Now, a randomised controlled study by Mark Ng Tang Ful and colleagues, published in BMC Medicine, suggests that treatment with testosterone may help promote diet-induced loss of fat mass and limit loss of muscle mass.
The study included 100 middle-aged men with obesity, who had a total testosterone level of or below 12 nmol/L, the lower limit reported for healthy young men.
Subjects received 10 weeks of a very low energy diet (VLED) followed by 46 weeks of weight maintenance during which they were randomly assigned to 56 weeks of 10-weekly intramuscular testosterone undecanoate or placebo.
Of the 82 men, who completed the study, participants treated with testosterone had an about 3 Kg greater reduction in fat mass with a greater reduction in visceral fat.
While both groups lost the same amount of lean mass during the VLED, participants treated with testosterone, quickly regained the lean mass so that they had about 3.4 more lean mass than the controls at the end of the study, so that virtually all of the greater weigh loss by these participants over the course of the trial was attributable to fat loss.
These findings are consistent with what is known about testosterone function in men with obesity.
Thus, as the authors remind us,
“Experimental studies in humans suggest that fat-derived adipokines and pro-inflammatory mediators may play a role in central gonadal axis suppression. In addition, preclinical evidence has shown that testosterone deficiency promotes adipose tissue accumulation but reduces myogenesis via an androgen receptor mediated pathway.”
Thus, these findings suggest that dieting men may benefit from adjunct treatment with testosterone to promote fat loss and conserve muscle mass.
Every two years the Canadian Obesity Network holds its National Obesity Summit – the only national obesity meeting in Canada covering all aspects of obesity – from basic and population science to prevention and health promotion to clinical management and health policy.
Anyone who has been to one of the past four Summits has experienced the cross-disciplinary networking and breaking down of silos (the Network takes networking very seriously).
Of all the scientific meetings I go to around the world, none has quite the informal and personal feel of the Canadian Obesity Summit – despite all differences in interests and backgrounds, everyone who attends is part of the same community – working on different pieces of the puzzle that only makes sense when it all fits together in the end.
The 5th Canadian Obesity Summit will be held at the Banff Springs Hotel in Banff National Park, a UNESCO World Heritage Site, located in the heart of the Canadian Rockies (which in itself should make it worth attending the summit), April 25-29, 2017.
Yesterday, the call went out for abstracts and workshops – the latter an opportunity for a wide range of special interest groups to meet and discuss their findings (the last Summit featured over 20 separate workshops – perhaps a tad too many, which is why the program committee will be far more selective this time around).
So here is what the program committee is looking for:
- Basic science – cellular, molecular, physiological or neuronal related aspects of obesity
- Epidemiology – epidemiological techniques/methods to address obesity related questions in populations studies
- Prevention of obesity and health promotion interventions – research targeting different populations, settings, and intervention levels (e.g. community-based, school, workplace, health systems, and policy)
- Weight bias and weight-based discrimination – including prevalence studies as well as interventions to reduce weight bias and weight-based discrimination; both qualitative and quantitative studies
- Pregnancy and maternal health – studies across clinical, health services and population health themes
- Childhood and adolescent obesity – research conducted with children and or adolescents and reports on the correlates, causes and consequences of pediatric obesity as well as interventions for treatment and prevention.
- Obesity in adults and older adults – prevalence studies and interventions to address obesity in these populations
- Health services and policy research – reaserch addressing issues related to obesity management services which idenitfy the most effective ways to organize, manage, finance, and deliver high quality are, reduce medical errors or improve patient safety
- Bariatric surgery – issues that are relevant to metabolic or weight loss surgery
- Clinical management – clinical management of overweight and obesity across the life span (infants through to older adults) including interventions for prevention and treatment of obesity and weight-related comorbidities
- Rehabilitation – investigations that explore opportunities for engagement in meaningful and health-building occupations for people with obesity
- Diversity – studies that are relevant to diverse or underrepresented populations
- eHealth/mHealth – research that incorporates social media, internet and/or mobile devices in prevention and treatment
- Cancer – research relevant to obesity and cancer
…..and of course anything else related to obesity.
