Update on technologies, medicines and treatments

1 THE EFFECT OF TYPE 1 DIABETES ON EDUCATIONAL ACHIEVEMENT

A new study has looked into the impact of type 1 diabetes on children's educational attainment. The study looked at school and higher education data sets for all children aged 6 to 18 in school in Wales between 2008 and 2016.¹ There were 263,426 children without diabetes and 1212 children with type 1 diabetes included in the study, and national diabetes audit data were linked for those with diabetes. The study also looked at socioeconomic status, neighbourhood deprivation and sex.

Despite children with diabetes being more likely to have absences from school—between 7 and 15 half-day sessions per year—there was no strong association between having diabetes and educational attainment. However, those with optimal diabetes management did do better than those with higher HbA1c levels. Children who were struggling to manage their diabetes achieved GCSE results that were a total of five grades lower than children without the condition. This group of children was also less than half as likely to attend university as children without diabetes.

However, the data suggest that this is less to do with biology and more to do with family circumstances, which are likely to affect the child's ability to self manage. We know that health inequalities exist across diabetes care and the degree of family support and socioeconomic factors may well be having an impact on the child's ability to focus on school.

The authors recommend that schools and healthcare teams need to work together to ensure that all children with type 1 diabetes and their families have the support they need to manage the condition. This is now probably even more important, especially in light of the growing challenges many families will face with the cost of living crisis.

2 CLOSED-LOOP SYSTEMS IN TYPE 2 DIABETES

A study from Cambridge has demonstrated the use of a fully closed-loop artificial pancreas system in people living with type 2 diabetes.²

The study recruited 26 people with type 2 diabetes who were randomly allocated to one of two groups. The first group trialled the closed-loop system for 8 weeks and then switched back to standard therapy of multiple daily insulin injections; the second group followed the control therapy first and then switched to the closed-loop system after 8 weeks. The closed-loop system combined a Dexcom G6 Continuous Glucose Monitor (CGM), a Dana Diabecare insulin pump and the CamAPS HX algorithm developed by the team.

Using the closed-loop system, which required no bolus short-acting insulin doses or carbohydrate counting for meals, doubled the amount of time patients were in the glucose target range of 3.9–10.0 mmol/L (66.3% with closed loop versus 32.3% with control). Those using the system also spent half the time with high glucose levels compared with the control group. HbA1c was also lower following closed-loop use—56 mmol/mol (7.3%) compared with 72 mmol/mol (8.7%). There was also no difference in hypoglycaemia, with no one experiencing a severe hypo and those using the system spending very little time in a range lower than the target.

The authors suggest that clinical inertia, which is known to delay commencing or increasing insulin therapy in type 2 diabetes, is often driven by fear of hypos, and such a closed-loop approach, as well as being easy for most of the patients to manage, could allay that fear. They also acknowledge that the patients had not used CGM systems before, so some of the improvements may have been a greater awareness of glucose levels in the patients using the closed-loop system.

Interestingly, all patients reported that they were happy to have their glucose levels controlled automatically by the system, and 89% reported that they spent less time managing their diabetes overall. They particularly welcomed no longer needing to inject or do finger-prick testing. There were slightly higher levels of hypoglycaemia-related anxiety during closed-loop therapy, but the main drawbacks to using the system were practical, such as wearing the devices and connectivity issues between devices.

Longer duration studies on a larger and more diverse population are needed, as is analysis to see whether this could be a cost-effective and sustainable approach to managing people with type 2 diabetes treated with insulin.

3 END OF THE ROAD FOR ORAL INSULIN?

Oramed Pharma, a company set up in 2006 with the aim of producing the world's first oral insulin, has conceded defeat in its attempt after its ORMD-0801 candidate failed to deliver in a phase 3 trial.

The ORA-D-013 study compared the efficacy of ORMD-0801 against placebo in 710 people with type 2 diabetes who were also taking two or three oral diabetes treatments. The study outcome was HbA1c in the oral insulin group compared with placebo but, after 26-week follow-up, there was no difference. Secondary outcomes, looking at improvements in fasting blood glucose also failed to deliver.

An earlier phase 2 trial of the same drug in people with type 2 diabetes and nonalcoholic steatohepatitis (NASH) had showed a ‘clinically meaningful’ trend in the reduction of liver fat from baseline.

As insulin is normally broken down in the gut before it can have an effect, Oramed protected the insulin by encapsulating it and delivering it alongside enzyme inhibitors and permeation enhancers. Early-stage trials had suggested that it was effective, but the failure of the latest trial challenges whether this type of protection is effective enough to allow the insulin to work.

The company has now announced that they are discontinuing the development of ORMD-0801 for use solely in type 2 diabetes, but they have not stated whether its use in NASH may continue, as there are no effective treatments for this other than lifestyle changes.

