Diabetes developments – by Simon O’Neill
In 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 rounds up the latest research and other news.
The FDA in the US has awarded Fast Track designation to a potential new drug for the treatment of T1D. Fast track status means that the FDA recognise that the drug could meet an unmet need and enables scientists to get drugs to patients more quickly. The drug in question is the excitingly named CLBS03 from Caladrius Biosciences.
The drug is currently being investigated in a Phase 2 clinical trial, The Sanford Project: T-Rex Study. This is a prospective, randomized, placebo-controlled, double-blind trial evaluating the efficacy and safety of CLBS03 in approximately 111 people with T1D. All participants are aged between 12 and 17 and all have some residual beta cell function. The study is investigating whether the drug can preserve C-peptide (an accepted measure for beta cell function), decrease insulin use, decrease severe hypoglycemic episodes, and improve glucose and HbA1c levels.
CLBS03 is a personalized therapy consisting of an individual’s expanded and functionally enhanced Tregs. Tregs are T Cells in the immune system that modulate the immune system and appear to help reduce autoimmune responses. By enhancing the number and function of the individual’s own Treg cells, the hope is that the autoimmune attack against the beta cells is prevented. In previous Phase 1 studies, data showed that treatment with these Tregs preserved beta cell function and reduced the need for insulin in the majority of patients treated.
Decline in death rates leading to increased prevalence in Scotland
A recent paper published in Diabetologia showed that Scotland has seen an increase in the prevalence of all types of diabetes between 2004 and 2013, growing from 3.2% to 5.1% of the population. But is this because more people are being diagnosed each year or because life expectancy in diabetes is increasing?
The study looked at trends from 2004 to 2013 in Scotland using data from the SCI-Diabetes database, which covers the vast majority of people with diabetes, as well as from National Records Scotland. They included information on diabetes diagnosis, population estimates, and numbers of deaths per year according to age, sex, and socio-economic status in people between the ages of 39 to 90 years.
Rather than seeing a rise in the number of new cases with T2D, the study actually found that overall incidence (the number of new cases in a year) was stable with 4.88 new cases per 1000 men and 3.33 per 1000 women. There were some slight differences in certain groups, with older women and men experiencing a decline in incidence rates, younger men experienced an increase until 2009 and then a slight decrease, and rates remained stable among younger women. Incidence decreased in all socioeconomic groups, though the decrease was slower for the more deprived groups and actually increased in the most deprived groups after 2010.
The reason for the stability may be because there are fewer undiagnosed cases, with better screening and awareness. Also the late 1990s/early 2000s saw a decrease in the diagnostic criteria cut offs, which meant that many more people were suddenly diagnosed with diabetes. This would have stabilized over time. The researchers also felt that there may also have been a stabilization of obesity rates over the same period.
However, death rates saw an 11.5% drop in men and a 15.7% drop for women in standardized rates from 2004 to 2013. However, the study stressed that we shouldn’t be complacent about this and that there is still scope to address the increased mortality associated with diabetes. But it is likely that people living longer with diabetes is what is causing the increase in prevalence (the number of cases in total).
You’ve heard of T1D and T2D, not to mention Gestational, MODY and LADA but of growing concern is something termed Flatbush diabetes, named after the area in New York where it was first described and now becoming much more common in Africa and in those of African descent although Asians and even Caucasians can also be diagnosed with it.
The unusual thing about this type of diabetes is that patients present in diabetic ketoacidosis (DKA) often with extremely high blood sugar levels (over 20mmol/l) and very high HbA1cs (over 10% or 86mmol/mol) but they match more of a T2D profile – middle-aged, obese, hypertensive and with a family history of T2D. Because of this, Flatbush diabetes has been called atypical diabetes, Type 1B diabetes, idiopathic T1D, and ketosis-prone T2D.
Unlike most people with T1D, people who develop Flatbush diabetes don’t have autoimmune antibodies against beta cells – so it doesn’t appear to be an autoimmune disease. The other difference is that the high blood sugar levels are lowered initially with insulin but then their insulin resistance seems to go away and they begin producing sufficient amounts of insulin again. They can often manage with oral medications or even just diet and exercise. This isn’t the same as the honeymoon period in T1D as it can go on for years before another episode of rising sugar levels and possibly DKA. After 10 years, about 60% will need insulin to maintain very good control, which is also true of T2D after long duration of the condition.
Flatbush diabetes is becoming more and more common in Africa, and in America. In South Africa and the US it now accounts for up to 50% of cases of Black African/African Americans who are diagnosed with DKA with no previous diagnosis of diabetes. But in one study 12% of those thought to have this type of diabetes were white Caucasians.
No one is sure exactly what causes it, but it seems to be a combination of insensitivity to insulin and short term loss of the ability to release adequate amounts of insulin. It may be that these patients are very sensitive to temporary damage to the beta cells by glucotoxicity and lipotoxicity, and when those conditions are reversed with insulin and diet, the beta cells are able to recover.
The good news is that people who presented in DKA, who don’t have a typical T1D profile, may not need to take insulin but might be able to manage with oral medication. It’s therefore important that doctors get the right diagnosis to ensure people can access the right treatment and can be made aware of the risks of further episodes of DKA and how to manage that.
