Obesity Medication Lorcaserin Neutral For Cardiovascular Events

Lorcaserin (trade name Belviq) is an obesity medication that is not available in Canada, but is used in USA and other countries as a treatment of obesity.  A recent study evaluated the cardiovascular safety of lorcaserin in people with obesity or overweight, with either established cardiovascular (CV) disease, or multiple cardiovascular risk factors but without established CV disease. (skip to BOTTOM LINE below as to why this study is important)

In the study, published in the New England Journal of Medicine, 12,000 people were randomized to receive either lorcaserin or placebo for a median of 3.3 years.  Seventy-five percent of participants had established cardiovascular disease. At one year, people on lorcaserin lost -4.2kg, compared to -1.4kg in the placebo group.   At 3.3 years, there was no difference in the rate of cardiovascular events (a composite of cardiovascular death + nonfatal heart attack + nonfatal stroke) between groups, at 2.0% per year on lorcaserin vs 2.1% per year on placebo.

In people who had diabetes at the start of the study (57% of the total population), diabetes control was improved slightly at 1 year (-0.3% greater reduction in A1C than placebo).  Amongst those with prediabetes at the start, the proportion of people on lorcaserin who went on to develop type 2 diabetes was slightly lower (3.1% per year) than those on placebo (3.8% per year).

The rate of discontinuation of study medication was similar between the two groups, at 12.0% per year in the lorcaserin group vs 12.7% in the placebo group.  In the lorcaserin group, the most common side effects leading to stopping treatment were known potential side effects of dizziness, fatigue, headache, diarrhea, and nausea.

Echocardiogram (heart ultrasound) was performed in a subset of 3270 study participants, because an related obesity medication previously available (fentermine-phenfluramine or Fen-Phen) was found to have an adverse effect on heart valves.  After a year of treatment, they found no statistically significant difference in heart valve problems between the two groups, with 23 cases of new onset, mild aortic valve insufficiency on lorcaserin vs 15 on placebo, and 13 cases of pulmonary hypertension on lorcaserin vs 8 on placebo.

So what's the BOTTOM LINE?    This is the first time that the cardiovascular safety of an obesity medication has been rigorously tested and proven to be safe. Some previously available obesity medications have been pulled from most markets due to safety concerns (eg sibutramine due to increased cardiovascular events in people with CV disease, rimonabant due to psychiatric side effects).

Regarding the three currently available obesity medications in Canada:

• Orlistat (Xenical) has not been tested in this fashion 
• Liraglutide as a diabetes treatment (Victoza 1.8mg) has been shown to reduce cardiovascular events and death in people with type 2 diabetes.  Though liraglutide as an obesity treatment (Saxenda 3.0mg) has not been specifically studied for CV safety, these data are accepted by regulatory agencies as reassurance for CV safety in the lower risk population of people with obesity without diabetes
• Naltrexone/bupropion (Contrave) had a study started but stopped part way through because of a release of interim results that was felt to compromise the integrity of the study. A new trial is now in the planning stages. 

Looking very forward to more safety outcome data in this area.


Disclaimer: I receive honoraria as a continuing medical education speaker and consultant from the makers of liraglutide (Novo Nordisk) and naltrexone/bupropion (Valeant).

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Unprecedented Weight Loss With Semaglutide

Semaglutide is a medication that is used to treat type 2 diabetes (trade name Ozempic).  Not only does it improve blood sugars more than any other medication that it has been compared to (so far) in the diabetes world, but it is also very effective to help with weight loss.  Thus, semaglutide is currently under study as a medication to treat obesity in people without diabetes.

We have now completed the first study of semaglutide as an obesity treatment.  The study, published in The Lancet, in which I was an investigator and also an author of this paper, randomized 957 people to receive various doses of once daily semaglutide, with liraglutide 3mg and placebo as controls. (Liraglutide 3mg is also called Saxenda, which is a medication already in use for treatment of obesity.)

At 1 year, 93% of patients were retained in the trial, which is much better than most studies of weight loss medication, which tend to have much less follow up data. Overall, 81% of patients completed the full year of treatment. A higher percent of the placebo group (24%) stopped treatment than did those on semaglutide (18%).

The weight loss after one year on semaglutide was impressive, ranging from -6.0% weight loss on the lowest tested dose of semaglutide (0.05mg per day) to an impressive -13.8% weight loss on the highest dose tested (0.4mg per day), compared to -2.3% weight loss on placebo and -7.8% on liraglutide 3mg per day.