4 MOVE OVER METFORMIN?

A new analysis of electronic health record data for more than 22,000 patients starting metformin at three US clinical sites has found that over 40% experienced ‘metformin failure’.³ This is defined as either a failure to achieve or maintain an HbA1c below 53 mmol/mol (7%) within 18 months or the need for other glucose-lowering therapies to be added within the same time frame. Those with the highest HbA1c levels at diagnosis are most likely to find metformin less effective as are older patients. Additionally, the median time to failure was only just less than 4 months.

The authors point out that they have no way of knowing whether the individuals whose records were studied actually took the metformin, only that their records showed they had been prescribed it. However, they do suggest that patients newly started on metformin should be closely monitored to ensure it is having the desired effect and to add in combination therapies at a much earlier stage, to ensure good glycaemic control, particularly in older patients or those with higher initial HbA1c levels. They also question whether metformin should always be the first-line treatment and whether a more individualised approach would be better.

5 TIDEPOOL WINS FDA APPROVAL

Tidepool, a nonprofit organisation founded by people with diabetes, carers and HCPs, has announced that their automated insulin dosing app, Tidepool Loop, has been approved by the FDA for the management of type 1 diabetes in those 6 years old and above. This makes it the first FDA-approved ‘do-it-yourself’ automated insulin delivery system.

What is interesting about this app is that it is a stand-alone automated insulin delivery system designed to work alongside a variety of compatible CGM systems and alternate controller-enabled insulin pumps. The app works on the iPhone and is the first to enable insulin delivery from a compatible Apple Watch. They are also working to develop an app for Android phones. This marks the first step towards an interoperable world where individuals can choose the pump, CGM and algorithm that best suit them rather than being tied to a fixed combination of the three.

As with other hybrid closed-loop systems, the app can instruct the pump to automatically increase, decrease or suspend delivery of basal insulin based on CGM readings and predicted glucose values. It can also recommend and deliver correction boluses when glucose values are predicted to exceed predefined thresholds. The system also lets users adjust the amount of insulin after a meal by entering the estimated amount of carbs into the app by tapping on different food emojis to indicate different amounts of carbohydrates. This allows the system to adjust for anything from a small amount of fast-acting carbs to a larger meal with a longer extended 5-h bolus.

Coming from the ‘#WeAreNotWaiting’ movement, Tidepool has been supported by grants from the JDRF and the Helmsley Charitable Trust and others, as well as a large number of individual funders often living with diabetes.

The range of devices with which Tidepool can work have not yet been announced, although they have a development partnership with Dexcom and are working with other companies to include their pumps and CGMs. There is also not yet a launch date for the system.

6 SUGAR TAX TACKLING OBESITY

A study has shown that the introduction of the soft drinks industry levy (SDIL) in England in 2018 was followed by a drop in the number of older primary school girls developing obesity.⁴

In England, around 10% of 4- to 5-year-old children and 20% of 10- to 11-year-olds were recorded as obese in 2020 and evidence suggests that, in the UK, young patients consume significantly more added sugars than is recommended, with sugar-sweetened beverages being the main source.

The study used data from the National Child Measurement Programme on over 1 million children at ages 4–5 years and 10–11 years. This programme includes annual repeat cross sectional measurements, which allowed the researchers to examine trajectories in the monthly prevalence of obesity from September 2013 to November 2019, which was 19 months after the implementation of the SDIL.

The team reviewed previous trends in obesity levels to estimate absolute and relative changes in obesity prevalence, both overall and by sex and deprivation. They then compared obesity levels after the SDIL with predicted levels had the tax not been introduced.

Although they found no significant association with obesity levels in younger children or older boys, there was an overall absolute reduction in obesity prevalence of 1.6% in 10–11-year-old girls. This equated to an 8% relative reduction in obesity rates compared with the estimated trend rate prior to the SDIL. They estimated that this was equivalent to preventing 5234 cases of obesity per year in this group of girls alone.

They also found that reductions were greatest in girls whose schools were in the most deprived areas, where children are known to consume the largest amount of sugary drinks. The greatest reductions in obesity were observed in the two most deprived quintiles, equivalent to a 9% reduction in those living in the most deprived areas.

What is interesting though is that no difference was seen in obesity prevalence in older boys, who tend to be higher consumers of sugar-sweetened beverages. One explanation is the possible impact of advertising. Physical activity and celebrity endorsement are often used to promote junk food, and boys, compared with girls, have been shown to be more likely to believe that these foods will boost physical performance, affecting their choices.

The authors suggest that the UK SDIL has led to positive health impacts but that much is still to be done and additional strategies will be needed to reduce obesity prevalence overall and particularly in older boys and younger children.

The Obesity Health Alliance called on the Government to press ahead with policies that make it easier for everyone to eat a healthier diet, including extending the soft drinks industry levy to include other less healthy foods and drinks and measures to take junk food out of the spotlight.

