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Adverse Metabolic Effects of Exercise?

obesity-exerciseWarning – this is not an April Fool’s post! Rather, it is a follow up to yesterday’s post warning that even “lifestyle” or behavioural interventions can have adverse effects – at least for some people.

Point in case, is this paper by Claude Bouchard and colleagues, published in PLOS one back in 2008, clearly documenting clinically significant harmful metabolic effects of exercise in some individuals (about 1 in 10).

I would probably have disregarded this paper, except for the fact that the authors include a who-is-who of exercise experts, Steven Blair, Timothy Church, Nathan Jenkins, just to name a few. These are all enthusiastic supporters of increasing physical activity with rock-solid expertise in exercise physiology.

Their findings are based on completers from six exercise studies involving a total of 1,687 men and women.

Although metabolic parameters in general improved (as expected) in most participants, 8.4% had an adverse change in fasting insulin, 12.2% has a clinically significant increase in resting systolic blood pressure, 10.4% had a relevant increase in fasting triglycerides, and 13.3% had a reduction in HDL-Cholesterol. About 7% of participants experienced adverse responses in two or more risk factors.

While the authors note that the explanation for these findings remain unclear,

“…the adverse response traits are not explained by prior health status of subjects, age, amount of exercise imposed by the program, or lack of improvement in cardiorespiratory fitness. No evidence could be found for the hypothesis that adverse responses were the result of drug-exercise interactions.”

Which brings me back to yesterday’s post, that even the best meant behavioural recommendation (in this case “move more”) can carry risks for some individuals and may require personalised and ongoing monitoring.

Funnily enough, I would imagine that if you packed exercise into a pill with these types of “adverse effects”, I wonder if the FDA would actually let you sell it.

Incidentally, Claude Bouchard will be one of the key note speakers at the upcoming 4th Canadian Obesity Summit in Toronto, April 28-May 2. I’m sure he will be presenting some of these data and the fascinating genetic studies that have since been done on this issue.

@DrSharma
Edmonton, AB

Hat tip to Morgan Downey for reminding me of this study.

To preregister for the Canadian Obesity Summit click here

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Does Liraglutide Mimic The Vascular Benefits Of Gastric Bypass Surgery?

sharma-obesity-glp-1On the last day of the 8th Annual Obesity Symposium here in Norderstedt, Germany, Marco Bueter from the University of Zurich presented a fascinating series of studies (just published in Circulation), demonstrating the “weight-independent” benefits of gastric bypass surgery on endothelial function (using an animal model).

Besides showing that 8 days after bypass surgery rats with diet-induced obesity had higher plasma levels of bile acids and GLP-1, that were associated with improved endothelium-dependent relaxation, not seen in sham-operated weight matched controls, but also that these effects could be prevented by blocking GLP-1 receptors with exendin 9-39.

In contrast, similar effects to those seen on vascular function in bypass rats were seen in sham-operated rats treated for 8 days with the GLP-1 analogue, liraglutide, or as the authors describe it,

“liraglutide restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB”

Together these studies suggest that GLP-1 may well play an important causal role in the improved vascular function seen in patients undergoing gastric bypass surgery.

These findings are all the more interesting as liraglutide has now been approved for obesity treatment in the USA, Canada and Europe.

While these data are certainly not enough to describe liraglutide as “surgery in a pen”, they are indeed promising in terms of potential benefits of this treatment that may well be weight independent.

All the more reason to anticipate the outcome of the ongoing LEADER trial, which is currently evaluating the effect of liraglutide treatment on cardiovascular outcomes in patients with type 2 diabetes.

@DrSharma
Norderstedt, Germany

Disclaimer: I have served as a paid consultant and speaker for Novo Nordisk, the maker of liraglutide.

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MetAP2 Inhibitor Beloranib Produces Weight Loss in “Simple” Obesity

sharma-obesity-insulin-injectionReaders may recall a previous post on the remarkable efficacy of beloranib, a methionine aminopeptidase 2 (MetAP2 ) inhibitor, in patients with hypothalamic obesity.

