Structural racism and inequity in global diabetes care; obesity & cancer risk; lawsuits against compounded GLP-1s; and, the end of BMI???

• Additional stories of people who have been taking Ozempic, and the ‘…surprising and potentially game-changing way to treat addictions, including alcohol-use disorder and smoking…’ are surfacing more routinely, with the potential of a ‘…a big public-health impact.’ Michael McCluskey, a 59-year-old from Nova Scotia, Canada ‘…would typically have four-to-five drinks a day but after starting Ozempic, he only drinks a handful of times a year…’ with the comment that ‘…It just sort of clicked off.’ GLP-1 is well known in academic circles to reduce ‘…the response of the brain’s reward system to dopamine…’ with ‘…reductions in binge-eating-like behaviors in rodents…’ and potential to treat ‘…a variety of addictions: cocaine, opioids, nicotine, alcohol…’ as per neuroscientists Scott Kanoski at the University of Southern California, and Heath Schmidt, at the University of Pennsylvania. Research studies are now underway in human subjects with alcohol-use disorder, at the University of North Carolina, and University of Copenhagen. Dr. Brian P. Lee, a liver-transplant physician at the University of Southern California Keck School of Medicine states, ‘…If you’re able to treat both obesity and alcohol use at the same time, you could just imagine the effects from a public health standpoint.’
• Linda Searing at The Washington Post stands out with the headline ‘Obesity increases risk of 13 types of cancer.’ These include cancers of the breast, brain, colon and rectum, prostate, uterus, stomach, kidneys, liver, ovaries, pancreas and thyroid, and multiple myeloma and meningioma. In the article, a reference is made to the American Cancer Society in that ‘…excess weight is thought to be responsible for about 11 percent of cancers in women, about 5 percent of cancers in men and about 7 percent of all cancer deaths…’ and ‘…cancer risk increases with the more weight a person has and the longer a person is overweight.’ Does this not sound like lung cancer and smoking – the more one smokes, and the longer period of time one smokes for, the greater the risk? The mechanism of this effect are ascribed of long-lasting inflammation, and hormones estrogen, insulin and insulin-like growth factor, all of which are more prevalent with obesity. And to align with my earlier comment on smoking, the article notes from the Centers for Disease Control ‘…in addition to not smoking – keeping a healthy weight is one of the most important steps people can take to lower their risk for cancer.’
• The New York Times publishes a guest essay from Drs. Anupam B. Jena and Christopher M. Worsham, two public health and economic policy researchers at Harvard Medical School, on ‘The Science of What We Eat Is Failing Us.’ In reference to the recent advice from the World Health Organization for people to avoid using artificial sweeteners for weight loss, which was low level evidence at best, Jena and Worsham comment ‘…The state of nutrition research is poor.’ They cite the lack of large-scale randomized trials, and even when the data points to a significant relationship, that correlation is not akin to causation, or put another way – we need to establish whether it is cause or effect. The main gist of this essay is to advocate for nutrition researchers to adopt natural experiments, related to policy changes, genetics, or other environmental factors, referred to by the authors as accidental randomization.
• Drs. Stoops and Dar, write in The New England Journal of Medicine, from the University of Massachusetts Chan Medical School, to discuss the oversimplified treatment approach to obesity ‘…focused solely on calorie-restricted dieting and increased physical activity…’ supplanted by placing ‘…blame on individual patients.’ The higher obesity rates among some 80 million people in the U.S. covered by Medicaid, the ‘…public health insurance program for those with low income, which serves as a safety net for more than one in five Americans…’ are discussed, together with variations in coverage for lifestyle and medication therapies. The authors make a call ‘…to include multimodal approaches involving comprehensive lifestyle intervention programs and FDA-approved adjunct pharmacotherapies…’ in addition to the extensive coverage of bariatric surgery across 49 of 50 U.S. states.
• The Obesity Action Coalition notes ‘…Connecticut Governor Ned Lamont approved a bill that expands Medicaid and Husky B coverage for prescription weight-loss drugs, nutrition counseling and bariatric surgery…’ with OAC members sending over 2,000 letters to decision makers. Dr. Neil Floch, a bariatric surgeon was quoted ‘…I applaud my state for prioritizing access to care for my patients.’
• The Weekly Gist, a newsletter providing commentary and insights in healthcare, writes on ‘…How GLP-1 agonist drugs could change healthcare demand.’ The focus is upon a math calculation on Wegovy’s $1,300 list price being offered to 70 million U.S. adults with obesity, that would translate to around $1.2 Trillion of annual costs. The authors refer to $0.2Tr of annual obesity-related expenditures, which is highly conservative, in reference to the 2018 Milken Report that calculated $480B of direct medical spend associated with obesity, and an additional $1.2Tr of lost economic productivity, making almost $1.7Tr in total annual expense to the U.S. economy. Whilst the uptake in terms of access, cost, and impact of anti-obesity medications are unknown, it is highly probable that ‘…Incidence of chronic diseases like diabetes and cardiovascular disease could also drop, potentially raising life expectancy…’ and with it, a fall in rate of obesity-related cancers too. I am unsure on the predicted drop in bariatric surgeries – the greater awareness of obesity as a chronic disease, with biological roots, will, in my opinion, lead to a comprehensive, multimodal approach to care, incorporating nutrition, behavioral and exercise therapies for all, and additional pharmacotherapy or bariatric surgery for those who need and desire it.  

