This week was my fifth diaversary. It is a word you will not find in the dictionary and is used exclusively in the diabetes community. In short, it is five years since I was diagnosed with Type 1 diabetes.

It may seem a strange thing to celebrate, the acquisition of a chronic, damaging, sometimes fatal disease but it is important, at least to me.

To celebrate I went all out with Italian:

• Half of a 14″ meat-lovers pizza
• 4-inch square of lasagne
• half a garlic bread roll
• single serve of tiramisu

A nightmare to manage for most Type 1s. Being a honeymooning LADA, albeit an insulin-independent one, helped although I still spiked, peaking at around 12.2mmol/L (220mg/dl) and then headed down.

So why subject my body to such a stress? Because sometimes it is the healthiest thing you can you do for yourself.

My Usual Eating Routine

I characterise my diet at “lowish carbohydrate”. Where there is an obvious, practical low/no carbohydrate alternative to a food, I will eat it. I do not drink sugary drinks, opting for the ‘diet’ alternatives. I am very comfortable with sugar substitutes such as phenylalanine and sucralose. As a general rule I try to make sure anything solid I eat has 10% net carb or less and, for liquids, zero carbs. That is it.

The result, when I stick to this, are blood glucose traces like this.

The thing is, even with these relatively light rules, it still requires commitment and effort to maintain. If I am eating out, I need to scan the menu for the friendliest options. I need to make sure, if I order a soft drink, that the diet version has been served and not its sugar-filled cousin and so on.

Other Common Eating Regimens

Other common eating regimens for people with diabetes are even stricter. If we consider Bernstein’s approach we are eating:

• 30g of net carb or less per day
• Roughly the same amount of carb every day for breakfast, lunch, and dinner e.g. 6g, 12g, 12g
• Eating at roughly the same time every day

That is a lot to keep on top of and while I am sure the ‘Gritters’ will say it is not a big deal and worth it because “we deserve normal blood sugar levels” there is no doubt it does require effort and will impact social interactions with those not complying with this routine.

The strictest of all is probably the zero-carb carnivore diet. This pretty much speaks for itself; if it was not once part of an animal (or is a drink with practically no calories) it is off the list.

At the other end of the spectrum we have the Forks Over Knives advocates, where eating involves a “plant-based diet”. In short a “small v” vegan diet where no foods are off-limits but some (those from animals) are to be avoided.

This one is relatively friendly and, for those looking to reduce insulin resistance the benefits of avoiding animal fats may outweigh the additional carb intake.

Whatever system that is followed, assuming a person with diabetes is adopting some kind of food management, rules mean conscious effort.

The Risk To Mental Health

Orthorexia nervosa is defined as “an unspecified feeding or eating disorder characterized by an exaggerated, unhealthy obsession with healthy eating”. “The affected individual might be driven by dietary asceticism, cherry-picked evidence, or even by evidence-based recommendations, leading to a restrictive dietary pattern in pursuit of improved health”. Overly strict diets which individuals religiously follow, and myths about the food we eat feed, reinforce this kind of unhealthy thinking.

Another aspect is willpower (also known as volition) is a finite resource. A person can only perform conscious actions for so long before they need to take a break. A person with diabetes is ‘on’ 24-7 (except possibly the closed loopers but they are still the exception rather than the rule). They know that maintaining their blood sugar is necessary to stay alive and stay healthy. So what happens when they run out of willpower to manage their disease? Diabetes Burnout. They simply stop managing the disease because they need to take a break.

Obviously there is a lot more to managing diabetes than food intake but it certainly contributes and can be overly burdensome when it becomes all-consuming.

Food Myths Which Contribute To Orthorexia And Diabetes Burnout

There are a few myths when it comes to blood sugars and food which focus on 140mg/dl (7.8mmol/L)

“Damage Starts Happening When Your Blood Sugar Goes Over 140mg/dl”

I tackled this in a previous blog. In short, there is no evidence that damage begins over 140mg/dl. There is literally no study which has examined people with blood sugars at 141mg/dl and observed cellular damage occurring. It is a myth used to sell books but has no basis in scientific fact. It is true that having a sustained high blood sugar will do damage in the long term but this is better measured through metrics such as the HbA1c or Time in Range (TIR).

