SELECT Provides HOPE For People With Obesity And Heart Disease
On January 20, 2000, Salim Yusuf and colleagues published the seminal Heart Outcomes Prevention Evaluation (HOPE) Study in the New England Journal of Medicine.
The HOPE Study included over 9,000 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure, who were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years.
A total of 651 participants who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001).
Thus, the HOPE study established the benefits of angiotensin converting enzyme inhibition in the prevention of cardiovascular complications in high-risk individuals, which remains a leading principle for the treatment of such patients to this day.
Today (November 11, 2023), Michael Lincoff and colleagues presented the results of the long-awaited SELECT trial of the GLP-1 analogue semaglutide (2.4 mg) vs. placebo in over 17,000 participants 45 years of age or older who had preexisting cardiovascular disease and a BMI of 27 or greater but no history of diabetes.
According to the results of SELECT, published in the New England Journal of Medicine, a primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001).
Thus, SELECT shows a reduction in cardiovascular risk with semaglutide 2.4 mg, of a magnitude virtually identical to that reported for ramipril in the HOPE trial.
It must, however be noted that the SELECT trial results are in fact far more impressive that those of the HOPE study.
For one, while almost 40% of participants in HOPE had diabetes, the SELECT study specifically excluded people with diabetes.
Secondly, whereas the mean age of HOPE participants was 66 years, the SELECT population was five years younger.
Thirdly, SELECT was conducted on participants receiving today’s standard of care, which includes routine use of ACE/ARBs, statins, anti-platelet agents and liberal use of revascularisation.
Notably, this being a study of an anti-obesity medication in people with obesity, the BMI of participants was 33, i.e. five points higher than that of the HOPE trial.
It should perhaps also be mentioned here that participants on semaglutide lost about 10% of their body weight compared to less than 1% on placebo.
Incidentally, adverse effects, including those leading to discontinuation of semaglutide, were pretty much as expected given its mode of action (largely limited to GI side effects).
Within a few months of the publication of the HOPE trial, ACE inhibition pretty much became part of the global standard treatment for high-risk cardiovascular patients.
Whether or not this will be the case for semaglutide, given the cost and limited availability remains to be seen.
Nevertheless, SELECT will surely go down in the history of medicine (as did the HOPE trial) as the first randomised placebo-controlled trial documenting the beneficial effect of an anti-obesity medication (and intentional weight loss?) in individuals with obesity and established cardiovascular disease (without diabetes).
Congratulations to everyone involved!
@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.
The Difference Between “Ozempic-Face” and “Mounjaro-Babies”
Followers of social and other media will have by now heard the term “Ozempic-” or “Wegovy-face”, which refers to the facial changes associated with the use of the anti-obesity medication semaglutide. These facial changes have been said to deepen facial folds, increase wrinkles, and often make people look older and, in extreme cases, rather unhealthy.
Nothing about this is in anyway directly attributable to the specific action of semaglutide. In fact, these are the very facial changes that we routinely see in anyone losing a significant amount of weight, irrespective of the reason.
Thus, we could call this “Keto-face”, “Atkin’s-face”, “Formula-diet-face”, “Gastric-Bypass-face”, or even “Marathon-face”, if that’s the reason you went and lost a significant amount of weight, respectively.
Thus, “Ozempic-face” has nothing to do with any particular biological action of semaglutide that specifically affects facial body fat depots but, rather, is simple the natural consequence of weight loss.
This, however, is not entirely the case for “Mounjaro-babies”, a term that has been used for the occasional unplanned pregnancy in patients taking the GLP-1/GIP dual agonist tirzepatide or Mounjaro.
Part of this is of course related to the fact that weight-loss (by any means) will increase fertility in women of child-bearing age. Thus,anyone working in bariatric medicine has probably seen “keto-babies”, “formula-diet babies”, and “bariatric-surgery babies” (and of course “Ozempic” and “Wegovy babies”), all attributable to the impact of weight-loss on fertility.
However, this is only part of the story. It should be well-known by now that GLP-1 analogues can directly affect gastro-intestinal motility, often resulting in delayed gastric emptying, and in some cases, vomiting or even diarrhoea, especially during the early phase of treatment. This can markedly change the effectiveness of oral contraception – leading to unplanned pregnancies.
Thus, pregnancies in patients on a GLP-1 or a GLP-1/GIP analogue can be due to the rather unspecific effect of weight loss on fertility, but also due to the medication-specfiic effects on gastro-intestinal motility and emesis.
