Will the Blood Pressure-Lowering Effect of Semaglutide Explain the Positive Outcome of the SELECT Trial?
While we eagerly await the final publication of the results of the SELECT Trial of semaglutide in participants with overweight or obesity with established cardiovascular disease (but without diabetes), it may be of interest to speculate on the mechanisms by which treatment may have resulted in the reported 20% reduction in major adverse cardiovascular events (MACE). After smoking, elevated blood pressure is the single most important risk factor for macrovascular atherosclerotic disease (even in people with type 2 diabetes!). Previous studies with semaglutide have shown a consistent lowering of both systolic and diastolic blood pressure. In SUSTAIN-6, which showed significant reduction in MACE with semaglutide in participants with type 2 diabetes, the effect of semaglutide on blood pressure was only modest, however, the main driver of positive outcome was non-fatal strokes, an outcome which is particularly sensitive to changes in blood pressure. Likewise, in the family of STEP studies with semaglutide in participants with overweight or obesity, reductions in systolic and/or blood pressure reduction were regularly noted. Although the reported effects of semaglutide on blood pressure (ranging between 3 to 7 mmHg) may seem modest, this is likely to be an underestimate, given that blood pressure in participants was generally well-controlled to begin with and the studies only report office blood pressure, which is highly susceptible to white-coat effects. In fact, out-of-office and 24-hour ambulatory blood pressure measurements have been consistently shown to be more reliable measures of blood pressure than office measurements. Furthermore, the nocturnal drop in blood pressure, the lack of which (in non-dippers) is well recognised as a major CV risk factor, can only be assessed with 24-hour ambulatory measurements and would be completely missed by office measurements. This is of particular interest, as previous weight-loss studies (both surgical and non-surgical) using 24-hour ambulatory blood pressure measurements have notably reported significant improvements in dipper status. Until proven otherwise, I would maintain that a significant proportion of the potential benefits of semaglutide (and other weight-loss medications) on cardiac function and cardiovascular outcomes is likely related to their beneficial effects on blood pressure, the magnitude of which may well be underestimated with office measurements alone. DrSharmaBerlin, 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.
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… Read More »
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… Read More »
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. @DrSharmaBerlin, D
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… Read More »
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… Read More »
For the past 30 years or so, I have given countless talks to diabetologists urging them to pay more attention to obesity management – all to little avail. Interestingly enough, now, that we have new effective medications for obesity, which come with loads of pharma funding for research, education and conferences and as we near the end of significant new pharmacological developments in diabetes care, we are witnessing a sudden surge in interest amongst diabetologists and their professional organisations in taking on obesity as part of their “portfolio”. This is good! Not only is there considerable overlap between patients with type 2 diabetes (T2DM) and those with obesity (indeed, it is hard to find a T2DM patient without obesity), effective treatment of obesity can lead to substantial improvements in glycemic control (and even complete remission of T2DM), and the incretin-based medications for obesity are also of use for managing T2DM. Moreover, given the sheer number of diabetologists out there, together with the rather extensive and well-established infrastructures for diabetes care, expanding their mandate to also managing obesity appears a logical and long-overdue step. However, there are some important caveats. For one, the majority of people with obesity do not have diabetes and will probably never get it. For these individuals, going to a diabetes centre would seem strange, given that glycemic control is the least of their worries. Anyone who has any experience with obesity medicine knows that people presenting at obesity and bariatric centres are rarely there because they are concerned about their HbA1c levels. Their problems are chronic pain, sleep apnea, infertility, polycystic ovary syndrome, fatty liver disease, urinary stress incontinence, osteoarthritis, GERD, migraines, and a host of other issues that have nothing to do with glycemic control. Furthermore, a substantial proportion of patients presenting at bariatric centres have depression, anxiety, ADHD, BED, history of trauma, chronic grief, addictions, internalised weight bias, and plain old emotional eating, all of which need to be properly diagnosed and managed as part of obesity care. Finally, no one can claim to have expertise in obesity medicine, who is also not comfortable with the pre- and post-surgical management of patients undergoing bariatric surgery (so far, despite strong evidence, diabetologists have rarely referred a patient for bariatric surgery never mind getting involved in their post-surgical care). While there is no reason why diabetologists should not be able to learn about and attend to… Read More »
Last week I gave a Keynote presentation to dignitaries and attendees at the 5-Year Anniversary of the Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG) in Leipzig. Tasked with summarising where we stand in obesity prevention and management for attendees who were not obesity experts, I boiled down the message to three points. We are where we are in addressing obesity both in terms of prevention and management because of the 3Ds: Discrimination, Disinformation, and Disinterest! Not much needs to be said about discrimination, as it is well documented that people living with obesity experience discrimination on a daily basis, be it in educational settings, workplaces, or when moving about in public. In my talk I zeroed in on the discrimination people with obesity face in health care settings: doctors spend less time with them, order fewer tests, prescribe fewer treatments, and generally have little advice to offer beyond “Eat Less Move More”. No wonder, people with obesity turn to doctors as a last resort after all their do-it-yourself approaches have failed. Much of this weight-bias and discrimination is directly fueled by a barrage of disinformation by a multi-billion weight loss industry that has little to offer beyond useless dietary supplements, fad diets, exercise machines, and loads of other stuff that they can happily unload on desperate victims under a barrage of nonsense or half-truths (all those weight-loss secrets your cardiologist does not want you to know!). Unfortunately, governments and policy makers are complicit in this by announcing successive unachievable population goals, that focus largely on food and activity policies, none of which have yet made a dent in the obesity epidemic but do serve as a fine excuse to not provide treatments to those who already have the problem. Finally, it is hard to fathom the amount of disinterest and lack of knowledge that the vast majority of healthcare providers show in the management of obesity. This is particularly true for most of academic medicine, which has bemoaned but otherwise largely ignored the problem. By any metric, be it in the number of academic chairs, PhD theses, research projects, research funding or publications, obesity ranks aeons behind any other major health problem of our time. We are still licensing doctors and other medical personnel that have never managed a single patient for their obesity (not just with obesity). Fortunately, we are now finally seeing some movement in all… Read More »