“Muggles (Non-Diabetic Folk) Never Go Above 140mg/dl”

This is simply not true. A recent article gave a great summary of some of the research that has been done in this area. Here are quotes from the studies examined:

• Muggle Study #1: “On average, their daily glucose levels stayed between 70–140 mg/dl for 93% of the day, with very small portions of the day spent above 140 mg/dl or below 70 mg/dl”
• Muggle Study #2: “Levels were lower than 70 mg/dl for 1.7% of the time and greater than 140 mg/dl, only 0.4% of the time.”
• Muggle Study #3: “Participants spent 93% of time between glucose values of 70-140 mg/dl, with 3% of the time below 70 mg/dL on average and 4% of the time above 140 mg/dl on average”
• Muggle Study #4: “2.1% of glucose sensor values were >140 mg/dl”
• Muggle Study #5: “Glucose was above 140 mg/dL for only 0.8% of the day”
• Muggle Study #6: “Participants spent 1.6% of the time above 140 mg/dl”

Literally every study showed that while going above 140mg/dl was the exception, even Muggles do it for short periods of time every day.

In other words, not only are these myths untrue, anyone believing them is putting themselves under unnecessary mental stress for effectively no discernible gain.

Diaversary As A Mental Steam-Release Valve

This is why I celebrate my diaversary. My diaversary is a day when I give myself permission to not to be as concerned with my blood sugars, secure in the knowledge that one day of spiking is going to do little but give me a mental break and help me recharge for the other 364 days. I genuinely believe the one day of poor bloods is a small price for sustained mental wellbeing. While maintaining healthy blood glucose levels is important, so is managing my mental health. My diaversary is a key element in my approach.

For Part 1, looking at reconciling the reports for diagnosis, go here.

Thanks to the generosity of #dedoc°, I recently had the privilege of virtually attending the world’s largest Diabetes conference: EASD 2021. Arguably the biggest news at the conference was an international consensus on the diagnosis, treatment, and management of Type 1 Diabetes. Interestingly, last year an international consensus was released for the diagnosis, treatment, and management of LADA. In Part 1 I reviewed how the two differed in terms of the diagnosis of Type 1 and LADA. In this second and final part I will look at the two reports’ recommendations for treatment and consider questions such as:

• Should someone diagnosed with LADA go onto insulin immediately?
• Are there treatments for Type 1 other than insulin?
• If I do use insulin what are the pros and cons of the various methods of delivery?

As usual, for those who want the short version, you can go to the tl;dr section at the end.

Where We Landed In Part 1

In Part 1, I concluded the diagnosis flow chart from the Type 1 report was the more detailed and effectively covered LADAs flow chart.

So, assuming someone has LADA or Type 1 diabetes means either:

• We have some reason to suspect diabetes (unintentional weight loss, ketoacidosis, glucose > 20 mmol/L (>360 mg/DL) etc.)

AND

• Auto-antibody presence OR
• Low C-peptide (less than 200 pmol/L (0.2 nmol/L) ) OR
• No features of Type 2 diabetes (BMI >= 25 kg/m^2, no weight loss, no ketoacidosis, less severe hyperglycaemia etc.)

Treatment According to the LADA Report

The LADA report has a flow chart for treatment which looks like this:

The Type 1 C-peptide limit is different (0.2 nmol/L vs 0.3 nmol/L) but, given there are two other options available which do not consider the C-peptide level in the Type 1 report (auto-antibody presence and no Type 2 features), there is still the possibility that someone with Type 1 could have a C-peptide in any of the above three ranges.

I go through the LADA and Type 2 guidelines in detail in my “Gold Standard” LADA article. In short, if your C-peptide is over 0.7nmol/L (700 pmol/L) options include:

• Metformin
• GLP-1 RA
• SGLT-2i
• DPP-4i
• Basal insulin
• TZD

While part of the Type 2 algorithm, there is a notable exception of Sulfonylureas not being used with LADAs because “The panel concluded that sulfonylureas are not recommended for the treatment of LADA, as deterioration of b-cell function as a consequence of this treatment cannot be ruled out”.

For patients with a C-peptide below 0.7 nmol/L, there are two flow charts. The first is if heart (ASCVD/HF) or kidney (CKD) disease is present with the same medications as before except TZDs which may have been excluded because of the limited evidence of benefit and increased risk of bone fracture.

For patients without heart or kidney disease, we have this chart where the SUs are still not present but which does include TZDs.

What is good is this set of flow charts covers the entire Type 1 C-peptide spectrum which means, even when someone with LADA becomes a “classic” Type 1 because of declining C-peptide levels, we have a prescribed course of action. What is missing is a complete answer to the question “When should someone with LADA start using insulin?” The answer from the above flow charts is “If the HbA1c is above target” but no target is firmly established. Let us move to the Type 1 report.

