Diabetes developments – Simon O’Neill

Simon O'NeillIn a regular blog series, Simon O’Neill, Diabetes UK’s Director of Health Intelligence and Professional Liaison, rounds up the latest diabetes news.

This week Simon updates on technologies, medicines and treatments.

Big and bigger data

Sugar.IQ is the first app to come out of a collaboration between Medtronic and IBM’s Watson supercomputer and it gives some indication of the way apps are moving from being simply a way of tracking data to actually giving advice on diabetes management.

The more data you have, the more you can use it to make meaningful decisions. We all know that one blood glucose test per day can’t give you as full a picture as four tests at different times of the day. But with new technology, the amount of data can be overwhelming and can only be really useful if the individual can successfully interpret it to help them make decisions on their diabetes management. A simple example of this can be seen with continuous and flash glucose monitoring data. These provide a measure of blood glucose between 96 and 288 times a day.

The wearers of these devices can very easily see what is going on with their blood glucose levels at any time without having to do a fingerprick test. This may help in making immediate decisions on bolus insulin doses or to take action to treat a rapidly falling or rising blood glucose. But the real benefit comes in looking at all those thousands of data points stored in the device.

Many devices, including Dexcom’s CGM system and the Abbott Libre are now using something called the ambulatory glucose profile (AGP) report – which is quickly becoming the standard one-page report for this sort of data. The AGP report displays a glucose profile that charts glucose values and variability by time of day.

The data from a number of days are combined to show daily trends in blood glucose over that period. The individual can set the range that they ideally want their blood glucose levels to be between and the report shows where the median blood glucose (the dark line) has been at each hour of the day over the previous few weeks. The report also shows the 25th and 75th centiles, in darker blue, indicating the variability of blood glucose at different times of the day. 50% of readings will be in that band. There is also a 10th-90th centile band, the lighter blue, which indicates that 80% of readings have been within that range.

Looking at this data (left), the user can see simple trends and decide what action to take. Because it combines many days’ worth of data, it can also highlight risks that may not be noticed over a shorter period.

In this example, there is generally quite a lot of daily variability, indicated by the wide blue bands – the narrower the bands, the nearer blood glucose readings are to the median line, and the less day to day variability. It is also clear that many of the readings are falling above the set target range and the majority are above 5mmol/l. This amount of time above the target range suggests that there is insufficient background insulin, so that might be the first thing that this person might need to consider changing.

This variability in the bands also gives additional helpful data. If we look at the 6am to noon readings, we can see that early morning glucose levels seem to go high and stay that way until lunch time, with no episodes of hypoglycaemia. This may mean that the person isn’t taking sufficient insulin with their breakfast, and they might want to consider increasing their breakfast dose. However, if you look at the data between 4pm and 8pm, although there is a lot of variability and the blood glucose does tend to go high, the wide bands also show that the person is probably over-treating that high, potentially leading to hypos later in the evening, so they may need to look at the individual days and see if there are specific patterns when a hypo has occurred.

But how much insulin to take? A number of apps were discussed at the ADA meeting in June which will give dosing advice based on an individual’s glucose trends.

Bigfoot Biomedical have bought out Timesulin, who produce a Bluetooth-enabled insulin pen cap that records when and how much insulin has been taken. With this data, linked with data from a CGM system, they hope to produce smart dosing guidance based on previous glucose trends and insulin doses with a launch expected in 2019. (Interestingly, in July, Bigfoot announced a new partnership with Abbott to use their next generation Libre device within this system and also with their existing pump technology. Apparently the next generation Libre will be able to talk continuously to the pump, making it a CGM system rather than the Flash system that is available now, where the user has to swipe the sensor to get a reading. If this is the case, they will be working towards the first “artificial pancreas”, closed loop system that won’t require calibration. Trials are due to start in 2018.)

Bluetooth-enabled Ascensia meters (Contour Next One and Contour Plus One) will automatically send blood glucose readings to the Insulia app, which will then provide recommendations for basal insulin adjustments for people with T2D.

AgaMatrix’s Jazz Wireless 2 Bluetooth blood glucose meter will automatically send glucose data to Glytec’s eGlycemic Management System. This can then recommend adjustments to both basal and bolus insulin, though these will be shared only with HCPs in the first instance during a pilot trial. The eGlycaemic Management System has already been shown to reduce hypoglycaemia and improve time in range in an inpatient setting.

