96 (CI 0.73–1.26) a. HR 1.0 In people with T2D there is no effect of quitting smoking on major coronary events or cerebrovasculat events b. Cerebrovascular event b. HR 0.81 (CI 0.57–1.15) b. HR 1.0 (continued on next page) M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 7 Table 2 (continued) Reference, year Study design Study population Median duration of follow-up Outcome Reference group Outcome in quitters Outcome in continuing smokers Summary of effects conducted in 20 countries. Al-Delaimy et al. [39], 2001 A prospective cohort study of U.S. female registered nurses (The Nurses’ Health Study) 7401 women with T2D (current, past, or never smokers). Current smokers were categorized into 1–14, 15–34, and ≥35 cigarettes/ day 20 years (67,420 personyears) Cardiovascular mortality Never smokers RR 1.30 (CI 1.00–1.68) RR 1.58 (0.82–3.07) for 1–14 cigarettes/day In women with T2D cigarette smoking is associated in a dose-response manner with increased cardiovascular mortality and quitting smoking appears to decrease this excess risk. RR 2.56 (1.69–3.88) for 15–34 cigarettes/day RR 1.85 (0.74–4.64) for ≥35 cigarettes/day Al-Delaimy et al. [33], 2002 A prospective cohort study of U.S. female registered nurses (The Nurses’ Health Study) 6547 women with T2D (current, past, or never smokers) 20 years (68,227 personyears) Development of CHD Never smokers RR 1.21 (CI 0.97–1.51) RR 1.66 (1.10–2.52) for current smokers of 1–14 cigarettes per day, and 2.68 (2.07–3.48) for current smokers of 15 or more cigarettes per day In women with T2D quitting smoking seems to decrease the excess risk of CHD Liu et al. [34], 2020 9688 people with T2D, who were current smokers, never smokers, recent quitters (quit smoking in the period of 2–6 consecutive years) or longterm quitters – (quit smoking >6 consecutive years) 153,166 person-years a. Cardiovascular disease Continuing smokers a. HR 0.77 (CI 0.62–0.95) in recent quitters without weight gain a. HR 1.0 b. HR 1.0 In people with T2D smoking cessation without subsequent weight gain is associated with a reduced risk of cardiovascular disease among smokers with T2D. Weight gain after smoking cessation attenuates the reduction in risk of developing cardiovascular disease. Long-term quitters had lower CVD mortality, regardless of weight gain within the first 6 years after quitting b. Cardiovascular mortality HR 0.72 (CI 0.61–0.84) in longer-term quitters without weight gain HR 0.99 (CI 0.70–1.41) in recent quitters with weight gain of 0.1–5.0 kg HR 0.89 (CI 0.65–1.23) in recent quitters with weight gain of more than 5.0 kgb. HR 0.66 (CI 0.46, 0.95) in long-term quitters with weight gain of 0.1–5.0 kg HR 0.47 (CI 0.32, 0.67) in long-term quitters with weight gain of more than 5.0 kg HR 0.84 (CI 0.63, 1.12) in recent quitters without weight gain Clair et al. [36], 2013 Prospective community-based cohort study using data from the Framingham Offspring Study 370 people with diabetes (99 % with T2D). 25 years (SD, 9.6) Cardiovascular disease Continuing smokers HR 0.49 (CI 0.11–2.20) in recent quittersHR 0.56 (CI 0.28–1.14) in HR 1.0 In people with diabetes there is no effect of quitting smoking on CVD Smoking status was categorized as smoker, recent (continued on next page) M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 8 Table 2 (continued) Reference, year Study design Study population Median duration of follow-up Outcome Reference group Outcome in quitters Outcome in continuing smokers Summary of effects long-term quitters quitter (≤4 years), long-term quitter (>4 years), and nonsmoker. Cho et al. [37], 2018 Prospective study using the Korean National Sample Cohort data 17,204 male patients with newly diagnosed T2D. 12 years Cardiovascular disease Continuing smokers HR 1.09 (CI 0.71–1.68) in patients who lost BMI HR 1.0 In men with T2D quitting smoking did not significantly affect the risk of CVD, such as strokes and myocardial infarction Quitters - smokers before the diagnosis but exsmokers in the health checkup survey after the diagnosis. HR 0.79 (CI 0.58–1.07) in patients without BMI change HR 0.94 (CI 0.60–1.47) in patients with BMI gain Choi et al. [38], 2020 Prospective study using the Korean National Health Insurance ServiceNational Health Screening Cohort database 13,377 Korean men aged ≥40 