Part 2 - Why It Is So Hard To Avoid Weight Regain

In last week's post, I talked about the decrease in energy burn that happens with weight loss.  Today, let's focus on the other major driver of weight regain - the powerful changes in hormones that happen with weight loss, which drive us to eat more and regain the weight we worked so hard to lose.


In humans, there is only one hormone that is known to increase hunger, called ghrelin.  Interestingly, there are many hormones that signal satiety, telling us that we feel full.  Several hormones tell us we feel full in the short term (release 10-15 minutes into a meal), including hormones called GLP-1, cholecystokinin (CCK), PYY, oxyntomodulin, and others.  There are also hormones circulating that are long terms signals of fat and energy storage, which are also fullness hormones: leptin, which is made by fat cells, and insulin, which is made by the pancreas.  These hormones act in the hypothalamus in our brain to regulate when and how much we eat.  (there are also many emotional and social drivers of eating, called 'hedonic' mechanisms... stay tuned for more on this important factor another day :).


When we lose weight, leptin and insulin both drop precipitously, which result in a powerful drive to eat and regain the lost weight.  The short terms regulators of hunger and fullness are affected as well, including a decrease in GLP-1, PYY, and CCK, and an increase in ghrelin, all of which work in concert to beg our brains to eat more, eat more!  Studies have shown that even a year after weight loss, these hormone changes persist - an unrelenting drive to regain the lost weight.

So what can we do to combat these hormonal changes?  It's not easy - evolution has made it so to drive us HARD to look for food and eat during times of food scarcity.  Keeping the energy burn up with activity helps to offset the powerful hormonal drive to increase energy intake, but a whole lotta exercise can be 'cancelled out' by what we can eat in just a minute or two.  Fortunately, medications are now available or in development to combat these hormonal changes, which can help to maintain weight after weight loss.  The only medication along these lines available in Canada is called liraglutide or Saxenda, and it has been shown not only to help people to maintain an average 6% weight lost from diet and exercise, but actually helped people lose an additional 6% weight loss over a year on top of that (with the ever critical lifestyle changes continued throughout).


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 obesity and type 2 diabetes.

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Why Is It So Hard To Avoid Weight Regain?

One of the biggest challenges in successful weight management is prevention of weight regain after weight loss.   Studies show that most often, people regain weight after intentional weight loss, with many people regaining most or all of their lost weight over time (and then some, in some cases).

There are two major drivers of weight regain:

1.  Many powerful changes in hunger and fullness hormones happen with weight loss, which drive us to eat and regain weight.

2.  Our energy burn (called 'energy expenditure') drops - more than we might expect.

Today, we are going to focus on #2 above. (stay tuned for much more on #1 another day!)


So, just how much does our energy burn drop with weight loss?

Well, it turns out that we are geared towards retaining energy and downregulating metabolism in the face of weight loss, as a strong defence mechanism genetically engineered to protect our weight to survive times of famine.  This happens thanks to a decrease in thyroid hormone levels, decrease in sympathetic nervous system tone, an increase in skeletal muscle efficiency, and other changes as well.  While we do expect a proportional decrease in energy burn simply due to the weight loss itself, the decrease in energy burn is actually much more than that, thanks to these changes.


Here's an example: When a person loses 10% of their body weight, one might think that their daily energy burn (called Total Energy Expenditure or TEE) would also drop by 10%, reflecting 10% less body mass that needs daily care and energy, and 10% less body mass for the person to physically carry around in a day.  In fact, studies show that the total energy burn of this person will actually drop by 20-25%, - in other words - to 10-15% less than what would be predicted.

Said another way, it will take 300-400 fewer calories per day to maintain the 10% loss in body weight, compared to a person of the same body shape, size, and weight, who hasn't lost 10% of their weight.

This decrease in total energy expenditure may not persist forever - the POUNDS LOST study suggested that the TEE comes back up to expected baseline after 2 years (though others have suggested that the reduced energy burn lasts as long as 7 years or more).   Some research has also suggested that the drop in energy expenditure may be less with a low carb diet, higher with a low glycemic index diet, and the highest on a low fat diet (my speculation on this is that this may be related to higher protein intake in the low carb diet - it takes more calories to burn and digest protein compared to carbs compared to fat).

