Review: The complex liaison of Nicotine and Diabetes and role of NRT

Smoking tobacco has been linked with diabetes for the last two decades backed by sound research data. The detrimental effects of cigarette smoking on glycaemic status are well known. Physicians in their day-to-day practice are often confronted by questions like- can smoking cause diabetes? What are the effects of smoking on macro and microvascular diabetic complications?

The following review aims to summarise all the available evidence about the dangerous links between nicotine and diabetes and highlights the contemporary pharmacological agents to tackle this problem. 

Can smoking cause diabetes?

Cigarette smoking is one of the most important modifiable risk factors for Diabetes Mellitus (DM). Smoking accelerates progression from normoglycemia to impaired glucose tolerance status possibly by eliciting the development of insulin resistance, thus increasing the risk of developing diabetes in smokers. (1)

More than two decades of research have incriminated smoking as a causal factor for diabetes. (1) In 1997, Kawakami et al showed that those who were currently smoking 16–25 cigarettes per day had a 3.27 times higher risk of developing non-insulin-dependent diabetes mellitus (NIDDM) than never smokers. (2) In 2007, the first meta-analysis of 25 prospective cohort studies showed a dose-dependent association between smoking and incident T2DM (3); with the highest relative risk (1.61) observed in those who were smoking >20 cigarettes/day.

In another meta-analysis from 2015, the authors estimated that at least 25 million cases of T2DM worldwide could be directly attributable to cigarette smoking alone. (4) 

 Does quitting help?

Quite counterintuitively, the research data to date represents a confusing relationship between cessation and diabetes. There is a short-term increased risk of diabetes after cessation in those who have quit <5 years. (1) But beyond this threshold, the risk continuously decreases, and by 10 years of quitting the risk of new-onset diabetes is almost the same as the non-smokers. (4) 

Smoking and vascular complications of diabetes

Macrovascular complications of DM are ischemic heart disease, stroke, and peripheral arterial disease. Smoking increases the risk of macrovascular complications in patients with DM. The risk of cardiovascular events increases up to 4 times than in the general population(5,6). In a systematic review and meta-analysis by Pan et al, it was found that for patients with diabetes, smoking increased the pooled relative risk (RR) for total cardiovascular disease as 1.44, coronary heart disease (CHD) as 1.51, stroke as 1.54, and heart failure as 1.43. (7)

Another study found that smoking is one of the five strongest predictors of death and acute myocardial infarction among patients with T2DM; (the other predictors are glycated hemoglobin, systolic blood pressure, LDL cholesterol, and physical activity). (8)

Microvascular Complications. There is accumulating evidence that smoking increases the risk of incidence and progression of nephropathy in people with diabetes, particularly in those with T1DM. (9) Similar relationships have been observed for other microvascular complications like retinopathy (10) and neuropathy (11). 

Impact of quitting smoking on diabetes complications

In T2DM patients, smoking cessation is known to decrease both short- and long-term CVD risk, even independently from weight gain (12,13). Therefore, diabetic patients should be routinely reminded that cigarette smoking increases their risk of developing disease complications, adversely affects their blood glucose control, and increases their insulin resistance. Smoking cessation in diabetics is as rewarding as in non-diabetics for lowering the CV risk as shown in the study by Luo et al (13) The currently available smoking cessation therapies have been shown to double or even triple the people who quit smoking when compared to placebo in controlled studies (14,15).  

Quitting strategies:

For treatment, the first-line drugs used to increase the likelihood of success in smoking cessation include nicotine replacement therapy (NRT), bupropion, and varenicline (16).

NRT is available in different formulations: chewing gum, inhalers, lozenges, sprays, and transdermal patches. Their main mechanism of action is that of replacing the nicotine delivered by cigarette smoking, thus decreasing the severity of withdrawal symptoms and helping the smoker to quit (16). NRT-based treatment doubles the chances of success in quitting smoking, regardless of the specific formulation (17,18 )

Does nicotine replacement itself pose a cardio-metabolic hazard?

There has been some speculation that nicotine replacement therapy can also potentially worsen glycemic control by promoting insulin resistance in the same way that nicotine does. (19,20). A cohort study of 50,214 smokers who tried to quit smoking (21) with 4-weeks use of NRT did not find any impact on cardiovascular risk. Any cardiovascular events are primarily reported for patients who continued to smoke while using NRT 

Conclusion:

The increased recognition that regular smoking and DM is a dangerous liaison should stimulate greater efforts to develop effective smoking cessation programs and encourage avoidance strategies. The high smoking prevalence among patients with diabetes, their poor level of glucose-metabolic control, and their low success rates of stopping smoking all highlight the importance of systematically counseling smokers with DM and using first-line therapies like NRT early in the course of illness. 

 References

1. Campagna, D., Alamo, A., Di Pino, A., Russo, C., Calogero, A. E., Purrello, F., &Polosa, R. (2019). Smoking and diabetes: dangerous liaisons and confusing relationships. Diabetology& metabolic syndrome, 11, 85.

2. Kawakami N, Takatsuka N, Shimizu H, Ishibashi H Effects of smoking on the incidence of non-insulin-dependent diabetes mellitus. Replication and extension in a Japanese cohort of male employees. Am J Epidemiol. 1997 Jan 15; 145(2):103-9.

3. Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2007 Dec 12; 298(22):2654-64.

4. Pan A, Wang Y, Talaei M, Hu FB, Wu T Relation of active, passive, and quitting smoking with incident type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015 Dec; 3(12):958-67.

5. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M, McGuire DK, Sattar N, Rosengren A, Gudbjörnsdottir S Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes. N Engl J Med. 2017 Apr 13; 376(15):1407-1418.

6. Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015. GBD 2015 Tobacco Collaborators. Lancet. 2017 May 13; 389(10082):1885-1906.

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8. Rawshani A. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. NEJM. 2018 doi: 10.1056/NEJMoa1800256.

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10. Chaturvedi NSJ, Fuller JH. The relationship between smoking and microvascular complications in the EURODIAB IDDM complications study. Diabetes Care. 1995;18:785–792.

11. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341–350.

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13. Luo JH, Rossouw J, Margolis KL. Smoking cessation, weight change, and coronary heart disease among postmenopausal women with and without diabetes. JAMA. 2013;310:94–96.

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17. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012;14:CD000146.

18. Hajek P, West R, Foulds J, Nilsson F, Burrows S, Meadow A. Randomized comparative trial of nicotine polacrilex, a transdermal patch, nasal spray, and an inhaler. Arch Intern Med. 1999;159:2033–8.

19. Eliasson B, Taskinen MR, Smith U. Long-term use of nicotine gum is associated with hyperinsulinemia and insulin resistance. Circulation. 1996;94:878–81.

20. Eliasson B. Cigarette smoking and diabetes. ProgCardiovasc Dis. 2003;45:405–13.

21. Dollerup J, Vestbo J, Murray-Thomas T, Kaplan A, Martin RJ, Pizzichini E, Pizzichini MMM, Burden A, Martin J, Price DB. Cardiovascular risks in smokers treated with nicotine replacement therapy: a historical cohort study. ClinEpidemiol. 2017;9:231–43.