DATA

• Fast on the heels of last week’s American Medical Association statement to move away from BMI as a measure of obesity, Dr. Aayush Visaria from the Rutgers Robert Wood Johnson Medical School reports that ‘…BMI vastly underestimates true obesity…’ and ‘…We’re at the start of the end of BMI.’ Visaria presented data at the The Endocrine Society Annual Meeting in Chicago, on almost 10,000 adults who underwent a DEXA, or bone density scan, and ‘…found that DEXA rated 74% of participants as having obesity based on body fat compared with 36% based on BMI.’ Further, the rate of missed obesity diagnoses ‘…was highest among all women, with a 59% prevalence of obesity by DEXA among women with a normal-range BMI…’ and in people of Hispanic or Asian ethnicity, there was ‘…a 49% rate of obesity by DEXA among those with normal-range BMIs.’ Probably most important in a real-world sense, adding ‘…waist circumference to BMI… cut the percentage of adults missed as having obesity by BMI alone nearly in half…’ and should be measured in conjunction with BMI.
• My past colleague at Imperial College London, Dr. Carel Le Roux, and world renown clinician scientist in diabetes and obesity, presented data on survodutide, a glucagon/GLP-1 receptor dual agonist developed between Boehringer Ingelheim and Zealand Pharma, at the recent ADA meeting in San Diego. The trial is a dose-finding study, comparing 0.6mg through to 4.8mg shots of subcutaneous survodutide in 387 people with overweight or obesity without type 2 diabetes, with almost 15% total weight loss in those assigned to the highest 4.8mg dosing group, over a 46 week period; and 18.7% total weight loss in those who reached and stayed on the 4.6mg dose. Dr. Le Roux was quoted ‘…Given the prevalence of obesity and its many disease-related complications, there is a dire need for treatments that can help treat the disease of obesity effectively…’ though, the data did report treatment discontinuation in almost a quarter, or 25%, of participants, mainly due to gastrointestinal adverse events. Of interest here is the addition of glucagon to the GLP-1 mode of action; glucagon works to increase energy expenditure through liver metabolism, which is in addition to the effect of reduced appetite through GLP-1 activation.
• Also presented at ADA this week, was data on SURMOUNT-2, of tirzepatide in 938 participants with type 2 diabetes who were overweight or obese. After 72 weeks of treatment, an average of 15% total weight loss was achieved, with a reduction in HbA1c, or glycated hemoglobin – a measure of diabetic control, from 8% to 5.9%. Even more impressive was that almost half of the subjects moved into the range of a normal HbA1c, below 5.7%, and would be considered in remission from diabetes. Study lead author, Dr. W. Timothy Garvey, MD, MACE, MABOM, of the University of Alabama at Birmingham, called out ‘…a weight-centric approach to treating type 2 diabetes’ in reference to the ‘…weight loss and glycemic control results, especially as weight loss interventions are typically less effective in patients in diabetes.’
• A combination of ‘…GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide…’ or CagriSema, in 92 patients with type 2 diabetes and a BMI of greater than 27, led to a 2.2% percentage decrease in HbA1c levels, and over 15% total weight loss, over a 32 week period, published in The Lancet this week. Amylin, a relative newcomer to the main stage of anti-obesity medication targets, is a hormone secreted by the pancreas that slows gastric emptying and the feeling of fullness, through activation of neurons in the brain.
• Eli Lilly just reported results on their oral GLP-1 drug, orforglipron, in 383 subjects with type 2 diabetes and a mean BMI of 35, with a mean reduction in HbA1c of 2.2% and 10kg bodyweight reduction. A key differentiator to the currently available oral form of semaglutide, Rybelsus, is that orforglipron does not need to be taken in a fasted state, and may be taken with or without food, with the intent that this would increase its acceptability, adherence, and efficacy. However, the higher rates of adverse events, mostly gastrointestinal, remain as per other medications in this class.

Kind regards, Raj