Do SGLT-2 Inhibitors Change Fat Metabolism?

Do SGLT-2 Inhibitors Change Fat Metabolism?


Do SGLT-2 Inhibitors Change Fat Metabolism?

Posted: 13 Sep 2016 05:00 AM PDT

sharma-obesity-blood-sugar-testing2Since 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┬áresulting 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┬áloss seen with these compounds than just the urinary┬áexcretion of glucose.

@DrSharma
Edmonton, AB

Metformin Attenuates Long-Term Weight Gain in Insulin-Resistant Adolescents

Posted: 12 Sep 2016 05:00 AM PDT

metformin-300x217The 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 10ÔÇô16 years old with insulin resistance, who received 2000ÔÇëmg 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.

@DrSharma
Edmonton, AB

The Weight Of Living

Posted: 09 Sep 2016 05:00 AM PDT

weight-of-livingIn its approach to addressing weight bias and discrimination, the Canadian Obesity Network recently launched the “Weight of Living” (WoL) project on its facebook page.

Modelled on “Humans of New York”, WoL presents images and stories of Canadians living with obesity in all their diversity and variation.

After all, nothing is more effective in breaking down stereotypes and barriers than realizing that people living with obesity are no different from everyone else, in their hopes, their dreams, their challenges, their aspirations – doing their best to cope and overcome what life throws at them.

Rather than promoting a culture of fat-shaming and blaming, the Canadian Obesity Network seeks to destigmatise those living with obesity by encouraging them to share their real stories in their own words.

Thus, this project seeks to dismantle the stereotypes that surround the lives of people who live with obesity, including the notion that everyone who has overweight or obesity wants to lose weight because they are unhappy with themselves.

Many of the stories you will see in the upcoming weeks do not reflect this. The Canadian Obesity Network hopes that, by sharing these experiences, we all will realize that people who have overweight or obese have goals, dreams, and aspirations just like everyone else, and that their weight is not necessarily a barrier to achieving these, nor is it something that needs to be a source of fear and shame.

In contrast to many other “weight-loss” sites, the Canadian Obesity Network will not┬ápublish stories that glorify weight loss journeys, commercial programs or products, or extreme weight loss attempts.

“While we respect the importance and validity of each story we receive, publishing stories like these only serve to reinforce the idea that people who are overweight or obese are living unhappy, unfulfilling lives – and we know you are worth so much more than that.”

Check out the first WoL stories here, here, here, and here

For more information on how to participate in this project click here or send an e-mail to levitsky@obesitynetwork.ca.

@DrSharma
Edmonton, AB

Can Planned Cheating Help You Stick With Your Diet?

Posted: 08 Sep 2016 05:00 AM PDT

pepperoni-pizza-slice-3Many diet plans praise the importance of strict adherence to whatever the storyline of the diet happens to be. This includes tips on what foods to avoid or to never eat. Indulging in these “forbidden” foods, is considered cheating and failure.

Now, research by┬áRita Coelho do Vale and colleagues, published in the Journal of Consumer Psychology, explores the notion that planned “cheats” can substantially improve adherence with restrictive diets.

Using a set of controlled dietary experiments (both simulated and real dieting), the researchers tested the notion that┬ágoal deviations (a more scientific term for “cheats”) in the plan helps consumers to regain or even improve self-regulatory resources along the goal-pursuit process and can thus enhance the likelihood that the final goal is attained.

That, is exactly what they found:

Compared to individuals who followed a straight and rigid goal, individuals with planned deviations helped subjects┬áregain self-regulatory resources, helped┬ámaintain subjects’ motivation to pursue with regulatory tasks, and (3) has a positive impact on affect experienced, which are all likely to facilitate long-term goal-adherence.

Thus, the authors conclude that, “…it may be beneficial for long-term goal-success to occasionally be bad, as long it is planned.

This is not really that new to those of us, who recommend or use planned “treats” as a way to make otherwise restrictive diets bearable.

Good to see that there is now some research to support this notion.

@DrSharma
Edmonton, AB

How Do People With Obesity Spend Their Time?

Posted: 07 Sep 2016 05:00 AM PDT

time spiralWe live in a time where most of us┬ácomplain about the lack of it. Thus, I often remind myself that our ÔÇ£fast-food cultureÔÇØ is more a time than a food problem.