The weight loss had not plateaued by one year on the highest doses of semaglutide, suggesting that if the study had been longer than a year, even more weight loss may have been seen.

In terms of side effects, gastrointestinal were most common (e.g. nausea), in keeping with what we already know about this class of medication; these side effects increased with higher doses of semaglutide, and were a little higher on the highest semaglutide dose than on liraglutide 3mg.  There was also a higher risk of gallbladder side effects (e.g. gallstones), which was a little more common on the highest dose of semaglutide compared to placebo.

The weight loss seen in this study is more than has been seen with any other existing weight loss medication.  The next phase of studies of semaglutide for weight loss is underway.


Disclaimer: I was a principal investigator in this research trial and an author of the paper discussed. I am/have been involved in other trials of semaglutide and liraglutide as an obesity treatment.  I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide and liraglutide (Novo Nordisk). 

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www.drsue.ca © 2018

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Could Intermittent Fasting Benefit Our Metabolism?

(this figure is from the study discussed below)

Intermittent fasting (IF) is a popular dietary strategy these days amongst people who are looking to shed pounds.  While IF has not been shown to be any better than daily calorie restriction for weight loss, many have speculated that IF may improve cardiometabolic health, with conflicting data as to whether this is actually the case.

A new study suggests that IF at the right time of day may actually improve metabolic health.

The study was small but elegant - 8 men with pre diabetes, who were assigned to intermittently fast using a new technique called 'time restricted feeding' by eating during only 6 hours per day (with dinner before 3pm), or to eat over a more typical 12 hour period each day.  They followed this eating pattern for 5 weeks, and later crossed over to the opposite eating assignment for another 5 weeks.
All meals were supervised, and were geared towards keeping body weight the same (i.e. this was not a weight loss study).

They found that eating only 6 hours per day resulted in improved insulin sensitivity, blood pressure, appetite, and markers of oxidative stress.

How does this work?  Well, there is a hypothesis that after 12 hours or more without food, our bodies flip a 'metabolic switch' of sorts, turning to fat as a fuel source once liver glycogen (sugar) stores have run out (there is an interesting review from the journal Obesity on this).

Interestingly, the time of day when food is eaten seems to be important - while this study showed a metabolic benefit to restricting food intake to 6 hours earlier in the day, other studies restricting food intake to the late afternoon or evening have shown either no benefit or worsening of metabolic parameters (these studies are referenced in the article).  This may be because eating earlier in the day fits better with our circadian rhythm of hormones, as our insulin sensitivity, and also the calories we burn while digesting food are higher in the morning.

We often recommend: "Eat breakfast like a king, lunch like a prince, and dinner like a pauper."  While this principle was founded on the idea of avoiding overeating in the evening due to not eating enough during the day, it seems that there may be a physiologic basis for eating earlier in the day to promote metabolic health.

Perhaps our new slogan should be: Eat breakfast like a king, lunch like a prince... and have your dinner early.

Stay tuned to www.drsue.ca for discussion of a brand new study on intermittent fasting in people with type 2 diabetes, coming soon!

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www.drsue.ca © 2018

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Should Fertility Clinics Deny Treatment To Women With Obesity?

As blogged previously, due to concerns about poor clinical outcomes and maternal/fetal risks, many fertility clinics in Canada impose an upper body mass index (BMI) cutoff of about 35-40 kg/m2, above which they will not offer fertility treatments.  Is this the right thing to do?

The new Canadian Clinical Practice Guideline for the delivery of fertility care to women with obesity reviews the evidence on this very controversial topic.

Based on survey studies of fertility clinics, whether a BMI cutoff is used, and what BMI cutoff is used if so, is highly variable and not based on any specific or clear evidence.  Most clinics that have an upper BMI cutoff beyond which they will not offer fertility treatments cite anesthesia risk as the main reason for the cutoff.

Not only are BMI cutoffs arbitrary and without consensus, getting below the BMI cutoff goals may be very difficult for many women with obesity to achieve.  Furthermore, one study suggested that over half of the fertility clinics with a BMI cutoff did not offer any weight loss instructions or guidance to their patients - sounds to me like telling a person to row a boat but not showing them how to use the oars.

