Diabetes Medication Liraglutide Saves Lives

In follow up to my recent blog post – as promised - the hotly anticipated LEADER trial results became available this week, in a simultaneous release at the American Diabetes Association meeting, as well as published in the New England Journal of Medicine.

The LEADER trial examined the effect of a type 2 diabetes medication called liraglutide (trade name Victoza) on cardiovascular events, in a group of people with type 2 diabetes who were deemed to be at high cardiovascular risk (age 50 or more with at least one existing cardiovascular condition such as a history of heart attack or stroke; or age 60 or more with at least one cardiovascular risk factor (for example, hypertension).

The goal of this study, as for all hard outcome studies of diabetes medications, was to prove cardiovascular safety of liraglutide.  

Not only did liraglutide prove to be safe in people at high cardiovascular risk – it actually REDUCED cardiovascular events.  Amongst 9,340 patients from 32 countries, followed for a median of 3.8 years, there was a 13% reduction in the risk of (a composite endpoint of) death from a cardiovascular causes, non fatal heart attack, and non fatal stroke. Cardiovascular deaths were reduced by 22%, and death from any cause was reduced by15% compared to placebo.  The benefit of liraglutide was particularly pronounced in people who had established cardiovascular disease at baseline, and in those with moderate reduction in kidney function at baseline.

To put the results another way:  

• 66 people would need to be treated for 3 years to prevent one of (cardiovascular death or heart attack or stroke)
• 98 people would need to be treated for 3 years to prevent one death of any cause.

These numbers needed to treat are similar to the protective effects of statins (cholesterol medications) and ACE inhibitors (blood pressure medication).

Now that we know that liraglutide has a distinct cardiovascular benefit, a question that arises is whether this is an effect shared by other medications in this class, called GLP-1 receptor agonists.  The ELIXA trial, a study of lixisenatide (not available in Canada), did not show a cardiovascular benefit.  Studies of other medications in this class (eg dulaglutide, exenatide) are still underway, so for these, we don’t know the answer yet.  

We also don't know if the cardiovascular benefit of liraglutide exists in people with type 2 diabetes who aren't in these high risk groups, or in people with obesity without type 2 diabetes (liraglutide is also available as an obesity treatment, called Saxenda).  However, this trial gives us additional confidence in the safety of liraglutide, given that the LEADER trial was conducted in the highest cardiovascular risk population.

The effect of liraglutide to reduce cardiovascular events is important, as we know that cardiovascular disease is the leading cause of death in people with type 2 diabetes.  So far, other diabetes medications that have shown a cardiovascular benefit are metformin (with somewhat scanty data) and empagliflozin (based on the EMPA-REG trial, which you can read about here). Thus, in Canada, metformin is considered the first line treatment for type 2 diabetes, with empagliflozin to be considered in patients with existing cardiovascular disease who are not at target blood sugar control with metformin.  

Liraglutide will likely join the ranks of empagliflozin as a second line treatment option, with the decision making process as to which to choose based not only on the characteristics of each medication, but most importantly, on the characteristics and desires of each individual patient.

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www.drsue.ca © 2016

Disclaimer: I have been involved in research trials of liraglutide, other GLP-1 receptor agonists, and SGLT2 inhibitors like empagliflozin.  I receive honoraria as a continuing medical education speaker and consultant from the makers of liraglutide (Novo Nordisk) and empagliflozin (Boehringer-Ingelheim/Eli Lilly).  

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Diabetic Ketoacidosis After Bariatric Surgery in Type 2 Diabetes

Diabetic ketoacidosis (DKA) is a potentially life threatening complication that can occur in people with diabetes.  While we typically associate DKA with type 1 diabetes, it can also rarely happen in type 2 diabetes.   DKA can occur if insulin levels are low, and can be precipitated by a stress on the body, including infection or illness, dehydration, heart attack, and so forth.

A case series was recently published, describing four cases of DKA after bariatric surgery, in three people with type 2 diabetes.   The average time to presentation of DKA was 13 days after surgery (range 3-27 days). All patients were on insulin prior to surgery.  Factors contributing to DKA included omission of insulin and dehydration.