Because of this reduction in energy burn with weight loss, as well as the powerful hormone changes that happen to drive hunger, it is very difficult to maintain weight loss.  Fortunately, the American National Weight Control Registry has provided some useful information regarding habits that help keep the weight off (though these are not easy either) - check it out!

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Could A Virus Cause Obesity?

Among the numerous complex contributors to obesity, it has long been wondered whether infections, such as viruses, could be a contributor to the obesity epidemic.

In fact, it turns out that a common cold virus, adenovirus-36 (AD-36), has a link with obesity.

Antibodies to AD-36 (showing evidence of previous exposure) have been found in 30% of adults with obesity, compared to only 11% in normal weight adults.  In kids, the story is similar, with 22% of kids with obesity carrying AD-36 antibodies, versus only 7% of kids with normal body weight.

Also interestingly, in parallel with the rise in obesity, AD-36 antibody positivity has increased from 7% in 1992-1998 to 15-20% in 2002-2009.

There are a number of mechanisms by which AD-36 may induce obesity, including:

• Induction of fat cell formation (in scientific terms: adipogenesis from stem cells via PPAR-gamma signalling pathways)
• Inflammation induced by the virus (release of inflammatory chemicals has a number of effects on human physiology which contribute to obesity)

Interestingly, while people exposed to AD-36 have a higher rate of obesity, they seem to also be protected from metabolic complications associated with obesity, such as type 2 diabetes and fatty liver.  Mechanisms include: 

• increased uptake of sugar into cells (increased GLUT4-mediated glucose uptake)
• an increase in adiponectin, which is an anti-inflammatory hormone made by fat

So, the ultimate success would be if we could vaccinate against AD-36, but also harness its power to decrease the risk of metabolic syndrome.  We are not close to either goal currently, but empowered with this knowledge, research is underway with both of these goals in mind.

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What's The Beef On Processed And Red Meat?

BIG NEWS in the nutrition world this week - the World Health Organization's International Agency for Research on Cancer (IARC) has stated that processed meat causes colon cancer. 

The science:  IARC assessed more than 800 epidemiological (population based) studies to evaluate the link between red meat, processed meat, and cancer, giving the greatest weight to prospective cohort studies, and taking additional evidence from high quality population based case-control studies.  They made a point of focusing on data that included large sample sizes and controlled for possible confounding factors (these are other factors that could be responsible for the same result, for example smoking).   Their meta-analysis found:

1.  An 18% increased risk of colon cancer per 50g of daily processed meat consumption (with confidence that there was no confounding or other explanation for the results);

2.  A 17% increased risk of colon cancer per 100g of daily red meat consumption (with less confidence that there was no other explanation for the results)

3.  Positive associations between consumption of processed meat and stomach cancer;

4.  Positive associations between consumption of red meat and cancers of the pancreas and prostate.


Based on these results, they have classified processed meats as being carcinogenic (cancer causing), and red meat as 'probably carcinogenic' to humans. 

It seems that how meat is cooked or processed is relevant to this discussion.  Meat processing, such as curing or smoking, can result in the formation of cancer causing chemicals such as N-nitroso-compounds and polycyclic aromatic hydrocarbons (PAH).  Cooking meat can produce chemicals also suspected of causing cancer, including heterocyclic aromatic amines and PAH.  High temperature cooking (pan frying, BBQ, or grilling) produces the highest amounts of these chemicals.

While red meat does contain lots of good quality protein and important nutrients such as B vitamins, iron and zinc, these nutrients can be found in other, healthier food choices.

So, meat lovers: you're best off to limit your intake of processed meats and red meats; consider healthier alternative such as poultry or fish.

A scientific discussion of the evidence can be found in The Lancet Oncology, and you can read more about the IARC (if interested) here.

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Secrets To Success - Keeping Weight Off

Have you ever wondered what the secret to success might be, for people who have lost weight and have been able to keep it off?

While the answer to this question will be different for each individual, the American National Weight Control Registry was established in 1994 to try to identify behaviors associated with long term weight loss success.   It is the largest prospective observational study of weight maintenance out there, and includes individuals who have maintained a weight loss of at least 30 lbs for at least 1 year.

