Diabetes Medication Semaglutide Decreases Cardiovascular Events

Hot off the presses from the New England Journal of Medicine – an emerging type 2 diabetes medication called semaglutide has been shown to decrease cardiovascular events in a high risk population with type 2 diabetes.

The two year study, called the SUSTAIN-6 study and in which I was an investigator, enrolled 3,297 people from 20 countries around the world who had established cardiovascular disease, or at least one cardiovascular risk factor.   They were randomized to receive either semaglutide 0.5mg, semaglutide 1.0mg, or placebo as once weekly subcutaneous injections.

The primary outcome of the study, which was a composite outcome of first occurrence of nonfatal heart attack, nonfatal stroke, or cardiovascular death, was found to be reduced by 26% compared to placebo, with 6.6% of patients on semaglutide experiencing an event, vs 8.9% of patients on placebo.   When we look at these endpoints individually, there was a significant reduction of 39% of nonfatal stroke, whereas the differences in nonfatal heart attack and death were not significant.  

Although all patients in the study were treated to achieve target glycemic control, blood glucose control was better in the semaglutide groups, with hemoglobin A1C reduced by 0.7% and 1.0% in the semaglutide 0.5mg and 1.0mg groups respectively, compared to placebo, despite the fact that insulin needed to be started twice as often in the placebo group than in the semaglutide group.

In terms of other complications that we are aiming to prevent in people with diabetes, rates of new or worsening kidney disease was reduced with semaglutide.  The risk of retinopathic (eye) complications was higher, experienced by 3% of patients on semaglutide vs 1.8% of patients on placebo.  Rarely, achieving glycemic control rapidly (particularly when sugars start off very high) can paradoxically increase the risk of eye complications.  It is not clear if this was the reason in these patients; a direct effect of semaglutide cannot be ruled out.

So what does this mean for the care of people with type 2 diabetes?  The above results suggest that 45 people with type 2 diabetes and high cardiovascular risk would need to be treated for 2 years in order to prevent one cardiovascular event.  In the diabetes world, this is an impressive benefit, similar to the benefit of statins for cholesterol, and also in a similar realm to the two other diabetes medications, empagliflozin and liraglutide, that have been shown to prevent cardiovascular events (read more here and here).  The data showing cardiovascular benefit on all three of these medications has come out within the last year – before that, we did not have definitive evidence that any diabetes medication clearly reduces the risk of cardiovascular events.

It is indeed wonderful that we now know that some glucose lowering medications are able to prevent cardiovascular events in people with type 2 diabetes.  While semaglutide has not yet been approved for use, this study suggests that it will be a beneficial addition to our type 2 diabetes treatment armamentarium.

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

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www.drsue.ca © 2016

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Barrier to Exercise - Low Sugars in Diabetes

A healthy lifestyle includes exercise, and is part of standard recommendations to most people for maintenance of health and well being.  People with diabetes who take medications that can cause low blood sugar usually have to alter medications and/or food intake to avoid having a low blood sugar induced by the exercise.  A low blood sugar can be a very frightening experience -  sadly, as a recent study shows, the fear of having low blood sugars may actually prevent people with type 1 diabetes from engaging in exercise.

The study, published in the Canadian Journal of Diabetes, surveyed over 500 adults with type 1 diabetes, asking about how they manage their diabetes in the context of exercise.

The majority of these people said that they increased carbohydrate intake before (79%) and after (66%) exercise, and about half of them decreased their meal time insulin before and/or after exercise.  Despite making these adjustments, however, 70% of people reported that they still experience low blood sugars after exercise.  Fear of low blood sugars was identified as a barrier to exercise.

While people with type 2 diabetes were not surveyed in this study, I can attest to the fact that people with type 2 diabetes who are taking medications that can cause low blood sugars (insulin, sulfonylureas, and meglitinides) share these concerns and struggles in preventing low sugars with exercise.

Newer insulins are becoming available to decrease the risk of low blood sugars, and much work is being done to advance the technology in glucose sensing and insulin pump devices as well. For people with type 2 diabetes, medications that do not cause low blood sugar may be an option.    But for those who do take insulin or medications that can cause low sugars, the most important part of avoiding lows around exercise as much as possible is working closely with your diabetes educator to find strategies that work for you.  Each person will be different in terms of what medication they are taking; what kind of exercise is being done and for how long; eating patterns; and how your body responds to that particular exercise.  If you have diabetes and are struggling with preventing lows around exercise, be sure to see your diabetes educator to explore strategies that will work better for you.

