The Golden Age of Medicine; GLP-1 drugs are “having a moment…”; impressive data from trials; and multimodal approaches to align with surgical therapies.

AT A GLANCE

• One-third of U.S. adults say they would indefinitely pay whatever they can afford to get the drugs, in reference to Ozempic and other weight-loss medications.
• ‘Weight loss drugs are having a moment…’ in relation to the recent splurge of data presented at the American Diabetes Association.
• The UK’s National Health Service has reviewed Eli Lilly’s drug tirzetapide, or Mounjaro and ‘…not recommended, within its marketing authorization, for treating type 2 diabetes alongside diet and exercise in adults.’
• What is the role of surgical and endoscopic approaches to treat obesity?
• A huge slew of articles, from the ADA and ASMBS meetings in the past week.

NEWS

• STAT and Harris Poll report on a survey of just over 2,000 adults in American that ‘…one-third say they would indefinitely pay whatever they can afford to get the drugs…’ in reference to Ozempic and other weight-loss medications, as per Ed Silverman and Elain Chen. One quarter would spend up to $250 per month, and 17% as much as $500 each month. Despite this consumer drive, ‘…an overwhelming majority – 84% – believe insurance companies should cover the injectable medicines.’ This only adds further fuel for this class of medications ‘…to become some of the biggest-selling medicines in the history of the pharmaceutical industry…’ with upwardly mobile ‘…parents with kids under age 19, millennials, and members of Gen X were among those most interested in taking the medicines.’ In addition, ‘…51% cited their self-image as a reason to…’ take the drugs, though ‘…three-quarters of those polled said they believe the weight-loss medicines are a quick fix and do not have long-term benefits…’ indicating skepticism of long-term value. Gail Boudreaux, CEO at Elevance Health, stated ‘…We’re making decisions based on the health outcomes and longitudinal data of what we see.’ which is in alignment with the stance from other major health plans and at-risk entities.
• Pfizer, the American multinational pharmaceutical and biotechnology corporation with roots from German immigrants in 1849, announced it’s halting of work on oral GLP-1 agonist lotiglipron, based data from phase 1 trials that revealed elevated liver enzymes, with possibility of liver damage. Pfizer still has another molecule in the race, namely danuglipron, which is still under development. Notably, danuglipron is a twice-daily oral pill, which could affect its uptake compared to the once-daily oral forms from Eli Lilly and Novo Nordisk that are in development right now.
• Robert Gabbay, the ADA’s chief science and medical officer, referred to published recommendations for ‘…all adults with type 2 diabetes or prediabetes should be screened for nonalcoholic fatty liver disease…’ with a focus upon GLP-1 drugs as an option for patients. Dr. Gabbay continues ‘…In many ways, type 2 diabetes and obesity are becoming the leading causes of liver disease, and that’s not really on the radar of people thinking about diabetes.’ NAFLD, or non-alcoholic fatty liver disease affects one in four American adults, and is a precursor to liver failure and liver cancer, that may necessitate liver transplant, and is treatable ‘…through lifestyle changes and [consider] prescribing a GLP-1 drug.’ Newer GLP-1 medications with an additional glucagon effect may be ideal for treating liver disease in patients with obesity and/or diabetes too.
• Alice Park, from TIME, begins ‘…Weight loss drugs are having a moment…’ in relation to the recent splurge of data presented at the American Diabetes Association meeting last week from Eli Lilly in terms of tirzetapide, orforglipron and retatrutide. A nice summary of the data presented, with commentary that ‘…obesity treatment can, and should, become more personalized, and doctors should get better at matching patients to the medications that will work best for them…’ with ‘…options that inch closer to matching those achieved by interventions such as surgery…’ to ‘…ultimately slow the growing epidemic of obesity.’
• The Wall Street Journal contemplates a future where ‘…drugs would further transform treatment of obesity, turning it into a condition like hypertension or high cholesterol that can be controlled by prescriptions after years of often ineffective reliance on diet and exercise.’ Dr. Louis Aronne, an obesity-treatment specialist at Weill Cornell Medicine in New York, rightly states ‘…People have different causes for their obesity…’ and continues ‘…Each of these may benefit from a different medical treatment which specifically targets the problem.’ My past colleague from Imperial College London, Dr. Carel Le Roux, who has been working in the field of obesity medicine for over two decades, is quoted ‘…This is way beyond my wildest dreams…’ and continues ‘…To see something like this in my lifetime is pretty impressive.’ Congratulations my friend – a notable and huge achievement to you, your colleagues, and all our patients who will directly benefit!
• The UK agency enlisted to provide recommendations for use of therapies within the UK’s National Health Service, The National Institute for Health and Care Excellence, or NICE, has reviewed Eli Lilly’s drug tirzetapide, or Mounjaro and ‘…not recommended, within its marketing authorization, for treating type 2 diabetes alongside diet and exercise in adults…’  The main focus of the decision was cited on a lack of evidence on clinical efficacy and cost-effectiveness, especially in the long-term, and in comparison to currently available treatments. Helen Knight, director of medicines evaluation, at NICE was quoted ‘…Our committee can see the promise in tirzepatide but it requires more evidence to be able to evaluate both its clinical and cost effectiveness…’ and to ‘…working with the company to ensure our committee receives the evidence it has requested…’ to ‘…fully understand the benefits and the value of this new treatment option.’ Of note, NICE has previously recommended Ozempic for patients with type 2 diabetes, and Wegovy for patients with obesity, though only available through specialized obesity providers, and for a maximum period of two years.
• The American Society of Anesthesiologists issued guidance this week on the use of GLP-1 medications prior to invasive procedures, in reference to adverse gastrointestinal effects such as nausea, vomiting and delayed gastric emptying, that may ‘…increase the risk of regurgitation and pulmonary aspiration of gastric contents during general anesthesia and deep sedation.’ Despite limited data, the recommendation is to hold oral GLP-1 medication on the day of surgery, and a week prior for those on weekly injectable therapies.

