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).

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2018

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2018 Diabetes Canada Guidelines Are Out!

The Diabetes Canada (formerly Canadian Diabetes Association) Guidelines are issued in full every 5 years.   As a coauthor of the Weight Management Chapter, I can tell you that these Guidelines have truly been a labor of love for all of us - more than two years with several rounds of evidence review, drafting, re-drafting as new data comes out.... and this is what makes our guidelines one of the most respected diabetes documents in the world!

The 2018 Guidelines are exciting, with a number of substantial changes from the 2013 edition in terms of approach, rigour of methodology, and recommendations.

Each chapter in the Guidelines is structured with a framework including:

Key Messages

Key Messages For People With Diabetes (this is new and awesome, and reflects that the Guidelines are intended not only for the use of health care providers, but also for people with diabetes)

Recommendations


Over the next weeks, I will be posting blogs highlighting some of the key points and changes to the guidelines, and I'll always include a link to the chapter itself if you'd like to read it in full.

Enjoy!

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www.drsue.ca © 2018

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Ketogenic Diet Controversies

Last week, the Journal of the American Medical Association (JAMA) was rather aggressively promoting an opinion article about the ketogenic diet.  I know I'm getting into some rather controversial waters here, but I feel it is important to point out some concerns that I have about this article.

A ketogenic diet is an eating plan that restricts carbohydrates to a maximum of 20-50g per day (which is very low), which causes the body to burn fat as fuel instead.  The liver converts fatty acids to ketone bodies, which serve as an energy source.  There is often a reduction in hunger on this diet, and perhaps less reduction in energy burn with weight loss.

In support of the ketogenic diet, the first piece of science that the JAMA article discusses is a meta analysis of 13 randomized controlled trials that suggested that more people lose weight and keep it off on a ketogenic diet than people on low fat diets.

A reality check on this analysis: The difference in weight between these two groups was only 0.9kg (2 lb) at one year, and when they analyzed the four studies that continued out to 2 years, there was no difference in weight between the groups at all.

The JAMA article also comments on improvements in several metabolic parameters - but in the meta analysis, the only thing that was significantly different at 2 years was a small improvement in good cholesterol (HDL).

The article goes on to discuss the potential benefits of the ketogenic diet to people with type 2 diabetes.  I am very glad to see that they point out that medications like insulin and some oral medications for diabetes can cause low blood sugars, and have to be adjusted to avoid low blood sugars.

However, nowhere do I see mention of safety issues for people on SGLT2 inhibitors [canagliflozin (Invokana), dapagliflozin (Forxiga), empagliflozin (Jardiance)] - as blogged previously, there is a low risk of diabetic ketoacidosis (DKA) with these medications, and that risk could be increased on the ketogenic diet.   Some people with type 2 diabetes who require multiple doses of insulin per day may also have quite low to absent insulin production of their own, which could be a recipe to increase the risk of DKA on the ketogenic diet.

My third concern about this article is that it suggests that the lifestyle change to a ketogenic diet may not need to be permanent, and that some people may be able to add back a limited amount of carbs.  To me, this encouragement goes against the foundation of long term successful weight management - that lifestyle changes made to manage weight should be permanent changes that can be sustained lifelong. I'm concerned that this opens the door to the yo-yo weight pattern that is consequent to trying a diet plan that is not permanent nor sustainable for many.   

Finally, they include an image of coconut oil in their article. Seriously?  As blogged previously, coconut oil is actually one of the least healthy oils you can eat.

I do appreciate that the ketogenic diet can work for some people. Avoiding carbs helps to avoid a lot of the unhealthy and quick-grab food that permeates our society, from muffins to burgers to snacks at the grocery store checkout.   

We also know that what will work for one person is very different from the next.  So while the meta analysis shows no difference in weight on the ketogenic vs low fat diet at 2 years, there will be people within each of these groups who had success, and others who did not.

I also appreciate that the authors of the JAMA article note that "this is not a do-it-yourself-diet" for both safety and efficacy reasons. 

But I do feel that their review of the ketogenic diet is overly optimistic, misses some important safety concerns in people with type 2 diabetes, and gives inappropriate hope that this diet can be a non-permanent approach, when no lifestyle change that is not permanent is unlikely to result in sustained success over the long term.

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www.drsue.ca © 2018

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Could Your Cholesterol Medication Cause Diabetes?

With any medication, there are benefits and risks that need to be considered.  Medications are generally recommended to a patient when the potential benefit of the medication is felt to be greater than the potential risks.

While it is extremely important for both doctors and patients to be well informed of potential side effects of medications, the media unfortunately loves to hype up side effects, often making it seem like the risks of taking a medication must outweigh any potential benefits.

Statins, a group of cholesterol medications, have taken a particular beating in the media over the years.   A colleague of mine approached me not too long ago saying that he was worried about his patients being afraid of taking their statin cholesterol medications because of fear of developing diabetes as a side effect, and asked me if I would publish a post on this topic.

An excellent review was published in The Lancet, which does a great job of addressing the question of benefit vs risk of statin therapy.

