New Obesity Medication - Liraglutide On The SCALE

Liraglutide, a medication that we currently use to treat type 2 diabetes, will soon become available in Canada as a treatment for obesity.  Hot off the presses, the biggest clinical trial to study liraglutide as an obesity treatment has just been published this week in the New England Journal of Medicine.

This SCALE obesity trial enrolled just over 3700 participants, and evaluated the effect of liraglutide 3.0mg vs placebo on body weight, with both groups receiving counselling on lifestyle modification.  To participate in the study, patients had to have a BMI of at least 30, or a BMI of 27 plus high blood pressure or high cholesterol (treated or untreated).  After a year, patients on liraglutide lost 8.4kg of body weight, compared to 2.8kg in the placebo group.

We generally consider a weight loss of 5% to be clinically important, in that a 5% loss of body weight has been shown to be associated with a decreased risk of developing many complications of obesity.  In the SCALE trial, 63% of patients lost at least 5% body weight, compared with 27% in the placebo group.

While patients with type 2 diabetes were not included in this study, patients with prediabetes were included, and were equal between groups receiving medication vs placebo at the start of the study.  After a year on liraglutide, 70% of patients who had prediabetes at the start of the study had normal blood sugar levels; after a year on placebo, only a third of patients with prediabetes at the start of the study had normal blood sugar levels.

In terms of side effects, the most common side effect in the liraglutide group was gastrointestinal side effects (such as nausea or vomiting); 94% of these symptoms were mild to moderate in nature.  Gallbladder related side effects were also more common on liraglutide.  Pancreatitis occurred in 0.4% of patients on liraglutide vs less than 0.1% of patients on placebo; the majority of these cases were related to gallstone disease.


Liraglutide will become available as an obesity treatment in Canada later this summer, and is already available in USA.  As the first obesity medication approved by Health Canada in 19 years, it will provide a useful tool in our toolbox to treat obesity, in addition to permanent lifestyle changes.  Our next challenge is now to convince payors (both provincial and private insurance companies) of the need to truly consider obesity as a chronic disease, and accordingly provide financial coverage for obesity medications.

Disclaimer: I was involved in the research trials of liraglutide as an obesity treatment.  I receive honoraria as a continuing medical education speaker and consultant from the makers of liraglutide (Novo Nordisk). I am involved in research of medications similar to liraglutide for the treatment of type 2 diabetes.

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We Think Fat. Why?

While the balance between calories in and calories out is closely monitored by our brains, our brains tend to ‘think fat’ – meaning that this regulation favors an accumulation of fat stores.  The extent to which our brains ‘think fat’ is very different from person to person – genetics may in fact underlie as much as 70% of human obesity.   So exactly how and why do our brains think fat?

The answer to this question is exquisitely complex, and we are only beginning to get an understanding of what is going on.  We know that there are many nerve cells throughout the brain that sense glucose and fatty acids, and some that can sense amino acids (the building blocks of proteins) as well.  While these nutrient signals may signal us to stop eating, the drive to start eating is much less clear.  Leptin and insulin, hormones that signal us to stop eating, decrease in the fasting state, and it is thought that the withdrawal of these two powerful hormones (as well as an increase in the hunger hormone ghrelin) are the main physiologic stimuli for hunger.   That being said, in human obesity, leptin and insulin levels are both high, yet people with obesity certainly still feel hungry – it appears that people with obesity become resistant to the effects of both leptin and insulin, which also means that these hormones lose their gusto to tell the person that they feel full. 

However, it is much, much more complex than that, as it is not only hunger that drives us to eat.  For example, why can we go all night without food and not be hungry, whereas during the day, we often become hungry just a few hours after the last meal?

There are many factors playing in here, including the circadian (day/night) rhythm of several hormones, as well as social cues to eat.  Although we have the ability to make conscious decisions and choices, many of our actions have a subconscious component that escapes voluntary control.  This is why we might eat a tasty treat like chocolate, even if we are not hungry, even if we recognize the negative consequences of the extra calories.  These subconscious urges are driven by a complex interplay of emotional, sensory, and cognitive information from several parts of the brain.  The rewarding properties of food, which stem from the dopamine system in our brain, are so powerful that they can easily override the neurons involved in sensing nutrients which rather weakly try to send the message that we are full while our dopamine system puts our brain into a state of nirvana.

The next question is, why is it so hard to keep weight off after a person with a weight struggle loses the weight?    With short term calorie deficits (=weight loss), leptin and insulin levels fall precipitously, resulting in a powerful drive to eat and regain weight.  To make matters worse, low insulin and leptin levels also lead to a reduction in the body’s energy expenditure (calorie burn).  This state persists for years in humans, and is only alleviated when the previous body weight is regained.  In other words, our bodies have a metabolic memory, such that our bodies spend potentially the rest of our lives trying to get back to the highest weight we have ever been. 