One of these patients was on canagliflozin prior to surgery.  Canagliflozin is a medication in a class of type 2 diabetes medications called SGLT-2 inhibitors, which slightly increase the risk of DKA, particularly if insulin is not taken as directed by the health care team.  Also, if a person taking an SGLT2 inhibitor becomes unwell or dehydrated for any reason while taking the medication, this increases the risk of DKA.  The DKA case in the patient on canagliflozin in this study also had omission of insulin and poor food intake post operatively as contributory factors.

These findings teach us the following:

1.  Patients with type 2 diabetes having bariatric surgery need to be followed closely postoperatively, with meticulous attention to blood sugars and insulin needs.  Some people with type 2 diabetes who were on insulin before surgery do not require insulin after surgery, but others do.   There must also be a low threshold for concern if they become dehydrated due to difficulty tolerating oral intake.

2.  SGLT2 inhibitors should be stopped prior to bariatric surgery (possibly before starting any low calorie diet plan), and if there is still a need for medication to control blood sugar post op, it should not be restarted until the patient is eating and drinking well after discharge home from surgery.

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www.drsue.ca © 2016

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What The Biggest Loser Teaches Us About Metabolism After Weight Loss

Well, I never thought I would say this, but the show The Biggest Loser has been useful for something: it has taught us some important scientific lessons about just how much, and for how long, metabolism drops after weight loss.

(I say that the show is useless otherwise for a host of reasons: It portrays unsafe, dramatic means of weight loss that are not sustainable and gives many incorrect and inappropriate messages about obesity.  I could go on...)

Fourteen participants of The Biggest Loser agreed to have their metabolism measured before the weight loss program, at the end of the 30 week competition, and again 6 years later.

The study was conducted at the National Institute of Health and published in the medical journal Obesity.  The baseline weight amongst these six men and eight women was 148.9kg, and they lost an average of 58kg at the end of the 30 week competition.   After 6 years, most participants regained a significant proportion of the weight lost during the show, with only one person not regaining any weight, and five people having returned to their baseline weight or above.

When they measured metabolism in these people before the competition and compared it to their metabolism 6 years later, they found that on average, their metabolism burned 499 fewer calories per day, compared to what would be expected for a person of that gender, age and body composition who had not previously lost weight.

Similar to an older study I previously blogged about, this teaches us that metabolism decreases markedly after weight loss, not only due to carrying around less weight, but also due to an additional, evolutionarily designed adaptation to defend our body weight. For The Biggest Loser contestants, this means that on average, they have to eat 500 calories less, every day, than they would if they weighed the same but had not come down from a higher weight in the past.  This metabolic adaptation goes on for at least six years after weight loss (based on this study) - and of course may well go on much longer, possibly indefinitely.

So how does a person handle this new lower metabolism after weight loss, to keep the weight off?  We can look to the American National Weight Control Registry to learn about habits that are associated with keeping weight off - the themes are lots of activity (at least an hour a day) and lots of self monitoring - read more on this here.

If you'd like to read more about The Biggest Loser study and the individual participants, the New York Times wrote an excellent article about it, including interviews with several participants - check it out here.

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2016

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Type 2 Diabetes Medication Semaglutide Reduces Cardiovascular Risk

Great news from the diabetes world: semaglutide, a medication in development for the treatment of type 2 diabetes and obesity, has been shown to reduce the risk of cardiovascular events.

The SUSTAIN-6 study (a study in which I was an investigator) was a global study of about 3,300 people with type 2 diabetes, who were randomized to receive semaglutide subcutaneously (injected under the skin) once weekly vs placebo for treatment of their diabetes. They found that after 2 years of treatment, semaglutide reduced cardiovascular events (defined as a sum of non fatal heart attack, non fatal stroke, and cardiovascular death).  Exactly how much the risk is reduced is not yet public knowledge - the information is currently available in a press release only, with the exact data to be released at a later date.

