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.

Follow me on twitter! @drsuepedersen

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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.

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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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