OPINION

• David Wallace-Wells writes at the New York Times on ‘…the horizon of new possibility seems almost blindingly bright…’ in reference to his self-titled ‘Golden Age for Medicine’. The article reviews the work of Nobel Laureate Jennifer Doudna on ‘…Crispr, the gene-editing Swiss Army knife that has been called a word processor…’ and goes on to discuss the rapid development of Covid vacccines, and the onward ‘…countless potential applications of mRNA tools for other diseases…’ considered ‘…a new frontier for immunotherapy.’ Included here are a take on anti-obesity medications, notably with ‘…Ozempic and Wegovy have already changed the landscape for obesity in America…’ The author asks ‘…we are riding an exponential curve upward toward radical life extension and the total elimination of cancer.’ My take is a Moore’s Law approach to the revolution in medical science, with application through digital and artificial intelligence technologies, to automate care processes and augment health care providers, enabling the delivery of whole-person care outcomes, at individual and population levels, in a cost-effective and highly accessible manner, for all who need and want it.
• A question that has been somewhat forgotten in the race to lose weight through GLP-1, GIP, and glucagon medication therapies, is the role of surgical and endoscopic approaches to treat obesity. Lizzy Lawrence in STAT News reports on ‘…a rich opportunity to capitalize on new interest in the condition and an existential threat to their market share.’ Dr. Lee Kaplan, formerly Director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, states a ‘…device that may give you 15% weight loss… is now going to look weak in comparison to drugs.’ Allurion’s CEO Shantanu Gaur, whose company makes a swallowable gastric balloon, and just engaged in partnership with Medtronic, a device maker, considers the new wave of medications have ‘…created an influx of patients who are now thinking about weight loss as more of a medical issue…’ akin to an all boats rise approach to care. John Morton, a bariatric surgeon at Yale University ‘…envisions a world where the two therapies work together, helping patients stave off weight pre-operation or maintain weight loss post-op…’ in relation to surgery and medications. Morton’s approach is to engage with ‘…drugs before surgery, lock in the results with the surgery, and maintain the results with another drug…’ consistent with how we treat cancer today, with pre-surgical chemotherapy, then surgical excision, and the potential for additional chemotherapy later, to prevent or delay disease recurrence. Right now, the ‘…hard question is, does the device add anything to the drug over the long-term…’ as per Dr. Kaplan, in reference to balloon and endoscopic devices. I think we are a far away from drugs replacing gastric sleeve and gastric bypass surgeries, with a greater drive toward multi-modal therapies, along a multi-year care journey.
• Whose fault is obesity? is the question posed to the reader by Tamar Haspel, writing in The Washington Post this week. In relation to 73% of Americans being overweight or obese, her approach is when ‘…three-quarters of humans can’t navigate the system successfully, the problem is the system, not the humans.’ The litany of culprits are the food industry for developing ‘…product after product that was deliberately designed to be overeaten…’, restaurants in the ‘…fight for stomach share, too, and one of the weapons they have is portion size…’, diet purveyors for whom ‘…weight loss is more about what you eat than how much you eat…’, nutrition scientists who have ‘…fueled some important misconceptions about diet and health…’, the media who ‘…play a big role in dietary confusion…’, and finally, us, the eaters, with ‘…collective susceptibility to dumb diets and quick fixes.’
• In a follow up to Yasmin Tayag’s write up in The Atlantic earlier this year to Ozempic being old news, Daniel Engber recognizes ‘…a parade of better treatments for obesity…’ based upon recent presentations and publications at the ADA meeting on new oral and injectable therapies, and the post-Ozempic era.
• In a Daily Briefing, the Advisory Board Company, a consulting firm focusing on health care organizations and educational institutions, now owned by Optum, focuses upon why weight-loss drugs don’t work for everyone. First, semaglutide and its variants may not be effective for everyone – in the published clinical trial for semaglutide, 13.6% of subjects lost less than 5% of their total body weight; second, gastrointestinal side effects led to 10-15% of study subjects unable to complete the trial. Important data for patients and their providers to be aware of – the highly touted game-changer GLP-1 class of medications are not effective for everyone.