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www.drsue.ca © 2016

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Duodenal Mucosal Resurfacing for Treatment of Type 2 Diabetes?

Our knowledge and understanding about the role of gut hormones in type 2 diabetes continues to grow, as we get a better understanding of the mechanisms involved in the often dramatic improvement in diabetes that is seen after bariatric surgery.  In gastric bypass surgery, we know that at least one of the mechanisms involved is food literally bypassing the first segment of the small intestine, called the duodenum.  This effect may be seen because food is more rapidly delivered to the intestine further down, causing a more powerful release of hormones from the more distal intestine (called the hindgut hypothesis).  However, there may also be an as yet unidentified hormone (or hormones) secreted by the first part of the gut that have an antidiabetic effect, and by having food skip over this part of the gut, this mystery antidiabetic hormone is not released, thereby improving blood sugar control (called the foregut hypothesis).  We do know that the surface of the duodenum in a person with diabetes is altered, with a sort of overgrowth of cells in the duodenal mucosal (called hypertrophy and hyperplasia).

For believers of the foregut hypothesis, a novel approach called Duodenal Mucosal Resurfacing (DMR) is now being studied to see if diabetes control can be improved by doing a sort of 'thinning out' of the lining of the upper part of the intestine.

The first human study of DMR, recently published in the journal Diabetes Care, performed the DMR procedure in 39 patients with type 2 diabetes.  They found an improvement in diabetes control at 6 months post procedure, with greater improvement in those who had a longer segment of the duodenum ablated than those that had a shorter segment treated. Improvement in blood sugars was seen as soon as 1-2 weeks after the procedure, despite no restrictions in diet or calorie intake being recommended.  The improvement in diabetes control was not as powerful as what is seen with gastric bypass surgery, suggesting that there are many additional elements at work in gastric bypass surgery.  The authors also noted that there was some erosion of the improvement in diabetes control at 6 months, so certainly larger and longer studies need to be done to understand what the effect of this procedure is over the long term. There was little weight loss in this study (only a few kg), so the DMR does not hold promise as a weight management strategy.   The procedure was well tolerated overall, though there were three cases of duodenal stenosis that were treated with balloon dilatation.  The authors noted no signals for malabsorption (eg no calcium abnormalities or iron deficiency anemia), but this would need to be evaluated carefully in long term studies as well.

It will be interesting to see further study of the DMR procedure.

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Do Electric Assist Bikes Count As Exercise?

While highly frowned upon when snuck into the Tour de France (are you kidding me?!), electric bikes can be a very useful piece of equipment to zip around town.  These are bicycles that are equipped with electrical assistance, which is activated only when the rider is actively pedalling.  You may wonder – does using these bikes still count as exercise?  A recent study tells us – yes!

The study, published in the European Journal of Applied Physiology, enrolled 20 people who led sedentary lifestyles, and evaluated several measures of health after 4 weeks of using the electrically assisted bike for at least 40 minutes, three days per week. 

They found that using the ‘pedelec’ bikes provided a moderate level of exertion, similar to walking (4.9 METs on average).  After just 4 weeks, there was an improvement in their glucose tolerance, and an increase in their power output and VO2max (a measure of maximal aerobic capacity).    Participants also found the bikes to be fun, to the point where over half of participants ended up cycling over 50% more than the required amount.

So, while using a regular bicycle would provide more exercise, a pedelec bike is a great option for people who have knee problems, struggle to get uphill on a bike, or if you want to get further in a day than you otherwise would on a regular bike.  (We used them on a trip Kyoto last year so we could make it to all the far flung temples we wanted to see – fantastic!)    Pedelecs remove the potential deterrents of cycling such as longer distances or hills, and they can be incorporated into daily life as a means of transport when the weather/climate permits (rather than having to find specific extra time in the day to exercise).  

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www.drsue.ca © 2016

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Does Losing Weight Improve Fertility in Polycystic Ovary Syndrome?

Polycystic ovary syndrome (PCOS) is a very common cause of infertility.  Women with PCOS often have infrequent periods, decreased or absent ovulation, and can also have unwanted hair growth (eg to face or abdomen) and/or acne.  The underlying problem is that of insulin resistance, which (long story short) causes the ovaries to overproduce testosterone.  While about half of women with PCOS have a normal and appropriate body weight, the other half have overweight or obesity; also, we know that PCOS gets worse with weight gain and better with weight loss (in those who carry excess weight).

So, a natural question to ask is whether weight loss could improve fertility in women with PCOS and overweight or obesity.