Now a study by Viral Patel and colleagues, published in OBESITY, takes a detailed look at how US Americans spend their time according to different BMI categories.

The researchers analyse data from over 28,503 observations of individuals aged 22 to 70 from the American Time Use Survey, a continuous cross-sectional survey on time use in the USA.

In a statistical model that adjusted for various sociodemographic, geographic, and temporal characteristics, younger age; female sex; Asian race; higher levels of education; family income >$75 k; self-employment; and residence in the West or Northeast census regions were all associated with a lower BMI relative to reference categories whereas age 50 to 59 years; Black, Hispanic, or ÔÇ£otherÔÇØ race; and not being in the labor force were associated with a higher BMI.

That said, here are the differences in time use associated with higher BMI:

Although there were no substantial differences among BMI categories in time spent sleeping, overweight individuals experienced almost 20 fewer minutes of sleeplessness on weekends/holidays than individuals with normal weight. Furthermore, there was a U-shaped relationship between BMI and sleep duration such that BMI was lowest when sleep duration was approximately 8 h per day and increased as sleep duration became both shorter and longer. Less sleep on weekends and holidays (5 to 7 h) was also associated with higher BMI than 8 to 9 h or sleep.

There were also no major differences between BMI categories and the odds of participating in work or in the amount of time working. However, working 3-4 h on weekends/holidays was associated with the lowest BMI. Individuals with obesity were more likely to be working between 3:30 a.m. and 7:00 a.m. on weekdays than normal-BMI individuals, again perhaps cutting into restful sleep.

Individuals with obesity were less likely to participate in food and drink preparation than individuals with normal weight on weekdays but spent about the same amount of time eating or drinking as the reference category.

Interestingly, individuals with obesity were more likely than individuals with normal weight to participate in health-related self-care, and overweight individuals spent over 1 h more on weekdays than individuals with normal weight on health-related self-care and also spent an additional 15 min (almost double the time) on professional and personal care services.

While individuals with higher BMI were less likely to participate in sports, exercise, and recreation on weekdays and weekends/holidays compared with individuals with normal weight, those who did participate did not differ from individuals with normal weight in the amount of time spent participating. In contrast, overweight individuals were more likely to attend sports/recreation events during the week and spent an additional 47 min (almost 25% more) on this activity than individuals with normal weight.

Overall, there was a positive and generally linear association between time spent viewing television/movies and BMI, with individuals with obesity more likely to watch television almost all hours of the day during the week and weekends.

On weekends/holidays, individuals with obesity were more likely to participate in care for household children and household adults. It was also observed that individuals with obesity spent an additional 15 min on religious and spiritual activities on weekends/holidays, compared with normal-BMI individuals (who spent 116 min).

While these data are of interest and are largely consistent with the emerging data on the role of optimal sleep duration and the detrimental impact of sedentary activities like television viewing on body weight, we must remember that the data are cross-sectional in nature and cannot be interpreted to imply causality (as, unfortunately, the authors do throughout their discussion).

Also, no correction is made for increasing medical, mental, or functional limitations associated with increasing BMI levels, which may well substantially affect time use including sleep, work, participation in sports or work-related activities.

Thus, it is not exactly clear what lessons one can learn regarding possible interventions ÔÇô it is one thing to describe behaviours ÔÇô it is an entirely different thing to try and understand why those behaviours occur in the first place.

Thus, unfortunately, findings from these type of studies too often feed into the simplistic and stereotypical ÔÇ£obesity is a choiceÔÇØ narrative, which does little more than promote weight bias and discrimination.

@DrSharma
Edmonton, AB

Effectiveness of Exercise Interventions After Bariatric Surgery

Posted: 06 Sep 2016 05:00 AM PDT

sharma-obesity-pedometer2There is no doubt that exercise is good for you and that individuals with obesity, both before and after bariatric surgery (like everyone else), would stand to benefit from increasing their levels of physical activity.

Following bariatric surgery, exercise may be particularly important not just to increase physical fitness, but also to limit the obligatory loss in muscle mass that generally accompanies weight loss.

Now, a study by David Creel and colleagues, published in OBESITY, compares three levels of exercise intervention in patients following bariatric surgery in terms of effectiveness and adherence.

A total of 150 patients undergoing bariatric surgery were randomised to either standard care (SC), pedometer use (P), or exercise counseling group (C).

