Going With The FLOW?
This week, Novo Nordisk announced the early stop of the FLOW trial, a Phase 3 trial comparing kidney outcomes for injectable semaglutide 1.0 mg vs. placebo in T2D and CKD. The stop was prompted because, “results from an interim analysis met certain pre-specified criteria for stopping the trial early for efficacy.” As a nephrologist, who established his early academic career with a focus on hypertension, I cannot help but speculate on the mechanisms behind these apparent renoprotective benefits of semaglutide. Obviously, improved glycemic control is part of the story but hardly enough. Weight loss (in part the reason for improved glycemic control) is likewise a possible factor. But clearly, given the abundance of GLP-1 receptors throughout the kidney, it is only reasonable to suspect that specific renal actions of semaglutide may contribute to its benefits. For one, GLP-1 analogues can inhibit the sodium-proton exchanger located in the proximal tubule, thereby increasing natriuresis. Increased sodium reaching the macula densa would in turn suppress overactivation of the renin–angiotensin–aldosterone by restoring tubulo-glomerular feedback. The combined result of these effects would not only reduce blood pressure but also reduce hyperfiltration. I have previously noted that the blood-pressure lowering effects of GLP-1 analogues are currently largely underappreciated. There is also some evidence suggesting that GLP-1RA may inhibit mesangial expansion, reduce the endothelial expression of profibrotic molecules, increases the availability of intraglomerular nitric oxide, and reduce the release of free oxygen species, all of which would be expected to slow the progression of chronic kidney disease. While we wait for further details from the FLOW trial, it may be in order to speculate whether or not the renal benefits of semaglutide will extend to non-diabetic CKD, as has been demonstrated for SGLT-2 inhibitors. @DrSharmaBerlin, D
What I Took Away From EASD 2023
Last week at EASD 2023 in Hamburg, the greatest buzz was clearly around incretin-based weight loss treatments and their potential metabolic benefits. In the many sessions on incretin mimetics, data were presented with the promise of weight loss of 25% and beyond, results that are only rivalled by surgical treatments. There were also several sessions that focussed on the increasingly complex biology of adipose tissue and the various obesity phenotypes that may be defined according to metabolic parameters. Does this mean that diabetes is now poised to take over the fast evolving field of obesity medicine? Not quite! Although clearly, weight-centric (rather than gluco-centric) management of type 2 diabetes is gaining in acceptance and importance, there is more to obesity medicine than lowering body weight or optimising glycemic control. For one, most people with obesity do not have diabetes and even if they do, normalising their HbA1c is often the least of their problems. Rather, their issues often revolve around chronic pain, osteoarthritis, sleep apnea, reflux disease, incontinence, fertility, and a host of other problems including the social and psychological burden of living with excess weight, all of which markedly impair their quality of life. As one may guess, none of these topics featured anywhere in the EASD plenaries – in fact I did not note a single presentation on the topic of weight bias and discrimination – probably the single most import issue to be aware of and be able to deal with when working in obesity medicine. Also, given that obesity is largely driven by ingestive behaviour and the principal mode of action of incretin-based weight-loss treatments is to markedly alter eating behaviour through its central actions on the brain, it may be surprising that short of the excellent presentation by Timo Müller on the role of GIP and GLP-1 on energy homeostasis (58th Minkowski Lecture – which unfortunately ran parallel to the the SURMOUNT-4 session), there was rather little focus on the central modulation of eating behaviour, the real reason why these treatments work to reduce weight. So, while I was happy to see the excitement at EASD around incretin-based treatments for weight management and appreciated the many excellent presentations on adipocyte biology, this is still a far cry from fully embracing the complexity and diversity of obesity medicine. Clearly, I expect that the presentations this week at Obesity Week in Dallas will paint a very different… Read More »
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.
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… Read More »
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… Read More »
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. @DrSharmaBerlin, D
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