7 SOCIAL STIGMA AND TECHNOLOGY USE

A survey presented at the International Conference on Advanced Technologies & Treatments for Diabetes (ATTD), has shown that diabetes-related social stigma was common, especially in relation to the use of diabetes devices.⁵ The online survey was conducted by the Diabetes Research Company and had responses from 1543 people living with diabetes in the United States. Two validated measures (Diabetes Stigma Assessment Scale-1 and DSAS-2) were used to assess diabetes stigma.

The respondents included 595 adults with type 1 diabetes, 580 adults with insulin-treated type 2 diabetes and 368 people with type 2 diabetes not on insulin. 42% of the people with type 1 diabetes used a CGM alone, 4% used only an insulin pump, 42% used both a CGM and insulin pump and 12% used no device. Among those with insulin-treated type 2 diabetes, 38% used just a CGM, 3% used only an insulin pump, 16% used a CGM and insulin pump and 43% used no device. For people with type 2 diabetes not on insulin, 29% used a CGM only and 71% used no device. Any device used in people with type 2 diabetes is probably higher than in a similar UK population.

The majority of respondents reported experiencing social stigma—79% of those with type 1 diabetes, 70% of those with insulin-treated type 2 diabetes and 64% of those with non-insulin-treated type 2 diabetes. Worryingly, when looking at patients who were not using any technology, 25% of those with type 1 diabetes, 22% of those with insulin-treated type 2 diabetes and 17% of those with non-insulin-treated type 2 diabetes said that stigma had a modest or significant negative impact on their willingness to use a device.

Device users also reported that device-related stigma was common. 63% of adults using an insulin pump and CGM, 37% of those using a CGM only and 30% of adults using only an insulin pump had had at least one experience of device-related stigma. This included device alerts or alarms causing unwanted attention in public, being asked to remove devices for nonmedical reasons or patients staring or pointing at the device.

8 OLD TABLET, NEW USE

A study presented at ATTD has shown that a tablet, widely used for treating high blood pressure since the early 1980s, can slow down the destruction of insulin-producing ß-cells for up to a year.⁶

The randomised, double-blind, trial involved 113 young patients, between the ages of 7 and 17 years, who had newly diagnosed type 1 diabetes. The main aim of the trial was to compare the use of commercially available automated insulin delivery systems (hybrid closed loop) with standard care, to test the effects of intensive glucose control on C-peptide levels over 52 weeks. Eighty-eight young patients were further randomised to daily extended-release verapamil or placebo for the same period.

The results found that those who had been given the placebo within a month of diagnosis had a 30% decrease in C-peptide secretion (a measure of preserved ß-cell function) at 52 weeks, compared with those on verapamil, whose C-peptide levels had remained steady, without serious adverse events.

Although a relatively small and preliminary study the authors suggested that verapamil should be considered for people newly diagnosed with type 1 diabetes to preserve some remaining insulin production. It was not as effective as teplizumab, an immune-modulating agent, which preserved greater C-peptide levels for longer—but it is cheap, safe and easy to take. More studies are obviously needed to see the full potential.

Interestingly the other aim of the study, to test the hypothesis that reducing high glucose levels could preserve ß-cell function, was not successful and those on the hybrid closed-loop system, although they had much better HbA1c and greater time in range, still experienced the expected decline in C-peptide levels.

9 TIME IN TIGHT RANGE

Time in Range (TIR) has quickly become established as a useful metric for patients using CGM systems. The normal range is 3.9–10 mmol/L, and patients are encouraged to try to spend 70% of their day within that range in order to achieve their target HbA1c. Most CGM devices are set to display this metric and to show the user exactly how much time they spend within this range and how much time below or above it. A TIR of 70% equates to an HbA1c of about 53 mmol/mol (7.0%).

However, there was an interesting discussion at ATTD as to whether we should actually now be moving to Time in Tight Range (TITR). TITR would measure the amount of time the CGM user spends between 3.9 and 7.8 mmol/L, which is basically normal glycaemia. Children without diabetes have been found to be within TITR 96% of the time. The presenters argued that aiming for TITR would, by default, reduce the risk of long-term complications.

Experience shows us that achieving the standard TIR is not easy, so it is clear that achieving TITR would be an even more challenging goal. However, the presenters suggested that the increasing use of technology, like CGM with alarms and automated insulin delivery systems (AID), could help make it possible. They also suggested that focussing on a tighter target, particularly in those who were achieving the 70% TIR goal, could also help identify the remaining spikes in blood sugars that could then be more closely targeted. A TITR of 50% should equate to an HbA1c of about 48 mmol/mol (6.5%).

The presenters also highlighted that children who are identified as having autoantibodies, increasing their risk of developing type 1 diabetes, could also be monitored against TITR. Spending more than 18% of time above 7.8 mmol/L is a clear predictor of progression to requiring insulin.⁷

Although challenging, and having the potential to increase the risk of diabetes burnout, with the extra pressure of a tighter target, this is really a conversation that should be had, allowing the individual to make that choice particularly with those already achieving 70% TIR. Most CGM systems allow the user to set the TIR target, so it is possible to set this to TITR.