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
We all know that BMI is not a good measure of body fat. In fact, all anthropometric measurements (waist circumference, skin-fold thickness, etc.) have important limitations when applied to individuals.
Currently, the two most common clinical approaches to measuring body composition are measuring bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA).
But just how practical and reliable are these methods in clinical or research settings when applied to individuals with higher BMI levels?
This is the subject of a review article by Carlene Johnson Stoklossa and colleagues from the University of Alberta, published in Current Obesity Reports.
The researchers looked at 12 studies that applied these methods to individuals with a BMI of 35 or greater.
Largely because of its sensitivity to fluid balance, BIA overestimated fat-free mass with scaling errors as BMI increased.
In contrast, DXA provided accurate and reliable body composition measures, but equipment-related barriers prevented assessment of some taller, wider, and heavier subjects.
From these findings, the authors conclude that BIA must be regarded as a largely unreliable method to assess body composition in individuals with class II/III obesity.
In contrast, DXA, although reliable, will likely need some technological improvements that will allow more inclusive testing of taller and larger individuals.
What exactly, clinicians are to do with this information or how such measurements can potentially improve obesity care remains to be determined.
Yesterday, I posted about the significant weight loss seen with the glucagon-like peptide 1 (GLP-1) analogue semaglutide in patients with type 2 diabetes, a finding that holds promise for the use of this agent for obesity treatment.
Now, Juan Frias and colleagues, in a paper published in Lancet Diabetes & Endocrinology, present data showing an additive weight-loss effect of combining the GLP-1 analogue exanatide with the SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes.
The DURATION-8 trial randomised 695 patients with type 2 diabetes to a combination of once-weekly GLP-1 agonist exenatide (Bydureon(R)) and the SGLT-2 inhibitor dapagliflozin (Farxiga(R)) vs. either drug as monotherapy for 28 weeks.
While the combination was superior in all diabetes-related end-points to monotherapy with either substance, I was particularly interested in also seeing superior weight loss with the combination.
Thus, overall patients on dual therapy with exenatide and dapagliflozin lost 3.41 kg vs. 1.54 kg and 2.19 kg on monotherapy, respectively.
However, participants with a baseline A1c between 8% and 9% appeared to experience a greater, more additive weight loss, with participants treated with both dapagliflozin and exenatide experiencing a mean weight loss of 4.5 kg weight reduction, compared to 1.9 kg with exenatide and 2.2 kg with dapagliflozin.
Importantly perhaps, adverse events occurred with approximately equal frequency in each group, suggesting that the combination was as well tolerated as either substance alone.
Again, it is important to note that this was a diabetes study in patients with diabetes and not a study designed to test the efficacy of this drug combination for weight loss, a study design that would have also included diet and exercise recommendations to maximise the effect of this combination.
As I have argued before, given the complexity of the body’s defence mechanisms against weight-loss, the future probably lies in the use of combination treatments for obesity (not unlike the widespread use of combination therapies for diabetes or hypertension).
Thus, it is certainly of interest to see that combining two drugs with different modes of action does indeed produce additive effects on body weight.
Disclaimer: I have received speaking honoraria from Astra Zeneca, the maker of dapagliflozin
Anyone who follows these pages is aware of the fact that we desperately lack better medical treatments for obesity.
Last year, Health Canada approved the glucagon-like peptide 1 (GLP-1) analogue liraglutide (Saxenda(R)) for obesity treatment, which although effective and generally well-tolerated, has to be administered by daily injections.
Now, the results of the SUSTAIN-6 trial, published in the New England Journal of Medicine, show that the once weekly injection of the GLP-1 analogue semaglutide, not only decreases cardiovascular events, but also significantly lowers body weight, a promising finding for future obesity treatment with this drug.
The SUSTAIN 6 trial randomised 3297 patients with type 2 diabetes to once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks.
At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both.
The primary outcome (MACE) occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74).
Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74); nonfatal stroke occurred in 1.6% and 2.7%, (hazard ratio, 0.61).
While average body weight at week 104 remained stable in the placebo group, it decreased by 3.6 kg in the semaglutide 0.5 mg group and and 4.9 kg in the semaglutide 1.0 mg group.
