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.
Melanocyte-stimulating hormone (a-MSH), which is produced from the hormone precursor proopiomelanocortin (POMC) and acts on the hypothalamic melanocortin-4 receptor, plays a key role in the regulation of satiety and energy expenditure.
In very rare instances, mutations of the gene coding for POMC can cause severe early onset obesity characterised by increased appetite. Due to other effects of POMC deficiency, patients will present with pale skin, red hair and clinical signs of hypocortisolism.
Now, a paper by Peter Kühnen and colleagues published in the New England Journal of Medicine, shows that treating patients with the melanocortin-4 receptor agonist, setmelanotide, can result in significant reduction in appetite and body weight.
The open-label study was performed in two adult patients with POMC deficiency, in cooperation with Rhythm Pharmaceuticals, which provided the study medication and regulatory support.
Both patients weighed around 150 Kg with marked hyperphagia and both responded to treatment with a substantial reduction in appetite and dramatic weight loss of over 20 Kg over 12-13 weeks.
After a brief interruption, one patient was again treated for 42 weeks, ultimately losing 51 kg (32.9% of her initial body weight).
As the authors note,
“Setmelanotide appeared to completely reverse hyperphagia, leading to impressive weight loss and normalization of insulin resistance. More important, both patients reported a dramatic improvement in their quality of life after the initiation of setmelanotide therapy. Moreover, the substantial and ongoing reduction in body weight was similar to the changes observed after leptin administration in patients with leptin deficiency.”
Over all the treatment was well tolerated with no major adverse effects.
While these observations were made in very rare patients with documented POMC deficiency, these findings may have broader implications for individuals with more common “garden-variety” obesity.
“Both patients described here had very high leptin levels before treatment, suggesting leptin resistance. In patients with proopiomelanocortin deficiency, the leptin signal is probably not properly transduced into anorexigenic responses, given the lack of melanocyte-stimulating hormone. Setmelanotide substitutes for melanocyte-stimulating hormone and binds at its receptor, thus overcoming leptin resistance. On the basis of the observation that obese patients without known genetic abnormalities have severe leptin resistance and regain weight owing to a post-dieting increase in appetite, we speculate that setmelanotide may also be effective in nongenetic forms of obesity.”
Appropriate studies in patients with non-POMC deficient obesity are currently underway.
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.”
Thus, following weight loss, not only does the body need fewer calories, doing the same amount of physical work uses fewer calories than before (the joke is that, if you ran 5K a day to lose weight, you have to run 10K a day to keep it off).
Now, a study by Maria Fernström and colleagues, published in Obesity Surgery, shows increased mitochondrial efficiency following bariatric surgery.
The researchers performed skeletal muscle biopsies in 11 women before and at 6 months after gastric bypass surgery.
Measurements in isolated mitochondria showed a marked increase in coupled respiration (state 3) and overall mitochondrial capacity (P/O ratio) with a non-significant increase in uncoupled (state 4) respiration.
Thus, at 6 months following gastric bypass surgery, both the mitochondrial capacity for coupled, i.e., ATP-generating, respiration increased as well as the P/O ratio improved.
As the authors note, not only would this increased “fuel efficiency” in part explain the decreased basal metabolism often associated with weight loss but also the propensity for weight regain that often follows weight-loss interventions.
Obviously, due to lack of a control group, this study does not demonstrate that these changes are in any way specific to weight-loss following bariatric surgery.
Also, given that the nadir of weight loss is generally not achieved until about 18 months following surgery, the changes observed in this study may not represent the maximum increase in mitochondrial efficiency to be achieved with further weight loss.
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.
A popular narrative by proponents of low-glycemic index foods is the notion that high-glycemic index foods lead to a surge in plasma glucose, which in turn stimulates a spike in insulin levels, resulting in a rapid drop in blood glucose levels and an increase in appetite (“crash and crave”).
While this narrative is both biologically plausible and has been popularised by countless low-GI diets and products, the actual science of whether this story really holds true is less robust that you may think.
Now, a study by Bernd Schultes and colleagues, published in Appetite, seriously challenges this narrative.
The study was specifically designed to test the hypothesis that inducing glycemic fluctuations by intravenous glucose infusion is associated with concurrent changes in hunger, appetite, and satiety.
Using a single blind, counter-balanced crossover study in 15 healthy young men, participants were either given an i.v. infusion of 500 ml of a solution containing 50 g glucose or 0.9% saline, respectively, over a 1-h period.
On each occasion, the infusions were performed one hour after a light breakfast (284 kcal).
I.v. glucose markedly increased glucose and insulin concentrations (peak glucose level: 9.7 vs. 5.3 mmol/l in the control group); peak insulin level: 370 vs. 109) followed by a sharp decline in glycaemia to a nadir of 3.0 in the glucose study vs. 3.9 mmol/l at the corresponding time in the control condition.
Despite this wide glycemic fluctuation in the glucose infusion condition, the subjective feelings of hunger, appetite satiety, and fullness did not differ from the control condition throughout the experiment.
Clearly, these findings speak against the conventional narrative that fluctuations in glycemia and insulinemia represent major signals in the short-term regulation of hunger and satiety.
Or, as the authors put it,
Our findings might also challenge the popular concept of low glycemic index diets to lose body weight. Advocates of this dietary approach often argue that large glycemic (and concurrent insulinemic) fluctuations induced by the intake of high glycemic index foods can trigger feelings of hunger and, thus, on the long run favor weight gain. Our results argue against this notion since the sharp drop in circulating glucose after the end of the glucose infusion remained without effect on hunger ratings, at least within the time period covered by our experiment.
As they further note, these findings may explain why,
“…several clinical dietary intervention trials have failed to show an advantage of low glycemic index dietary approaches for weight loss in overweight/obese subjects in comparison with other dietary approaches.”
The lesson here, I guess is that, just because there is a seemingly compelling narrative to support an idea, it does not mean that that’s how biology in real life actually works.
Over the past weeks, I have presented a miniseries on the pros and cons of calling obesity a chronic disease.
Clearly, I am convinced that the arguments in favour, carry far greater chances of effectively preventing and controlling obesity (defined as abnormal or excess body fat that impairs health) than continuing to describe obesity merely as a matter of ‘lifestyle’ or simply a ‘risk factor’ for other diseases.
That said, I would like to acknowledge that the term ‘disease’ is a societal construct (there is, to my knowledge no binding legal or widely accepted scientific definition of what exactly warrants the term ‘disease’).
As all societal constructs are subject to change, our definitions of disease are subject to change. Conditions that may once have been deemed a ‘normal’ feature of aging (e.g. type 2 diabetes or dementia) have long risen to the status of ‘diseases’. This recognition has had profound impact on everything from human rights legislations to health insurance to the emphasis given to these conditions in medical education and practice.
People living with obesity deserve no less.
Thus, I come down heavily on the ‘utilitarian’ principle of calling obesity a disease.
When, calling obesity a ‘disease’ best serves the interests of those affected by the condition, then, by all means, call obesity a ‘disease’ – it is as simple as that.
We can only hope for the same impact of the Canadian Medical Association declaring obesity a disease – the sooner, the better for all Canadians living with obesity.