What Does the Positive Outcome of the SELECT Trial Mean For People Living With Obesity?
This week Novo Nordisk released the topline results of the SELECT trial, apparently showing that once-weekly treatment with 2.4 mg semaglutide s.c. results in a 20% reduction in the composite endpoint of CV death, nonfatal MI or nonfatal stroke (three-component MACE) compared to placebo.
This is no doubt a landmark achievement, given that enrolment into the SELECT Trial was limited to individuals with overweight or obesity and established cardiovascular disease (CVD) but WITHOUT diabetes (the reduction of CV outcomes with semaglutide in people with high CV risk and diabetes has already been demonstrated in the SUSTAIN-6 trial).
The main question that pops up is whether or not these findings are related to and largely explained by the weight-loss effects of semaglutide. Indeed, at this point we don’t even know how much weight the treatment group lost or sustained over the five year duration of the study.
But if we assume that people on semaglutide did experience and sustained more weight-loss than those on placebo, and that there may even be a demonstrable dose-effect relationship, such that those who lost the most weight experienced the greatest benefit, one should hope that this study will make a strong case for better access to obesity treatments – at least for people with overweight or obesity who also have established CVD.
But, what will these results mean in terms of better access to obesity medications for people with overweight or obesity WITHOUT established CVD?
Probably not much. In other words, for younger people with excess weight not (yet) presenting with established CVD, even if they are experiencing other health problems that may be improved by obesity treatments, SELECT may change little.
Demonstrating that early treatment of obesity will reduce morbidity and perhaps mortality in those with EOSS Stage 2 or even Stage 1 obesity (rather than just EOSS Stage 3 as in SELECT), would require a much larger and probably longer study and is unlikely to happen anytime soon.
Thus, while SELECT may well open the door to obesity treatments for people with obesity, who have established CVD, most people living with obesity will probably continue to struggle with access.
On a more positive note, however, SELECT should clearly reassure us that the long-term use of 2.4 mg semaglutide, even in high-CV-risk individuals, is rather safe and may even save lives.
This alone is a major landmark in terms of medical treatments for people living with obesity.
@DrSharma
Disclaimer: I have received honoraria as an independent medical, research and/or educational consultant from various companies including Aidhere, Allurion, Boehringer Ingelheim, Currax, Eli-Lilly, Johnson & Johnson, Medscape, MDBriefcase, Novo Nordisk, Oviva and Xenobiosciences.
What Do Playing The Violin And Exercise Have in Common?
This week’s blog is a joint post written by myself and my good friend and colleague, Dr Sue Pedersen.
Standard lifestyle advice from any doctor will include being active. General health guidelines recommend being active at least 150 minutes to achieve health benefits and prolong life. The Canadian Obesity Guidelines recommend 30-60 minutes of moderate to vigorous intensity aerobic activity most days of the week to improve cardiovascular health, mobility, metabolic health, mental health, and quality of life, even if no weight is lost with this strategy.
Most people are familiar with these benefits of exercise, yet the majority of adults in most countries do not follow this advice. Why not?
Let’s park that for a minute, and let us first ask: What if your doctor advised you to play the violin?
Let’s say your doctor advises you that playing the violin 75-150 minutes per week is really important for your health. Playing the violin will reduce your risk of developing diabetes, help keep your weight in check, reduce your risk of having a heart attack, and help you live longer. It will even make you feel happier and improve your quality of life! You can do it in 10 minute bouts or longer durations, however you want to fit it in. You can play the violin on your own, or you can play your violin with friends. You can even join a violin class where you practice together (for a membership fee of course) – hey, you even get an unlimited supply of distilled water and a towel to wipe your brow while you are playing. You can set your smart watch to track the time you spend playing the violin, with fancy color-coded rings that complete when you’ve achieved your daily goals.
If your doctor told you all of this: Would you do it? Would you play the violin several times a week for the rest of your life?
The answer, for the vast majority, we’d bet, is no! Some may give the violin a try, but it would end up collecting dust in the corner somewhere. Likely only a small percentage of people would take up the violin and stick with it. Most probably wouldn’t give it a go at all. Why?
The answer has to do with the genetically ingrained brain response to particular activities (read on music here and exercise here). A small minority of people will get a rush of endorphins (happy hormones) from playing the violin, and these are the people who are likely to stick with it. Everyone else, who don’t derive particular pleasure from the violin or from creating music at all, are unlikely to stick with it (or even start it in the first place).
Now let’s pull that analogy back to exercise, and it helps us to understand why the majority of people do not heed the advice to exercise. For those lucky enough to get an endorphin response from exercise, it is a pleasant experience to exercise. It makes these people feel good, and thus more likely to want to stick with being active. For the rest, who don’t derive pleasure from being active, it becomes very difficult to stick with this advice. Some doubters may think that people who don’t enjoy being active are simply ‘out of shape’ and thus activity doesn’t feel good. Not true, friends – we just need to look to the group of people who do give exercise a go, get into shape, but don’t stick with it long term to see that.
