Diabetic Neuropathy

One of the main reasons why long term blood sugar control is so important in diabetes is the prevention of diabetes complications.   Diabetic neuropathy, which is damage to nerves caused by chronic elevation in blood sugars, is one of the complications we are trying to prevent.   Diabetic neuropathy affects a lot of people (you may be surprised by just how many - read on!), can be present in people who don't even have diabetes yet, can take many different forms, and can have a profound impact on the quality of life of people living with diabetes.

The American Diabetes Association has recently released a Position Statement (download is free) to help guide clinicians in understanding, diagnosing, preventing, and managing this complication of diabetes.

Some key points from this article:

1.  Diabetic neuropathy (DN) is a diagnosis of exclusion.  In other words, just because a patient with diabetes has findings of neuropathy, doesn't mean that the diabetes is necessarily the cause.  Other causes of neuropathy (discussed in the article) need to be ruled out before the nerve problem is attributed to diabetes as the cause.

2.  There are many types of diabetic neuropathy.  Distal symmetric polyneuropathy usually starts with symptoms in the feet, including numbness, tingling, pain, and burning, especially at night.  Autonomic neuropathies can affect/include the heart, ability to maintain blood pressure when standing up (orthostatic hypotension), the gastrointestinal tract, urinary tract, sexual dysfunction, or dysfunction in sweating. There are also forms of diabetic neuropathy that can affect specific nerves (cranial or peripheral), or bundles of nerves as they exit the spinal column.

3.  Diabetic neuropathy is common. Distal symmetric polyneuropathy affects 50% of people with type 2 diabetes after 10 years, and 20% of people with type 1 diabetes after 20 years.  Autonomic neuropathy involving the heart may affect up to 60% of people with type 2 diabetes after 15 years, and up to 30% of people with type 1 diabetes after 20 years.

4.  Diabetic neuropathy can be present in people with prediabetes.  Distal symmetric polyneuropathy may be present in 10-30% of people with impaired glucose tolerance, and autonomic neuropathy affecting the heart has been found in people with impaired glucose tolerance as well.

5.  Prevention of diabetic neuropathy is key, as there is no effective treatment available for established nerve damage.  Prevention is achieved primarily through optimizing blood sugar control. Lifestyle interventions are recommended for prevention in people with prediabetes or type 2 diabetes, and a multifaceted approach including targeting of cardiovascular risk factors is recommended for prevention of cardiac autonomic neuropathy in people with type 2 diabetes.

6.  Management of established diabetic neuropathy is directed towards the particular type of neuropathy each patient has.  This can include pain control medication, fall prevention, and specific treatments to manage symptoms of the autonomic neuropathies.

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The Bugs In Your Gut - Could They Cause Obesity or Diabetes?

Did you know that you have more bacterial cells inside your intestines than you have human cells in your entire body?  Not only that, but they house somewhere between 250 to 800 times more genes than we have human genes in our body.   Perhaps it's not so far out, then, for us to learn that these bacteria (called the 'microbiome') play an important role in our metabolism, and are very likely to contribute to the risk of both obesity and type 2 diabetes.

A wonderful Viewpoint article in JAMA (free to read online here) outlines what we know about this topic so far.

The microbiome has many important functions, including the production of important amino acids (protein building blocks) and vitamins, and they also help to degrade toxins.  The genes in these bacteria also produce hormones and inflammatory molecules that enter our circulation and effect our health.

These bacteria also play a role in how many calories we absorb from food, because they make enzymes that help us to digest polysaccharides, a type of carbohydrate.  Some types of gut bacteria are better at this than others, and studies have shown that people with obesity carry more of the carb-digesting bacteria (called Firmicutes) than people without obesity.  Interestingly, some studies have shown that when a person with obesity loses weight, particularly after bariatric surgery, the proportion of 'good' bacteria (called Bacterioides) increases relative to the 'bad' Firmicutes. Overall, the studies suggest that the gut bacteria may be both a cause and a consequence of obesity.

Along with the increased capacity to absorb carbs in people who carry more Firmicutes bacteria, so comes an increased risk of having not only obesity, but also type 2 diabetes.  Altered production of short chain fatty acids by gut bacteria, as well as low grade gut inflammation caused by chemicals made by the microbiome, also contribute to insulin resistance and diabetes risk.

So how does this play out in terms of treatment of obesity or diabetes? Well, some studies (mostly done in rodents, but some in humans too) have shown that manipulation of the gut microbiome by way of stool transplants (yep, transplanting poo), or perhaps by other modalities such as change in diet or probiotics, may be able to have an effect on the type of bacteria we have, but we are far from developing concrete treatment approaches.   However, as we learn more about our gut bugs and the genes they carry, we come steps closer to learning how we may ultimately be able to incorporate microbiome modification into our treatment options for obesity and metabolic syndrome.

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New Canadian Diabetes Association Clinical Practice Guidelines Update

While the full Canadian Diabetes Association (CDA) Clinical Practice Guidelines are formally updated every 5 years (with the next edition due in 2018), interim updates are published if new evidence emerges that is considered to be practice changing.  As such, the CDA has just released an interim update with revised recommendations, in light of the new cardiovascular outcome trial of a diabetes medication called liraglutide.

As blogged previously, in people with type 2 diabetes who were at high risk of cardiovascular disease, the liraglutide cardiovascular trial (called the LEADER trial) demonstrated that liraglutide reduced the risk of cardiovascular events by 13%.  Put another way: if 66 people are treated for 3 years with liraglutide, one cardiovascular event would be prevented.