years diagnosed with new onset T2D. 7.2 ±1.4 years Cardiovascular death Continuing smokers HR 0.74 (CI 0.46–1.18) in short-term quitters HR 1.0 In men with T2D quitting smoking did not significantly affect the risk of death from CVD Smoking status was categorized as current smokers, shorttermquitters (after T2D diagnosis), longterm quitters (before T2D diagnosis) HR 0.64 (CI 0.39–1.07) in long-term quitters Chaturvedi et al. (40), 1997 An international prospective cohort study 4427 individuals with diabetes (IDDM or NDDIM) n/a Probable CHD (either a previous history of ischemic heart disease or infarction or the presence of Q waves on an electrocardiogram) Never smokers OR over subsequent time intervals since quitting were as follows: 1–9 years - 1.61, 10–19 years - 1.13, 20–29 years - 0.83, ≥30 years - 1.10 n/a Quitting smoking reduces CHD risk in people with diabetes (the prevalence of CHD decreases in the years following cessation) Luo et al. (41), 2013 Prospective study, using data from the Women’s Health Initiative (WHI) 6338 postmenopausal women ages 50–79 years with diabetes (type 1 or type 2). Never smokers and former smokers did not smoke at either time point of study, continuous smokers smoked at both time points, and new quitters smoked at baseline but not at year 3. 8.8 ±2.8 years CHD cases (clinical myocardial infarction, silent myocardial infarction, or death due to CHD). Continuing smokers HR =0.36 (CI 0.17–0.78) for new quitters HR 1.0 Compared to continuing smoking, smoking cessation was associated with a lower risk of CHD among postmenopausal women with diabetes. HR 0.41 (CI 0.29–0.59) for former smokers Qin et al. (42), 2013 Meta-analysis of observational prospective studies 130,000 people with diabetes (T1D and type T2D) n/a a. Stroke Non-smokers a. RR 1.34 (CI 1.007–1.67) a. RR 1.64 (CI 1.36–1.97) Smoking amplified the risk of cardiovascular events in people with diabetes; among quitters a trend of decreasing risk was observed. b. Death due to CVD b. RR 1.19 (CI 1.02–1.39) b. RR 1.56 (CI 1.34–1.81) c. CHD c. RR 1.03 (CI 0.84–1.26) c. RR 1.66 (CI 1.40–1.97) d. MI d. RR 1.25 (CI 0.94–1.66) d. RR 1.53 (CI 1.18–1.98) (continued on next page) M. Walicka et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 18 (2024) 103044 9 6338 women with diabetes for 3 years with check-ups every 6–12 months, both recent quitters and former smokers exhibited a lower risk for CHD compared to current smokers. Notably, weight gain after quitting appeared to weaken this association, especially among those who gained 5 kg or more, though the small number of cases in this subgroup limited statistical power. A meta-analysis of 46 observational, prospective studies encompassing approximately 130,000 people with diabetes indicated an excess risk of cardiovascular events among both former and current smokers. However, the risk was higher in current smokers. For former smokers, compared with non-smokers, pooled analyses suggested a significantly increased risk of stroke and death due to cardiovascular, but not for incident CHD and myocardial infarction (MI) [42]. Similar conclusions also result from the meta-analysis of Pan et al. [14]. Active smoking was associated with increased risk of cardiovascular mortality (the association remained significant in studies among both type 1 diabetes patients and type 2 diabetes patients), cardiovascular disease, coronary heart disease, stroke, peripheral arterial disease, and heart failure. In comparison with never smokers, former smokers were at a moderately elevated risk of cardiovascular mortality, cardiovascular disease, and coronary heart disease, but not of stroke, however smoking cessation was associated with reduced risks in comparison with current smoking. Studies assessing the impact of smoking cessation in people with type 2 diabetes and mixed populations of people with type 1 and type 2 diabetes on cardiovascular events are summarized in Table 2. Quitting smoking has been associated with decreased risks of myocardial infarction and ischemic stroke, emphasizing the benefits of cessation. However, the impact of smoking cessation on cardiovascular mortality in people with diabetes shows variability across studies, with some indicating no significant effect, potentially due to factors like study