Treatment According to the Type 1 Report

In fact, the Type 1 report immediately addresses the issue of targets for Type 1 in their first table.

Here the target HbA1c is 7.0% with the caveat that “all glycemic targets should be individualized and agreed with the person with diabetes.” So, unless we have discussed and agreed on a different target with our health care team, achieving an HbA1c equal to or below 7.0% is a good benchmark for considering moving to the use of insulin. This is in agreement in my post where I considered how high someone’s HbA1c could be before a significant risk of long term damage.

For the specific question of when someone with LADA should consider bolus insulin, we also have guidelines for post-prandial (after meal) insulin levels with the suggestion that 1-2 hours after a meal a person’s glucose level should be less than 10 mmol/L (180 mg/dL) and the option of pushing this to less than 7.8 mmol/L (140 mg/dL) if safe to do so.

In contrast to the LADA report, the Type 1 report takes an “insulin-first” approach saying “The cornerstone of type 1 diabetes
therapy is insulin replacement” and providing the following summary of the multi-pronged approach suggested for the newly diagnosed.

Given how difficult it can be to manage insulin therapy in the newly diagnosed, it acknowledges the need to prepare for hyperglycemia (“highs”) and hypoglycemia (“lows”).

The Type 1 report also talks about the relative merits for the different ways of delivering insulin.

Where money is no object, clearly, closed-loop technology is the winner.

Eventually (page 27 out of 37 pages), the Type 1 report talks about “Adjunctive therapies”. In other words, treatments which can be used alongside insulin.

There is common ground between the two reports with both reports mentioning Metformin, GLP-1 RA, and SGLT-2i. It also mentions pramlintide which is an amylin analogue (another hormone produced by the beta cells and, therefore, compromised in Type 1 diabetes). It fails to mention DPP4i and TZD. TZD may be because of the limited evidence but I am not sure why DDP4i’s were left off the list. They affect the same hormone cycle as GLP-1 RAs and therefore have similar effects/benefits.

Reconciling the Two Reports

In contrast to Part 1 where I sided with the Type 1 flow chart for diagnosis, here I am siding with the LADA report for treatment. There are a few reasons for this:

• It explicitly considers treatment in the presence of heart and kidney disease
• It offers a more comprehensive range of non-insulin treatment options e.g. DPP4i and TZD (but should likely include Pramlintide as well)
• It takes the approach that insulin may not be necessary in patients with high C-peptide levels and, given the inherent hypo/hyper risk that comes with using insulin, if target ranges can be maintained, this seems like a sensible approach to me

This being said, the Type 1 report is much more comprehensive in considering the various ways of delivering insulin to the body (injection, pumps etc.) and also has a lot to say about looking beyond medication for individualised treatment e.g. considering lifestyle factors and diabetes education.

One big takeaway for all people with Type 1 or LADA should be that treatment no longer begins and ends with insulin. There are a range of other medications which can help with managing long term blood glucose levels and have other benefits such as helping a patient lose weight or reduce blood pressure.

tl;dr

Arguably, the LADA report’s flow charts for the treatment of Type 1 diabetes are more detailed for treatment than what is presented in the Type 1 report. Not only, does the LADA report consider insulin independence for patients with high C-peptide levels, it considers which medications are appropriate in the presence of heart or kidney disease. However, the Type 1 report fills in a significant gap of providing target values to chase and which help inform decisions such as when to move to insulin therapy.

The Type 1 report also goes into more detail in the areas of:

• The relative merits and costs of different insulin delivery methods
• Treatment of Type 1 diabetes beyond medication e.g. lifestyle factors and education

If you have seen the Glucology or Frio insulin pouches you will already understand the concept of an evaporative cooling insulin pouch. They work really well but the downside is the price. For a two-pen pouch you are looking at around US$30. In this blog I will show you how to make your own for less than US$5 (if you have a sewing machine) or, if that is too much hassle, you can buy a ready-made one from my Etsy shop for around US$20 including shipping anywhere in the world or AU$25 including shipping within Australia. For every one purchased, I will be supplying an identical one to charities around the world who are supplying insulin in developing countries where refrigeration is unreliable.

How Do They Work?

