There are an estimated 420 million people worldwide suffering from diabetes, and that figure is set to rise to 700 million by 2025. Many diabetes patients develop devastating, chronic complications including coronary heart disease, stroke and peripheral vascular disease, as well as eye and kidney problems. These complications impose an immense burden on the quality of life of the patients and account for more than ten percent of the health care costs in Europe.
Currently there is a high therapeutic need for new treatments for diabetes complications beyond the existing diabetes treatments, which focus mostly on lowering blood glucose levels. Clinical trials to show the benefits of potential therapies are lengthy and costly. Therefore, the key objective of SUMMIT was to develop procedures, technologies and tools to make clinical trials to test novel medications for diabetes complications shorter and more focused.
Clues in patients’ blood
Not all patients are at equal risk of developing diabetic complications. In order to better predict, monitor and treat the patients at risk, the scientists of the SUMMIT project searched for biological clues (biomarkers) in the patients’ blood and urine that indicate if a patient is likely to develop complications. As part of the analysis, researchers measured almost 2 000 biomarkers, and identified some important predictors for diabetes complications. For example, they discovered a panel of 14 biomarkers which can differentiate between patients who will rapidly develop end-stage renal (kidney) disease, which requires dialysis, and patients who are less likely to need dialysis in the near future. A patent has been filed for this panel of biomarkers, and could become a valuable tool for doctors and hospitals in evaluating their patients and predicting their future treatment needs.
When it comes to the cardiovascular disease, the scientists also discovered a panel of six biomarkers which improve our ability to predict which patients will develop cardiovascular disease. They also found that an enzyme which softens the plaque that builds up in blood vessels is a risk factor in developing cardiovascular disease. If this enzyme is active it leads to plaque rupture, which in turn leads to a heart attack or a stroke.
Looking for answers in the genes
In addition to the biomarkers, SUMMIT scientists performed large examinations of genetic variants in different individuals to see if any variants are associated with a higher risk of developing diabetes complications. These studies were performed on almost 11 000 patients for kidney disease, more than 24 000 patients for cardiovascular disease, nearly 10 000 patients for retinopathy (a common eye disorder in diabetes patients) and more than 17 000 patients for lower extremity arterial disease. The comprehensive analysis – the largest such effort undertaken to date – showed that there are no obvious genetic markers which predispose patients to developing diabetes complications. The huge collection of genetic data which was generated during this effort will be a valuable asset in further research.
Of mice, rats and men
In order to improve preclinical trials, the SUMMIT team also performed a systematic review of 19 existing and newly generated animal models for diabetes complications. Such an effort had never been done before, and it helped clean up and clarify the situation in the field. A promising new rat model was developed, validated and a patent application for it has been filed.
Imaging and a new tool for predicting heart attacks and strokes
As part of its effort to improve imaging techniques to monitor the progress of atherosclerosis (the build-up of plaques in the blood vessels), the project has also developed a new, non-invasive ultrasound device capable of identifying patients at imminent risk of a heart attack or stroke. Although the device was developed for diabetes patients, it is now being validated for a range of other diseases. A patent application is pending and a start-up company, Mediscienta, has been created to develop this innovation commercially.
In addition to the work on biomarkers, genetic markers, imaging and animal models, the project recorded a number of other achievements.
- Scientists in the project completed a multi-centre study of diabetic cardiovascular patients, and created a database and a biobank with one of the best characterised diabetic cardiovascular patient groups in the world. Both will be an asset in future research.
- With 1 320 study subjects, the project created the largest dataset of optical coherence tomography (OCT) measurements in diabetes patents. OCT is a technique for obtaining images of the inside of the body at much higher resolution than other imaging modalities such as MRI or ultrasound. The project also developed a method to standardise OCT measurements in multi-centre trials and clinical practice.
- The project generated more than 100 scientific publications, with more publications still to come. It also resulted in 15 doctoral theses from different universities.
For the benefit of industry, academia and patients
Tools and techniques developed during this project, such as new biomarkers and imaging modalities, will improve the prediction of major diabetes complications in clinical trials. New animal models developed will make it easier to choose the right models for specific research questions in preclinical trials. All this will make drug development faster and more efficient, benefitting both the pharmaceutical industry and patients.
