Eric Topol: “The GLP-1 and now triple G-Agonists are exceeding expectations as weight loss drugs. Benefits for cardiovascular outcomes, possibly Type 1 diabetes, addiction, and more are reviewed in the latest Ground Truths.” His newsletter also describes the early results of these medications with MASH/NASH with improvement in ~90%.
To get the full review, go to Ground Truths: http://erictopol.substack.com (can sign up to get regular emails on many current medical topics)
Until a few years ago, I had controlled my depression and anxiety through decades of counseling. I was reluctant to try medications because the medical understanding of them seemed vague…We also can’t explain why some people benefit from S.S.R.I.s and others do not. Because of this, many people still believe those who take them don’t really need them. I also believed that, if I was strong enough, I didn’t need medication…
I was wrong to doubt. It’s had a remarkable effect on my mood, and almost everyone around me noticed the difference. I was more optimistic, friendlier and more engaging. I was forced to reconsider why I had avoided taking the medication for so long. I think it’s because — even though I realize this isn’t true — taking it felt like an admission of failure…
I’ve recently faced a similar scenario with new drugs for obesity. I’ve struggled with my weight for most of my life. I’ve always been overweight, and in the last few years, I’ve slipped into obesity, according to my body mass index. I exercise regularly and carry the weight well, but it bothers me immensely. It especially troubles me because I have a fair amount of self-discipline and eat quite healthfully…
Despite all the advances in science, we don’t know why some people, even when they try desperately, can’t seem to lose weight. Because of that, we often assume it must be a lack of willpower…
These drugs are expensive, but I was determined to see what would happen if I took one. It is hard to explain what life is like on this medication to people who don’t have trouble controlling their weight. I’m not hungry all the time. I’m not thinking about food incessantly. I’m not obsessing about what I wish I could eat and what I can’t. My mental health, and even my temperament, improved so much that my whole family rejoiced…
Before writing this essay, I had told just a few people I’m on the drug. I think it’s because, on some level, I still feel shame. I felt the same when I finally started taking an antidepressant…
Medical treatments should not be dismissed just because we don’t fully grasp their mechanisms; people who use them are not cheating.
“That’s all well and good in practice… but how does it work in theory?” I saw this quote many years ago when I was visiting the University of Chicago.
This quote came to mind as I was reading this article which showed relatively little change in the efficacy between more and less stringent elimination diets for eosinophilic esophagitis. This meta-analysis included 915 children and 847 adults and assessed the efficacy rates of 4 major dietary treatment regimens in eosinophilic esophagitis: 6-food (SFED), 4-food (FFED), 1-food (OFED), and a targeted elimination diet (TED).
Key findings:
The overall rate of histologic remission was 53.8% and in the individual dietary groups was 61.3% for SFED, 49.4% for FFED, 51.4% for OFED, and 45.7% for TED.
The overall rate of clinical response was 80.8%, with response rates of 92.8% for SFED, 74.1% for FFED, 87.1% for OFED, and 69.0% for TED.
Percentage of food antigen triggers identified via endoscopic and clinical evaluation after food re-introduction.
My take: It is clear to me that more restrictive diets can yield better response rates; however, in clinical practice they are difficult to maintain and this study shows that the improvement with more food restrictions may be quite limited.
Another reference on eosinophilic esophagitis: CJ Ketchem et al. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2252-2259. Open Access! Higher Body Mass Index Is Associated With Decreased Treatment Response to Topical Steroids in Eosinophilic Esophagitis. Key finding: Histologic response (n=296) to topic steroids was higher for those who were nonobese compared with obese at fewer than 15 eosinophils per high-power field (61% vs 47%; P = .049); in addition, nonobese patients had significantly greater endoscopic and symptomatic responses.
S Wharton et al. NEJM 2023; DOI: 10.1056/NEJMoa2302392. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity
In this phase 2 randomized, double-blind trial with 272 adults with obesity (mean weight at baseline 108 kg), participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. “The pharmacokinetic profile of orforglipron, with a half-life of 29 to 49 hours, supports once-daily oral administration.”
Key findings:
At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo.
A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo.
Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists.
Weight reduction of at least 10% at week 36:
My take: This is an exciting time for drug development for obesity. Given the low success rates of traditional ‘lifestyle’ management approaches, these medications have the potential to reduce a great deal of morbidity. Oral agents, rather than injections, would hasten the use of these agents more broadly. Long term outcomes are still unclear.
AM Jastreboff et al. NEJM 2023; DOI: 10.1056/NEJMoa2301972. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial.
Background: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors.
Methods: This study enrolled 338 with BMI of at least 27 in a a phase 2, double-blind, randomized, placebo-controlled trial with once-weekly injections of retatrutide.
Key Findings:
The number who achieved at least a 10% weight loss:
“The safety profile of retatrutide was consistent with reported phase 1 findings in persons with type 2 diabetes13 and similar to those of therapies based on GLP-1 or GIP–GLP-1 for the treatment of type 2 diabetes or obesity”
My take: There are a number of effective agents for obesity that have been developed very recently. Long term efficacy and safety are still not well-understood.
“As of 2020, the Center for Disease Control (CDC) notes that 40% of the ~258 million US adults suffer from obesity. This represents just more than a 100 million people suffering from obesity. In addition, about 23 million people suffer from severe obesity with a body mass index >40 kg/m2.” Fatty liver disease (aka NAFLD), driven primarily by obesity, is a leading cause of liver transplantation. In addition, fatty liver disease is impacting the ability to treat liver failure.