Evaporative cooling pouches work off of the idea that if water is evaporating from something, that something gets cooler. This is how humans cool themselves i.e. sweating. The key technology in the cooling pouches that allow them to remain cool for well over 24 hours are the little beads inside the pouch. These hydrophilic beads (a big word meaning they hold onto water) are the same ones you might know as Orbeez or those squishy spheres you see flowers in sometimes.

Same technology, different application. While the beads love holding onto water, it still evaporates and, while it does, they and anything they are surrounding feels cool to the touch. Embed them in material and that material, and anything it is surrounding also becomes cool.

DIY Step One: The Materials

Firstly, you will need two cooling scarves. They look like this:

You can buy these from Amazon but this will set you back about US$4 each before postage. Go to Ebay and select the international option and, while it might take a little longer to arrive, you can pick them up for around US$1 each.

You will also need a sewing machine or someone with the time to hand stitch them.

DIY Step Two: Stitching

Lay one on top of the other. For symmetry, I have put the seam of one (the white stitching on the edge) to the non-seam side of the other.

Then you will want to do a straight stitch along the edges so the two pieces form a long tube.

The dark line at the bottom on the scarf in the above picture is the straight stitch you need to do on the top and bottom. There is one at the top in the image as well but, because I was using a light brown thread in my bobbin, it is a little tricky to see. While I went a little over in the above picture, you want to go up to the white stitching which runs up and down on the left hand side in the above picture. This gives you the ties on the end of the scarf to secure the pouch, once finished.

DIY Step Three: Inverting

Arguably the fiddly bit, you now push the tube inside of itself to invert it and hide the stitching. I found the best way was to pull it out, rather than trying to push it through with a stick. In the end you will have an inverted tube which looks something like this.

You are now the proud owner of a cooling insulin pouch. Well done!

How To Use Your Pouch

Before use you will need to soak your pouch. I recommend no more than five minutes. Any more than this and the beads will absorb too much water and make it too hard to insert the pens/cartridges/vials. There is probably a risk of splitting the stitches as well.

Once soaked, dry it off with a dishcloth or towel. The material does not have to be wet for it to be effective. It is the beads inside which do the work.

Then, you can insert your hardware.

In the above example, I have my basal and bolus insulin pens and a MedAngel (a Bluetooth thermometer which connects to your phone).

Once inside, you can use the those end ties to keep it all together.

Does It Really Work?

While I am still insulin independent, I always carry insulin whenever I travel overseas for work. Just before the world locked down, I took my pouch to Singapore. Even with Singapore’s humidity, the pouch, within my backpack, was effective at keeping my insulin cool as I walked, in the direct sun, to the office each morning. Tests I have conducted in more controlled conditions show the pouch is as effective as its commercial counterparts.

Here you see three temperature gauges measuring (in Celsius) the temperature in my house (the middle one), the temperature of a commercial pouch (on the left) and my one (on the right). Even inside, both pouches shaved off 2-3 degrees Celsius (4-6 degrees Fahrenheit). The effect becomes even stronger in direct sunlight where I have seen temperature differences of 10 degrees Celsius (20 degrees Fahrenheit) between the ambient temperature and the pouch.

“Recharging”, Storage and Care

The pouch will continue to keep the contents cool for over 24 hours. When you want to “recharge” it, immerse it in water for no more than two minutes. Again, if you over-immerse, you risk expanding the beads too much and making it impossible to insert your pens etc. or breaking the stitching.

If you are not planning on using your pouch for a while, let it completely dry out in the sun or on an air vent and, when completely dry, store it in a cool, dry place.

Most diabetics, certainly most Type 1s, know their HbA1c. As described previously, the HbA1c is a measure of the ‘average sugariness’ of the blood over the last three months. As a diagnostic test, the HbA1c has been with us for a little over 40 years and has served us well. However, as technology has improved for the management of diabetes, the ways we keep tabs on our blood has also evolved and a new measure: Time in Range is growing in popularity among both diabetics and researchers alike. In fact, quite a few talks at EASD 2020 spoke directly at Time in Range and linked it to the long term health of diabetics.

In this blog I will talk about what the HbA1c tells us, its limitations, and the additional insights we can gain through the Time in Range. As usual, at the end, we have the ‘Cliff Notes’ tl;dr.

Benefits of Measuring the HbA1c

As I have shown previously, many papers examine the relationship between long term HbA1c and complications and this was reiterated by Professor Pratik Choudhary at EASD 2020 with this excellent graph.

The Limitations of the HbA1c

While of diagnostic value, there are limitations with the HbA1c measure.