While this may not seem spectacular, it is important to remember that weight loss is notoriously difficult in patients with type 2 diabetes and that this was a diabetes and not an obesity trial, in which case participants would have also been counselled to change their diet and activity levels to achieve weight loss.
Thus, one can only speculate on what the differences in body weight would have been had the participants been actually trying to lose weight.
That said, it was perhaps surprising to note that fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.
It will be interesting to see how well semaglutide fares in studies in which this treatment is assessed for the obesity indication, which will hopefully bring us closer to a once-weekly medication for obesity.
In the meantime, once-daily liraglutide 3.0 mg is certainly a welcome addition to medical management of obesity, but clearly there is more to come in terms of harnessing GLP-1 for obesity management.
Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the makers of liraglutide and semaglutide
However, for many dietitians, keeping up to date with the many issues related to obesity – from our evolving understanding of the complex neurobiology of energy homeostasis that make obesity a chronic disease to the issues of emerging pharmacotherapy and nutritional care for the bariatric surgery patient – is always a challenge.
This is why the Canadian Obesity Network has partnered with Dietitians Canada to, for the 6th time, to bring you this popular intensive course on obesity management (exclusively for dietitians only).
Those, who have attended this course before may wish to attend again – those who have not, you are in for a course that is guaranteed to change your practice.
For more information on this retreat (limited spots open) – click HERE
To see the final program – click HERE
To register – click HERE
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!
Since the introduction of SGLT-2 inhibitors (“gliflozins” or “glucoretics), as an insulin-independent treatment for type 2 diabetes, that works by blocking glucose reabsorbtion in the kidney resulting in loss of glucose (and calories) through the kidney, much has been written about the (albeit modest) weight loss associated with this treatment.
Several studies have documented that the weight loss leads to a change in body composition with an often significant reduction in fat mass.
Now, Giuseppe Daniele and colleagues, in a paper published in Diabetes Care, show that treatment with these compounds may enhance fat oxidation and increase ketone production in patients with type 2 diabetes.
The researchers randomized 18 individuals with type 2 diabetes to dapagliflozin or placebo for two weeks.
As expected, dapagliflozin reduced fasting plasma glucose significantly (from 167 to 128 mg/dL).
It also increased insulin-stimulated glucose disposal (measured by insulin clamp) by 36%, indicating a significant increase in insulin sensitivity.
Compared to baseline, glucose oxidation decreased by about 20%, whereas nonoxidative glucose disposal (glycogen synthesis) increased by almost 50%.
Moreover, dapagliflozin increased lipid oxidation resulting in a four-fold increase in plasma ketone concentration and and a 30% increase in fasting plasma glucagon.
Thus, the authors note that treatment with dapagliflozine improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.
While this may explain the recent observation of a greater (albeit still rather rare) incidence of ketoacidosis with the use of these compounds, these findings may also explain part of the change in body composition previously noted with SGLT-2 treatment.
While this still does not make SGLT-2 inhibitors “weight-loss drugs”, there appears to be more to the fat loss seen with these compounds than just the urinary excretion of glucose.
The biguanide metformin is widely used for the treatment of type 2 diabetes. Metformin has also been shown to slow the progression from pre to full-blown type 2 diabetes. Moreover, metformin can reduce weight gain associated with psychotropic medications and polycystic ovary syndrome.
Now, a randomised controlled trial by M P van der Aa and colleagues from the Netherlands, published in Nutrition & Diabetes suggests that long-term treatment with metformin may stabilize body weight and improve body composition in adolescents with obesity and insulin resistance.
The randomised placebo-controlled double-blinded trial included 62 adolescents with obesity aged 10–16 years old with insulin resistance, who received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months.
Of the 42 participants (mean age 13, mean BMI 30), BMI was stabilised in the metformin group (+0.2 BMI unit), whereas the control group continued to gain weight (+1.2 BMI units).
While there was no significant difference in HOMA-IR, mean fat percentage reduced by 3% compared to no change in the control group.
Thus, the researcher conclude that long-term treatment with metformin in adolescents with obesity and insulin resistance can result in stabilization of BMI and improved body composition compared with placebo.
Given the rather limited effective options for addressing childhood obesity, this rather safe, simple, and inexpensive treatment may at least provide some relief for adolescents struggling with excess weight gain.