Semaglutide is a GLP-1 receptor agonist, which helps the pancreas control the release of hormones involved in blood sugar control (insulin and glucagon), and also stimulates the fullness centre in the brain to tell a person that they feel full.  Thus, not only does it help with blood sugar control, it is also effective for weight loss.  Semaglutide is currently in development as both a type 2 diabetes treatment and as a treatment for obesity in people with or without diabetes (it is not yet available as a prescription).   Interestingly, while all GLP-1 receptor agonists currently available are administered by injection under the skin (similar to how insulin is administered), semaglutide is also currently under development as an oral medication. (ie as a pill)

This marks the third time in the last eight months that we have been so thrilled to hear that a medication designed for the treat type 2 diabetes decreases the risk of cardiovascular events: empagliflozin (trade name Jardiance) (read here) and liraglutide (trade name Victoza) (read here) reduce cardiovascular events as well.  These are landmark times for the world of type 2 diabetes, as prior to these studies, we had not definitively proven that a medication for treatment of type 2 diabetes could decrease the risk of cardiovascular events.  In fact, we have had great difficulty proving that improving blood sugar control by any means reduces cardiovascular events (though it is clear that improving blood sugar control reduces the eye and kidney complications of diabetes).

Amongst the class of GLP-1 receptor agonists, both liraglutide and semaglutide have shown that they reduce cardiovascular events (though the numbers on this are not yet available on either one), whereas lixisenatide (not available in Canada) did not decrease cardiovascular events.  It remains to be seen what effect the other GLP-1 receptor agonists available in Canada have on cardiovascular events (exenatide (trade names Bydureon and Byetta) and dulaglutide (trade name Trulicity)) - these studies are still underway.


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

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2016

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Just How Much (And For How Long) Does Metabolism Slow Down After Weight Loss?

Many people who struggle with excess weight find that they are able to get weight off, but keeping it off seems next to impossible.

So what exactly happens to our metabolism when we lose weight?  And are any changes in our metabolism temporary, or there for the long term?

A very elegant study was conducted that answers this question – and you may be surprised by the results.

The study enrolled people in groups of three, all three of which were of the same gender and weight: one who was weight stable at their maximum lifetime weight (ie had not had any weight loss); one who had lost at least 10% of body weight and kept it off for at least a year; and one who lost at least 10% of body weight over the most recent 5-8 weeks (using a liquid diet for 1-2 months before the study testing was performed).  The average body weight of people in the study was 98 kg (216 lb), and the age range was 19-41 years. All participants lived at the research centre for the duration of the study, and were fed only a liquid formula diet, to ensure their weights were stable for at least 2 weeks before measurements of metabolism were taken.  (a very impressive and dedicated protocol for both participants and investigators, wow!)

They found that in these study participants, the 24h calorie burn was about 450 calories lower for the people who had previously lost weight, regardless of whether that weight loss was just weeks ago, or whether it was years ago (and similar for males and females in the study).  Many full meals come in under 450 calories - I googled this recipe website to give you an idea (though I have not reviewed the recipes per se).  So this means that the person who has lost weight has to eat this much less, EVERY DAY, for years (and possibly forever) in order to maintain that body weight, compared to someone who weighs the same but has never weighed more than that.

Here's an example from that website: it's a lot of food!

While this 450 calorie drop in 24h calorie burn was partly due to a drop in energy burn at rest, the biggest drop was seen in the energy burned by activity (called non-resting energy expenditure). (Read more about all components of daily energy expenditure here). 

So does this mean that people who have lost weight simply exercise less?  No.  Actually, the literature overall suggests that it is energy burn during low-grade activity that declines (ie activities of daily living), because our muscles become more efficient at low levels of physical activity with weight loss. 

So what can you do to combat this reduction in energy burn that happens with weight loss?  Two things.

1.  Be NEAT! NEAT, or non exercise activity thermogenesis, is low grade activity of daily life.  Give up your parking pass and take public transit (which involves more physical activity than driving). If you do drive, park at the far end of the parking lot.  Stand while you talk on the phone.  Take the stairs instead of the elevator.   Read more on NEAT here!

2.  Exercise more.  Easier said than done, and not all may be able to do this because of physical limitations - but it is because of this drop in metabolism that the US Obesity Guidelines recommend more moderate physical activity to prevent weight gain (200-300 mins per week) than they do for weight loss (150 mins per week).  We have only to look at the National Control Weight Registry to see the proof – 90% of Americans who have lost 30 lbs or more, and kept it off for more than a year, exercise for at least an hour each day.

