Thank you so much for your clear, fair description and assessment of this study. Reading this together with your post on ultra processed foods offers a powerful demonstration of the skewing of our health care system toward profit-making over seeking the most beneficial pathways to better health. Your final point brings this home: “To me the biggest concern is that these companies appear to be promoting a lifelong duration of therapy, as evident by their zero attention to getting people off the drugs, without reverting back for both weight gain and risk of adverse outcomes. That is clearly unacceptable and major pressure is needed to get all companies making this class of drugs to test and validate durable and safe exit strategies.”
I’ve seen such elation in people finally losing 40-80 pounds who had struggled mightily before these game changers. I think as clinicians it is an imperative to develop best practices and consensus off ramps so these meds are not chronic meds for life for most people, although some will “need” them indefinitely. I have stopped bp meds, diabetes meds, pain meds in many patients after successful weight loss reverses conditions like hypertension diabetes etc, so there is sometimes a trade off between being on a Glp 1 agonist longer term, but being off 4-5 other meds because of the weight loss achieved.
Rarely have I participated in such a satisfying intervention for people, so I’m not going to cast too much shade on the pharma companies yet (novo, Lilly, etc).
But this has inspired me to do a formal post soon proposing some ways to taper off Glp 1 meds once weight loss goals have been achieved. Are you aware of any guidelines from medical organizations/authorities yet?
Avoiding an all or nothing approach with being on these meds seems prudent, with a stepwise leisurely taper down over whatever time works for the patient. Maybe in/off like we do for diuretics and chf based in monitoring vital signs/weight. Calorie counting and exercise to maintain success would be foundational principles I think.
You are such a good and caring primary doctor! Can we clone you? This is a great set of questions, and really smart thinking. I do think it’s fine, and actually important, to critique pharma where it’s due, while at the same time recognizing the potential and actual gains. I don’t see these two things as being in conflict. Indeed, it’s really important, to continue to make gains, to recognize the insufficiencies as well as the advantages. One of the things I appreciate so much about Dr. Topol’s articles (in addition to how informative they are), is how he does exactly this by being scrupulously even-handed in setting forth the information.
In the U.S., the obesity epidemic is the consequence of the corporate food epidemic. The "invisible hand" of unregulated free markd capitalism ceated both the fast food resturarant epidemic, which is built on shifting our diets to addict us to our hunter-gatherer food cravings - saturated fats, super-glycemic carbs, and the modern Ameriican supermarket, which profits from ultra-processed foods, emerging from the labs of large corporations ,which create easily-prepared, food-like toxins, where "new and improved" meals, means more sugar, more fat , more "mystery" ingredients, often added to replace nutritious ingredients that have been removed. Forget the fact that to get to a fast food restuarant, or supermarket, by any means other than sitting in a car is often either impossible, or dangerous. Scientists do not understand the multiple, extraordinarily complex, physiology and pathophysiology of nutrition, nor the consequences of not exerting our bodies regularly, which we evolved to do as well. Mediciations can do many wonderful things. but Medications cannot "fix" physiological systems that we do not understand - medications can reduce the damage we self-inflict. As physicians, if we are to claim to be evidence-based, we need to speak truth to power - currently the evidence base indicates we are grossly neglecting the causes of the diseases - our food, and our designed environments, which are built to maximize proift, regardless of the fact that they destroy our heatlth.
One comment on the cost though- the pharma companies are paying very large rebates back to the PBMs, some of which get shared back with the employers and CMS who are actually paying for these, so the actual cost of these drugs is not $1,000 - $1,600 per month.
No doubt that with the huge % of Americans that are obese (and the additional % that have a BMI >27), even 1/2 that cost per month is a huge economic burden.
The clinical findings are important and yes- the absolute reduction in significant outcomes is small.
What are the realistic interventions here?
Here are the questions running through my mind.
Over the course of a life, would bariatric surgery be more cost effective? Probably but what entity has the financial obligation for an individual over the course of their lifetime?
The long term adherence rate of lifestyle and diet attempts to lose weight are dismal. Although they need to be part of the answer, we know that they are not the complete answer.
Are the oral GLPs or triple hormone targeted drugs going to be more cost-effective than the current injectables? Probably not.
Could the oral drugs expand the actual user base so much that we can't afford these therapies at all? Probably.
Will cardiac, cancer and other obesity related consequences increase again in a pragmatic world once patients are off these meds? Evidence shows most gain their weight back but what happens to these co-morbidities?
How do we compare the costs of other lifelong branded drugs to these that have a similar benefit? It will be a long time before we have generics in these classes.
I don't have the answer but a multi-pronged approach including a glide path off these drugs seems like the best approach.