DATA

• An elegant history of gut hormone co-agonists ‘…for the treatment of diabetes and obesity…’ and how they may be ‘…considered a transformative breakthrough in the field…’ is reviewed by Dr. Matthias H. Tschop from Technical University of Munich. Dr. Tschop is considered a global scientific leader in the molecular underpinnings of diabetes and obesity, describing the development of molecules in 2009, as forerunners of current GLP-1 medications. The article ‘…summarize the discovery, development, mechanisms of action and clinical efficacy of the different types of gut hormone co-agonists, and discuss potential challenges, limitations and future developments.’
• Dr. Sean Wharton and colleagues, report in The New England Journal of Medicine, on the ‘…nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.’ Some 272 participants with a mean BMI of almost 38, and without diabetes, were provided ‘…one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks.’ Across the orforglipron groups, there was a mean weight loss of between 9.4% to 14.7%, with ‘…weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron.’ As per other GLP-1 agonist medications, there was a ‘…discontinuation of orforglipron in 10 to 17% of participants across dose cohorts…’ due mostly to gastrointestinal side effects that were mild to moderate. The continued evaluation and potential application of oral, by mouth, medications for patients with obesity is certainly worth watching.
• Elaine Chen at STAT News covers the publication from Dr. Wharton in reference to ‘…heating up the growing competition among drugmakers to develop an effective oral obesity therapy.’ The oral forms of currently available injectable GLP-1 medications ‘…could be more accessible and more attractive to many patients for their convenience.’ Randy Seeley, director of the Michigan Nutrition Obesity Research Center, is quoted ‘…We need more tools in the tool box, and having non-injectables in the toolbox would be really helpful.’
• In follow up to the ADA meeting, two studies published in The Lancet this week on oral semaglutide, OASIS 1 for ‘…for the treatment of overweight or obesity in adults without type 2 diabetes…’ and PIONEER PLUS on ‘…a new formulation of oral semaglutide at higher investigational doses… in adults with inadequately controlled type 2 diabetes.’
• OASIS 1 recruited 709 participants ‘…at 50 outpatient clinics in nine countries across Asia, Europe, and North America…’ and assigned to oral semaglutide 50 mg or placebo, with 15·1% of total body weight loss in those on oral semaglutide, compared to 2.4% in the placebo group. One-third of subjects in the treatment group achieved greater than 20% bodyweight reduction, though with a reported rate of gastrointestinal adverse events in 80% of participants, albeit at mild to moderate levels. This is impressive stuff – my key thought is whether these results will be repeated in the real world, with issues upon medication adherence, and effectiveness in terms of required fasting before and after pill ingestion.
• PIONEER PLUS recruited 1606 subjects ‘…at 177 sites in 14 countries…’  with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0−10·5%, and a BMI of 25·0 kg/m² or greater, on oral semaglutide 14 mg, 25 mg, or 50 mg, over a period of 68 weeks. There was a 2% lowering of HbA1c levels in the highest 50mg dose group, down to 1.8% in the 25mg dose group, and 1.5% in the currently available 14mg group – branded as Rybelsus. Gastrointestinal adverse events were reported in almost 4 out of 5 subjects, with more frequency and severity in the higher dosing groups. Despite this, a 2% reduction in HbA1c levels is highly significant for the care of patients with diabetes, to improve their current and forward lives.
• Dani Blum, reporting from the American Diabetes Association Scientific Sessions conference in San Diego on behalf of The New York Times, quotes Dr. Robert Gabbay, the chief scientific and medical officer of the American Diabetes Association, ‘…I suspect there are a lot of people that are not using these treatments because it requires an injection…’ in reference to the OASIS 1 and PIONEER PLUS studies. An important reference to the study data is also made in terms of race, gender, and age, that the ‘…majority of study participants were white and female… which means the results may not apply to the broader population of people with obesity.’ Ms. Blum quotes Dr. Scott Hagan, at the University of Washington on the ‘…lower barrier to entry to swallowing a pill, for some people, than injecting a drug.’