A study was recently published to answer this question.  In the study, which was a post hoc analysis of two concurrently run randomized clinical trials, four approaches were compared in women with PCOS, infertility, and overweight or obesity:

• immediate treatment with clomiphene
• birth control pill for 4 months followed by clomiphene
• lifestyle treatment and antiobesity medication for weight loss for 4 months, followed by clomiphene
• birth control pill and lifestyle treatment and antiobesity medication for weight loss for 4 months, followed by clomiphene

They found that women who were treated with clomiphene without weight loss treatment had an ovulation rate of 45%, and a birth rate of 10.2%.  These numbers were nearly identical in the women who were on the birth control pill for 4 months before getting clomiphene.

In contrast, women who had lifestyle/antiobesity medication (with or without the birth control pill) had a higher rate of ovulation (63%) and a higher birth rate of 25%.  They lost an average of 6.5% body weight in the four month treatment period before receiving clomiphene.

For a woman with PCOS and infertility who carries excess body weight, these finding could present a dilemma: does one go ahead with fertility treatment and hope for the best, or is it better to try to lose weight first, before embarking on fertility treatments?  Women are more likely to start thinking about getting pregnant well into their 30s in this day and age, so there may be a palpable time pressure against taking the time to try to lose weight first.  An important point to consider is that not only does weight loss improve fertility (as per this trial), but it also decreases the risk of the future child developing obesity and type 2 diabetes.  In addition, going into pregnancy with a healthier weight and carrying a healthier weight in pregnancy also decreases the risk of many complications of pregnancy, including gestational diabetes, pregnancy induced hypertension, and babies born large for gestational age (which carries a host of risks and potential complications).

Finally - a note that antiobesity medications must be stopped before attempts to become pregnant, as there is no safety data on these medications in conception/pregnancy.

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www.drsue.ca © 2016

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Does Exercise Improve Fatty Liver Disease?

Nonalcoholic fatty liver disease is a potential consequence of carrying excess body weight, and is essentially caused by extra fat being stored in the liver. It is the third most common cause of liver cirrhosis, and affects up to 30% of the world’s population. 

Weight loss has been clearly established as the first line treatment for NAFLD, and we know that most successful weight loss strategies focus most attention on reducing calorie intake, with exercise playing only a minor part.  However, we know that exercise can have many cardiometabolic benefits even if a person doesn’t lose weight because of it, so it would be interesting to know if exercise itself could improve NAFLD.

A study was recently published in JAMA Internal Medicine which addresses this question.  In the study, 220 participants with NAFLD were randomly assigned to moderate exercise (brisk walking for 30 mins, 5 days per week) for a year, vigorous exercise for 6 months followed by moderate exercise for 6 months, or no additional exercise for a year.

They found that moderate and vigorous exercise were equally effective to reduce fat content in the liver, and that most (but not all) of the effect was mediated by weight loss. 

So, while actual reduction in weight remains the key factor in improving fatty liver, exercise may play some role even if the exercise itself doesn’t shed a whole bunch of pounds.  And it is good news that moderate activity is just as good as intense activity, as moderate exercise regimens like walking are more likely to be adhered to in the long run.

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www.drsue.ca © 2016

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(In)Accuracy of Your Wrist Technology for Estimating Calorie Burn

There are many different kinds of wrist technology out there - Garmin, FitBit, and Jawbone UP just to name a few.   In response to concerns that these devices may not be accurate to measure energy burn, researchers have now conducted a study to test how accurate they are.


The study, published in JAMA Internal Medicine, examined several brands of wearable energy tracking technology, and compared them to gold standard research methods of measuring energy burn, including both a standardized day (indirect calorimetry using metabolic chamber) and fifteen free living days (doubly labeled water method).  Brands studied included the Garmin VivoFit, Jawbone UP24, and FitBit Flex.

They found that these wearable devices were overall quite inaccurate, with inaccuracies ranging as high as 590 calories per day. !  Most of the inaccuracies were underestimates of caloric needs, while some overestimated needs.

So does this mean that these devices are totally useless?  No.  They can be great motivation for keeping track of daily activity and steps taken per day (pedometer) - though there are inaccuracies here as well.  But I do see a lot of people with weight struggles feeling frustrated that they seem to be burning way more calories (according to their device) than the food they are eating, yet they are not losing weight.   Overall, the biggest benefit of these devices is probably motivation to move, and keeping us engaged in mindful eating (ie we think more about what we are eating if we are keeping track of it).

Follow me on twitter! @drsuepedersen

www.drsue.ca © 2016

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