Regular readers may recall previous posts on the novel anti-obesity compound belanorib, a MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic obesity.
Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a risk mitigation strategy.
As announced by the company in a press release earlier this week,
“Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.”
The press release also describes the new compound ZGN-1061 as a,
“…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class. Like other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source. ZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.”
According to the press release,
“The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.”
Screening of patients for a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway.
Disclaimer: I have served as a consultant to Zafgen.
Regular readers will be well aware of the Edmonton Obesity Staging System (EOSS), which classifies individuals living with obesity according to the presence and severity of medical, mental and functional complications on a 5-point ordinal scale.
We have previously shown that EOSS provides a better assessment of mortality risk than BMI, waist circumference, or the presence of metabolic syndrome.
Now, a paper by Sonja Chiappetta and colleagues from Offenbach, Germany, published in SOARD, shows that EOSS strongly predicts early surgical complications and mortality in patients undergoing bariatric surgery.
The authors analysed data from 534 patients, collected prospectively, for patients undergoing laparoscopic sleeve gastrectomy (LSG), laparoscopic Roux-en-Y gastric bypass (LRYGB), or laparoscopic omega-loop gastric bypass (LOLGB).
As typical for a bariatric surgery population, the mean BMI was around 50 kg/m2.
While the total postoperative complication rate for the entire patient sample was 9%, the complications rates were 0% for patients with EOSS Stage 0 (5% of patients), 1.6% for Stage 1 ( (12%), 8% for Stage 2 (71%), 22% for Stage 3 (13%) and 100% for Stage 4 (0.2%).
There was no significant difference in BMI levels across EOSS stages and not consistent association of EOSS stage with age.
From these findings the authors conclude that,
“Patients with EOSS≥3 have a higher risk of postoperative complications. Our data confirm that the EOSS is useful as a scoring system for the selection of obese patients before surgery and suggest that it may also be useful for presurgical stratification and risk assessment in clinical practice. Patients should be recommended for obesity surgery when their EOSS stage is 2 to prevent impairments associated with metabolic disease and to reduce the risk of postoperative complications.”
That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation.
Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation.
For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum.
During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight.
Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study.
Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability.
Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults.
Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption.
Next in my miniseries on the pros and cons of calling obesity a ‘disease’, I turn to the issue of medical education.
From the first day in medical school, I learnt about diseases – their signs and symptoms, their definitions and classifications, their biochemistry and physiology, their prognosis and treatments.
Any medical graduate will happily recite the role and function of ADH, ATP, ANP, TSH, ACTH, AST, ALT, MCV and a host of other combinations of alphabet soup related to even the most obscure physiology and function – everything, except the alphabet soup related to ingestive behaviour, energy regulation, and caloric expenditure.
Most medical students and doctors will never have heard of POMC, α-MSH, PYY, AgRP, CART, MC4R, or any of the well studied and long-known key molecules involved in appetite regulation. Many will have at best a vague understanding of RMR, TEE, TEF, or NEAT.
The point is, that even today, we are graduating medical doctors, who have at best a layman’s understanding of the complex biology of appetite and energy regulation, let alone a solid grasp of the clinical management of obesity.
Imagine a medical doctor, who has never heard of β-cells or insulin or glucagon or GLUT4-transporters trying to manage a patient with diabetes.
Or a medical doctor, who has never heard of renin or aldosterone or angiotensinogen or angiotensin 2 trying to manage your blood pressure.
How about a medical doctor, who has never heard of T3 or T4 or TSH managing your thyroid disease?
Elevating obesity to a ‘disease’ means that medical schools will no longer have an excuse to not teach students about the complex sociopsychobiology of obesity, its complications, prognosis, and treatments.
As I mentioned in a previous post, suddenly, managing obesity has become their job.
No longer will it be acceptable for doctors to simply tell their patients to control their weight, with no stake in if and how they actually did it.
Thus, if there is just one thing that calling obesity a ‘disease’ can change, it is expecting all health professionals to have as much understanding of obesity as they are currently expected to have of diabetes, heart disease, lung disease, and any other common disease they are likely to encounter in their medical practice.
Apparently, simply treating obesity as a ‘lifestyle’ problem or ‘risk factor’ was not enough – hopefully, recognising obesity as a ‘disease’ in its own right, will change the attention given to this issue in medical training across all disciplines.
Next, in this miniseries on arguments for and against calling obesity a disease, I turn to the issue of stigma.
One of the biggest arguments against calling obesity, is the fear that doing so can increase stigma against people living with obesity.
This is nonsense, because I do not think it is at all possible for anything to make stigma and the discrimination of people living with obesity worse than it already is.
If anything, calling obesity a disease (defined as excess or abnormal body fat that impairs your health), could well serve to reduce that stigma by changing the narrative around obesity.
The current narrative sees obesity largely as a matter of personal choice involving poor will power to control your diet and unwillingness to engage in even a modest amount of regular physical activity.
In contrast, the term ‘disease’ conjures up the notion of complex biology including genetics, epigenetics, neurohormonal dysregulation, environmental toxins, mental health issues and other factors including social determinants of health, that many will accept are beyond the simple control of the individual.
This is not to say that other diseases do not carry stigma. This has and remains the case for diseases ranging from HIV/AIDS to depression – but, the stigma surrounding these conditions has been vastly reduced by changing the narrative of these illnesses.
Today, we are more likely to think of depression (and other mental illnesses) as a problem related to “chemicals in the brain”, than something that people can pull out of with sheer motivation and will power.
Perhaps changing the public narrative around obesity, from simply a matter of motivation and will power, to one that invokes the complex sociopsychobiology that really underlies this disorder, will, over time, also help reduce the stigma of obesity.
Once we see obesity as something that can affect anyone (it can), for which we have no easy solutions (we don’t), and which often requires medical or surgical treatment (it does) best administered by trained and regulated health professionals (like for other diseases), we can perhaps start destigmatizing this condition and change the climate of shame and blame that people with this disease face everyday.