If 10,000 people are treated with statin therapy for 5 years: (with the example given of 40mg of atorvastatin (Lipitor) daily)

Benefits:

• if these 10,000 people had a past history of 'blocked arteries' (occlusive vascular disease) - eg prior heart attack or stroke: 1,000 would be saved from another heart attack or stroke
• if these 10,000 people had no history of vascular disease: 500 would be saved from a heart attack or stroke

Risks: 

• 50-100 will develop diabetes because of their statin
• 5-10 will have a bleeding type (hemorrhagic) stroke
• 5 will develop serious muscle complications

The risk of developing diabetes due to statin medications is higher with the more powerful statins (atorvastatin (Lipitor) and rosuvastatin (Crestor)), and with higher doses.  However, it is precisely these particular statins at the higher doses that have the biggest benefit to prevent heart attacks and strokes in people who have a past history of vascular disease.

People with risk factors for developing diabetes (eg, prediabetes, obesity) are at higher risk of statins tipping them up into diabetes range blood sugars. However, even if a person develops diabetes due to their statin, the health benefit in preventing heart attacks and strokes is much greater than the adverse effect of diabetes on their health, provided the diabetes is well managed.

For people who already have diabetes, statins also have a powerful benefit in preventing heart attacks and strokes, which is felt to far outweigh any small increase in blood sugars that may occur (and can be managed with adjustment to diabetes medication).

As to how statins increase the risk of developing diabetes, another study in The Lancet suggests that it may be related to the mechanism of statins to inhibit an enzyme called HMG CoA reductase, and may be genetically mediated.

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www.drsue.ca © 2018

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Do Low Fat Diets Prolong Life?

There is hot debate (and much buzz in the media) these days as to whether low fat diets are good or bad for us, and whether we have gone overboard in promoting low fat as the way to go in guidelines over the last several decades.

A recent study, published in the British Medical Journal, conducted a systematic review and meta analysis, with their goal actually being to determine whether dietary lifestyle interventions targeting weight loss reduces mortality, cardiovascular disease, and cancer in people with obesity.  They hadn't intended to study low fat diets in particular, but out of the 54 randomized clinical trials that they identified for analysis, all but one of these trials described a low fat diet being included as at least one of their interventions (and all but three trials included some form of exercise advice). The diets were also usually low in saturated fat.

In this analysis of over 30,000 clinical trial participants in studies of at least 1 year duration, they found that weight loss interventions decreased mortality by 18%, corresponding to 6 fewer deaths per 1000 participants in the studies.  Weight loss after 1 year was 3.4kg (7.5lb), and about 2.5kg (5.5lb) after 2-3 years.

That this study found that dietary interventions reduce mortality in people with obesity is noteworthy, as the amount of weight lost was fairly low, and also because singular diet studies have not shown a reduction in mortality.  In fact, the only obesity studies that have really shown a reduction in mortality are those of bariatric surgery.  It is encouraging that perhaps a mortality benefit from lifestyle intervention emerges when we look at enough people together (as in the current study).

But does this mean that low fat diets are the way to go?   Not necessarily.

It is true that we cannot know if the benefits seen in this study were because of the weight lost, because of the low fat nature of the diets, or a combination of both.

However, a problem with the low fat diet approach in real life (ie outside of a clinical trial) is that it most often results in overconsumption of carbohydrates, which has likely contributed to the increase in obesity that we have seen in the last several decades.  The Mediterranean diet, which is not a low fat diet (fat intake is 35-47% of total calories, with a focus on the healthier unsaturated fats), has been shown to be associated with a reduction in mortality (in systematic reviews and meta analyses of cohort and case control studies). 

We must also remember that all systematic reviews and meta analyses of studies are subject to limitations in interpretation as they are compiling data from a variety of different studies, so they must all be taken with a grain of salt.

BOTTOM LINE: This study suggests that weight reducing diets (which happened to be mostly low fat diets) may reduce mortality.  I would now like to see more studies of diets with moderate carbohydrate restriction and more generous unsaturated fat intake to understand if these diets may have the same benefit.

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www.drsue.ca © 2017

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Could Artificial Sweeteners Cause Weight GAIN?

While artificial sweeteners have previously been touted as an excellent way to replace sugar in your diet and help with weight loss, they have in recent years been found to impact our biology in ways that may have adverse effects on our metabolism.  Rather than helping in a quest for weight loss, is it possible that sweeteners could actually cause weight gain and metabolic disease?

A recent systematic review and meta-analysis was recently published in the Canadian Medical Association Journal, which collected the currently available evidence to try to answer this question and received worldwide attention in doing so.  They included 37 trials (including 7 randomized controlled trials and 30 cohort studies), looking at a total of over 400,000 individuals (about 1,000 of whom were in the randomized studies).

In their analysis of the randomized controlled trials, over a median follow up of 6 months, they found no significant effect on body mass index (BMI) or measures of body composition.  So, use of sweeteners did not result in weight loss, but there was no weight gain seen either.

In the cohort studies, over a median follow up of 10 years, they found an increase in weight, BMI, and waist circumference, and a higher incidence of obesity, metabolic syndrome, type 2 diabetes, high blood pressure, stroke, and cardiovascular events.