The academic community also reaped many benefits, such as access to the resources, expertise and knowledge of the pharmaceutical industry. Additionally, the project has opened up many new funding opportunities and new avenues for future collaborations between industry and academia.
Last but not least, SUMMIT raised the profile of the European research community globally; before SUMMIT, the diabetes research field was dominated by US consortia, but now Europe is increasingly seen as the leader in the field.
What happens next?
SUMMIT generated a lot of data and opened up many avenues for future research. Two new IMI projects, BEAT-DKD and RHAPSODY, will build on the legacy of SUMMIT to further advance research in the diabetes field in coming years.
Achievements & News
Scientists have identified a genetic variant that affects how well diabetes patients respond to the drug metformin. As well as paving the way for a more personalised approach to diabetes treatment, the findings also reveal how metformin actually works. The study, funded in part by IMI’s diabetes projects DIRECT and SUMMIT, was published in the journal Nature Genetics. ###For 50 years, metformin has helped type 2 diabetes patients worldwide to control their blood sugar levels and avoid the heart, eye and kidney problems that often come with diabetes. However, over a third of patients do not respond to normal doses of the drug. Furthermore, despite its widespread use, little is known about how metformin works. In this study, researchers analysed the genomes of over 13 000 people in a hunt for genetic variants associated with different responses to metformin. They found that a variant of the gene SLC2A2 is associated with a stronger response to the drug. This gene is behind the creation of a protein called GLUT2 that is involved in transporting glucose around the body, and people with the gene variant were found to have lower levels of this protein in their liver and other tissues, impairing their bodies’ ability to handle glucose. Metformin reverses this deficiency, explaining why these people respond so well to the drug. What’s more, the genetic variant had a stronger effect in overweight people. In fact, overweight people with two copies of the variant had a response that was equivalent to taking an extra 500 mg dose of metformin. ‘This is an exciting discovery that demonstrates how a patient’s genetics can determine how well, or poorly, a drug works,’ said Ewan Pearson of the University of Dundee and the DIRECT project. ‘We need to undertake further clinical studies before we can change the way we use metformin, but this finding suggests that some patients should be treated with higher doses than others to achieve the same effect. This really does move us a step closer to truly targeted therapy in the treatment of diabetes.’
Diabetes project SUMMIT will hold a symposium entitled ‘A leap forwards for diabetes complications’ in Malmö, Sweden on 22 April 2015. SUMMIT is working to improve our ability to identify and treat diabetes patients at greatest risk of diabetes complications such as eye, kidney, and cardiovascular disease.### At the symposium, members of the SUMMIT team will present highlights from their research, while speakers from outside the project will put SUMMIT’s findings into a broader context. Participation in the symposium is free but registration is obligatory.
- Download the agenda (which also includes information on registration).
Scientists from the IMI project SUMMIT have shed new light on the causes and development of atherosclerosis in diabetes. Diabetic patients often suffer from a widespread and aggressive form of atherosclerosis, with a high risk for myocardial infarction, peripheral vascular disease and stroke.### Despite the enormous burden caused to patients, the molecular mechanisms leading to accelerated damage are still unclear.
Led by Professor Maria Gomez, researchers at Lund University in Sweden have made a giant step forward in unveiling the causes and development of atherosclerosis in diabetic mice. Specifically, the team revealed that a protein called nuclear factor of activated T-cells (NFAT) causes atherosclerosis in diabetic mice. Furthermore, when the team blocked the activity of NFAT, this halted progression of the atherosclerosis. The researchers also believe that these findings may constitute a novel therapeutic target to reverse diabetic macrovascular complications.
SUMMIT is one of the three research consortia in IMI’s Diabetes Platform, together with DIRECT (DIabetes REsearCh on patient stratification) and IMIDIA (Innovative Medicines Initiative for Diabetes). SUMMIT’s key objective is to develop procedures, technologies and tools to make clinical trials testing of novel medications in diabetic complications shorter and more focused.