Firstly, the measure assumes the lifespan of the red blood cells as part of the calculation so, if this assumption is invalid, it can affect the HbA1c. Common causes of false HbA1c readings include:

• Anaemia
• Excessive alcohol consumption
• Excessive use of opiates
• Pregnancy
• Blood transfusions

The second and arguably biggest limitation of the HbA1c measure is while it speaks to the ‘average sugariness’ it says nothing of the variation. This is why, historically, doctors have erred on the side of a higher HbA1c with Type 1s, often to the diabetic’s frustration. The reason is simple: if the diabetic’s glucose levels fluctuate significantly, and they keep a lower glucose level, they are at an increased risk of hypo whose effects are immediate (groggy, fall over, go unconscious etc.) whereas running a little ‘high’ and fluctuating mitigates the risk of hypos at the expense of increasing the risk of long term nerve damage. To put it simply, with limited visibility of the fluctuations using strip glucose monitors, it makes sense that doctors err to minimize risk today and encourage their patients to run a little higher with a view that the longer term risks can be managed later.

Interestingly, in his talk, Professor Choudhary blamed his patients for running high and having high fluctuations, suggesting they are driven by fear of a hypo which then leads to over-correcting and large fluctuations.

Fortunately, Continuous Glucose Monitoring (CGM) technology gives a much clearer picture of the fluctuations, informing both the doctor and patient, and allowing them to proceed informed, rather than out of fear.

Time in Range

It has taken a while for a standardization of Time in Range guidelines but in August 2019 we got one from the ADA.

The standard is adjusted for various sub-groups of diabetics.

What is more, these ranges are not random, or at the whim of some group of doctors, but backed up by statistically significant links to both long term complications and the equivalent HbA1c.

Some of these were highlighted by Professor Richard M. Bergenstal.

and Anass El Malahi at EASD 2020.

As we can see, we can link changes in Time in Range to changes in the risk of retinopathy, microalbuminuria, microvascular complication, and nephropathy.

Professor Bergental also showed, using the CGM data of three of his patients, how much more insightful Time in Range can be, compared to HbA1c.

Here the three patients have exactly the same HbA1c but very different experiences with their diabetes. with the third patient spending a lot more time in hypo and much less time in range.

Bringing together the Time in Range with the latest data on what it means for long term complications, the Ambulatory Glucose Profile (AGP) Report captures the key metrics along with statistically significant guidelines in one page.

As we can see the report captures:

• Percentage time in the different BGL ranges
• Average Glucose
• Glucose Management Indicator (GMI): an estimation of the HbA1c
• Glucose variability: a measure of fluctuation

which, given the GMI on its own is a proxy for the HbA1c, shows we are considering a lot more information in the AGP report than simply ‘average sugariness’.

The Big Problem with Time in Range

The big problem with Time in Range analysis is it requires a Continuous Glucose Monitor (CGM) to capture the data: it is a metric of privilege. While many of us have no exposure to it in the West, in places like Mexico, some Type 1 diabetics are given literally one strip per day to manage their blood glucose levels. Fortunately, research shows the proportion of finger pricks in, below or above range can still be correlated to HbA1c estimations and, therefore, give an indication of long term risk.

Also, with an increase in Time in Range of 10% leading to a lowering of HbA1c of 0.5%, using the above, we see that for someone whose finger pricks are in range 70% of the time, this correlates to an HbA1c of roughly 7%, as with the CGM data. This means the AGP Report and the guidelines it contains can be applied to CGM or finger pricking equally. So, while a diabetic’s management technology may change over time, their reporting for their health care team does not have to.

tl;dr

With the advent of Continuous Glucose Monitoring (CGM) we have new and insightful ways of examining our data beyond what is available with finger pricking and the HbA1c. One such way is analysing the Time in Range of our data. Time in Range provides a wealth of knowledge about both average sugariness and the glucose level fluctuations. One way to present this information is with an Ambulatory Glucose Profile (AGP) Report.

While driven by CGM technology, it is possible to use the AGP Report with finger pricking by considering the proportion of results that fit in the low medium or high categories. This now means we have a common report whether we are finger pricking or using CGMs.

Clinical research using Time in Range analysis has also established that it is predictive for a range of long term diabetes complications. This means, Time in Range analysis and the AGP Report are now a viable alternative to the HbA1c and provide much richer insights.