“The end result of this epidemic is that we are identifying a greater proportion of organ donors with varying degrees of liver steatosis. Transplantation of steatotic livers is associated with an increased degree of ischemia-reperfusion injury (IRI) and release of inflammatory cytokines from the graft. The consequences of this can range from severe reperfusion syndromes with immediate vasoplegia and circulatory collapse to distant organ dysfunction with acute kidney injury, liver allograft dysfunction, and primary nonfunction (PNF).”
In order to try to identify suitable liver organs for transplantation, researchers are trying to identify strategies to utilize steatotic grafts safely. Patrono et al (Liver Transplantation 2023; 29: 508-502) examined the feasibility of using normothermic machine perfusion (NMP) in the setting of macrovesicular steatosis (MaS) ≥30%. They identified 10 patients who had liver transplants using NMP in patients with MaS ≥30%; 4 additional organs were not used despite NMP. 8 of 10 patients showed good liver function, representing 57% (8 of 14) of NMP fatty organs.
Another study in the same issue (NB Ha et al.Liver Transplantation 2023; 29: 476-484) showed that patients with sarcopenic obesity (=low muscle mass obesity) had high waitlist mortality of 40% compared to 21% and 12% for those with sarcopenia without obesity and for those with obesity without sarcopenia, respectively.
My take: Obesity increases the risk of fatty liver associated cirrhosis/liver failure, and is impacting the availability of suitable organs for those in need. Furthermore, in those with obesity, the presence of sarcopenia increases the risk of death on transplant waitlist.
JPH Wilding et al. Diabetes, Obesity and Metabolism 2022. https://doi.org/10.1111/dom.14725 Open access! Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension “One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.”
This article discusses several conditions like Prader-Willi and pregnancy that can result in increase hunger and then elaborates on genetic tendency towards obesity in an age of abundant ultra-processed high calorie foods. Excerpts:
A famous 1990 study of identical twins born in Sweden showed that pairs who were separated at birth and adopted had weights more similar to each other than to their adoptive families…The ability to sense such fullness — and hunger — varies, the result of genetic differences in brain circuits that control appetite.
The new drugs are the first to manipulate the hormonal regulatory systems governing energy balance. The drugs simulate the action of our native GLP-1 but with longer-lasting effects, amplifying the fullness signal inside the body…At the very least, though, the way the drugs work can teach us that people who are larger did not necessarily choose to be, just as people who are smaller did not — and are not morally superior. This “isn’t a free pass, either to individuals who do have the capacity to choose better, nor does it take the heat off of food industries,” said a University of Sydney nutritional biologist, Stephen Simpson, but it’s “evidence that obesity isn’t a personal lifestyle choice.”
My take: For those who benefit from GLP-1 medications, it is important to recognize that weight gain is likely when the medications are discontinued; this indicates once treatment is started, the goal would be to use indefinitely –until something better comes along.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition
Anyone who follows this blog closely knows my inherent attraction for study acronyms; it is too bad I am not a leading researcher because it would be really fun to come up with some hilarious acronyms.
The Primary Obesity Surgery Endoluminal (POSE) Procedure for the treatment of obesity (GL Nava et al. Clin Gastroenterol Hepatol 2023; 21: 81-89) prospectively enrolled 44 adult patients who underwent “a novel pattern of full-thickness gastric body plications to shorten and narrow the stomach using durable suture anchor pairs.”
Key findings:
This procedure used an average of 19 suture anchor pairs, with a mean duration of 37 ± 11 minutes, and was technically successful in all subjects
Mean percentage total body weight loss (%TBWL) at 12 months was 15.7% ± 6.8%. >15% TBWL was achieved by 58%
Improvements in lipid profile, liver biochemistries, and hepatic steatosis were seen at 6 months
Repeat assessment at 24 months (n = 26) showed fully intact plications. No serious adverse events occurred
My take: This study shows that endoscopic therapies for obesity are quite promising. However, endoscopic therapies and bariatric surgery may become 2nd or 3rd line therapies if oral medications are available that can achieve similar success. Though, medications could require indefinite treatment.
D Weghuber et al NEJM 2022; DOI: 10.1056/NEJMoa2208601. Once-Weekly Semaglutide in Adolescents with Obesity
Methods: In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled 201 adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. 180 (90%) completed treatment. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention.
Key findings:
The mean change in BMI from baseline to week 68 was −16.1% with semaglutide and 0.6% with placebo
At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group
Improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo
“The safety of semaglutide in this adolescent population appeared to be consistent with findings among adults with overweight or obesity… Gastrointestinal disorders (primarily nausea, vomiting, and diarrhea) were the most frequent adverse events with semaglutide (occurring in 62% of participants, as compared with 42% in the placebo group) and were generally mild or moderate in severity and of short duration (median duration, 2 to 3 days for nausea, vomiting, and diarrhea in the semaglutide group)”
“Permanent discontinuations because of gastrointestinal disorders were very low. Furthermore, semaglutide did not appear to affect growth or pubertal development during the trial period”
My take: As in adults, treatment with semaglutide results in weight loss.
AGA released new evidence-based guidelines strongly recommending patients with obesity use recently approved medications paired with lifestyle changes.
The following medications, paired with healthy eating and regular physical activity, are first-line medical options and result in moderate weight loss as noted as a percentage of body weight (reported as the difference compared to percent weight loss observed in the placebo group).
Semaglutide (Wegovy®), weight loss percentage: 10.8%
Phentermine-topiramate ER (Qsymia®), weight loss percentage: 8.5%
Liraglutide (Saxenda®), weight loss percentage: 4.8%
Naltrexone-Bupropion ER (Contrave®), weight loss percentage: 3.0%
