Hello, and welcome to JAMA Network Open Conversations. I'm Angel Desai, associate editor for JAMA Network Open. Today, we are speaking with Dr. Cristina Russo and Dr. Riccardo Polosa about efficacy and safety of varenicline for smoking cessation in patients with type two diabetes. Welcome to the both of you.
Dr. Cristina Russo (00:22):
Thanks for the invitation.
Dr. Riccardo Polosa (00:22):
Hi there, and thank you very much for inviting.
Dr. Russo, why don't you introduce yourself first? I know you were at the University of Catania, Italy with Dr. Polosa. Can you tell us a little bit about your research interests?
So, my name is Cristina Russo. I'm a medical doctor and PhD. My background is endothelial research and cardiovascular risk factor. So, definitely diabetes offer the best background to study cardiovascular risk factor. And in this case, varenicline, was a great opportunity to be tested in a special population, which is people suffering from diabetes, where there is not very much in terms of options for reducing cardiovascular risk factor beyond the control hypertension, control lipidation.
Varenicline, it was definitely a very novelty option to be introduced, and we were lucky to have the opportunity to run this trial, which was extremely successful. And we were hoping that varenicline could have been another medication to be added to the guidelines, for smoking cessation.
Dr. Polosa, can you please introduce yourself?
My name is Riccardo Polosa. I'm a professor of internal medicine at the University of Catania. In relation to this study, I think the most important thing that needs to be said is that this is the first randomized controlled trial using varenicline, a very well known drug for smoking cessation, in a type two diabetes patients who are also smokers.
Smoking and having a diabetes together is not good for your health, and actually accelerate complication of type two diabetes mellitus. One of the reason why this paper would be so important is because it will show that FDA approved smoking cessation drugs in this particular population of patients is going to be very beneficial.
So to follow that up, Dr. Russo, can you just talk us through a little bit about what is potentially unique about tobacco use or cessation in patients with diabetes compared to those without?
It's very important to say that smoking is definitely the leading cause of preventable death in population. Preventable death, it means that we can work on modify this risk factor. And the population with diabetes suffer from high glucose level. And high glucose level, they can be very detrimental for the vessel, and this particular population is suffering from developing damage to small vessel and big vessel in our body.
At the same time, smoking is another risk factor for vessel disease, big vessel and small vessels. So, it's like both of them together, they can increase the possibility to suffer from example from heart attack, from stroke, or from what we call peripheral vascular disease. That it means that the vessel in all our body, at risk to become clogged and suffer from, for example, at some point amputation.
Normal population is already exposed to risk of heart attack, stroke, and peripheral vascular disease. But if you have diabetes, it's like if this risk is definitely much more higher than it's supposed to be in the normal population. And I feel that population will suffer from chronic disease, they are much more vulnerable and the specific program needs to be addressed because they have already, as we say, a severe background for developing complication. So, use varenicline or in general smoking cessation program in diabetic population becomes of extreme importance for blocking developing complications.
So, this was a multi-centered, double blind randomized clinical trial. Dr. Polosa, can you tell us a bit about the population for the study and what you did?
It was conducted across six outpatients clinics in five different hospitals. We basically randomized 300 patients with type two diabetes who were also smokers of at least 10 cigarettes per day for at least five years, regular smokers, and they were keen to quit. So, the level of motivation in quitting was quite high.
I think one of the important point of this study is to try and identify what are the main differences from other similar studies using varenicline. Varenicline has been already used in, let's say, healthy smokers, but also in patients with COPD, and also in patient with mental illnesses with great success.
In this particular studies, I think the uniqueness of the study is that for specific reasons, people with diabetes tend to be extremely scared of putting on weight when they quit smoking. So, one of the major points in this study was, are we going to see the same smoking cessation level in this specific population as opposed in the other population that have been previously studied with varenicline in other randomized control trials? The answer is we found more or less the same level of efficacy with varenicline, and probably this was due to the fact that most of the people were not gaining weight quite surprisingly, because of cessation weight gain is expected when you quit smoking.
One of the arms obviously received the placebo, the other had varenicline, and I think both received counseling as well. Is that correct?
All patients randomized in the study received intensive professional counseling, which was tailored to smokers with diabetes. So, most of the narrative in the cessation counseling adopted by our clinical psychologist was tailored to the problem of diabetes and potential side effects of the drug in the context of diabetes.