Some interesting facts about NWCR members:

• 80% are women, 20% men
• average age is 45-50 years
• 45% lost weight on their own, and 55% with a program

Here are the winning patterns of NWCR members:

• 98% modify their food intake in some permanent way: portion control, low fat diet
• 90% exercise at least 1 hour per day, burning at least 400 calories per session
• 78% eat breakfast every day
• 75% weigh themselves once a week
• 62% watch less than 10 hours of TV per week
• average daily calorie intake for women = 1306 cal
• average daily calorie intake for men = 1685 cal

While the causes and contributors to excess weight, and the challenges in maintaining weight loss are different from person to person, it would be worthwhile to consider these permanent habits to improve the likelihood of long term weight management success!

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Could Antibiotics Cause Diabetes?

The more we learn about type 2 diabetes, the more we appreciate that there are many, many factors that play into the development of this complex medical condition.  The bugs that live in our intestines (called microbiota) are falling under increased scrutiny in how they affect our metabolism.  A new study suggests that antibiotic use (which changes our microbiota) increases the risk of type 2 diabetes.

The study, conducted by Mikkelsen and colleagues and published in the Journal of Clinical Endocrinology & Metabolism (a journal that we endocrinologists love to geek out over) looked at 12 years of data from the entire population of Denmark.  They found that those who had filled 2-4 prescriptions for antibiotics has a 21% higher risk of having type 2 diabetes, compared with those who had filled 0-1 antibiotic prescriptions.  The higher the frequency of antibiotic usage, the higher the risk of having type 2 diabetes. The higher use of antibiotics in type 2 diabetes patients was seen for up to 15 years before the diagnosis of type 2 diabetes, as well as after the diagnosis of diabetes.  

So does this clearly tell us that antibiotics destroy our gut bacteria and cause diabetes?  No.  The data could also be interpreted to reflect that diabetics (diagnosed or not yet diagnosed) are at higher risk of infection, therefore more likely to need antibiotics.  That being said, the fact that the association between antibiotic use and diabetes was seen for up to 15 years before diabetes was diagnosed, makes it unlikely that these data simply reflect diabetics needing treatment for infections. (while diabetes has often been present 5-7 years before diagnosis, 15 years of undetected diabetes is unlikely). 

We are still in the early stages of understanding how our gut bugs affect our metabolism, but there is increasing evidence that they play an important role not only in the development of obesity, but also potentially in the development of type 2 diabetes. I will be watching this area with interest!

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Mediterranean Diet With Olive Oil Prevents Breast Cancer

It's tough to navigate all of the health claims of various food products out there.  Many claims are unsubstantiated, and those that have evidence behind them are often not derived from high quality data.  In that context, I was impressed to see a recent randomized controlled clinical trial, suggesting that a Mediterranean diet supplemented with extra virgin olive oil reduces the risk of breast cancer in postmenopausal women.

The PREDIMED trial randomized 4,282 women to receive either a Mediterranean diet supplemented with extra virgin olive oil; a Mediterranean diet supplemented with nuts; or a control diet with advice to reduce dietary fat.

After 4.8 years, they found that the olive oil supplemented diet reduced the risk of breast cancer by 62%, and the nut supplemented diet reduced the risk by 41%, compared to the control diet.

While these numbers look super impressive, the absolute numbers are actually fairly small: rates of breast cancer per 1000 person years were:

• 1.1 for the extra virgin olive oil group
• 1.8 for the nuts group
• 2.9 for the control group

Still: what this means is that if 1000 women eat following the Mediterranean + oil diet, roughly 2 cases of breast cancer would be prevented.

While the total number of breast cancer cases in the entire study was small (35 total), and only included postmenopausal caucasian women at high risk of vascular disease, the results are certainly interesting and worthy of further research in broader and larger populations.  One must also be careful not to eat too many calories in oil or nuts - these are highly calorie dense foods which can quickly add up and contribute to weight struggles if eaten to excess, and obesity is a known risk factor for breast cancer.

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Diabetes Medication Empagliflozin Saves Lives

In follow up to the press release I blogged about last month, we now have the data which has rocked the foundation of the diabetes world:  the diabetes medication empagliflozin has been found to reduce the risk of cardiovascular deaths and all cause mortality in patients with type 2 diabetes and cardiovascular disease.

