The Dawn of Obesity Centric Medical Practice?
Last week at Obesity Week, Ildiko Lingvay (UT Southwestern Medical Center, Dallas) presented a plenary talk in which she discussed weight-centric vs. gluco-centric approaches to managing patients with type 2 diabetes mellitus (T2DM). Despite the fact that we have long seen the strong association between body fat and the development of T2DM, the recommendation of weight loss in all T2DM guidelines, and ample data showing that weight loss can markedly reduce the risk for T2DM, improve glucose control, and even lead to diabetes “remission”, Lingvay noted that we have so far lacked the tools to effectively address obesity in our patients. Now, with the advances in Nutrient-Stimulated Hormone (NuSH) based therapies, resulting in weight loss paralleled only by surgical interventions, we can foresee a future, where obesity treatments may well prove to be the first-line treatment not just for T2DM, but for a host of other conditions causally related to or significantly aggravated by obesity. Thus, we can envision that anti-obesity medications (AOMs) become the primary treatment for patients with sleep apnea, hypertension, MASLD, and a laundry list of other health problems related to excess body fat. Obviously, much needs to happen before we get there. For one, we will need dedicated studies directly comparing obesity centric approaches to treatment to “usual care” – numerous such studies for various indications are already underway or in late-stages of planning. Secondly, access to such medications will need to vastly improve. Currently cost and a global demand that is far outstripping limited supplies are proving to be significant barriers. Thirdly, all of us have to get more comfortable with the appropriate and safe use of these medications, which should only be used in the context of patient-centric obesity care. Despite these limitations, it will be exciting to watch how increasing evidence will change our treatment approaches for a large proportion of people living with a wide range of non-communicable chronic diseases, for which obesity remains one of the primary drivers world-wide. @DrSharmaJeddah, KSA 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.
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 »
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