IMI diabetes project SUMMIT has developed a revolutionary new ultrasound device capable of identifying patients at imminent risk of a heart attack or stroke. Atherosclerosis occurs when plaques of fatty material build up on the inside walls of blood vessels.### If a plaque breaks up, the resulting blood clot could block the blood vessel and so cause a stroke or heart attack. People with diabetes are at a greater risk of both conditions. Currently, detecting plaques that are at risk of breaking up involves expensive, risky procedures as medical devices are inserted into the blood vessels themselves. The SUMMIT method is non-invasive, and for the patient it works in much the same way as a normal ultrasound, such as that used on pregnant women, although in reality it is much more complex. The SUMMIT team is now validating the new ultrasound technique at four centres across Europe. Although SUMMIT developed the device with diabetic patients in mind, it could be used on all patients at risk of heart attacks and stroke. The researchers behind the device applied for a patent earlier this year. ‘We are hoping to get a first response to our patent application by the end of the year,’ said Isabel Gonçalves of the University Hospital in Malmö-Skåne, one of the inventors of the device. ‘In my view our innovation is going to be a big hit if it continues giving positive results in the rest of the tests.’
- Find out more about the SUMMIT ultrasound device, as well as other news from the project, in the latest issue of the SUMMIT Newsletter
IMI currently has three projects working on diabetes – DIRECT, SUMMIT, and IMIDIA – which have a combined budget of just over €100 million. The projects tackle diabetes in different ways.### For example, IMIDIA focuses on studying the pancreatic beta cells which are responsible for producing insulin; it aims to use this knowledge develop treatments that can slow down the progress of diabetes. Meanwhile, SUMMIT’s work addresses the urgent need for new treatments to tackle the complications associated with diabetes, such as eye, kidney, and blood vessel problems. Finally, DIRECT takes a personalised medicine approach to diabetes, as it works to identify different varieties of diabetes and effective treatments to tackle them. The projects already work together on an informal basis (as evidenced by their new joint leaflet produced with the support of the IMI Executive Office). However, IMIDIA and SUMMIT have now taken their collaboration to a new level with the signature of a Memorandum of Understanding (MoU). The MoU covers the handling of intellectual property, the transfer of knowledge and materials, and confidentiality. The projects believe that the MoU could serve as a template for collaboration between other IMI projects in the future.
Scientists from the IMI-funded SUMMIT project have developed a software tool that beats the current state of the art when it comes to scanning multiple genomes for mutations that could raise people’s risk of developing a specific disease or condition. ###Scientists regularly scan and compare the genomes of large numbers of people, some healthy and some with the disease under investigation, hunting for Single Nucleotide Polymorphisms (SNPs – mutations where just one letter of the DNA code is changed) that could help to explain people’s genetic predisposition to the disease. Writing in the journal BMC Bioinformatics, the SUMMIT researchers set out how they tested their new ‘Bag of Naïve Bays’ (BoNB) software to identify SNPs that could predict the development of type 1 diabetes. They also compared BoNB’s performance against that of two other algorithms used in these studies. Not only did BoNB successfully identify the genetic markers already known to be associated with a raised risk of type 1 diabetes, it outperformed the two other algorithms tested in terms of predicted risk accuracy. The SUMMIT team will now use BoNB to identify the genetic factors that raise people’s risk of developing diabetes-related complications, such as eye, kidney, and blood vessel problems. The source code of the BoNB algorithm is available online.
EFPIA member companies Sanofi-Aventis and Pfizer have joined IMI project SUMMIT, which is investigating new ways of identifying the diabetes patients at greatest risk of developing complications such as heart disease and stroke, and damage to the blood vessels, kidneys and eyes.### The development of novel biomarkers (biological markers) and imaging technologies will help to better predict and monitor the progression of such complications and assess the efficacy of treatments. This will help to shorten clinical trials of novel medications. Among other things, Sanofi-Aventis will contribute to SUMMIT’s efforts to develop tools to identify patients at risk of kidney problems and atherosclerosis (hardening of the arteries). For example, it will develop an imaging probe to assess levels of calcification within atherosclerotic plaques in an experimental model of arterial stiffness. Pfizer will also contribute to SUMMIT’s work into the genes and proteins behind kidney disease in diabetics; their involvement will allow the partners to expand work that will help identify the patients who are more likely to develop kidney problems and progress rapidly through the stages of kidney disease.