• The Wall Street Journal too covers the recent publication on oral forms of GLP-1 medications, titled as ‘Pill for Obesity Has Wall Street Salivating’ from David Wainer. He writes on a ‘…pill could change things by making it easier for doctors to prescribe the medications and for patients to adhere to them…’ and continues that a ‘… simpler manufacturing process could also eventually bring the price tag down…’ noting ‘… that won’t happen quickly.’ The results on oral forms of semaglutide, at higher doses for those with diabetes, and the Eli Lilly experimental pill, orforglipron, are comparable to those of the once-weekly injection therapies. Disha Narang, director of Obesity Medicine at Northwestern Medicine in Chicago was reported to say ‘…an oral agent that is just as effective would be a big deal for some patients who, for whatever reason, are more hesitant to use injectables.’ As I have mentioned previously, I am concerned on the medication adherence issues of a once-daily pill, over a once-weekly injection.
  • The article also reports on stock price of ‘…Eli Lilly and Novo have each more than doubled in the past three years…’ to become ‘…the top two largest pure-play pharmaceutical companies in the world…’ driven by ‘…a bet that annual revenues from these drugs could eventually exceed $100 billion.’ From a manufacturing standpoint too, ‘…Small molecule pills like orforglipron could be as much as 70% cheaper than injectables while still generating similar profits…’ as per Will Sevush, a healthcare strategist at Jefferies.
• Retatrutide, or LY3437943 as per Eli Lilly, a triple hormone agonist of the GIP, GLP-1, and glucagon receptors, also dubbed Ozempic 3.0, was tested by Dr. Jastreboff and colleagues, in 388 adults with a BMI of 30 or greater than 27. At 48 weeks, a remarkable 24% total body weight loss was achieved in the highest 12mg dosing group, compared with 2% in the placebo group.
• Elain Chen at STAT News referred to the retatrutide trial report as ‘…the greatest amount seen yet with an obesity drug.’ The presentation in San Diego last Monday at the ADA meeting was ‘…a grand finale of sorts…’ with appropriate caution too, as per the high rate of gastrointestinal side effects, one case of acute pancreatitis in a patient on the highest does during the trial, and instances of arrhythmia, or irregular heartbeats. I do appreciate the quote from Steven Heymsfield, at Pennington Biomedical Research Center in Baton Rouge, to focus on ‘…quality of weight loss now that the weight loss is so large.’
• A further publication on retatrutide was published the The Lancet, reported on 281 participants across 42 research and health-care centres in the USA, with type 2 diabetes, glycated hemoglobin (HbA1c) of 7·0–10·5%, and BMI of 25–50. There was a 2.0% reduction in HbA1c and an almost 17% reduction in body weight for the highest dosing group, compared to no change in HbA1c and 3% body weight loss in the placebo, or control, group.
• At the American Society for Bariatric and Metabolic Surgery, Dr. Aminian and colleagues at the Cleveland Clinic reported on over 13,000 patients with obstructive sleep apnea, or OSA, a condition that affects over a billion people worldwide, and is strongly linked to obesity and cardiovascular disease. Almost 1,000 if their patients underwent metabolic surgery, who over a ten year period had a 37% lower risk of major adverse cardiovascular events, or MACE [composite of coronary artery events, cerebrovascular events, heart failure, atrial fibrillation, and mortality], than those patients with OSA who did not undergo surgery. Dr. Aminian states ‘…No other therapy has been shown to reduce the risk of dying or developing heart attack or heart failure in patients with obesity and obstructive sleep apnea…’ with added gusto that ‘…Bariatric surgery is a very powerful tool that can help patients with sleep apnea live longer and healthier lives.’ In this context, it is important to remind ourselves that less than 1% of patients who meet eligibility requirements are able to undergo bariatric or metabolic surgery in any given year, from a historical total number of around 26 million Americans, right up to over 100 million Americans as per guidelines published last year.
• Away from all of this week’s big news at the ADA meeting on GLP-1 and akin therapies, the Annals of Internal Medicine published an article from researchers and clinicians at the University of Illinois Chicago, on intermittent fasting, or time restricted eating [TRE], compared to calorie restriction [CR], and usual care, in 90 adults with obesity. First off, one-third of subjects were Black, and almost half were Hispanic, which is a welcome change in racial diversity of clinical trials, in contrast to the usual study population of Caucasians. There were no differences in weight loss between the TRE and CR groups, at around 10 pounds over a 12-month period, and despite not being told count calories, the TRE group ate 400 fewer calories per day. All in all, both calorie counting and intermittent fasting are effective therapies for low to moderate weight loss over a 12 month period, and so we may not need to put one approach against the other.

Kind regards, Raj