duration and post-cessation weight gain. 3.2. Diabetic nephropathy Diabetic nephropathy (DN) is defined by persistent albuminuria and a progressive decline in renal function, underlining the importance of identifying modifiable risk factors for its management [43]. Cigarette smoking is known to adversely affect glomerular structure and function [44], initiating pathophysiological pathways that contribute to albuminuria, such as increased oxidative stress, inflammation, and production of advanced glycation end products (AGEs) [45]. A meta-analysis of 13 studies found that smokers with T2D had 2.13 (95 % CI 1.32–3.45) times higher odds of developing albuminuria than non-smokers, alongside a 21 % increased annual risk of albuminuria [46] confirming findings from an earlier meta-analysis of 19 observational studies, including 105,031 participants with T2D, with significantly higher risk of developing albuminuria among current smokers compared to never-smokers (with a relative risk of 2.61; 95 % CIs 1.86–3.64) [47]. Research in Taiwanese men showed a dose-response relationship between cigarette smoking and the development of proteinuria in T2D, where higher levels of consumption significantly increased the risk. Notably, smokers progressed from microalbuminuria to overt proteinuria and terminal renal failure more frequently than non-smokers, regardless of optimal blood pressure control [48]. The same large meta-analysis of 105,031 participants with T2D, also showed that the risk of developing albuminuria is significantly reduced in former smokers. Compared to never-smokers, the relative risk of developing albuminuria among current smokers decreased from 2.61; 95 % CIs 1.86–3.64) to 1.86 (95 % CIs 1.37–2.52) in former smokers [47], highlighting the tangible benefits of quitting smoking. Further, Ohkuma et al. [49] showed a decrease in urinary albumin-creatinine ratios and in the proportion of chronic kidney disease with increasing years after quitting smoking in former smokers with T2D. The inverse association with smoking cessation implies the reversibility of the harmful effects of smoking. The benefits of smoking cessation were also evident in subjects with newly diagnosed T2D and microalbuminuria, where a significant reduction in microalbuminuria prevalence was observed within a year of quitting smoking [50]. Similarly, there is also evidence that smoking cessation could reduce chronic kidney disease progression by ameliorating microalbuminuria and reducing macroalbuminuria in patients with diagnosed T2D [51,52]. The collective evidence from various studies convincingly supports the notion that smoking cessation plays a critical role in mitigating the risk of nephropathy progression in individuals with T2D. Despite this positive evidence, the ADVANCE study [35] presented a contrasting finding, showing that smoking cessation had no impact on nephropathy progression. This discrepancy underscores the complexity of the relationship between smoking, smoking cessation, and diabetic nephropathy, suggesting that additional factors may influence the progression of renal disease in individuals with T2D. Studies assessing the impact of smoking cessation in people with T2D on nephropathy are summarized in Table 3. The overwhelming evidence underscores the detrimental impact of smoking on diabetic nephropathy (DN) progression in individuals with type 2 diabetes mellitus, highlighting the critical role of smoking cessation. Meta-analyses and key research studies reveal risk reduction in nephropathy markers and improvements in renal function over time among those who quit smoking. Table 2 (continued) Reference, year Study design Study population Median duration of follow-up Outcome Reference group Outcome in quitters Outcome in continuing smokers Summary of effects Pan et al., (14), 2015 Meta-analysis of prospective cohort studies n/a n/a a. Cardiovascular mortality Never smokers a. RR 1.15 (CI 1.00–1.32) a. RR 1.49 (CI 1.29–1.71) Active smoking was associated with significantly increased risks of cardiovascular events among people with diabetes, while smoking cessation was associated with reduced risks compared to current smoking b. CVD b. RR 1.09 (CI 1.05–1.13) b. RR 1.44 (CI 1.34–1.54) c. 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