Denying fertility care to women with obesity is highly stigmatizing and discriminatory, and can worsen feelings of low self esteem, social isolation, anxiety, and depression. Denying older women fertility care until they have lost weight may cost them valuable time and any chance of pregnancy.

There is no doubt that there are risks of obesity to both the mother and the unborn child, and weight loss should be encouraged and supported.  However, as the guidelines point out, the risk of obstetrical obesity-related complications does not clearly exceed the risk of complications with other pre-existing medical conditions like hypertension, diabetes, or epilepsy. In addition, obesity related health status is a better predictor of pregnancy with fertility treatment than BMI, and also a better predictor of overall health outcomes in general, so why is there so much focus on the numbers on the scale in the first place?

As the Guideline states:

In the absence of simple, safe, and effective strategies that reliably help patients with obesity lose weight in a timely fashion, it is difficult to advocate for a universal BMI cut-off in place of careful counselling, screening for metabolic abnormalities and informed consent. 

Programs that impose BMI cut-offs should offer resources for patients to help them lose weight, and should inform patients about both the risks and benefits of delaying fertility treatment.

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www.drsue.ca © 2018

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Fertility Care For Women With Obesity

Obesity has a profound impact on reproductive health from many perspectives. We now have a brand new Canadian Clinical Practice Guideline which provides us evidence based recommendations for fertility care for women with obesity.

The Guideline, published in the Journal of Obstetrics and Gynecology of Canada, provides 21 key recommendations that answer the following questions (highlights discussed here - please see the full article for details):


What is the impact of obesity on female fertility?

Women with obesity have a risk of infertility due to a lack of ovulation that is more than twice that of women without obesity.   Even if ovulating, the physiologic ability to reproduce is still reduced.


What is the impact of obesity on MALE fertility?

While men with obesity have lower testosterone levels, it is unclear whether obesity has an impact on sperm quality and semen parameters. Men with obesity do have a higher risk of erectile dysfunction, which may be improved with weight loss.


What is the impact of female obesity on fertility treatments?

There is a lower oocyte (egg) yield with IVF. Implantation, pregnancy and live birth rates decline with increasing severity of obesity.  Live birth rates decline by 0.3-0.4% for every 1 increase in BMI over 25 kg/m2.


What is the impact of obesity on mum's health risk in pregnancy?

There is an increased risk of gestational diabetes, high blood pressure, prolonged labor, need for instrument assistance for delivery, shoulder dystocia, and C-section.   These risk increase with higher BMI.


What is the impact of obesity on baby's risk during pregnancy?

The risk of having a large baby or a baby with a congenital abnormality is increased.


What screening tests are appropriate for women with obesity seeking fertility care?

Screening should include testing for diabetes, cholesterol levels, high blood pressure, cardiovascular disease, breast cancer, and endometrial cancer.   These screenings should be done before starting fertility treatment.


What are the most effective treatments to help infertile women with obesity lose weight?

Modest weight reductions (5-10%) improve metabolic risk. Help should be offered for lifestyle modifications.  Medications to treat obesity, or bariatric surgery, should be considered for those who do not have success with lifestyle changes.

Women in their late reproductive years who have had bariatric surgery should be advised that the possible benefits of waiting for 1-2 years after surgery to conceive should be balanced against the decline in fertility related to advancing age. 

Bariatric surgery lowers the risk for large babies, gestational diabetes and hypertension, but increases risk for small babies.


Is there data demonstrating a difference in fertility outcomes for women who lose weight before pregnancy, compared to women who proceed directly to fertility treatment?

Yes - weight loss improves spontaneous fertility rates.


Should there be a national BMI cutoff for access to fertility care?

In Canada and around the world, concerns about poor clinical outcomes and maternal/fetal risks have resulted in many fertility clinic medical directors imposing an upper BMI cutoff to their program, above which they will not offer fertility treatments.  Stay tuned on this one - I am going to dedicate a whole blog post to discuss this very important and hotly debated topic.

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www.drsue.ca © 2018

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How Weight Loss Affects Different Body Tissues, Fat Genes, And Inflammation

(this is fat tissue under a microscope)

We know that a 5-10% weight loss improves many health conditions associated with obesity.  However, it is very interesting to note that some health issues like blood sugar starts to improve with as little as 2-3% weight loss, whereas other health issues like sleep apnea require closer to 10% weight loss before we start to see improvements.  Why is this?