Several partnerships are providing systems that people can subscribe to in order to improve their diabetes control. Most of them, at a cost, provide test strips and meters, which linked to an app can give advice on dosing. But some also then link through to a coaching service, if you appear to be having problems with highs or lows. These include Livongo’s Diabetes Program which has shown that users experienced an average 16.4% and 18.4% decrease in high and low blood glucose readings respectively; and Roche are now working with mySugr, whose app and coaching service led to an average drop in HbA1C levels of 1.3%. Presently the coaching element is only available in the US but firms are beginning to see if they can roll out similar programs in the UK, though currently they wouldn’t necessarily be funded by the NHS.

Tools like this are helping people to understand more about their own diabetes but apps, such as Sugar.IQ, are moving things to the next level, not just allowing people to view their own data, but also to help them interpret it beyond recommending an insulin dose.

This app analyzes past data to uncover blood glucose patterns but then shares those insights with you – and the more data you enter (such as the food you’re eating or the amount of physical activity you’re doing) the more the app can help. For example, if you tell the app that you are having salad for lunch, it might remind you that you tend to go hypo after a salad, so you might want to take a little less insulin. It can also see trends and alert you to them, such as reminding you if you tend to go hypo at a regular time at the weekend.

Data from the beta launch of the app showed positive results, with more time in target and a reduction in time spent too low or high. The next version of the app is also likely to include a hypo predictor, giving you advanced warning of when you are likely to go low though no release date has yet been announced.

And taking this one step further, others are trying to enable people to learn not only from their own data and experiences but from the wider diabetes community. Ayuda Heuristics, who I mentioned in an earlier report, now have a CE mark as a Class 1 medical device and have a beta version of their app being used by some people with diabetes. Their aim is for the data to be shared so that not only can people be advised on how to manage their diabetes with insights from their own data but, eventually, will be able to get advice from others like them.

Type 2 Treatments in Type 1 diabetes

Following on from the various studies looking at the use of metformin in Type 1 diabetes, several studies were presented at the ADA meeting which have shown that other drugs, more commonly used in people with Type 2 diabetes, may have a benefit in Type 1 diabetes.

One study looked at the potential benefit of using sotagliflozin, an SGLT1/2 inhibitor. This is a new drug in development which blocks the action of both SGLT1 and SGLT2. These transporter proteins normally make the kidney reabsorb glucose – so by blocking them, glucose is passed out of the body in the urine. Currently only SGLT2 inhibitors are available for people with Type 2 diabetes. The thought is that blocking only one of the two proteins leads to only half of the glucose being excreted – so by blocking both, you may lower blood glucose levels more effectively.

The study looked at 793 people with T1D with HbA1cs between 53 and 97 mmol/mol (7-11%) and treated them with either placebo or one of two strengths of sotagliflozin. After 6 months more than twice as many of the sotagliflozin treated people had achieved an HbA1c under 53mmol/mol, compared with those on placebo, with no increase in rates of severe hypoglycaemia and only a slight increased risk of DKA. People on the drug also lost weight – on average 3.5kg – compared with the placebo group and were able to reduce their bolus insulin to some degree. The main downside was an increased risk of genital fungal infections, particularly in the women.

In a separate study, researchers looked at adding liraglutide, a GLP-1 receptor agonist, commonly used in people with Type 2 diabetes, to insulin pump therapy in people with Type 1 diabetes. GLP-1 agonists increase the level of hormones called ‘incretins’. These hormones help the body produce more insulin only when needed and reduce the amount of glucose being produced by the liver when it’s not needed. They also reduce the rate at which the stomach digests food and empties, and can also reduce appetite. They are normally associated with weight loss in Type 2 diabetes.

The people with Type 1 diabetes given liraglutide saw significant improvements in HbA1c, weight loss, and time spent in target range compared to those taking placebo. There was no significant difference in hypoglycemia between the two groups.

Among others, these studies suggest that therapies once thought to be appropriate only for people with Type 2 diabetes may also improve outcomes for people with T1D. Further research is needed, but rather than relying solely on insulin, we may be able to better manage Type 1 diabetes, and reduce the risk of complications, by the addition of some of these therapies.

Access to technology

A new funding scheme has been announced by the government to speed up patient access to innovative digital technologies. The £86 million fund is intended to help implement recommendations outlined in the Accelerated Access Review (AAR) and streamline the journey of new technologies developed by small and medium enterprises (SMEs) to the NHS.

The new funding scheme is broken down into four packages:
• £39 million for the 15 Academic Health Science Networks (ASHNs) to speed up digital technology adoption in their localities, helping them assess new technology benefits and support NHS uptake. They will coordinate ‘Innovation Exchanges’ so that innovative new diagnostic tools, treatments and medical technologies reach patients faster. These Exchanges will bring partners together across health, care and industry.
• £35 million for innovators through the Digital Health Technology Catalyst to fund patient and NHS technology development.
• Up to £6 million to help innovator SMEs test their technologies in real-world settings.
• A further £6 million will be made available through the Pathway Transformation Fund to help NHS organisations integrate new technologies into everyday practices.

