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Do SGLT-2 Inhibitors Change Fat Metabolism?

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 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.

@DrSharma
Edmonton, AB

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

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 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.

@DrSharma
Edmonton, AB

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What Behaviours Are Important For Optimal Outcomes With Bariatric Surgery?

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

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Zafgen Abandons Belanorib Program But Continues Exploring MetAP2 Inhibitor For Obesity

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. 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.

@DrSharma
Edmonton, AB

Disclaimer: I have served as a consultant to Zafgen.

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The Edmonton Obesity Staging System Predicts Early Complications After Bariatric Surgery

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 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.”

@DrSharma
Edmonton, AB

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