MRC APBI STratification and Extreme Response Mechanism IN Diabetes - MASTERMIND

Context

The present clinical guidelines for the treatment of type 2 diabetes propose that treatment given to patients is primarily determined by the cost of the therapy and assumes that all patients respond similarly to treatment. This ignores the fact that for many therapies there is enormous variation in response between individuals with type 2 diabetes. If it was possible to understand the reasons why patients responded differently to therapy then it would be possible to choose the therapy most likely to be effective for an individual patient thus maximising the benefit and minimising the risk of a particular treatment.

Aims and Objectives

The aim of this research is to develop a scientific framework which will be used to develop the stratification of treatment in Type 2 Diabetes; that is individualising treatment for a patient or subgroups of patients with the aim of giving the right drug to the right patient at the right time.
In Strand 1, the main aim is to define the biological mechanisms involved in patients' extreme response to second and third line treatment in type 2 diabetes. The objectives are to define exactly why some patients respond very differently to the same drug. We will define the clinical characteristics which relate to whether patients are more or less likely to respond to a drug, including whether the patients who do not respond are just those that do not take their tablets. We will also define those characteristics related to rapid deterioration of the blood glucose. We will determine whether if a person does not respond to one type of drug they are likely to not respond to other drugs or whether that person simply does not respond to all diabetes treatment. We will determine how consistent someone's response is by asking patients to stop their drug treatment briefly; someone who is a consistent good responder to the drug will have a rapid in rise in blood sugar when the drug treatment is stopped. Finally, we will set up a resource to enable future genetic and non genetic markers of drug response to be developed.
In Strand 2 we will develop critical information that is required before an approach using stratification can come into clinical practice. We will develop a model which allows us to predict a patient's likely response to a particular therapy. We will then work out in theory when it would be both effective and cost effective to use treatment stratification in type 2 diabetes.

Potential applications and benefits

There are enormous potential benefits to giving drugs to patients who are likely to respond to them and not to patients who are unlikely to respond. This would have considerable benefits in improving the patient's blood sugar control and hence reducing their risk of complications, cutting down on the number of tablets that they need to take (hence saving money on unnecessary therapy) and reducing the risk of side effects to therapies that were ineffective. For the pharmaceutical industry it would enable targeted drug development for patients where other therapy was ineffective and also to define patient subgroups that were most likely to benefit from new drug development. In addition this new understanding about why patients responded very well to drugs already developed would aid in the future modification of therapy to give improved patient outcome.

The work in Strand 1 is to assess the mechanisms explaining differences in response to hypoglycaemic therapy and in Strand 2, to develop the appropriate tools to apply stratification in clinical practice and the theoretical models to assess when this would be effective and cost effective.
In Strand 1 the principal approach will be to study the extreme responders to both drug therapy and rate of glycaemic deterioration. In a large cross-sectional study, clinical characteristics, DNA, and serum and plasma (for the biomarkers studied) will be collected from 6000 subjects. The pathophysiology associated with the extreme response to therapy will be assessed by in depth studies of groups of 80 responders and non responders for each drug class. Further studies will assess what the 'best' drug is for an individual i.e. in someone who has an extremely good or poor response to one drug, is an alternative drug that works via a different mechanism similarly effective, better or worse. Finally, the fundamental question of durability of response will be addressed by assessing if the extreme initial response to a therapy wears off over time, as this will guide whether drugs should be continued as new drugs (e.g. insulin) are added or stopped.

In Strand 2, large amounts of individual and group patient data will be used to develop a model allowing prediction of response to specific therapy types. This will be based on existing trial data and then validated in longitudinal observational patient data. We will develop theoretical models to assess when and to what extent stratification results in a more effective use of treatment. We will go on to create further models, which will look at the cost effectiveness of this approach including taking into account the impact on morbidity and mortality of improved glycaemic control in such an approach. We will develop a theoretical framework dealing with the issues of implementing the stratified approach in the treatment of type 2 diabetes.

This grant offers the possibility of defining the mechanism, effectiveness and cost effectiveness of stratification for 2nd and 3rd line treatment in type 2 diabetes. It will also answer fundamental questions about whether therapy should be discontinued when glycaemic targets are no longer met, whether patients who do not respond to one drug are unlikely to respond to another and whether the response to therapy changes over time. These are fundamental pieces of information required in the treatment in type 2 diabetes which have considerable potential and wide ranging impact.

Who will benefit from this research?
The people who will benefit the most are patients with diabetes. The answers provided by this project will directly influence the choice of what treatment they should take. We hope that this will mean that they are taking the right treatment at the right time and importantly also avoiding treatments which are ineffective for them. It will also be of clear benefit to doctors in primary and secondary care who treat patients with type 2 diabetes. For providers of healthcare it will be enormously important to ensure that patients are treated with appropriate drugs with the more expensive newer agents being used in those who will gain the most benefit. A major beneficiary will be the pharmaceutical industry who will get early information on a new approach to the treatment of type 2 diabetes. The definition of people that will clearly not benefit from generic medication or alternatively will clearly benefit from recently introduced novel therapies will give a clear target of where pharmaceutical companies should be aiming their therapy. In addition the establishment, even if for only 1 drug, that strata can occur and it can be beneficial to be selective in who receives the drug will open new opportunities for drugs which do not show efficacy across a broad range of patients but might be very effective for a smaller subgroup. The development by a very strong academic team of the theoretical basis of stratification is likely to be very resonant with organisations advising on prescribing such as NICE and hence be very relevant to companies. In addition the information on what determines the mechanism of response will be important to inform the development of new therapies with less response heterogeneity and increased effectiveness.

There will also be a clear benefit for people working in other fields as this could develop a blueprint for how to investigate stratification for conditions where the tissue is not available for detailed study. It is not over stating the case to say that defining that stratification is clearly beneficial in a single sub group of type 2 diabetes medication could change thinking for many common conditions such as hypertension.
At a national level given the very large number of patients with type 2 diabetes there will be improvement in the health of the nation by achieving better glucose control and hence preventing the development of complications. There would also be an advantage in the wealth of the nation by reducing healthcare costs in not prescribing unnecessary medication and also in providing a clear focus to the appropriate use of current medication and directions for the development of future medication for type 2 diabetes.