TODAY IS DIWALI AND CELEBRATION INVOLVES THE LIGHTING OF LAMPS AND LOTS OF SWEETS. WE MIGHT NEED THAT WEGOVY YET 😉 . HAPPY DIWALI everyone! Triumph of good over evil... light over dark.. in todays world of war and strife, a welcome reminder of the blessings of peaceful living.
EDIT: This post and the comments assume a deep ironic level in light of the tittle of your blog, "ground truth". Thank you for enlightening us !!
I literally upgraded to paid just to avoid these substacks becoming prey of self-reinforcing bias coming from the fact that who doesn't agree, doesn't pay, and doesn't comment. I'll make an exception and highlight how regarded are the "not so good" points 1 and 3 (especially after reading the comment that labeled your post as "fair").
On 1. How is a 1.5% absolute risk reduction actually disappointing, especially considering that it comes in the form of any cause mortality. Or asked differently, how many other drugs do you know that have a better/comparable reduction on such a large population? And commenting on that just because the price is high is also hmm... how do I say.. regareded. Go express that concern with your vote ? And by the way, prices are that high just because companies have supply constraints now, they'll come down as competition intensifies.
On 3a. "We know that people lose muscle mass" : do you have evidence of people not losing muscle mass when losing weight without GLP-1s ? Can you provide evidence that shows that the fat/muscle ratio is lower in GLP-1s than other ways of losing weight? (spoiler: you can't)
On 3b. "We know that people lose bone density". What do we know that from? Are you told these things in dreams?
- The SCALE (Satiety and Clinical Adiposity−Liraglutide Evidence in individuals with and without diabetes) Obesity and Prediabetes trial was a randomized controlled trial that showed a lower rate of fractures in the group treated with liraglutide compared to the placebo group, which could indicate a potential protective effect on bone.
- The AWARD-7 (Assessment on Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes) trial, which compared the effects of the GLP-1 agonist dulaglutide with insulin glargine in people with moderate to severe chronic kidney disease and type 2 diabetes. Bone turnover markers were evaluated, and there was no significant difference between the treatment groups regarding changes in bone turnover markers or the numbers of reported fractures.
- A systematic review and meta-analysis of randomized controlled trials published by Su et al. in 2015 did not find a significant association between GLP-1 receptor agonist treatment in type 2 diabetes and fracture risk, implying a neutral effect on bone.
It’s hard to call the absolute risk reduction disappointing when in was the effect size that the trial was designed to detect: a 20% risk reduction in a high-risk population. It would have been one thing if the % risk reduction was less than expected but still statistically significant because the background event rate was even higher than expected. Or that a 20% reduction lacked statistical significance because the background rate was lower than anticipated. If achieving the results that the trial was designed to achieve is disappointing then they should have designed a smaller less expensive and, possibly, shorter trial powered to show an effect that justified the cost of the drug.
As a card carrying endocrinologist, it would be heresy for me not to throw my considerable physical weight on this band wagon. Dr Topol has done a very good job of thoughtfully analyzing and doing a critical appraisal of the semaglutide weight loss study . There can be no question that weight loss is difficult for patients and this approach is certainly a great step forward.
We, therefore, have to exercise some caution. The real world data suggests a greater than 50% drop off in adherence to these medications after 1-2 years even in individuals with diabetes where the end point is continuing glucose control. In obesity, the drop off may be greater, given that the weight loss plateaus and the need to continue treatment is attenuated. At this time, factors away from weight loss come to the fore: cost, and no continuing weight loss as well as the loss of hedonistic drives beyond food may all play a role. Furthermore, insurance forces may start to play a role based on a precedent certainly in Ohio law that decrees that weight loss medications be discontinued if there is no continuing weight loss. Whatever the reason, on discontinuation, there is a very rapid weight regain, and, at least as a personal observation the rate of weight gain is very rapid. More troublesome the weight gain is associated with a steep rise in hs-CRP indicating a significant inflammatory drive. It therefore behooves us to define this weight gain: mainly subcutaneous , balanced visceral and subcutaneous or mainly visceral. The latter, especially in epicardial fat may well presage an increase in cardiovascular risk. The evaluation is the premise of large CV departments headed by individuals like Drs Topol and Lincoff which have the ability to measure epicardial fat and would be able to assess the rate of increase if any. In addition, we need to target diminishing the increase in epicardial fat and the inflammatory response. Besides GLP- agonists, statins have been shown to decrease epicardial fat and decrease hs-CRP indicating an anti-inflammatory response. Pioglitazone may also be useful by providing more preadipocytes in subcutaneous tissue diverting fat away from ectopic sites; it is also anti-inflammatory and in low doses is not associated with significant weight gain or fluid retention. It has to be stressed that while instructing patients on lifestyle modifications remains important, we, as the clinical care treatment team, need to accept the fact that lifestyle modifications have proven of limited success and we need to proactively look into measures to limit the risk of rapid weight gain after induced weight loss.