Many drugs nowadays are used for more than one purpose. High dose liraglutide (a GLP-1 agonist used in T2D) is now licensed in the US for weight loss in those without diabetes. Metformin is being investigated for use in certain cancers. ACE Inhibitors, a blood pressure lowering medication, is also used in people with diabetes, with normal blood pressure, who have early stages of kidney disease. In cancer care just over half of drugs used have more than one indication, and this is likely to rise to 75% of drugs by 2025.
But should you pay the same amount for the drug if it is being used to treat something different from its original license? This is leading to a push for value-based approaches to pricing, creating different pricing levels for different indications. But how do you determine what is a reasonable price to pay in light of what the drug can really do?
If the current single price reflects the value of treating a more complex or serious indication, then the drug probably wouldn’t be recommended for use in a lower-value indication. Conversely, if a lower value price has been set and then benefit is found in a higher-value indication, this could be of huge benefit to health economies (consider generic metformin at 3p a tablet being used to prolong life in cancer, where drugs tend to be very expensive) but of little benefit to the pharma industry, who would have had to pay for the trials to prove effectiveness in the new indication.
Obviously when a company launches a new drug, they don’t know the full range of potential indications that the drug may be used for over time. They must therefore try to determine a price, at launch, that is likely to work across all indications over the lifetime of that drug. So they are trying to set an average price across all potential indications that will allow the greatest access to the drug as well as generating the best income for the industry. This approach can actually make it harder for those who pay for the drugs to assess the value – as they only look at the single indication that has been licensed. They therefore may find this ‘averaged’ price too high, greatly limiting access to the new drug.
One way around this has been to rebrand drugs for different uses. So, in the US, liraglutide for use in T2D is called Victoza (at a dose of 1.8mg) whereas liraglutide for weight loss is called Saxenda (at a dose of 3mg). Obviously those with T2D and the need to lose a lot of weight can use Saxenda to address both issues. But this rebranding is expensive to do and can be confusing for doctors and patients.
An example of where Multi-indication pricing (MIP) has been successful is with aflibercept. This is marketed as two separate products for use in ophthalmology and oncology with different prices for both – although, as with liraglutide, the price difference also reflects differences in drug strength and the route of administration.
Apart from these single examples, the system most geared up to deliver MIP is Italy, who developed web-based registries to collect drug usage data by indication since 2005. More than 350,000 patients are included in these registries, which are managed by the Italian Medicines Agency. Although not developed to introduce MIP, the registries are providing data of drug use and effectiveness and have allowed them to alter reimbursement for drugs at different times, depending on performance results. As they have the information on indications as well, there is no reason why they shouldn’t reimburse differently for different indications in future.
The idea of introducing MIP is being considered in various countries, as we all struggle with the drug bill but want to use new developments to best help patients. In the UK, experts have highlighted that underpinning implementation of MIP would be data on use by indication and some areas are working to start collecting that data, so that we can understand exactly how drugs are being used and how cost effective they are in different conditions.
Digital excellence – but with a potential sting in its tail
NHS England has invited 26 of the most digitally advanced trusts to apply for a £100m+ funding pot to become centres of global digital excellence and drive forward better use of technology in health. To be one of the 10-16 trusts who will win the money, each trust will need to demonstrate their potential to become world leaders in health informatics.
The idea is that these 10-16 Trusts will then lead the way for the entire NHS to get better IT in place at scale, delivering benefits for patients and sharing learning and resources with other local organisations through networks. The main aim is to ensure that clinicians get real time access to accurate information, joining up healthcare systems to improve outcomes for patients and reduce workload for overstretched NHS staff.
The selected Trusts, which will be announced later in the year, will need to demonstrate their current ability in three areas.
• The use of comprehensive electronic patient records. This includes making patient records available to staff in real time both to access and input information; ensuring patients can access their medical records online and; use of electronic medicines management which can halve medication errors.
• Information sharing across the local health and care system. This means having digital correspondence and test results for patients and ensuring that the online medical record and care plan can be shared between health and care teams.
• Robust data security, with a plan to respond to threats to data security with senior accountability and fully supported operating systems throughout the organisation.
This last is particularly important, as this type of digital system has regularly been breached in the US. A recent example was a clinic in Arizona where hackers broke in to the system and may have accessed the records of nearly 900,000 patients – including names, health insurance ID numbers, diagnosis and treatment codes and some Social Security numbers. According to a healthcare IT security firm, approximately 29.3 million patient health records have been compromised in data breaches since 2009 and US health care companies experienced a 72% increase in cyberattacks between 2013 and 2014. This data is then being sold on the dark web for several hundred dollars per patient and being used for identity theft.
More worryingly is a newer trend for hackers to break into hospital equipment and then charge a ransom to give control back to the hospital. This has been seen in both the US and Canada. This could be as simple as locking computers and blocking legitimate users from accessing vital information, without which it is difficult to provide high quality care. But in more extreme cases, the hackers could change patient information or cause patients harm.
A legitimate firm has been showing how easy this is to do, in order to help hospitals tighten up their cyber security. They believe that health care is an easy target for hackers because medical equipment is expensive, difficult to fix and is not updated regularly. Medical equipment is often connected to the internet, including MRI scanners and defibrillators, and most don’t even have password protection because the local network is trusted. They have found how easy it is to get access to potentially sensitive patient data, but what is even scarier is that they could also alter the way in which medical devices routinely function, which could potentially harm or even kill patients.
So these Trusts will have a big challenge to ensure that their systems not only work effectively but safely.