Deadline for submission is October 24, 2016
To submit an abstract or workshop – click here
For more information on the 5th Canadian Obesity Summit – click here
For sponsorship opportunities – click here
Looking forward to seeing you in Banff next year!
It is now well established that the almost non-existant rates of long-term weight loss are not because of lack of will power or lack of motivation. Rather, they are firmly embedded in human (and animal) physiology, that is designed to defend body weight at all costs through complex neuroendocrine homeostatic mechanisms that will eventually wear out even the staunchest dieter.
But just how strong is the physiological drive to defend and regain lost body weight? Or even more specifically, how much does an increase in appetite counteract weight loss?
This is the topic of a paper by David Polidori and colleagues, prepublished on bioRxiv*.
The researchers use data from a 52-week trial of canagliflozin, a sodium glucose co-transporter (SGLT2) inhibitor leads to a urinary glucose loss of approximately 90 g/day throughout the duration of treatment.
This amounts to a net daily energy loss of ~360 kcal/day that occurs without directly altering central pathways controlling energy intake and without the patients being directly aware of the energy deficit.
Based on the observed changes in body weight over time, the researchers used a validated mathematical method to calculate changes in daily energy intake using principles from engineering control theory.
The complex mathematical formula takes into account a wide range of parameters including changes in the energy expenditure rate and density of fat and fat-free mass, energy cost of fat and protein turnover, dietary and adaptive thermogenesis as well as changes in physical activity (no change in physical activity was assumed in this study).
Subjects in the treatment arm showed the typical initial weight loss (of about 5 Kg) followed by the maintenance of a weight-loss plateau throughout the remainder of the study, a pattern which, in light of a continuing daily energy loss of about 360 kcal is consistent with a proportional feedback control system that serves to limit the amount of weight loss and creates a drive towards weight regain (think of this as the tension that counteracts a steady pull on a rubber band).
Based on their calculations, the amount of daily increase in caloric intake required to maintain the weight loss plateau (rather than continuing to lose weight), was in the order of about 100 Kg/day per Kg weight loss. This is substantially more than the reduction in metabolic rate generally seen with weight loss (of about 10-20% of body weight) is only about 30 kcal/day per Kg weight loss).
When applying these finding to the typical weight-loss curve seen in the usual commercial weight loss programs (an initial weight loss followed by gradual weight regain), the researchers show that the difference between the homeostatic drive to eat and the actual energy intake, a quantitative index of the ongoing effort to sustain the intervention in the face of the continuing biological signals to overeat, requires that subjects have to demonstrate a persistent effort to avoid overeating above baseline during the intervention even when the average energy intake returns to near baseline levels.
“…homeostatic feedback control of energy intake is likely a primary reason why it is so difficult to achieve large sustained weight losses in patients with obesity. Rather, weight regain is typical in the absence of heroic and vigilant efforts to maintain behavior changes in the face of an omnipresent obesogenic environment. Unfortunately, there is no evidence that the energy intake feedback control system resets or relaxes with prolonged maintenance of lost weight – an effect similar to the long-term persistent suppression of energy expenditure in weight-reduced humans. Therefore, the effort associated with a weight loss intervention persists until either body weight is fully regained or energy intake increases above baseline to match the homeostatic drive to eat.”
If anyone thought that the medical establishment is slowly but surely embracing the notion that obesity (not unlike hypertension or type two diabetes), is a complex chronic disease that requires proper medical management, a recent Clinical Discussion published in the New England Journal of Medicine should be a clear sign that we are still a long way from home.
The presented case, is that of a 29-year-old woman with a BMI of 32, who has a history of past weight loss attempts, but otherwise appears in fairly good health. She does not smoke but does drink alcohol on occasion. She says that she “watches what she puts in her mouth” and reads the nutritional labels on food packaging. She eat out and orders take-out meals 8 to 12 times a week. She has a sedentary job but belongs to a fitness club which she attends irregularly. On physical examination, her blood-pressure is mildly elevated (144/81 mm Hg). The rest of the examination is unremarkable.
The two discussants are: Dr. Kushner, a past-president of The Obesity Society and one of the world leading medical authorities on obesity management from Northwestern University, Chicago and a certain Dr. Gordon Schiff, from Harvard Medical School, who, as far as I can tell from his short bio, has no apparent credentials in obesity management whatsoever.