Thank you so much for your clear, fair description and assessment of this study. Reading this together with your post on ultra processed foods offers a powerful demonstration of the skewing of our health care system toward profit-making over seeking the most beneficial pathways to better health. Your final point brings this home: “To me the biggest concern is that these companies appear to be promoting a lifelong duration of therapy, as evident by their zero attention to getting people off the drugs, without reverting back for both weight gain and risk of adverse outcomes. That is clearly unacceptable and major pressure is needed to get all companies making this class of drugs to test and validate durable and safe exit strategies.”
I’ve seen such elation in people finally losing 40-80 pounds who had struggled mightily before these game changers. I think as clinicians it is an imperative to develop best practices and consensus off ramps so these meds are not chronic meds for life for most people, although some will “need” them indefinitely. I have stopped bp meds, diabetes meds, pain meds in many patients after successful weight loss reverses conditions like hypertension diabetes etc, so there is sometimes a trade off between being on a Glp 1 agonist longer term, but being off 4-5 other meds because of the weight loss achieved.
Rarely have I participated in such a satisfying intervention for people, so I’m not going to cast too much shade on the pharma companies yet (novo, Lilly, etc).
But this has inspired me to do a formal post soon proposing some ways to taper off Glp 1 meds once weight loss goals have been achieved. Are you aware of any guidelines from medical organizations/authorities yet?
Avoiding an all or nothing approach with being on these meds seems prudent, with a stepwise leisurely taper down over whatever time works for the patient. Maybe in/off like we do for diuretics and chf based in monitoring vital signs/weight. Calorie counting and exercise to maintain success would be foundational principles I think.
You are such a good and caring primary doctor! Can we clone you? This is a great set of questions, and really smart thinking. I do think it’s fine, and actually important, to critique pharma where it’s due, while at the same time recognizing the potential and actual gains. I don’t see these two things as being in conflict. Indeed, it’s really important, to continue to make gains, to recognize the insufficiencies as well as the advantages. One of the things I appreciate so much about Dr. Topol’s articles (in addition to how informative they are), is how he does exactly this by being scrupulously even-handed in setting forth the information.
In the U.S., the obesity epidemic is the consequence of the corporate food epidemic. The "invisible hand" of unregulated free markd capitalism ceated both the fast food resturarant epidemic, which is built on shifting our diets to addict us to our hunter-gatherer food cravings - saturated fats, super-glycemic carbs, and the modern Ameriican supermarket, which profits from ultra-processed foods, emerging from the labs of large corporations ,which create easily-prepared, food-like toxins, where "new and improved" meals, means more sugar, more fat , more "mystery" ingredients, often added to replace nutritious ingredients that have been removed. Forget the fact that to get to a fast food restuarant, or supermarket, by any means other than sitting in a car is often either impossible, or dangerous. Scientists do not understand the multiple, extraordinarily complex, physiology and pathophysiology of nutrition, nor the consequences of not exerting our bodies regularly, which we evolved to do as well. Mediciations can do many wonderful things. but Medications cannot "fix" physiological systems that we do not understand - medications can reduce the damage we self-inflict. As physicians, if we are to claim to be evidence-based, we need to speak truth to power - currently the evidence base indicates we are grossly neglecting the causes of the diseases - our food, and our designed environments, which are built to maximize proift, regardless of the fact that they destroy our heatlth.
Very nice review of a significant study.
One comment on the cost though- the pharma companies are paying very large rebates back to the PBMs, some of which get shared back with the employers and CMS who are actually paying for these, so the actual cost of these drugs is not $1,000 - $1,600 per month.
No doubt that with the huge % of Americans that are obese (and the additional % that have a BMI >27), even 1/2 that cost per month is a huge economic burden.
The clinical findings are important and yes- the absolute reduction in significant outcomes is small.
What are the realistic interventions here?
Here are the questions running through my mind.
Over the course of a life, would bariatric surgery be more cost effective? Probably but what entity has the financial obligation for an individual over the course of their lifetime?
The long term adherence rate of lifestyle and diet attempts to lose weight are dismal. Although they need to be part of the answer, we know that they are not the complete answer.
Are the oral GLPs or triple hormone targeted drugs going to be more cost-effective than the current injectables? Probably not.
Could the oral drugs expand the actual user base so much that we can't afford these therapies at all? Probably.
Will cardiac, cancer and other obesity related consequences increase again in a pragmatic world once patients are off these meds? Evidence shows most gain their weight back but what happens to these co-morbidities?
How do we compare the costs of other lifelong branded drugs to these that have a similar benefit? It will be a long time before we have generics in these classes.
I don't have the answer but a multi-pronged approach including a glide path off these drugs seems like the best approach.