So why does it seem that our metabolism is set against us?  This is genetically powered and evolutionarily driven – our bodies were designed as super efficient systems to help us keep calories on board so that we would survive a famine.  Our brains and bodies are so good at this, in fact, that there is much redundancy in this system – if one system promoting weight gain fails or is blocked (eg by an obesity medication), there are backup systems ready to take over and drive weight gain in other ways.  The learning point here is that a single obesity medication, for example, may not be successful in resulting in large amounts of sustained weight loss – multiple targets may need to be approached simultaneously.  This of course depends on the individual, their genetic background, and the myriad of other factors that are playing into their weight struggle.

It seems we have our work cut out for us to find successful ways to treat obesity.

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Peeing At Night? Could Be Sleep Apnea

Many people get up to pee at night.  This could simply be a reflection of drinking water before bedtime, caffeine, or alcohol, or it could be a symptom of a medical problem, one of which is sleep apnea.

Obstructive sleep apnea (OSA) is a condition where the upper airway is obstructed during sleep, causing pauses in air intake despite an effort to breathe.  The severity of OSA is determined by the number of apnea (no airflow) or hypopnea (decreased airflow) during an hour, measured during overnight testing:

• mild OSA: 5-15 events per hour
• moderate OSA: 15-30 events per hour
• severe OSA: over 30 events per hour

Obesity is a common cause of OSA, but it can also be caused by decreased muscle tone of the upper airway (due to neurologic conditions or substances such as alcohol, sedatives, or muscle relaxants), or variance in the structure of the upper airway. 

So how does OSA cause a person to pee excessively at night?  Research has shown us that the negative pressures generated in the chest by trying to inhale against a blocked airway cause increased blood return to the right side of the heart.  This, in combination with other pressures placed on the heart by OSA, cause the heart to release a hormone called atrial natriuretic peptide (ANP) that tells our kidneys to excrete more sodium and water.  

Other common symptoms of OSA include daytime sleepiness, morning headaches, difficulty concentrating, restless sleep, and snoring. OSA is not thought of or tested for enough, and as a result, there are many unrecognized cases of OSA out there.

There are many other medical problems that can cause a person to pee at night, ranging from bladder issues, to prostate problems, to uncontrolled diabetes, to congestive heart failure, to several others.   For health care providers, it's important to consider obstructive sleep apnea on this list when a patient tells us they are urinating often at night.   If you are a patient urinating excessively at night, be sure to speak to your doctor about it.

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Could Artificial Sweeteners Cause Diabetes?

Artificial sweeteners are commonly touted as a healthy alternative to natural sugar. Sweeteners contain low to no calories (read about the types of sweeteners here), and they do not make blood sugars spike in diabetics.   However, a growing body of research lends a growing amount of concern to possible negative side to artificial sweetener use. 

A fascinating set of studies was collected and published recently in Nature, looking at how artificial sweeteners affect the bacteria in our intestines, and how these effects in turn may actually increase the risk of developing diabetes or pre-diabetes.  For the scientist with a couple of hours and a day with a good attention span may want to read the article for themselves – it’s heavy but super.  Here are the key results of their studies:

Both lean and obese mice who were fed artificial sweetener (saccharin, sucralose, or aspartame) were more likely to develop prediabetes compared to mice fed glucose or sucrose. (read more about different types of sugar here).

They showed that the development of prediabetes in these mice was caused by a change in the types of bacteria in the mice’s intestines.  These altered bacteria are better at making calories from food accessible for absorption, meaning that mice (or humans) more readily absorb these calories, thereby contributing to higher blood sugars (and probably weight gain as well).

In humans, survey type studies have shown that people who use artificial sweeteners are more likely to be people with weight struggles and diabetes, but whether the artificial sweeteners cause these problems, or whether it is simply that people who have these problems are more likely to consume artificial sweeteners to help fix these problems, is difficult to separate.    The authors therefore looked at a very small group of seven study participants who didn’t normally consume artificial sweeteners, and they found that when they ate artificial sweeteners for a week, four of the seven participants developed an increase in their blood sugars by the end of the week.  An examination of these people’s stools (oh yes they did) showed a marked change in the bacteria growing in their intestines after a week of artificial sweeteners. When they transplanted the stool of the people who developed higher blood sugars into mice (oh yes they did), the mice then went on to develop higher blood sugars as well.

So, in summary, these elegant studies suggest that artificial sweeteners may change the types of bacteria that grow in our gut, to types of bacteria that cause us to absorb more calories from food into our bloodstream, with the increase in sugar absorption increasing the risk of diabetes.  

So what is the best solution?  Eating added natural sugar undoubtedly increases our risk of diabetes, obesity, and metabolic syndrome, and there is now emerging evidence to suggest that artificial sweeteners may not be good for our metabolism either.

The best answer is to avoid adding added sweetener period, be it sugar or artificial sweeteners. 

Thanks to my friend and colleague, Pam, for the heads’ up on this article.