So overall, none of the evidence assessed showed a benefit to weight, and the observational data suggested adverse effects of sweeteners on weight and health - none of which is good news.  And why is there a difference in conclusions between the randomized trials versus the observational (cohort) data?

Well, it's possible that the randomized trials were not long enough or big enough to show a negative impact on health, and that if they had been longer trials, perhaps results would have been different.

On the other hand, observational (cohort) data does not give us as trustworthy of an answer to any research question, because the results can be muddied by other factors. One concern is that these data may be confounded by 'reverse causation' - meaning that people with obesity, or those more prone to develop obesity (eg family history of obesity) are more likely to use sweeteners to help manage their weight (rather than the sweeteners being the cause of weight gain).

Either way, there is research to suggest biological mechanisms by which sweeteners could have an adverse impact on our metabolic health, particularly in relation to changes they induce in our gut bacteria, as well as our neurobiological response to these chemicals.  Further research is clearly needed to better understand their effect on our health.

Remember also that there is no doubt that excess sugar consumption is associated with weight gain and all of the above metabolic complications - so swapping sugar back in is not the answer either.

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www.drsue.ca © 2017

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Testing Blood Sugar - Is There A Point?

In the management of people with diabetes, we routinely equip patients with glucose meters and ask them to check sugars at home.  While the importance and utility of checking sugars at home for people using insulin is clear, there is much debate about whether this is useful for people with type 2 diabetes who are not on insulin.  A recent study, which got a lot of media hype, tackled this question.

The study, published in JAMA Internal Medicine, randomized 450 people with type 2 diabetes and not using insulin, to either a) no home glucose montoring; b) checking sugars once daily; or c) checking sugars once daily plus automated educational/motivational messages delivered to the patient from the meter.

The researchers found that there was no difference in diabetes control (A1C) nor health related quality of life after 1 year, and concluded that glucose monitoring in people with non-insulin-treated type 2 diabetes should not be routine.

I have some major beefs with this conclusion:

1.   Testing once a day does not tell a person very much about their blood sugar.   In order for home testing to be useful, I advise 'paired meal testing': checking before a meal, and checking again 2 hours later.  This can be very helpful to see how certain types of food affect your blood sugar, and can be help to eat mindfully and manage portion control.  I don't necessarily advise doing this every day: checking each of breakfast, lunch, and dinner once per week can be enough.  However, depending on what kind of medication a person is taking, I may recommend more often.  Also, if diabetes control is not great, then checks (in my opinion) should be done more frequently so that we can figure out how to bring down the sugars effectively and safely.

2.  As the authors note, the study was not powered to determine if there are benefits to checking sugars around the time of medication or dose changes.  It is very difficult for a doctor to know what the next best medication may be without knowing the pattern of blood sugars through the day.  Knowing the pattern of blood sugars is extremely important when new medications are added onto sulfonylureas and insulin in particular, because these medications can cause low blood sugar.  For example, if sugars are highest in the morning and lower later in the day, there is a risk of causing low sugars if a treatment is added that brings down sugars in the morning (as sugars later in the day will go down too).

3.  Compliance with sugar checks in the study was poor by one year, declining gradually over the year, with only about 55% of people in the monitoring groups checking sugars each day by the 1 year mark.  Interestingly, the diabetes control (A1C) was better at 3, 6, and 9 months in the glucose monitoring groups, compared to those not monitoring - perhaps the lack of difference in A1C by 1 year was due to the poor compliance with glucose checks by that point in time.

4.  The study team did not engage with patients after their baseline visit - meaning patients were on their own to interpret their blood sugars without help from the study team.  Their family doctors received a copy of blood sugar results, but the study did not collect info on what was done with that data, and these clinicians had minimal interaction with the study team.  

Diabetes is a team sport - an important part of the benefit of checking blood sugars is to discuss these results with your health care team for help in optimizing control.  While the setup of this study was intended to be 'real world', I would submit that what patients perceived as their 'health care team' during the study (their usual doctors plus study investigators) were not working as a team and this may have limited the best possible use of home glucose monitoring.  And perhaps compliance with checking sugars in the study would have been better if that team was working together and more engaged with the patients, as is the ideal model of care.  We are blessed in Canada to be able to say that for most people in our country, the 'real world' does consist of free access to a team to help each individual with their diabetes care.

5.  For any patient on a sulfonylurea (and of course insulin), sugars must be checked before driving.   For a paper to conclude that glucose monitoring should not be routine (in a study where 36% of patients were on sulfonylurea!) is inappropriate.

Unfortunately, the media took hold of this study and has been shouting from the rooftops that people with non-insulin-requiring diabetes do not need to check their blood sugar.    I would be most saddened if patients get the message that they should stop testing their blood sugars, and would strongly advise people to continue to follow their doctor or diabetes educator's recommendations on how frequent of sugar checks is appropriate.

I hope this blog helps to provide some balance and perspective on what I feel is a study full of limitations.

Disclaimer: I have received speaking honoraria from makers of glucose meters.

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2017

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