And can you define what the continuous quit rate is, as that was part of the primary outcome? Is this a common metric that's used in the smoking cessation literature?
It's becoming more and more used. The continuous abstinence rate, it's a very sound and stronger efficacy endpoint compared to the seven day point prevalence. So yes, to your question, it's more widely used and it's a very sound efficacy endpoint.
Dr. Russo, I was very interested in this study, and particularly reading about some of the clinical and demographic features found to influence smoking abstinence in the context of the study. Can you discuss these further?
Absolutely. I want just to spend a couple of words about varenicline, because I think varenicline, it was a very interesting medication. Because varenicline blocks the ability of nicotine to activate these receptors, which are called Alpha-4 beta-2, and they are linked to the dopamine system, which is a reinforcement, a reward experience system. So, varenicline docks with this receptor and trigger a release of dopamine, such as nicotine does, but not quite as much, and this is the reason why probably the abstinence was successful in this population.
We had, as the endpoint, this abstinence rate, and this study was very interesting because we can divide the study in actually two part. We have the treatment phase, and the great success was that they were able to remain abstinent for very long time. Even when we went to check the following visit of no treatment phase, we noticed they were able to not smoke anymore. So, this was the great success of the study. Because as we say, we fix a primary endpoint, which was the abstinence rate at weeks 9 to 24.
And then the secondary efficacy endpoint was just to maintain the abstinence. So obviously, then we went to double check the safety of the varenicline by studying the adverse event and the serious adverse event. First of all, we didn't report any serious adverse event. And the side effects of varenicline, they were very much tolerable to every single patient because we reported obviously nausea, insomnia, abnormal dream, anxiety, and irritability that are actually the normal withdrawal symptoms that we record for every single SOCO. So for example, in alcohol withdrawal and in smoking withdrawal.
I really enjoyed reading this study, particularly because I think this topic is something that we come across so frequently in clinical practice. What do you think some of the next important and potentially unanswered questions in this area may be, or that you may be conducting in the future?
This is something that working as a doctor, I daily ask myself. There is a lot we still need to cover when it comes to alcohol, when it comes to smoking, and when it comes to body weight. There is so much that we still don't know, and this is the reason for research, try to cover the gray area.
In nearly 20 and more year of clinical practice, what I do notice that most of the time we have some answer under our eyes and we simply don't notice them. And the experience show that especially in clinical trial, we experiment something and then we get result even for something else. We just need to continue to observe. Definitely the brain is the most difficult area to cover when it comes to addiction or reinforcement behavior, and there is a lots to do. So, I hope that varenicline can offer an extra solution. And I'm convinced that varenicline, such as metformin, is a drug, which can offer many potential advantages for patient. Probably we need to discover even more about that.
Dr. Russo, Dr. Polosa, any final thoughts regarding the study or anything that we may have not covered?
Going forward, that there are a number of things that needs to be further investigated, in my opinion. First off, it is clear that the success of the study is also linked to the potentiation of the effect of the drug by professional, tailored motivational interviews. So, probably the message there is that we need to spend more time training clinical psychologists and doctors in the art of motivational interview.
Another point that requires more in depth investigation is that when you use questionnaires that evaluate the scoring of ritualistic behavior associated with the use of cigarettes more than the physical dependence associated with nicotine, we will immediately see that these people and this population will represent a completely different population which will not respond so well to varenicline intervention. So, this is another area for sub and post-doc analysis and secondary analysis.
And finally, I think we were very much surprised to see very little post-cessation weight gain, which is normally seen in most of the studies where people quit smoking. Of course, once again, some secondary analysis and post-doc analysis is needed by stratifying the population according to their smoking phenotype, but we have identified possibility and an explanation for these findings. 80% plus of the patients in the study were taking metformin, and it is very likely that metformin was acting as a weight gain suppressor somehow. And we know for sure that metformin is useful as a weight management therapy also in people taking antipsychotics, which tend to increase the weight in people with mental illness.
Thank you so much to the both of you for speaking with me today about this really important study. This episode was produced by Shelly Steffens at The JAMA Network. The audio team here also includes Daniel Morrow, Jesse McQuarters, Lisa Hardin, Audrey Forman, and Mary Lynn Ferkaluk. Dr. Robert Golub is The JAMA executive deputy editor. To follow this in other JAMA Network podcasts, please visit us online at JAMANetworkAudio.com. I'm Angel Desai. Thanks for listening and stay safe.