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Gut Bugs and Obesity

There is a lot of interest and excitement in the research going on about the microscopic organisms that reside in our intestines (called 'gut microbiota').  And so there should be! Did you know that human beings are not actually 100% human, but that we are actually made up of 90% gut microbiota cells and only 10% human cells?  Mind boggling, isn't it.

It turns out that we have evolved to welcome gut microbiota into our own personal ecosystems, such that these bugs actually do some work for us behind the scenes.  For example, while simple and complex polysaccharides (ie, dietary fiber) escape digestion by our upper gastrointestinal (GI) tracts, they can be transformed by bacteria into digestible substances such as sugars or short chain fatty acids.   These short chain fatty acids are involved in regulation of fat storage in the liver and throughout the body via numerous mechanisms that we are only just beginning to understand.

The type of gut bugs we carry is important, but the story is far from clear.  In studies of rodents, obesity seems to be associated with carrying more of the Firmicutes phylum and less of the Bacteroides phylum, but the research is quite conflicted on this when it comes to humans.   If there is a relationship between the type of bacteria and obesity,  it's unclear which is the chicken and which is the egg - in other words, did these bacteria contribute to obesity, or does developing obesity (or eating a poor diet, thus increasing the risk of obesity) change the gut bacteria towards this particular balance?

The gut microbiota also appear to play a role in the production of gut hormones (such as GLP-1) that signal our brains that we are feeling full during a meal, and this response differs depending on what type of bacteria we carry.   Certain types of gut bugs may also stimulate production of inflammatory chemicals by our immune systems that contribute to the risk of insulin resistance, type 2 diabetes, metabolic syndrome, and so forth.

There are probably more unanswered questions than answered ones at this point in the area of the gut microbiome and how it plays into obesity, and thankfully, there is a lot of research ongoing in this area.  A growing body of evidence supports the possibility of prebiotic or probiotic approaches to changing the composition of the gut microbiota in favor of certain types of gut bugs, thereby having a positive impact on obesity and related diseases.    I will be following this area with interest!

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Does Metformin Decrease Heart Risk in Polycystic Ovary Syndrome?

Metformin is a medication that is considered the first line treatment for type 2 diabetes globally.  One of the reasons why is because it is the only diabetes medication that has data to suggest that it decreases the risk of heart disease.  Metformin can also be used to regulate menses in women with polycystic ovary syndrome (PCOS)- could metformin help decrease heart risk in these women as well?   A recent study has endeavored to answer this question.

The study randomized 50 women with PCOS to receive either the birth control pill, or the birth control pill plus metformin, for 6 months, and they looked at the effect these treatments had on the thickness of the inner wall of the carotid artery (called 'carotid intima media thickness') as well as the ability of arteries to dilate (called 'flow mediated dilatation').

While their findings were not significantly different between groups, numerically, the carotid artery wall grew thicker in the women on the pill, whereas it became thinner in women who were also on metformin.  A thicker inner wall is considered a marker for heart disease risk.   The ability of arteries to dilate was also a little better numerically on metformin (but again, not statistically significant); arteries that are better able to dilate are healthier and are associated with lower risk of heart disease.

So, while this was technically a 'negative' study in that no statistically significant difference was shown, I agree with the authors that the numbers may have become significant if the number of patients in the study was larger (50 patients is a very small study).  There is good reason to think that metformin could decrease heart disease risk in these women, as PCOS is a condition where the body is more resistant to the effects of insulin, and metformin works by decreasing the body's resistance to insulin, thereby improving many metabolic parameters.

The ability of metformin to decrease heart disease risk in women with PCOS now needs to be studies in much larger clinical trials, so that we can get an answer to this important question.

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Is Lifespan Shortened By Obesity?

What is the impact of obesity on our lifespan?  The answer may be more complicated than you might think.

An interesting study published in Lancet Diabetes & Endocrinology looked at data from nearly 4.000 people, where they built a statistical model to estimate the effect on lifespan of having a body mass index (BMI) in the overweight category (25-29.9), obesity (BMI 30-34.9), 'very obese' (BMI 35 or higher), compared to an ideal BMI of 18.5-25.

They found that the effect of excess body weight on years of life lost was highest in younger individuals.  For example, very obese men aged 20-39 lost 8.4 years of life, whereas very obese men aged 60-79 years lost only 0.9 years.  Similarly, very obese women aged 20-39 years lost 6.1 years of life, whereas very obese women aged 60-79 lost 0.9 years of life.

The fact that excess body weight has less negative impact on lifespan as we get older may reflect that a little extra body weight may be protective as we age, as we then have more energy supply to sustain us if we become ill with a condition that causes us to lose weight (which could be anything from a bad flu to cancer). It may also be reflective of the obesity paradox - people with certain medical conditions (such as heart disease or kidney failure) with obesity have been found to have better survival than people with these conditions who are lean.  This may be because of the benefit of having extra energy stores on board, or could be because thin people with serious medical problems may simply be sicker.

So, while optimum weight management appears to be most important in our younger years, it is still important throughout our lives, with a slight shift in focus over time.

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