Now, a paper by Dennis Kim and colleagues present the results of a phase II study in individuals with “simple” obesity, published in Diabetes, Obesity and Metabolism.

The study included 147 participants with moderate obesity, who were randomised to 0.6, 1.2, and 2.4 mg beloranib or placebo for 12 weeks, with no specific diet or exercise recommendations.

At 12 weeks, participants had on average lost between 5.5 and 10.9 Kg in a dose-dependent fashion.

This reduction in body weight was associated with relevant improvements in waist circumference, lipids and blood pressure.

Adverse effects included dose-dependent increase in sleep latency and mild to moderate gastrointestinal symptoms.

Beloranib is an investigational weight loss therapy with a novel mechanism of action. This study assessed the efficacy, safety, and tolerability of beloranib treatment for obesity.

This is certainly a most remarkable degree of weight loss seen at 12 weeks and it will be interesting to see the results of the longer-term studies that are currently underway.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting honararia from Zafgen, the maker of belanorib.

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Accuracy of Forearm Blood Pressure Measurements in Severe Obesity

forearm bp measurementGetting reliable blood pressure readings in patients with obesity can pose a problem, even when extra-large cuffs are available. An often discussed alternative is the use of forearm readings using a regular cuff, but the reliability of these readings remains unknown.

Now a study by Marie-Eve Leblanc and colleagues from the University of Laval, Quebec, Canada, published in Blood Pressure Monitoring, shows that forearm measurements with an oscillometric device can be reliably measured and are highly predictive of intra-arterial blood pressure measurements in patients with sever obesity.

The study involved 25 participants with an average BMI of 50.9kg/m2. Overall, sensitivity (0.98) and predictive values (0.93) for the presence of systemic hypertension were excellent, indicating that the forearm approach is a promising alternative to systemic hypertension diagnosis in severe obesity.

This may well simplify blood pressure measurements in patients presenting with severe obesity, where upper arm measurements may be difficult.

@DrSharma
Calgary, AB

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Obesity Management Belongs In Primary Care

sharma-obesity-doctor-kidNo matter if and when obesity prevention efforts bear fruit, there are currently well over 6,000,000 Canadian adults and children, who could benefit from obesity management today.

Even, if one were to limit more intense obesity management (such as behavioral, pharmacological and/or surgical treatments) to those with more severe obesity (Edmonton Obesity Staging System 2+), this would still overwhelm the capacity of existing tertiary care systems.

Thus, as William Dietz and colleagues point out in their recent article in the 2015 Lancet Obesity Series, even the majority of severe (or complicated) obesity will still need to be managed in primary care.

“Care for adults with severe obesity has generally been delivered in tertiary-care centres. Although such programmes are efficacious, they are poorly suited to address the number of patients with severe obesity. Alternative approaches for the management of adults with severe obesity include primary-care settings or community settings to deliver care.”

However,

“Transition from efficacy to effectiveness will require substantial and challenging changes in how primary care is delivered. Practices often lack the organisational structure, such as patient registries and methods for systematic tracking to assess clinical interventions, care teams to manage patients with chronic illnesses, or health information systems that support the use of evidence-based practices at the point-of-care to provide longitudinal care for chronic illnesses.”

Where they exist, these structures are already at capacity dealing with other chronic diseases including diabetes, hypertension, COPD and other lifelong disorders.

Even if many of these problems are directly related to excess weight (or would at least substantially improve with weight loss), most primary care practitioners have yet to take on the challenge of managing obesity (not just the obese patient).

Surely enthusiasm for obesity management will increase in primary care settings as more effective obesity treatments become available – making these available to those who stand to benefit, needs to be a key priority of health care system planners and payers.

The fact that many payers chose not to cover obesity treatments by delegating this to the category of “lifestyle”, shows that they have yet to take obesity seriously as a chronic disease in its own right.

It may also demonstrates their biases and discrimination of people living obesity – after all the same payers have no problem shelling out billions of dollars to treat other “lifestyle” disorders like strokes, heart attacks, type 2 diabetes or COPD.

This is where health policies can and should make a difference to people living with obesity – the sooner, the better.

@DrSharma
Edmonton, AB

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