***Be sure to talk to your doctor before starting or ramping up your exercise program, and also to help you find assistance to learn about modified exercises that may work for you if you have physical limitations.***

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2016

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Liraglutide Reduces Heart Disease In People with Type 2 Diabetes

BIG news in the diabetes world was released on Friday - for the first time, a medication in the class called GLP-1 receptor agonists, called liraglutide (trade name Victoza), has been shown to reduce cardiovascular events in people with type 2 diabetes.

The LEADER trial enrolled over 9000 people with type 2 diabetes, who were at high risk of cardiovascular disease, and randomized them to receive either Victoza vs placebo with usual standard of care.

They found that Victoza was better than placebo to reduce the combination of death from cardiovascular disease, non-fatal heart attack and non-fatal stroke. A reduction in all three of these components contributed to the benefit that was seen.   The numbers and details are not yet available - we'll have to wait until the American Diabetes Association meeting in June to find out more.

Here's why this is ground-breaking news: 

We have long been uncertain whether we are actually preventing cardiovascular disease by treating diabetes - we know that the higher sugars are, the higher the risk of heart disease, but it has been evasive to actually prove that lowering blood sugars prevents heart disease. The next question is whether some medications to treat type 2 diabetes could be better (or worse) than others to protect from heart disease.  LEADER has now shown us that treating type 2 diabetes with liraglutide does indeed protect patients from cardiovascular events.

Within the GLP1 receptor agonist group of medications, a study of lixisenatide (called the ELIXA study) showed that it did not increase the risk of cardiovascular events, but it didn't prevent them either.  Studies of the other GLP1 receptor agonists available are currently underway.

As far as other type 2 diabetes medications go, the only other medication that has clearly been shown to reduce cardiovascular disease is empagliflozin, which you can read more about here and here.  Metformin, which is the #1 treatment advised for type 2 diabetes worldwide, has some weak evidence that it prevents cardiovascular events as well.

We will be waiting in anticipation for more details from the LEADER trial in June!


Disclaimer: I have been involved in research trials of liraglutide.  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

www.drsue.ca © 2016

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The Legacy Effect 30 Years Later - Good Control of Diabetes Prevents Heart Disease

A lot of people with diabetes wonder why their doctors and diabetes educators are seemingly obsessed with keeping blood sugars as close to normal as we can.  After all, blood sugars that are only mildly elevated usually don't come with much in the way of symptoms.

The point to keeping sugars as well controlled as possible is to prevent complications of diabetes developing over time - this includes damage to the eyes, heart, kidneys, and nerves in the feet and elsewhere in the body.

And - a new paper published has now shown us that the benefit of good control of diabetes to prevent cardiovascular disease persists for at least thirty years!

The study, which was recently published in the journal Diabetes Care, evaluated patients 30 years after their initial participation in the famed (well, famous in the diabetes world anyway) DCCT trial.  This was a clinical trial that enrolled 1,441 patients with type 1 diabetes, and assigned them to receive either more intense, or less intense, control of their blood sugars for a mean of 6.5 years.

During the 30 years of follow up, they found that the people who were in the tightly controlled group 30 years previously had a 30% reduction in the risk of developing cardiovascular disease, and a 32% reduction in the likelihood of having a heart attack, stroke, or dying from a cardiovascular cause, compared to those who were in the less tightly controlled group.  The tighter blood sugar control during the time of the original 6.5 year study was statistically responsible for all of the difference in cardiovascular disease between the two groups.

This data really impresses upon us the power of what we call the 'legacy effect' - good control of diabetes early on prevents complications later in life.  (Note: there is a similar trial in type 2 diabetics called the UKPDS study, which also showed that the legacy effect exists 10 years later.)

I think it is challenging for anyone to look forward 30 years into the future, and think about the importance of what we are doing now to our future self.  If you think about it, we actually spend a lot of our lives planning for our 30+ year future self.  Take financial planning, for example - most of us structure our home purchases, savings structures, and investments with the goal of planning for the distant future.  As I see it, planning for our health in the future is no different - and for people with type 1 diabetes, we now have very long term data to back this up.

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2016

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