So how can we get around this? Well, for some people, it works to tie in activity with something that does give them pleasure. Let’s say you find a good audiobook that you’re excited to listen to, or a Netflix series you’re binging, but you only allow yourself to listen while out on a walk or on an elliptical machine. The endorphins you are looking for come from the book or the show. For some, it’s all about the experience – they may feel that riding a bike in a gym feels horrible, but riding a bike in the great outdoors is beautiful and fun (and thereby the ‘happy hormones’ kick in). Catching up with a friend might be something you’re looking forward to – instead of doing it over a coffee, do it with a bout of activity!
So now we understand why some people (a minority) actually want to exercise, while most don’t – it comes down largely to genetics, and what gives you that endorphin response. Finding a way to bring enjoyment with activity can be a step in the right direction!
DrSharma,
Berlin, D
DrSue
Calgary, CND
PS – On a personal note: I love to play music (guitar) and Sue loves exercise, so we had a really great conversation, mutual understanding, and a good laugh over this topic!
Will Severe Obesity go the Way of Malignant Hypertension?
Back in the mid-eighties, when I was still training in nephrology, it seemed not a week would go by without being called upon to attend to a patient with malignant hypertension.
These patients, with blood pressures well over 200/120 mmHg, would often show up with no prior anti-hypertensive medication or, in some cases, not even a known diagnosis of hypertension. Without immediate attention, these patients were in acute danger of progressing to kidney or heart failure or experiencing strokes.
Today, 40 years later, malignant hypertension is a comparatively rare occurrence and can generally be well managed thanks to major advances in and widespread early use of anti-hypertensive medications.
Given the current splurge and momentum we are witnessing in ever more effective anti-obesity medications, I wonder if we will be looking back in a couple of decades remembering the days when we used to routinely see patients with BMIs of 50, 60, 70, 80, or even higher, with all of the accompanying complications.
Indeed, the only reason why so many patients with severe obesity exist today, is that this progressive chronic disease has largely gone untreated (with the exception of the tiny brave minority that may have undergone bariatric surgery).
After all, everyone living with severe obesity today, must at some point have had less severe obesity. That should have been the time where they should have been appropriately diagnosed and managed to halt progression and to avoid complications.
Thus far, that has not been the case. Even today, despite advances in obesity treatments, people living with early stages (or even later stages) of obesity receive virtually no obesity care, which is why we continue to see such large numbers of untreated individuals progressing to severe obesity with all its complications.
Now, with the recent developments in anti-obesity medications, I can foresee a future where severe obesity eventually goes the way of malignant hypertension – it goes back to being the rare disorder it once was.
How long will this take? It all depends on just how soon we can take obesity seriously, implement early detection and clinical care, and make effective obesity treatments available to everyone who needs them.
We have done it for hypertension – we can do it for obesity.
@DrSharma
Berlin, D
Are Lifestyle Zealots Promoting Weight Bias and Discrimination?
There are no doubt important benefits to be had from following a healthy lifestyle. A healthy diet, plenty of physical activity, restorative sleep, meditation, mindfulness, healthy relationships all contribute to maintaining good health and well-being.
And yes, all of the above can and probably should be part of any management regimen for any chronic disease.
However, the notion that these measures alone can constitute an effective and feasible treatment approach to obesity is neither supported by long-term randomised controlled studies nor by real-world experience of most individuals living with obesity, who have attempted controlling their weight with such measures.
Obviously, there are some anecdotal cases of individuals who have apparently “conquered” their obesity by drastically changing their lifestyle, mostly following rather restrictive dietary regimens (of which there are many) together with a punishing dose of daily exercise – but these rather exceptional cases in fact constitute fine examples of just what it takes to lose and sustain significant weight loss and should readily explain why this approach will simply not appeal to or prove feasible for the vast majority of people living with obesity.
Harping on about how lifestyle change is the real answer to obesity is simply promoting “fake news” and clearly implies that anyone who has tried lifestyle measures and failed, has simply not tried hard enough.
Such a message can only lead to even greater internalised weight bias and does little more than to reinforce the notion with the rest of us, that people with obesity are simply too lazy, lack motivation or willpower and are perhaps just not smart enough to get it.
Thus, every time another health zealot feels called upon to voice their opinion on how they may have personally conquered their obesity or have helped clients conquer theirs, I can only cringe at how my patients living with obesity perceive such messages.
Rather than freely acknowledging that trying to manage your obesity with lifestyle measures alone means a lifetime of restrictions and ongoing efforts, healthy living enthusiasts promote notions that do little more than to promote weight bias and ultimately reinforce stigma and discrimination.
Perhaps, even more importantly, now that we have effective medical treatments, their messages imply that anyone turning to these treatments is simply taking the “easy way out”, not willing to do the work and should probably be ashamed of themselves for failing to stick to the righteous path of living a clean and healthy life (perhaps with the addition of a super food or some magical dietary supplement) that can solve all their problems.
This message neither reflects an understanding of the biology of energy homeostasis, the realities of living with obesity, nor evidence-based medicine and comes from a position of privilege that is nowhere near or relevant to most of my patients, who are simply trying to get through one day at a time.
