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Non-Smokers Die of Lung Cancer and Teetotalers Die of Liver Cirrhosis

cause-effectIn all of my interactions with people who believe that the obesity epidemic is vastly overblown and that the links between excess body fat are imagined, I often hear the argument that obesity cannot “cause” [chose your health problem here] because “normal-weight” people can have [same health problem] too!

This is a rather naive argument, pretty much along the lines of, “Tobacco cannot cause lung cancer because non-smokers can get lung cancer too, or alcohol cannot cause liver cirrhosis because teetotalers get cirrhosis too”.

Or, “Drunk driving cannot cause road accidents, because non-drunk drivers get into accidents too”.

Or, “Flu vaccines don’t work, because vaccinated people get the flu too”.

I could go on….

What is missing in this perspective, is a very basic understanding of multiple cause and effect, as well as a fundamental understandings of probability and risk.

Firstly, almost all medical conditions can have more than one cause. Thus, although most lung cancer is by far attributable to smoking, it is also seen with exposure to asbestos, other environmental toxins, and of course sporadic mutagenesis.

Similarly, there are a multitude of reasons why someone may get liver cirrhosis, but, at least in Western societies, alcohol consumption is by far the number one cause of this problem.

And yes, some vaccinated people do catch the flu, but most vaccinated people don’t and when they do, it turns out to be less severe than it would have been without the vaccine.

So, just because “normal-weight” people can also have hypertension, diabetes, fatty liver disease, sleep apnea, osteoarthritis, gastroesophageal reflux, urinary incontinence, plantar fasciitis, and a host of other conditions, does not “prove” that excess weight does not also “cause” all of these conditions.

Yes, skinny people can have sleep apnea too but the overwhelmingly vast majority of sleep apnea is seen in people with excess weight – the same goes for virtually every obesity related health problem.

The other argument I often hear is that obesity cannot be the cause of [chose your health problem here] because not all people with obesity have [same health problem].

This argument is likewise stupid!

The fact that not every smoker dies of lung cancer, in no way “proves” that smoking does not cause cancer.

The fact that not everyone who regularly drinks a lot of alcohol gets a cirrhotic liver, does not disprove the link between alcohol and cirrhosis.

This is where we need to understand the basic concept of risk and probability.

When a certain factor (e.g. excess body fat) increases the risk of a certain condition, it does not mean that everyone exposed to that factor ends up with the condition. It just means that the risk for that condition is vastly higher.

Now let’s add a further level of complexity to the concept of risk, because, as we know, body fat is not body fat is not body fat is not body fat!

Whether or not my body fat actually causes any health problem, depends on a wide range of factors ranging from my underlying genetic predisposition (e.g. for diabetes, hypertension, etc.), my fat location (subcutaneous vs. ectopic), the cellular structure of my fat (hypertrophic vs. hyperplastic), fat-tissue inflammation, and probably countless other factors.

Add to this, that risk for obesity related conditions can be substantially modified by other factors including physical fitness, healthy diets, positive body image, good mental health – it is easy to understand why defining “sick” and “healthy” simply based on a measurement (direct or indirect) of body fat makes no sense.

Thus, we need to ensure that the medical term “obesity” is not used to label everyone above a certain (arbitrary) BMI cutoff.

Rather, we should reserve the medical term “obesity” only for the condition where excess or abnormal body fat directly impairs the health of a given individual (the actual WHO definition of obesity!).

Someone with the exact same amount of body fat (or even more), who does not experience any health impairment should not be referred to as having “obesity” – that person is just “fat” (a word that really needs to be destigmatised!).

Personally, I couldn’t care less about how “fat” anyone is. Only when “fat” becomes “obesity” does it become a medical issue.

@DrSharma
Edmonton, AB

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MetAP2 Inhibitors For Obesity – Take Two

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.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting honoraria from Zafgen

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Measuring Body Composition in Research and Clinical Practice

Screen Shot 2016-05-29 at 9.03.11 PMWe 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.

@DrSharma
Edmonton, AB

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GLP-1 Analogue and SGLT-2 Inhibitor Combination Provides Additive Weight Loss

1-plus-1Yesterday, 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.

@DrSharma
Edmonton, AB

Disclaimer: I have received speaking honoraria from Astra Zeneca, the maker of dapagliflozin

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How Far Are We From Once-Weekly Medications For Obesity?

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.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the makers of liraglutide and semaglutide

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