This is something all women of chid-bearing aged should be warned of when using GLP-1 or GLP-1/GIP analogues.
For e.g. the FDA-mandated label for Mounjaro clearly states for women of reproductive potential,
“Advise females using oral contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for four weeks after initiation and for four weeks after each dose escalation.”
As for women, who get pregnant whilst on Mounjaro, the FDA label states,
“Mounjaro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.”
And, as a clinical pearl, always remember to check for pregnancies in women of child-bearing age complaining of persistent nausea or vomiting when on a GLP-1 or GLP-1/GIP analogue.
DrSharma,
Berlin, D
What I Noticed at Obesity Week 2023
A few weeks ago, I attended Obesity Week, the annual scientific meeting of The Obesity Society, in Dallas.
As expected, there was a palpable buzz and excitement about the ever-expanding pipelines of nutrient-stimulated hormone (NuSH)-based treatments that bear the promise of dramatically changing the future clinical management of obesity.
Given this promise, I noticed based on the many random conversations that I had with participants and looking around the well-filled plenary sessions, that there is a substantial increase in the number of physicians attending this meeting.
Judging from the questions and the people I spoke to, most of these (often younger) colleagues appear to be actively practising obesity medicine.
This increased clinical interest in obesity management amongst MDs is also evident by the numbers of docs lining up to take the American Board of Obesity Medicine (ABOM), a clear indication that this is a fast-growing field of medicine.
Speaking of age, I was also delighted to see a younger cadre of obesity clinicians move up the ranks within the organization.
While there were still a rather large number of presentations from the more senior obesity experts, some of whom have been around for decades, there was a noticeable presence of younger clinicians, who are clearly poised to take on the obesity challenge.
This younger generation of obesity experts includes folks like Ania Jastreboff (Yale), Sean Wharton (Toronto), Scott Kahan (John Hopkins), Fatima Cody Stanford (Harvard), Sue Pedersen (Calgary) and TOS’ incoming President Jamy Ard (Wake Forest), all of whom have at least a couple of decades of working in the field ahead of them. They (and many others) represent the next generation of obesity leaders, which bodes well for the future of obesity medicine (and TOS).
The fact that they will have a lot on their hands was apparent from the substantial industry presence at this meeting (there is no scalable innovation without industry!).
Although the industry exhibition itself was rather modest (almost insignificant compared to what you would normally see at a diabetes or cardiology meeting), all major and many minor industry players in the field were in attendance and I had interesting meetings with most, if not all, of them.
As for content besides novel treatments, there were of course plenty of presentations on other important topics including prevention policies, definitions, stigma and discrimination, adipocyte and neuroendocrine biology, mental health and a host of other topics relevant to obesity science and care.
I’m certainly looking forward to the next Obesity Week in San Antonio next year.
@DrSharma
Dubai, UAE
Getting AOMs on Drug Formularies
Last week I chaired and moderated a workshop for formulary managers (mostly pharmacists and pharmacoeconomists) in Ryadh. The goal was to discuss what it would take to get anti-obesity medications (AOMs) onto formularies at their respective institutions.
For one, I was pleasantly surprised by the enthusiasm and sophistication of the discussion.
There was no doubt that obesity was recognised as a major health problem (about 60% of the Saudi population is living with overweight or obesity) and that medication was going to be part of the solution.
As far as I could discern from the discussion, the following considerations are important in any discussion around adding these (or any) medications to the formularies:
- Efficacy and health outcomes
- Safety and tolerability
- Cost effectiveness
- Availability of alternatives
- Availability and security of long-term supply chains
- Ease of administration
- Adherence and real-world effectiveness
- Ability to monitor, regulate, and assess usage
- Availability of HCP capacity and expertise to ensure appropriate use
- Overall budget impact
Obviously, for any medication, this would be a high bar to meet. While the new generation of nutrient-stimulated hormone (NuSH)-based medications may be highly efficacious and safe and patient need may be significant, demonstrating real-world effectiveness, security of supply, ability to monitor, regulate, assess usage, dearth of qualified HCPs, and the substantial budget impact remain significant challenges, particularly for anti-obesity medications.
Nevertheless, there was considerable optimism that most of these challenges will eventually be met and that in time, there is a good chance that anti-obesity medications will become part of formularies similar to medications for other chronic diseases.
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.
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.
@DrSharma
Jeddah, 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.
@DrSharma
Berlin, 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 picture of obesity care than I witnessed at EASD.
@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.
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.
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.