I first read about incretin mimetics in Dr. Bernstein’s fourth edition of “Dr. Bernstein’s Diabetes Solution” published in 2011. He devotes nine pages to this class of drugs and it is a good place as any to describe what they do. It should be noted for those unfamiliar with Dr. Bernstein, his focus is on the treatment of Type 1 diabetes. While incretin mimetics are sometimes hailed as a ‘Type 2 drug’, they can be of benefit to diabetics of all Types as I will show in this blog.

From there I will update the information based on some peer reviewed papers from recent years (specifically relating to LADA) and the presentations at the recent EASD 2020 conference and then onto my own experience using them. As usual, there is the tl;dr at the end if you want the short version.

What Are Incretin Mimetics?

To understand the role of incretin mimetics, it is important to understand that beta cells produce, not just insulin, but also another hormone called amylin. Amylin is a ‘satiety’ hormone i.e. it makes you feel full. So, as the beta cells become damaged they are less able to produce this hormone. Amylin is released in response to the presence of ‘gut hormones’ in the blood, released when the gut is stretched. These ‘gut hormones’ are called ‘incretins’.

Based on all this, Dr. Bernstein suggests that diabetics of all persuasions are likely to not feel as ‘full’ as their non-diabetic counterparts. For me, this poses the question: “If someone who has impaired beta cell function cannot effectively regulate their eating, is it possible Type 2 diabetes and pre-diabetes causes obesity and not the other way around?” but that is a blog for another day.

At the time of writing his book, Dr. Bernstein describes incretin mimetics as being used to lower blood sugar levels after meals and for weight loss. We now know they have many more effects on the human body.

GLP-1 Receptor Agonists (GLP-1RAs) are one such incretin mimetic. As per the above we see, among other things, they can:

• Lead to weight loss (likely due to the increased sensitivity to feeling full)
• Lower glucagon secretion (meaning the liver releases less glucose into the blood)
• Stimulate insulin secretion and production (to process the food that is causing the stomach to feel full)
• Decrease beta cell apoptosis (this is the fancy name for programmed cell death. Cells in the body are given a countdown clock. When that clock reaches zero the cell destroys itself. Incretin mimetics tinker with that clock to extend the life of beta cells)
• Offer protection from heart disease
• Lower blood pressure

I should note that while these drugs do stimulate insulin production like, say, sulfonylureas unlike ‘sulfs’ the evidence shows this does not accelerate the demise of the diabetic’s honeymoon. My guess is the suppression of apoptosis counters the effect. Another possible explanation is, because the insulin is getting triggered earlier and harder, the blood sugars are not getting the opportunity to rise as high. Dr. Bernstein talks about how it takes more insulin to bring blood sugar down by a fixed amount when it is at a high level than when it is lower. So, the mimetics get the insulin out early when it is more effective and therefore the net production for a given meal is less.

Types of Incretin Mimetics

There are three types of incretin mimetics. These are:

• Amylin analogs: To my knowledge the only one on the market is Symlin (pramlintide). This is available by injection. I have not tried this one. EASD 2020 had a presentation on using it in a dual-hormone therapy (pumps with insulin and pramlintide) but the benefit of the additional pramlintide, in this context, was minimal.
• GLP-1 agonists (mentioned above): This is mentioned above with the associated effects. Until recently this was also only available via injection. Recently an oral version has been released (more of that later). I am currently on a once-weekly injection of this drug. Here are the six GLP-1s on the market at the time of writing.

• DPP-4 inhibitors: DPP-4s destroy GLP-1s in the body so this drug opposes that destruction and therefore, in principle, eliminates the need to inject GLP-1s. DPP-4s are available in an oral form and I took these for at least six months before moving to the GLP-1 agonists.

Contraindications and Side Effects

I will list some of the more common side effects but this list, like for most drugs, is far from exhaustive so discuss your specific history with your health care team to get a full picture of how well these drugs might suit your circumstances and complication risk profile.

Firstly, incretin mimetics slow stomach emptying so this can make gastroparesis (a condition not uncommon in Type 1s) worse. This slowing can also induce nausea. People on social media will be more than willing to tell you how incretin mimetics made them violently ill. For me, I feel mild nausea a day after injecting the GLP-1 agonist (akin to very mild car sickness) but felt no such effect when taking the DPP-4 inhibitors.

One side effect that was actually beneficial for me was constipation. As I also take Metformin, I have found the GLP-1 agonist and Metformin balance themselves out nicely giving me a lot of freedom I did not have when taking Metformin with the DPP-4 inhibitor. It is different for everyone though as GLP-1 agonists are also reported to have diarrhoea as a side effect.