‘We took the lead over US-based projects’ – an interview with SUMMIT project coordinators
Before SUMMIT started in 2009, ongoing research on diabetic complications in Europe was scattered amongst various countries. Fast forward six years, and Europe – by joining forces and activities – has climbed to the top of the research ladder in this field, ### coming close to or even surpassing similar research projects in the US. In an interview with the IMI Programme Office, SUMMIT project coordinator Michael Mark of Boehringer-Ingelheim, and scientific coordinator Leif Groop of Lund University, explain how SUMMIT contributed to the diabetes complications field. ‘This IMI project also showed that academic centres and pharmaceutical industry can work together in a structured and collaborative way – something that has never been done before in this field,’ said Mark. ‘This IMI framework was new for the European academia as well as for the industry, but thanks to it we are now well positioned to compete or even surpass our colleagues in the US.’
- Read the full interview
- Find out more about the project's achievements in the project factsheet
- Visit the project website
IMI diabetes projects deepen cooperation
IMI’s three diabetes projects – IMIDIA, SUMMIT and DIRECT – are set to deepen their cooperation following the signature of a new Memorandum of Understanding (MoU) that formally creates the ‘IMI Diabetes Platform’. ‘With a combined budget of ###€100 million and the involvement of over 300 leading experts in diabetes, this is one of the world’s leading initiatives in this area focusing on overcoming key bottlenecks for novel therapies and improved disease management,’ the projects write in a press release announcing the MoU. ‘The importance of the findings of the IMI diabetes projects will be strongly increased by the multiple opportunities for information exchange now enabled by the implementation of a formal collaboration framework for the IMI Diabetes Platform.’ The projects have already been collaborating informally for some time. For example, they jointly organised a symposium to present their results at the recent annual meeting of the European Association for the Study of Diabetes (EASD) in Barcelona.
ParticipantsShow participants on map
- Astrazeneca AB, Södertälje, Sweden
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi-Aventis Deutschland GMBH, Frankfurt / Main, Germany
Universities, research organisations, public bodies, non-profit groups
- Goeteborgs Universitet, Gothenburg, Sweden
- Helmholtz Zentrum Muenchen Deutsches Forschungszentrum Fuer Gesundheit Und Umwelt GMBH, Neuherberg, Germany
- Istituto Di Ricerche Farmacologiche Mario Negri, Milano, Italy
- Itä-Suomen yliopisto, Kuopio, Finland
- Karolinska Institutet, Stockholm, Sweden
- Lunds Universitet, Lund, Sweden
- Samfundet Folkhalsan I Svenska Finland Rf, Helsingfors, Finland
- Terveyden Ja Hyvinvoinnin Laitos, Helsinki, Finland
- The University Of Edinburgh, Edinburgh, United Kingdom
- The University Of Exeter, Exeter, United Kingdom
- Universita Cattolica Del Sacro Cuore, Milan, Italy
- Universita Degli Studi Di Firenze, Florence, Italy
- Universita Degli Studi Di Padova, Padova, Italy
- Universita Degli Studi Di Pavia, Pavia, Italy
- Universita Di Pisa, Pisa, Italy
- University Of Dundee, Dundee, United Kingdom
- University of Cambridge, Cambridge, United Kingdom
- University of Oxford, Oxford, United Kingdom
- University of Turku, Turku, Finland
Small and medium-sized enterprises (SMEs)
- Biocomputing Platforms LTD Oy, Espoo, Finland
- Lunds universitets innovationssystem AB, Lund, Sweden
|Name||EU funding in €|
|Biocomputing Platforms LTD Oy||181 873|
|Goeteborgs Universitet||162 618|
|Helmholtz Zentrum Muenchen Deutsches Forschungszentrum Fuer Gesundheit Und Umwelt GMBH||592 320|
|Istituto Di Ricerche Farmacologiche Mario Negri||184 999|
|Itä-Suomen yliopisto||1 246 775|
|Karolinska Institutet||959 999|
|Lunds Universitet||4 413 330|
|Samfundet Folkhalsan I Svenska Finland Rf||450 258|
|Terveyden Ja Hyvinvoinnin Laitos||228 946|
|The University Of Edinburgh||309 749|
|The University Of Exeter||465 999|
|Universita Cattolica Del Sacro Cuore||319 999|
|Universita Degli Studi Di Firenze||150 000|
|Universita Degli Studi Di Padova||432 259|
|Universita Degli Studi Di Pavia||292 499|
|Universita Di Pisa||455 404|
|University of Cambridge||234 998|
|University Of Dundee||2 500 280|
|University of Oxford||701 629|
|University of Turku||370 625|
|Total Cost||14 654 559|