An eloquent study helps us to understand how different tissues in our body respond to weight loss.  This was a randomized controlled clinical trial, assigning 40 patients to a target 0%, 5%, 10%, or 15% weight loss, and then conducted an array of testing to understand the metabolic changes that occur at each of these degrees of weight loss.  Testing was extensive and included assessment of body composition, 24h blood pressure monitors, blood testing for metabolic parameters and inflammatory markers, tests of organ-specific insulin sensitivity, and even biopsies of fat tissue. Participants were weight stable for at least 3 weeks before testing was conducted.

Key findings were truly fascinating.

After a 5% percent weight loss:

• There was a decrease blood sugar, insulin levels, triglycerides, ALT (liver test)
• systolic blood pressure decreased (the top number), but not diastolic (bottom number)
• NO effect on good cholesterol (HDL), bad cholesterol (LDL), glucose tolerance test (OGTT)
• improvement in insulin sensitivity in fat, liver, skeletal muscle 
• improvement in beta cell function (the cells in the pancreas that make insulin)

After 11% weight loss: (the 10% group ended up losing 11%)

• continued reduction in insulin and triglycerides 
• altered gene expression in subcutaneous fat tissue - including genes involved in fat synthesis, cholesterol flux, and inflammation
• no additional benefit to insulin sensitivity in fat tissue or liver
• additional improvement in insulin sensitivity in skeletal muscle
• additional improvement in beta cell function

After 16% weight loss: (the 15% group ended up losing 16%)

• reduction in inflammatory markers (plasma free fatty acids, CRP)
• more marked altered gene expression in subcutaneous fat tissue - including genes involved in fat synthesis, cholesterol flux, and inflammation
• continued reduction in insulin and triglycerides
• no additional benefit to insulin sensitivity in fat tissue or liver
• additional improvement in insulin sensitivity in skeletal muscle
• additional improvement in beta cell function

So what is the BOTTOM LINE from this (rather complicated) study?   

1. A 5% weight loss has important benefits to our health, primarily related to a decrease in our body's resistance to insulin.  

2. Further weight loss continues to improve our body's insulin resistance (particularly in muscle), with additional improvements in our metabolic health.  

3.  At 11% weight loss, we start to see changes in how our fat tissue expresses genes, in favour of better health.

4.  At 16% weight loss, there is a decrease in inflammation in our bodies, and a more marked change in fat tissue gene expression.

While a smaller degree of weight loss (even just 2-3% based on other studies) has a very important impact on our metabolic health, the changes in inflammation and fat gene expression seen at over 10% weight loss may well be what it takes to see benefits in other medical conditions associated with obesity, such as obstructive sleep apnea and arthritis.

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How Your Diet Influences Where You Lose Fat

In weight management, our goal is to improve overall health.  In a perfect world, it would be preferable if we could melt away the fat around and inside the internal organs (called 'visceral fat') rather than the fat under the skin, as it is this visceral fat that contributes most to health complications of obesity such as diabetes, high blood pressure, and metabolic syndrome.

A recent study suggests that what we eat actually can help us to target this visceral fat.

The CENTRAL study, published in the journal Circulation, randomized 278 sedentary adults with either abdominal obesity or high cholesterol to follow either the Mediterranean diet versus a low fat diet for 18 months.  Six months into the trial, participants were also randomized to follow an exercise program or not. They used MRI scans to evaluate fat under the skin, fat around the organs, fat in the liver, pancreas, and even around the heart.

At the end of the 18 month study, weight loss was the same between all four groups (Mediterranean vs low fat diets, with or without exercise) at -3.2%.   However, where fat was lost from, and how this influenced health, was different between groups:

• People on the Mediterranean diet lost more fat from the liver, pancreas, and around the heart. 
• Exercise with either diet had a greater effect on reducing visceral fat. 

Whether or not total body weight was lost: 

• Losing visceral fat and/or liver fat improved cholesterol.
• Losing fat deep under the skin improved insulin sensitivity.
• Losing fat just under the skin had no effect on health and reduced levels of leptin (a hormone that tells our brains that we feel full). 

The findings that the Mediterranean diet preferentially reduces the more dangerous visceral fat may explain why it is the only diet that has been convincingly found to prevent cardiovascular events.  

These results also show us that it's not about numbers on the scale, as this does not reflect the important changes going on with fat deposit patterns inside. 

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www.drsue.ca © 2018

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