One of the more serious side effects is the risk of reversible pancreatitis. I am informed pancreatitis is one of the most painful things you can experience and is usually characterized as a sudden, severe abdominal pain extending through the body from the back to the front. As the name suggests, stopping the medication reverses the condition.

LADA-Related Studies on DPP-4 Inhibitors

Given I am a Type 1 LADA trying to preserve my beta cells as long as possible and avoid the financial and mental stresses of insulin management, many of the studies I have earmarked, up to EASD 2020, are focussed on blood glucose management and beta cells preservation. Here are a few:

• Investigating optimal β-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial : n = 64 GAD-positive insulin-independent Type 1s. Insulin vs a DPP-4 inhibitor over 21 months. It was found that for patients with low GAD levels, both approaches preserved beta cell mass.
• Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Maintains β-Cell Function in Patients With Recent-Onset Latent Autoimmune Diabetes in Adults: One Year Prospective Study : n = 30 LADAs. Half received insulin only and the other half received insulin and a DPP-4 inhibitor. Those who received the combined therapy produced similar levels of c-peptide as at the start of the study, compared to the insulin-only group who had significantly reduced c-peptide levels.
• Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA) : n = 2,709 GAD positive and negative diabetics (what I will call LADAs and Type 2s). Placebo controlled trial studying a DPP-4 inhibitor over 24 months. HbA1cs were reduced in both groups, LADAs had a reduction in fasting glucose and post-prandial glucose levels, beta cell function improved for both groups.
• Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel : Presents a flow chart for the treatment of LADA, depending on c-peptide levels. For high c-peptide levels, insulin is not recommended but a modified version of the Type 2 ADA/EASD guidelines are recommended which includes both DPP-4 inhibitors and GLP-1 agonists.

Presentations From EASD 2020

Tina Vilsbøll presented on Semaglutide, a new GLP-1 which can be taken as a once-weekly injection or as a once-daily oral pill, both being equally effective.

Juris Meier went into more detail as to the efficacy of the oral version, compared to other GLP-1 agonists, in Type 2s, showing it was more effective at reducing HbA1c.

The oral version of Semaglutide also compared favourably to the DPP-4 inhibitor Sitagliptin at doses above 3mg for Hba1c reduction and weight loss.

The downside was an increase in adverse reactions at the higher doses, compared to Sitagliptin.

So, if you are considering swapping out Sitagliptin for Semaglutide, understand that for a superior effect on HbA1c and weight loss you are also at a greater risk of those adverse effects.

Alice Cheng showed how the injectable version compared favorably to both DPP-4 inhibitors and other GLP-1 agonists for reducing HbA1c and weight loss.

For adverse effects, Semaglutide was comparable to other GLP-1 agonists.

My Experiences With DPP-4 Inhibitors and GLP-1 Agonists

As mentioned, I have used both in an attempt to preserve my beta cell mass. For me, the DPP-4 Inhibitor had no side effects or, at least, any side effects were washed out by the ones from Metformin. The DPP-4 Inhibitor did nothing for me in terms of HbA1c reduction (although it is already in the mid-5% for this is not surprising), satiety, or weight reduction.

My experience with the injected GLP-1 agonists has been very different. Given the trouble I was having with Metformin, I halved that dosage but found the two drugs balanced each other nicely, as touched on before. I have lost five kilograms over a couple of months (I have it to lose) which I attribute to my significantly reduced appetite and improved sense of satiety. It is only now I realise it has been years since I actually felt full eating food and the GLP-1 agonist has given this back to me.

tl;dr

While traditionally considered a ‘Type 2 drug’, there can be benefits in incretin mimetics for all Types of diabetics. For all Types we have the general benefits of:

• Lowering blood pressure
• Lowering the risk of cardiovascular disease
• A sense of feeling ‘full’ which may be lacking in diabetics
• A lowering of HbA1c
• Weight loss (especially for the GLP-1 agonists)

For Type 2s, the benefits also include the lowering of blood sugar levels through the increased release of insulin after meals and supressed release of glucose from the liver.

For Type 1 LADAs there is growing evidence that incretin mimetics can help preserve beta cell function and prolong the honeymoon. Certainly the latest guidelines for managing LADA fully embrace incretin mimetics even if, formally, they are not approved for use in Type 1s.