Dr Kushner, takes a rather sensible and otherwise rational approach to this patient including counselling her on the core principles of weight management, such as goal setting, building a plan for reduced caloric intake, increasing physical activity, reducing sedentary activity, and using self-monitoring strategies, and goes on to broach the topic of weight-loss medication, which may provide additional benefits.
In rather sharp contrast, Dr. Schiff launches straight into nothing short of a moralistic tirade on the evils of promoting or prescribing drugs to treat obesity, mainly for the reason that doing so,
“does a disservice to our patients, society, and ourselves“
“violates nearly every principle of careful, conservative prescribing, and they may well put patients at risk.“
His main argument regarding risk, is the rather appalling history of weight-loss drugs – essentially the story line is that, because weight-loss drugs in the past have raised safety concerns, current or even future drugs for obesity must in fact all be harmful.
I find this line of argumentation about as coherent as stating that, just because of the harmful history of mercurial diuretics or arsenic anti-syphillic agents, we should be vary of any drugs that could potentially help patients fight fluid retention or venereal disease.
No matter that we are now talking about a completely different and unrelated classes of diuretics or antibiotics – history should have taught us that trying to fight fluid retention or venereal disease with medications will only put patients at harm.
Indeed, to follow Dr. Schiffs deeply insightful line of reasoning, we have just to look at the safety concerns with diuretics (potentially life-threatening hypokalemia, hyponatremia, and dehydration – not to mention gout or impotence) or antibiotics (lethal anaphylaxis, seizures, diarrhea, fungal infections) to clearly understand that even the though of using medications to treat fluid retention (irrespective of the cause) or venereal infections (irrespective of the etiology) must indeed “violate nearly every principle of careful, conservative prescribing, and may well put patients at risk.”
So how does Dr. Schiff propose to help this patient?
By recommending a
“realistic, supervised, intensive, supportive plan to moderate caloric intake and exercise regularly, which often works as well as drugs without the negative effects and offers additional, proven positive health benefits.”
(Or, in other words – “eat less – move more”).
I have no doubt that in his, probably very busy clinical practice, Dr. Schiff routinely recommends that his patients with edema strictly monitor their fluid intake, while his STD patients are surely benefiting from his recommendation to faithfully abstain from any form of sexual intercourse.
After all, as Dr. Schiff argues, we should not even remotely consider medically treating conditions that affect millions of people just because they affect millions of people. Doing so would clearly be doing a “disservice to our patients, society, and ourselves”.
I am sure people living with obesity worldwide will be eternally grateful to Dr. Schiff for his forward thinking and evidence-based insights into the well-documented spectacular effectiveness (and I don’t mean efficacy) of “eating less and moving more” as the lasting “cure” for excess weight.
We must indeed all be deeply thankful to the esteemed New England Journal of Medicine for bringing us this timely ounce of wisdom, that is already having me rethinking my own practice.
Regular readers may recall that Zafgen, a Boston-based biopharmaceutical company, recently abandoned its development program for belanorib, a MetAP2 inhibitor. The program had to be abandoned, despite substantial weight loss in indiviuals with Prader-Wili syndrome, hypothalamic obesity, as well as “garden-variety” obesity, due to serious thrombotic adverse events.
Now, Zafgen reports that they have initiated a new round of Phase 1 studies of their 2nd generation MetAP2 inhibitor (ZGN-1061), which despite similar MetAP2 inhibition, appears to have much more favourable effects on coagulation.
The Phase 1 trial, designed to evaluate safety, tolerability, and weight loss efficacy over four weeks will enroll up to 48 healthy subjects across up to six cohorts of single escalating doses of ZGN-1061. The clinical trial also includes a multiple-ascending dose portion, which is evaluating twice-weekly ZGN-1061 over four weeks in up to 24 obese subjects.
The Company expects that top-line data from this clinical trial will be available by the end of the first quarter of 2017.
Given the rather spectacular weight loss seen with belanorib, this 2nd generation MetAP2 inhibitor study certainly warrants our attention.
Disclaimer: I have received consulting honoraria from Zafgen