The new programme will work in tandem with existing schemes, such as the NHS Innovation Accelerator programme, launched in 2015, which was set up to help support the development and launch of patient-friendly technologies.

The funding will be rolled out over the next three years.

An end to daily injections for Type 2 diabetes?

More and more people with Type 2 diabetes are using injectable therapies to manage their diabetes, either using insulin daily or a GLP-1 daily or weekly. But scientists at Duke University appear to have developed a GLP-1 injection that will last even longer, perhaps only requiring one injection a month.

The longer-lasting injectable formulation has been developed by combining the GLP-1 molecule with a heat-sensitive elastin-like polypeptide (ELP). Once this is injected, it reacts to body heat and forms a biodegradable gel-like “depot” that slowly releases the drug as it dissolves. This would have the added advantage of preventing the potential peaks and troughs of activity found with shorter acting drugs. It could also be used with other injectable medications, potentially even insulin.

Initial trials on mice found that the compound was effective in controlling blood glucose for up to 10 days. However, further studies in primates saw a longer duration of action, up to 17 days, and the scientists think that, in humans, who have a slower metabolism, it could be effective for up to a month. Overall HbA1c control in the animal tests was improved and the weight loss, associated with GLP-1 use, was maintained.

Currently GLP-1 has a short half-life and is cleared from the body quickly so researchers have been interested in seeing if they can make it effective for longer. Previous studies have used synthetic microspheres and biomolecules like antibodies, which have slightly increased the active half-life but not as much as this new study. A once weekly GLP-1 is already available (dulaglutide) but making this a once a month treatment option, with great day to day consistency of drug delivery, could be very beneficial.

The approach is still in the early stages of research and further work is needed to ensure that it is safe in the long term and whether it will work as effectively in humans.

Update on Libre

Abbott submitted the Freestyle Libre to the NHS Business Services Authority last year to apply to have it added to Part IX of the Drug Tariff.

The Drug Tariff outlines any rules prescribers must follow (such as who these products can be prescribed for) and what will be paid to pharmacy contractors for reimbursement or remuneration for these products. These prices don’t necessarily reflect what you or I would pay if buying these products over the counter, as the NHSBSA will negotiate a price with the manufacturer and, indeed, local commissioners may then negotiate even better price deals at a local level. An example would be blood glucose tests strips which are reimbursed by the NHS at about £15 for 50 but may cost you nearer £25 at Amazon or Boots.

Part IX lists non medicinal products such as dressings, syringes, catheters and, of course, blood glucose test strips. If a product is not included in any part of the Drug Tariff, it cannot be prescribed by GPs.

The NHSBSA don’t have a particular time limit to respond to an application, but are allowed to ask for any information to enable them to make a decision. Diabetes UK submitted an overview of comments from people who were using the system, to ensure that people with diabetes were able to have their voice included.

Normally it is the NHSBSA who would make a decision as to whether a new product can be added to Part IX of the Tariff, particularly when other, similar products are already prescribable. So a new type of blood glucose test strip, if it meets the legal CE mark requirements and accuracy, and if it is priced in accordance with other test strips, will probably get approval quite quickly. However, the Freestyle Libre is a novel product and it is not surprising that it is taking so long to get a final decision. The optimist in me thinks that that is actually a good thing, as they are obviously taking the decision very seriously.

However, at the very end of July we heard from Abbott that the NHSBSA had referred the decision to the Department of Health and the final decision now sits with Lord O’Shaughnessy, who is the Parliamentary Under Secretary of State for Health. We presume that the NHSBSA deliberations, and possible recommendations, will have been passed on. This suggests that, as with many things in the NHS, this will come down to the question of whether, with predicted uptake, the NHS can afford to invest in this technology.

Diabetes UK have been leading on a social media campaign to bring the voices of people with diabetes to the attention of the Minister -.

Hopefully we will get a positive response and the Freestyle Libre will be made available on prescription. However, even if that happens, the fight may well not be over for ensuring equitable access to the technology. Each CCG in England and Health Boards in other nations generally choose from the very extensive list of items on Part IX as to what will be prescribed in their locality. We regularly see this with blood glucose test strips, where a CCG may only prescribe one or two brands rather than all that are available. They may also set local criteria as to who is to have access. Because NICE, in England, haven’t carried out a Health Technology Appraisal on the Freestyle Libre, there is no guidance that says it has to be made available or to whom.

Diabetes UK, working with JDRF, Input, people living with diabetes and HCPs, have also produced some joint recommendations explaining the Libre technology and outlining who may benefit from it, which will be aimed at those commissioning local services. The document should be available very shortly.