None of this speaks against the benefits of trying to live as healthy as possible – but please stop suggesting that all it takes to conquer obesity is motivation and willpower (and following whatever path has apparently worked for you or you happen to be selling) – that is nothing less than an insult to people living with obesity.
@DrSharma
Berlin, D
Disclaimer: I have received honoraria as an independent medical, research and/or educational consultant from various companies including Aidhere, Allurion, Boehringer Ingelheim, Currax, Eli-Lilly, Johnson & Johnson, Medscape, MDBriefcase, Novo Nordisk, Oviva and Xenobiosciences.
Conflating Effects of Weight Loss With Adverse Effects of Anti-Obesity Medications
The introduction of a new generation of highly effective anti-obesity medications (AOMs) has brought on the “naysayers” with warnings about the “dangers” of using these drugs, especially long-term.
In this context, I often see a conflation of issues that are simply the normal and expected consequences of losing weight with the actual known adverse effects attributable to the biological action of these medications.
Thus, as we know from people experiencing significant and often rapid weight loss with the use of low-calorie formula diets or bariatric surgery, it is not uncommon to see transient hair loss or gall-bladder stones. Also, the issue of sagging skin and other body parts as a consequence of weight loss is nothing new and has little to do with the biological action of these medications (thus “Ozempic face” could also be called “bariatric surgery face” or simply “weight-loss face”, but that would not be half as catchy).
Another issue that has nothing to do with the mode of action of these medications, is that significant weight loss can lead to manifestation of complications due to other underlying conditions and their treatments. For example, the rapid improvement in glycemic control resulting both from weight loss and GLP-1 actions on insulin secretion can lead to hypoglycemia in patients with diabetes who are also on insulin or sulfonylureas. Similarly, the reduction in blood pressure due to weight loss can lead to orthostatic hypotension in individuals on anti-hypertensive medications. These problems should be anticipated and can be avoided by close monitoring of patients and reducing the dose or discontinuing medications that are no longer needed.
There has also been much ado about the potential for muscle loss and nutritional deficiencies associated with these medications. However, it is important to remember that any loss of body weight will also result in loss of muscle mass (generally around a third of the total weight loss) and any major reduction in food intake (irrespective of its cause) over time can result in nutritional deficiencies, especially in individuals who start out with sub-optimal nutritional status in the first place. Again, this issue has nothing to do with the biological action of these medications, as these problems can be routinely observed in individuals losing significant amounts of weight on other treatments including dietary restriction or bariatric surgery. Moreover, both issues can generally be managed by close monitoring, optimising dietary intake (especially protein) and increasing physical activity – which should anyway be part of any obesity treatment.
Another common criticism of the use of AOMs is that their discontinuation may result in excessive hunger and cravings potentially resulting in rapid weight regain. Why this should surprise anyone is anyone’s guess, given that this is the normal biology of weight loss, where the body will do what it can to replenish its energy stores the minute the intervention stops. This is no different from going off any diet or weight loss program and has nothing to do with the mode of action of these medications.
Clearly different and distinct from these problems, which may occur with any form of significant weight loss, are the adverse effects related to the biological action of these medications. For the GLP-1 analogues, these include a range of largely transient gastrointestinal symptoms like nausea (rarely vomiting), diarrhoea, or delayed gastric emptying (which can often manifest as heartburn), none of which pose major health risks and can generally be minimised through careful uptitration and medical management.
The only potentially major issue appears to be pancreatitis (sometimes but not always related to the effects of these medications on the gallbladder) which are rather rare occurrences but worth watching out for.
The often cited cancer risk may be largely limited to the rare individual with a history of medullary thyroid cancer (constituting only about 1-2% of all thyroid cancers reported in the US). Whether or not this risk actually exists in humans still remains largely speculative, as it has only been observed in rodents, which have a substantially different thyroid physiology than humans or primates.
Although it received much attention, a recent study associating the use of GLP-1 medications with increased risk for thyroid cancer (all types) has been criticised for methodological issues and overinterpretation of the data.
Thus, while it is impossible to fully rule out any possible risk for cancers with these medications, the risk is clearly extremely small and in a population without specific risk factors for thyroid (or other) cancers, the benefits of GLP-1 analogues when used appropriately will likely outweigh the potential harm by a large measure.
Finally, what we also often hear are the concerns about not knowing what may or may not happen with the long-term use of these medications, given that they are still relatively new (albeit that GLP-1 analogues have now been used for diabetes treatment for over 15 years). This of course is a “generic” objection that would apply to any new medication for any indication intended for long-term use. So again, nothing specific here with regard to AOMs or GLP-1 analogues in particular.
Thus, while we must always carefully assess risk-benefit ratios for each individual patient (also paying attention to the substantial risks that may be associated with not treating), there is very little to suggest that this new generation of prescription anti-obesity agents are particularly risky when used appropriately under medical supervision.
DrSharma
Berlin, D
Disclaimer: I have received honoraria as an independent medical, research and/or educational consultant from various companies including Aidhere, Allurion, Boehringer Ingelheim, Currax, Eli-Lilly, Johnson & Johnson, Medscape, MDBriefcase, Novo Nordisk, Oviva and Xenobiosciences.