The EMPA-REG study, published by Canadian Dr Bernie Zinman and colleagues in the New England Journal of Medicine, randomized 7020 people with type 2 diabetes and established cardiovascular disease to receive either empagliflozin 10mg, empagliflozin 25mg, or placebo, in addition to their usual care.

After a median of 3.1 years, they found that there was a significantly lower risk of death from cardiovascular causes (3.7% on empagliflozin vs 5.9% in the placebo group), a reduced risk of death from any cause (5.7% on empagliflozin vs 8.3% on placebo), and a reduction in hospitalization for heart failure (2.7% on empagliflozin vs 4.1% on placebo).

Put another way: empagliflozin decreased the risk of hospitalization for heart failure by 35%, reduces the risk of death from cardiovascular causes by 38%, and reduced the risk of death from any cause by 32%.

Put yet another way:  if 39 people were treated with empagliflozin for 3 years, one death was prevented.  This number is very comparable to the power of other medications that we use to prevent cardiovascular disease and death in people who are at high risk:  for example,

• simvastatin (a cholesterol medication): treating 30 people for 5.4 years prevents one death
• ramipril (a blood pressure medication): treating 56 people for 5 years prevents one death

These results are truly landmark, in that we have never before definitively proven that any diabetes medication clearly reduces the risk of cardiovascular disease or death.  There are two other medications in this class of diabetes medications (called SGLT2 inhibitors) which are available in Canada (canagliflozin (Invokana) and dapagliflozin (Forxiga)).  These medications have similar studies underway, but results are still a couple of years away. 

The EMPA-REG results have caused diabetologists around the world to have to reconsider current practice guidelines for type 2 diabetes, and whether this class of medications should take priority in the selection of treatment for our patients.   While it is always of paramount importance to consider benefits and risks of any medication, this data certainly suggests that the SGLT2 inhibitors should be considered high on our list of choices for treatment of type 2 diabetes.

Disclaimer: I receive honoraria as a continuing medical education speaker and consultant from the makers of empagliflozin (Boehringer-Ingelheim and Eli Lilly), canagliflozin (Janssen), and dapagliflozin (Astra Zeneca).  I am involved in research of SGLT2 inhibitors as a treatment of diabetes.

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Does Gastric Bypass Surgery Increase Energy Burn?

We know that Roux-en-Y gastric bypass surgery is effective to induce weight loss, causing an average weight loss of about 40% of total body weight.  How this actually happens is still far from completely understood.   Many mechanisms are likely at play, but one of the most hotly debated is whether energy burn (called energy expenditure) goes up, down, or does not change after gastric bypass surgery.

We have recently published the results of our randomized, controlled clinical trial in gastric bypass patients, to add to our understanding of this complex area.

In this trial, conducted at the University of Copenhagen and published in the International Journal of Obesity, we enrolled 28 patients, and placed them on a low calorie diet (1000 kcal/day) in preparation for their gastric bypass surgery.  Patients were randomized to have surgery either 8 weeks or 12 weeks after the start of the low calorie diet, such that we could compare them just before the second group had surgery.  (This protocol enabled us to use a 'pair-fed' control model, as there have been criticisms of other studies comparing post surgical patients to control groups who are eating totally differently, not on a low calorie diet, and not on a negative weight trajectory.)  We then repeated testing on the entire group at 1.5 years post surgery.

We found that at 3 weeks postoperatively, patients had lower body composition-adjusted 24 hour and basal energy expenditure compared to those who had not yet had their surgery.  However, at the 1.5 year mark, patients' energy expenditure was not different compared to their own preoperative values.   We also found that surgery increased the postprandial response to many hormones, including GLP-1, PYY, bile acids, and FGF-19.  Decreases in appetite were particularly associated with increased GLP-1, increased PYY, and decreased ghrelin.

So, our study suggests that the decrease in weight seen after gastric bypass surgery is not caused by an increase in energy expenditure, but that weight loss is more likely to be mediated by hormonally-induced changes in appetite.