Bovine insulin withdrawal

It has been announced at the end of July that bovine (beef) insulin will no longer be available in the UK to those who currently use it.

Up until the 1980s anyone using insulin had a choice of either beef or pork. However, from 1982 synthetically produced ‘human’ insulin became available and most people were switched over to this, as it was thought to be less likely to cause allergic reactions and lipohypertrophy/lipodystrophy (a build-up or breaking down of fat) at the injection sites. The synthetic insulin was also identical in structure to insulin that humans produce naturally, whereas pork and beef insulin have slightly different molecular structures with one or three amino acids situated differently.

The majority of people on insulin had no real problem with the change but for a reasonable minority, the move to human insulin caused problems, particularly with a loss of hypo warning signs. This may have been partly because, after using animal insulin for some time, they had built up antibodies to the insulin and so had gradually increased the dose they needed to manage blood glucose. Switching to a lower dose of human insulin often helped but this wasn’t always done initially. People also complained that their warning signs, which had come on gradually with animal insulin were no longer timely enough to take action, leading to severe hypos in some cases.

Diabetes UK and others pushed for animal insulin to remain available for those who needed it, and argued with most of the insulin manufacturers as they gradually stopped producing animal insulins, reducing choice for those who wished to continue to use them.

One company, Wockhardt UK, has continued to produce both pork and beef insulin but unfortunately they have now stated that, due to “global bovine insulin raw material unavailability” they have “no choice but to discontinue the Hypurin Bovine insulin range”. Since the BSE infection problems in cattle, acquiring safe sources of beef pancreases has become more difficult.

The Independent Diabetes Trust (IDDT), which was set up to fight for the continued availability of animal insulin, has issued a letter to all its members about the issue stating that, with only a very small number of people still using beef insulin (estimated at between 2-300 people), the situation is beyond anyone’s control. However, it is important to stress that the withdrawal only applies to beef insulin and the manufacturers have stated that supplies of pork insulin are still secure for many years to come.

Anyone currently using any Hypurin Bovine Insulin should contact their healthcare professional so appropriate changes can be made to their insulin therapy. It is likely that cartridges of beef insulin could run out by the end of the year, although 10ml vials should still be available until mid 2019. It is also very important to remember that, for those who would rather continue with an animal insulin, there should be the possibility of changing to a Wockhardt pork insulin and people with diabetes shouldn’t feel that they have to switch to a ‘human’ or analogue insulin. Whatever they decide, the switch should be managed carefully in partnership between the person with diabetes and their clinical team and consideration should be given to reducing the initial dose by at least 10%.

New flu jab?

A ‘painless’ sticking plaster flu jab that delivers the flu vaccine into the skin has passed important safety tests in the first trial in people.

The patch has a hundred tiny microneedles on its adhesive side that penetrate the skin’s surface. Unlike the standard flu jab, it doesn’t need to be kept in the fridge and people can easily stick it on to their own arm, where it has to be left for 20 minutes. Most of those trialing the plaster said that it was painless and preferable to the standard vaccination.

The developers claim that it will offer the same level of protection as a regular vaccination but because of the ease of self-administration, it could help improve uptake of the flu vaccine, especially in people who don’t like injections or can’t find the time to attend a pharmacy or clinic. This could also free up nurses time, who often run special flu vaccination clinics in the run up to the flu season. Because it doesn’t need to be specially stored, it could easily be stocked in pharmacies or even sent by mail order. There also isn’t a problem with sharps disposal as the microneedles dissolve after use.

Further clinical tests over the next few years are needed to get the patch system approved for widespread use. All people with diabetes should be having an annual flu jab but figures from NHS England suggest that only 65% of those eligible actually attend for the free vaccination – so anything which might increase that figure, and reduce the risk of flu related complications, should be welcomed.

Nanobots

Scientists have created a tiny magnetic robot that swims through liquid, including blood, at up to 10 micrometres per second. Why, you might ask! The proposal behind the miniature robot is that it could potentially be used to deliver medicines to very specific sites in the body.

The Chinese invention is 5 micrometres long and has three main parts, connected together by two silver hinges. Its gold body has two magnetic arms made of nickel. Applying a magnetic field to the robot makes the arms move. If the magnetic field’s direction is switched back and forth, it causes the robot’s arms to rotate and move it forward.

The theory is that they could be coated with medicine and injected into the bloodstream, as they are smaller than an average blood vessel. Once injected, they could be ‘steered’ around the body using external magnetic fields. However, they are so small that you would probably need several thousand of them to deliver an effective dose. That raises further questions about how you would control them all and what would happen to them when they’ve done the job.

The next stage of development is to see if they can be made from biodegradable materials before they could be used in animal trials.

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