TODAY IS DIWALI AND CELEBRATION INVOLVES THE LIGHTING OF LAMPS AND LOTS OF SWEETS. WE MIGHT NEED THAT WEGOVY YET 😉 . HAPPY DIWALI everyone! Triumph of good over evil... light over dark.. in todays world of war and strife, a welcome reminder of the blessings of peaceful living.
EDIT: This post and the comments assume a deep ironic level in light of the tittle of your blog, "ground truth". Thank you for enlightening us !!
I literally upgraded to paid just to avoid these substacks becoming prey of self-reinforcing bias coming from the fact that who doesn't agree, doesn't pay, and doesn't comment. I'll make an exception and highlight how regarded are the "not so good" points 1 and 3 (especially after reading the comment that labeled your post as "fair").
On 1. How is a 1.5% absolute risk reduction actually disappointing, especially considering that it comes in the form of any cause mortality. Or asked differently, how many other drugs do you know that have a better/comparable reduction on such a large population? And commenting on that just because the price is high is also hmm... how do I say.. regareded. Go express that concern with your vote ? And by the way, prices are that high just because companies have supply constraints now, they'll come down as competition intensifies.
On 3a. "We know that people lose muscle mass" : do you have evidence of people not losing muscle mass when losing weight without GLP-1s ? Can you provide evidence that shows that the fat/muscle ratio is lower in GLP-1s than other ways of losing weight? (spoiler: you can't)
On 3b. "We know that people lose bone density". What do we know that from? Are you told these things in dreams?
- The SCALE (Satiety and Clinical Adiposity−Liraglutide Evidence in individuals with and without diabetes) Obesity and Prediabetes trial was a randomized controlled trial that showed a lower rate of fractures in the group treated with liraglutide compared to the placebo group, which could indicate a potential protective effect on bone.
- The AWARD-7 (Assessment on Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes) trial, which compared the effects of the GLP-1 agonist dulaglutide with insulin glargine in people with moderate to severe chronic kidney disease and type 2 diabetes. Bone turnover markers were evaluated, and there was no significant difference between the treatment groups regarding changes in bone turnover markers or the numbers of reported fractures.
- A systematic review and meta-analysis of randomized controlled trials published by Su et al. in 2015 did not find a significant association between GLP-1 receptor agonist treatment in type 2 diabetes and fracture risk, implying a neutral effect on bone.
It’s hard to call the absolute risk reduction disappointing when in was the effect size that the trial was designed to detect: a 20% risk reduction in a high-risk population. It would have been one thing if the % risk reduction was less than expected but still statistically significant because the background event rate was even higher than expected. Or that a 20% reduction lacked statistical significance because the background rate was lower than anticipated. If achieving the results that the trial was designed to achieve is disappointing then they should have designed a smaller less expensive and, possibly, shorter trial powered to show an effect that justified the cost of the drug.
As a card carrying endocrinologist, it would be heresy for me not to throw my considerable physical weight on this band wagon. Dr Topol has done a very good job of thoughtfully analyzing and doing a critical appraisal of the semaglutide weight loss study . There can be no question that weight loss is difficult for patients and this approach is certainly a great step forward.
We, therefore, have to exercise some caution. The real world data suggests a greater than 50% drop off in adherence to these medications after 1-2 years even in individuals with diabetes where the end point is continuing glucose control. In obesity, the drop off may be greater, given that the weight loss plateaus and the need to continue treatment is attenuated. At this time, factors away from weight loss come to the fore: cost, and no continuing weight loss as well as the loss of hedonistic drives beyond food may all play a role. Furthermore, insurance forces may start to play a role based on a precedent certainly in Ohio law that decrees that weight loss medications be discontinued if there is no continuing weight loss. Whatever the reason, on discontinuation, there is a very rapid weight regain, and, at least as a personal observation the rate of weight gain is very rapid. More troublesome the weight gain is associated with a steep rise in hs-CRP indicating a significant inflammatory drive. It therefore behooves us to define this weight gain: mainly subcutaneous , balanced visceral and subcutaneous or mainly visceral. The latter, especially in epicardial fat may well presage an increase in cardiovascular risk. The evaluation is the premise of large CV departments headed by individuals like Drs Topol and Lincoff which have the ability to measure epicardial fat and would be able to assess the rate of increase if any. In addition, we need to target diminishing the increase in epicardial fat and the inflammatory response. Besides GLP- agonists, statins have been shown to decrease epicardial fat and decrease hs-CRP indicating an anti-inflammatory response. Pioglitazone may also be useful by providing more preadipocytes in subcutaneous tissue diverting fat away from ectopic sites; it is also anti-inflammatory and in low doses is not associated with significant weight gain or fluid retention. It has to be stressed that while instructing patients on lifestyle modifications remains important, we, as the clinical care treatment team, need to accept the fact that lifestyle modifications have proven of limited success and we need to proactively look into measures to limit the risk of rapid weight gain after induced weight loss.
-Dr. Adi E. Mehta