An enormous and heartfelt thank you to my ex-PhD student (now postdoc!) Dr Julie Berg Schmidt, and all of my dear colleagues at the University of Copenhagen, for years of fantastic collaboration to bring this study to fruition!  Stay tuned for many more publications stemming from this trial.

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Could Bariatric Surgery Cure My Diabetes?

Clinicians out there – have you ever been asked this question?

I get asked this question at least once a day.

There is an expanding body of data demonstrating the powerful ability of bariatric surgery to improve control of type 2 diabetes, and even put it into remission.  However, we are lacking in long term data on this important topic, with most higher quality data only being available to 2 years post surgery.  For the first time, we now have data from a randomized clinical trial to tell us a little more about what happens to patients with type 2 diabetes, 5 years after bariatric surgery. (Skip to 'So, my take on this?' below if you don't want the study details)

The study, published this week in The Lancet by Mingrone and colleagues, randomized 60 patients to receive either gastric bypass surgery (n=20), biliopancreatic diversion (BPD, n=20), or medical treatment (n=20) for their type 2 diabetes.  Participants were age 30-60, and had to have type 2 diabetes for at least 5 years.  Almost half of the patients in the study were using insulin as part of their diabetes treatment.  

The key findings of the study were:

• ·             At 5 years after surgery, 37% of patients who had gastric bypass, 73% of patients who had BPD, and none of the patients in the medical treatment group, were in remission from their diabetes.
• ·             About half of patients who achieved diabetes remission at 2 years, had relapsed by 5 years (in other words, their diabetes came back). However, when their diabetes came back, it required less medication and was under better control than before the surgery.
• ·             Amount of weight lost did not predict who would go into diabetes remission (or who would relapse).
• ·             Cardiovascular risk (defined as a composite endpoint of at least 2 parameters including reduction in heart/diabetes drugs and improvement in diabetes, cholesterol, or blood pressure control) decreased more in surgically treated groups.
• ·             Five major diabetes complications were seen in patients in the medical group, vs one in the gastric bypass group and none in the BPD group.

So, my take on this? These findings support what we have seen in previous nonrandomized 5 year data: bariatric surgery can be quite powerful to put diabetes into remission (with variable effect depending on the type of surgery), but by 5 years, about half of the diabetes cases come back.  This is a small study, but kudos to the study authors, as I know from my own experiences that it is very difficult to conduct randomized controlled clinical trials in this area.  That the amount of weight loss did not predict the effect of the surgery on diabetes reminds us of the powerful impact of other mechanisms of these surgeries on blood glucose control (for example, changes in gut hormone production).

It’s important to note that while diabetes complications were lower in the surgery group, the surgical and surgically related metabolic complications were (of course) higher in the surgical groups.  These risks were highest in the BPD group, which is a rather dramatic and extensive intestinal bypass procedure.  BPD is not accepted as a standard surgery due to the risk of complications, and in most places BPD is only available in a research setting.

Bariatric surgery can be a powerful and effective treatment for type 2 diabetes for the right individual, who is comfortable with the risk vs benefit profile of surgery, and for whom the benefits clearly exceed the risks.  Patients who experience remission of their diabetes after surgery need to be followed lifelong, as the diabetes can certainly come back.

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Diabetes Medication Empagliflozin Reduces Cardiovascular Events

BIG news in the diabetes world this week - empagliflozin, a medication used to treat Type 2 Diabetes, is the first diabetes medication to show a reduction in cardiovascular risk in a rigorous clinical trial.

The EMPA-REG trial enrolled over 7,000 type 2 diabetic patients who were considered to be at high risk of cardiovascular events and had suboptimally controlled diabetes, and randomized them to received either empagliflozin 10mg, empagliflozin 25mg, or placebo.  The primary outcome was time to first occurrence of cardiovascular death, non fatal heart attack, or non fatal stroke.  Treatment with empagliflozin was in addition to usual standards of diabetes care.

The trial found that empagliflozin reduced the risk of cardiovascular events compared to placebo.  I would love to look at further details today - but the data is embargoed until the European Association for the Study of Diabetes (EASD) meeting in Stockholm on September 17th.  Data on just how much CV events are reduced, or which patients may benefit most, is not yet available.