The standard care group (SC) received no exercise support by the bariatric center beyond a simple educational pamphlet.

Participants in the pedometer group (P) were given a pedometer and a one-page information sheet on using the device to increase physical activity. This handout promoted the progressive attainment of 10,000 steps/day. Individuals were asked to wear their device daily and record date, steps achieved, and whether they wore the device the entire day, part of the day, or not at all. Journals were collected, but no feedback was provided.

Participants in the exercise counselling group (C) were regularly seen at the bariatric centre and counselled by a certified exercise professional using motivational intervention techniques with individual goal setting.

Based on physical activity measurements using an accelerometer over two weeks before and 2, 4, and 6 months postoperatively, there was no difference between the SC and P groups, with a statistically significant but modest increase in daily steps in the C group that emerged at 4 months and was maintained at 6 months (about 1,000 extra steps per day compared to SC).

There was no notable difference in exercise tolerance, which increased in all three groups post surgery.

No group reached the 10,000 steps/day or 150 bout-minutes/week recommended for general health

As may be expected from these rather modest results, no significant differences in weight or weight change were found between groups at any time point.

Thus, these findings suggest that handing out a pedometer and asking patients to journal their activity is no more effective in promoting physical activity, than simply handing out a pamphlet; moreover, even adding in counselling by an exercise professional adds little (if anything) to the outcome.

Although the researchers discuss the possibility that an even more intense intervention may provide more benefit, the modest findings certainly question the effectiveness of activity interventions post surgery.

Certainly, simply handing out pedometers does nothing, and adding in expensive group meetings or meetings with exercise professionals adds little more.

These finding by no means speak against the value of exercise after bariatric surgery – they just speak against the indiscriminate use of expensive healthcare resources, when they achieve little more than can be achieved by handing out a pamphlet.

@DrSharma
Edmonton, AB

 

What Behaviours Are Important For Optimal Outcomes With Bariatric Surgery?

Posted: 05 Sep 2016 05:00 AM PDT

sharma-obesity-gastric_bypass_roux-en-y3Bariatric surgery is by far the most effective treatment for severe obesity but outcomes vary from one patient to the next.

Now a paper by James Mitchell and colleagues, published in JAMA Surgery, reports on the postoperative eating behaviors and weight control strategies that are associated with differences in body weight seen at 3 years after bariatric surgery.

The study looks at self-reported data from over 2000 participants in the The Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study, a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers in the USA. Participants completed detailed surveys regarding eating and weight control behaviors prior to surgery and then annually after surgery for 3 years.

The researchers assessed 25 postoperative behaviors related to eating, weight control practices, and the use of alcohol, smoking, and illegal drugs.

The three key behaviours associated with poor outcomes were lack of weekly self-weighing, continuing to eat when feeling full more than once a week, and eating continuously during the day.

Thus, a participant who postoperatively started to self-weigh regularly, stopped eating when feeling full, and stopped eating continuously during the day after surgery would be predicted to lose almost 40% of their baseline weight compared to only 24% weight loss in participants who did not adopt these behaviours.

Other behaviours that had negative influences on outcomes included problematic use of alcohol, smoking and illegal drugs.

Thus, as one may have suspected all along, helping patients adopt and adhere to behavioural changes that include self-montioring and mindful eating behaviours can be expected to substantially affect the success of bariatric surgery.

@DrSharmma
Seoul, South Korea

Zafgen Abandons Belanorib Program But Continues Exploring MetAP2 Inhibitor For Obesity

Posted: 22 Jul 2016 05:00 AM PDT

sharma-obesity-insulin-injectionRegular 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.┬áLike 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.┬áZGN-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.

@DrSharma
Edmonton, AB

Disclaimer: I have served as a consultant to Zafgen.

POMC Mutation Obesity Responds To Melanocortin-4 Receptor Agonist

Posted: 21 Jul 2016 05:00 AM PDT

sharma-obesity-hypothalamusMelanocyte-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 K├╝hnen 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.

@DrSharma
Atlanta, GA

The Edmonton Obesity Staging System Predicts Early Complications After Bariatric Surgery

Posted: 18 Jul 2016 05:00 AM PDT

sharma-obesity-bariatric-surgery21Regular 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 EOSSÔëÑ3 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.”

@DrSharma
Edmonton, AB

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