In terms of side effects, incretin mimetics can cause stomach issues and nausea but, generally, these are mild and much less pronounced in DPP-4 inhibitors.

New innovations in incretin mimetics include:

• An improved once-weekly GLP-1 injection and
• An oral GLP-1 taken once-daily

While superior to similar products on the market in terms of their effects on HbA1c and weight loss, it comes at the cost of increased risk of side effects such as nausea, diarrhoea, and vomiting.

I posted this Tweet based on one of the presentations at EASD 2020.

It is worth going through some of the details because it seems incredible that as little as one hour a week of cycling really reduces all-cause mortality by more than 20% in diabetics. It is also a great study to see the limitations of research and statistics. As usual, if you want to cut to the chase, head on over to the tl;dr section.

Details of the Study

Presented by Mathias Ried-Larsen, data was taken from the “European Prospective Investigation into Cancer and Nutrition” (EPIC). This is a massive study across 10 European countries with over half a million participants looking at factors such as diet, environment, lifestyle, and chronic disease.

They took the data and filtered it to people with diabetes at the start of the EPIC study and for which relevant data had been recorded. This brought the number of participants down to 7,513 of which 63% were confirmed to have diabetes with the others being self-reported. A second cohort was considered at the second examination point to see how a change in cycling habits changed mortality rates. This second group comprised of 5,506 people.

The forms of mortality looked at were all-cause mortality (dying for any reason) and cardiovascular mortality (presumably because it is a common killer and one which is a higher risk in diabetics).

Looking at other factors of the diabetes group, it was seen that the participants were mostly middle-aged and overweight, and most did no cycling at all.

Despite the shrinking cohort numbers, they still obtained the graph I tweeted.

The bars on the four points can be thought of as the error in the value (with this level of error we are 95% confident the value is correct, equivalent to a p-value of 0.05 and is considered statistically significant). So, for example, if I do between 1 and 59 minutes of cycling in a week, my risk of all-cause mortality (ACM) drops to somewhere between 60% and 95% of the baseline risk.

The presenter claimed the covariates (other factors we know about the people) were statistically removed from affecting the numbers attributed to the cycling. So, for example, given women generally live longer than men, this could have an effect on the results so this was accounted for when looking at the results.

The presenter further claimed that there was a j-curve relationship with the data i.e. the benefits are reduced at the 300+ minute mark. To explore this, rather than bucket the cycling times into four groups, they looked at the cycling times as they were i.e. a continuous spread of values between zero and nine hours of cycling per week.

While there is a curve with a maximum benefit around 4-5 hours, there is a fairly wide error margin (UCL = Upper confidence level, LCL = Lower confidence level i.e. the upper and lower values with a 95% confidence of being right). In other words, while the curve seems to head up after five hours, the error means it could just as easily be heading down to between 0.6 to 0.7. Similar results were obtained when cardiovascular mortality was specifically examined.

Next was the review of the effect of changing cycling habits.

The takeaway here is starting to cycle yields at least a 10% reduction in all-cause mortality while maintaining a cycling habit reduces risk by between 20% and close to 50%. For cardiovascular risk, maintaining a cycling habit had slightly better results with the risk reducing by 30-60%.

Recognised Limitations

The presentation did talk at some of the limitations:

• Confounding factors: As mentioned they looked at the influence other factors, such as age and smoking had but claim their results still stand
• Medication: There was no information on the medications being used by the diabetics and the effect they would have on mortality
• Underlying disease leading to less exercise and more mortality (reverse causation): As with the confounding factors, they looked at the potential influence and ruled it out as affecting the results
• There was no distinction in EPIC between Type 1 and Type 2 diabetes so no conclusions between the Types could be made but it is assumed the distribution in the study is close to the general population and, therefore 80-90% of the cohort was Type 2

tl;dr

For middle-aged Western European diabetics, the study showed:

• Cycling reduces all-cause mortality and cardiovascular mortality
• The level of benefit is harder to quantify but, the best benefit was shown to be at around 4-5 hours per week of cycling where the reduction in risk was roughly between 20-40%. Additional cycling may be of benefit but the error margins were too high to confirm this one way or the other
• Starting a cycling habit or maintaining one shows benefit with the most benefit being for someone who maintain a cycling habit with the reduction in risk being between 20-50% for all-cause mortality and 30-60% for cardiovascular mortality
• There was no distinction of Type so it is best to assume these results apply most strongly to Type 2 but I can see no reason why it would be different to Type 1s except for the additional risk of hypo if insulin dependent