Empagliflozin (trade name Jardiance) is one of a class of newer type 2 diabetes medications called SGLT2 inhibitors.  They block the kidneys' ability to reabsorb sugar from the urine back into the bloodstream, with the result that sugar is excreted in the urine (ie it causes you to pee sugar).  In addition to reducing blood sugar and improving diabetes control, these medications also reduce blood pressure (they have a diuretic like activity) and also cause an average weight loss of around 10 lbs.  Another excellent feature is that they do not cause low blood sugars as a side effect.  While the details of the EMPA-REG trial haven't been released yet, it is likely that all of these mechanisms of action contribute to the reduction in CV risk that was seen.

Empagliflozin has just been approved in Canada and will be available on shelves soon.  Canagliflozin (trade name Invokana) and dapagliflozin (trade name Forxiga) are available already.  The clinical trials of canagliflozin (called the CANVAS trial) and dapagliflozin (DECLARE trial) are currently underway, with results expected in a few years' time.  Clinical trials of other classes of type 2 diabetes medications are also underway, with results also rolling out over the next few years.

Until now, we have not had robust evidence that any particular diabetes medication clearly decreases the risk of CV events.  Metformin has some less robust data behind it in this regard; this data is one of the main reasons why it is considered the first line treatment for type 2 diabetes worldwide.   As the data and details of this study (and the other studies of medications in this class) become available to us, it will be interesting how these results may change the shape of how we approach type 2 diabetes treatment.

Disclaimer: I receive honoraria as a continuing medical education speaker and consultant from the makers of empagliflozin (Boehringer-Ingelheim and Eli Lilly).  I am involved in research of SGLT2 inhibitors as a treatment of diabetes.

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Fatty Liver - A Dangerous Complication Of Obesity

Amongst the long list of medical complications of obesity, one very common complication that is not considered often enough is fatty liver.

Non alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide.  It is divided into:

• fatty liver (fat deposition) only
• fatty liver with inflammation (steatohepatitis)
• fatty liver with inflammation and scarring (fibrosis), which in the most severe cases is called liver cirrhosis 

A recent review by Mary Rinella in the Journal of the American Medical Association (JAMA) reports some sobering statistics on this problem:

• non alcoholic fatty liver disease (NAFLD) affects 30% of the American population - in other words, between 75 million to 100 million Americans likely have this disease
• liver cirrhosis is the third most common cause of death in patients with NAFLD
• 66% of patients age 50 or older with diabetes or obesity are thought to have advances fibrosis (scarring) of the liver

The diagnosis of NAFLD presents a number of challenges.  Liver enzyme tests (ALT and AST) are normal in 30-60% of patients with fatty liver plus inflammation (steatohepatitis) on liver biopsy, so we clearly cannot rely on these blood tests to make the diagnosis.  Ultrasound can catch many cases of fatty liver, but can miss the milder ones.  MRI is the best non invasive test to detect fat in the liver, but is unfortunately expensive and in limited supply.  

To look for scarring (fibrosis) in the liver, a special kind of test called a Fibroscan (vibration-controlled transient elastography) can be done in a liver specialist's office and is fairly accurate.  MRI elastography may be more reliable, but again is costly and not widely available.  

The best test to look for fatty liver, inflammation, and scarring is a liver biopsy - but of course, this is not without risk.  

In terms of treatment, the only good therapy we are currently aware of is weight loss.   A weight loss of 10% has been shown to decrease liver inflammation.  It also appears that a lower carbohydrate diet is important.  Vitamin E has been shown to have some benefit, but may be associated with a higher risk of prostate cancer and hemmoragic (bleeding type) stroke.  A number of medications have been looked at (including pentoxyfylline, obeticholic acid, and pioglitazone), but none have been found to be sufficiently effective, and/or have too high of a side effect risk profile. 

It is important for health care providers to consider fatty liver as a possible medical condition in any patient with obesity.  As for treatments, we have a long way to go, but the importance of healthy lifestyle changes seems more important than ever.

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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.

Follow me on twitter! @drsuepedersen

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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.

Follow me on twitter! @drsuepedersen

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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.

Follow me on twitter! @drsuepedersen

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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.

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2015

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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.

Follow me on twitter: @drsuepedersen

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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.

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2015

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