In the LEADER trial, 81% of patients had a past history of established cardiovascular disease, while 19% of patients did not (but they were still considered to be at high risk of CV events due to their risk factors).  Subgroup analyses suggested that it was patients who had a history of established cardiovascular disease who had the reduction in risk with liraglutide. As patients had to be age 50 or older to be included in the study, we do not know if these findings apply to a younger population.

In the revised CDA Guidelines, liraglutide now joins another medication called empagliflozin, as medications to consider after metformin, in patients with type 2 diabetes and established cardiovascular disease, who are not at target blood sugar control.  As ongoing cardiovascular outcome trials of diabetes medications are completed and published, the CDA Guidelines will be updated accordingly.

I have pasted the new algorithm below, but the resolution isn't great - it's a little friendlier on the eyes here.

Disclaimer: I am a member of the Expert Committee for the writing of the Canadian Diabetes Association 2018 Clinical Practice Guidelines. 

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Poke Free Blood Sugar Monitor Helps Prevent Lows

On behalf of my patients who struggle with the discomfort of having to poke their fingers to check their blood sugars every day, I am super excited about a new poke-free technology that will hopefully be approved in Canada soon – the Freestyle Libre.  With this glucose monitoring system, a small patch is applied to the upper arm with a tiny filament underneath which inserts under the skin.  Wave your glucose monitor over the patch and voilà! – the last 8 hours of blood sugars, including current blood sugar, are transmitted to your monitor for evaluation.  Not only that, but it tells you the current trend in sugar (ie if your blood sugar is on its way up, down, or stable).

In the first randomized controlled trial of this device, it has now been show that monitoring with the Libre helps patients with type 1 diabetes prevent hypoglycemia (low blood sugars).  The study, published in The Lancet, randomized 241 patients with good blood sugar control to the Libre vs usual monitoring with finger pokes.  They found that over 6 months, people using the Libre spent 38% less time with low blood sugars than people using standard finger pokes.  (Despite this benefit, people using the Libre still spent a shocking 2 hours per day with low blood sugar, compared to 3.3 hours per day for people taking finger pokes - so clearly a better monitoring approach is only part of the solution.)

Ten patients reported concerns related to the sensor, primarily itching, allergic reaction, or redness at the site (not out of keeping of the usual risk of reactions to medical devices that stick to the skin).  Some aspects of quality of life were reported to be improved as well – not surprising,  since studies have shown that people with diabetes who have had severe low blood sugar in the past fear this occurring again as much as they fear blindness as a complication of their diabetes.

It would be interesting for this study to be repeated in people with type 2 diabetes, and also to compare the Libre to the continuous glucose monitoring system.

Bottom Line: The Libre would be a strong addition to our blood glucose monitoring options for diabetes in Canada.

Disclaimer: I have received honoraria as a continuing medical education speaker and consultant from the makers of the Freestyle Libre (Abbott). 

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www.drsue.ca © 2016

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Type 2 Diabetes Medications Exenatide Weekly and Dapagliflozin Studied In Combination

In the wake of the recent annual European diabetes (EASD) meeting, another important study (and heavy science blog post!) coming your way today.

In the care of people with type 2 diabetes, we have fully 9 classes of glucose lowering medications to choose from in Canada.  While some of these medications can cause weight gain, others are weight neutral, and some can cause weight loss, in addition to improving blood sugar control.  Two classes of medications can cause weight loss, namely the GLP1 receptor agonists, and the SGLT2 inhibitors.  As 90% of people with type 2 diabetes also have overweight or obesity, it is of interest to know whether these two classes of medications can be used together, for even better blood sugar control and greater weight loss.

Two of these medications, the GLP1 receptor agonist exenatide qweekly (Bydureon) and the SGLT2 inhibitor dapagliflozin (Forxiga) have now been studied in combination.  Recently published in The Lancet Diabetes & Endocrinology, the study randomized 695 patients with a baseline hemoglobin A1C of 8-12% to receive either exenatide qweekly, dapagliflozin, or the two medications in combination. 

After 28 weeks, hemoglobin A1C decreased by 1.6% in the exenatide group, by 1.4% in the dapagliflozin group, and by 2.0% in the combination group.   While the medications together were better than either drug alone, the benefit was not additive.  This does not surprise us, as we know that the higher starting A1C, the greater reduction we will see – so to be on two medications together would not expect to give an additive result compared to either medication alone.

The weight loss seen was additive, with a loss of -1.54kg in the exenatide group, -2.19kg in the dapagliflozin group, and -3.41kg in the combination group. Blood pressure reduction also exhibited an additive response, with a systolic BP reduction of -1.3mmHg on exenatide, -1.8mmHg reduction on dapagliflozin, and a full -4.2mmHg reduction on the combination.  These additive benefits make sense, given that each of these medications has a different mechanism of action on weight and blood pressure.

From a safety point of view, side effects that were seen were as expected from what we already know about each of these classes of medications, with no suggestion for any negative side effects of using the two medications in combination.

Finally, we have much awaited data that shows us that these two medications can be used safely in combination, with the result of better diabetes control, and an additive effect on both weight loss and blood pressure.

Disclaimer: I am involved in research trials of GLP-1 receptor agonists and SGLT2 inhibitors.  I receive honoraria as a continuing medical education speaker and consultant from the makers of exenatide and dapagliflozin (Astra Zeneca). 

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www.drsue.ca © 2016

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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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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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