By Inga Louisa Stevens, Contributing Writer
The success of personalised medicine, otherwise called stratified or precision medicine,
has been well documented in the treatment of certain diseases. In the case of cancer, the disease will have its own genetic makeup which will vary from individual to individual and knowing the genetic makeup of the disease could lead to individualised drug treatment plans that could reduce the risk of surgery. Similarly, other diseases with genetic components – such as Cystic Fibrosis or Sickle Cell Disease – are well positioned to take advantage of personalised medicine.
In a world where the epidemic rise of diabetes mellitus (DM) incidence is reaching crisis levels - the World Health Organisation (WHO) predicts that diabetes will become the seventh leading cause of death by 2030 – there is much hope that biological markers such as genetic variants can be used to predict the risk of diabetes more accurately and tailor individual treatment plans according to the phenotype of the disease.
Arab Health Magazine sat down with a leading expert Dr Sara Gaafar Ibnauf Suliman, who is a Consultant Endocrinologist and Diabetologist and Clinical Lead for Genetics of Diabetes and Endocrinology at the Imperial College London Diabetes Centre in Abu Dhabi, to learn about the future of diabetes in a world where personalised medicine can really start to make a difference.
Q: How can personalised medicine be applied to the risk assessment of diabetes?
Dr Sara Suliman: Personalised medicine is the ability to phenotype a disease into highly specific sub-groups in order to select targeted therapy; providing the right treatment, at the right time, at the right dose, for the right person.
Biomarkers can aid in the phenotyping and categorisation of specific disorders. ‘-Omic’ biomarkers (e.g. genomic, proteomic, and metabolomic) have been a major focus in personalised medicine, but it is also important to consider simple phenotypic biomarkers and traits, such as age, duration of disease, body mass index, and ethnicity, as well as biochemical, social, physical, and environmental conditions, for a better predictive value in determining the risk of disease and complications in disorders such as diabetes. For example, the heritability of type 2 diabetes suggests that a parent with diabetes confers a 40% lifelong risk of diabetes to their children, and having both parents with diabetes confers an 80% lifelong risk, whereas, all genetic loci identified from genome-wide association scans (to date) in type 2 diabetes (>100 loci) incur a risk of approximately 10%. However, this rule does not apply for specific types of diabetes where defects in a single gene can result in monogenic diabetes syndromes. In these conditions, a single mutation results in the disease, so identification of the mutation in a child of an affected individual suggests that they have an almost 100% chance of getting the specific type of diabetes.
Diabetes was classically thought to have only two types; type 1 DM due to autoimmunity and insulin deficiency or Type 2 DM; insulin resistance combined with insufficient insulin production due to beta cell failure. It is now recognised that diabetes is an umbrella of diseases ranging from monogenic disorders due to a single gene mutation such as MODY, mitochondrial diabetes, lipodystrophy and severe insulin resistance syndromes; to type 1 diabetes, latent autoimmune diabetes of adulthood (LADA) and type 2 diabetes. Molecular phenotyping, including genetics, has been used to identify various sub-types of diabetes. This, in turn, has helped identify the individual’s risk of diabetes and diabetes-related complications.
Genomics has made having a precise molecular diagnosis commonplace which helped clarify the risks associated with different types of diabetes. For example, a specific type of MODY that is associated with mutations in glucokinase (GCK-MODY), results in modestly increased fasting blood sugar levels with near normal blood sugar levels after meals and is not associated with an increased risk of micro- or macro-vascular complications. As such, these individuals do not require any anti-diabetic medication and can be reassured about their risk of complications, while genetic screening of their family can identify other family members wrongly diagnosed as type 1 or type 2 diabetes, allowing them to stop unnecessary treatment.
Q. Similarly, how can it be applied to the treatment?
SS: Personalised medicine and targeted therapy in diabetes has allowed patients to recover quicker, it improves drug safety by reducing the risk of adverse drug reactions, which in turn has the effect of significantly reducing costs for the health service. Finding the combination that fits with a person's specific diagnosis, their lifestyle, their likelihood of compliance and knowing when to adapt and change when the treatment fails are all important. Newer drug therapies are increasingly enabling clinicians to tailor therapies, thereby helping to provide personalised care.
Grouping patients into strata based on their genetic profile and treating them based on their stratification (rather than the symptoms they present with) has already improved healthcare. One example is neonatal diabetes (NDM), this is diabetes diagnosed in the first year of life where autoimmunity is absent (not type 1 diabetes). NDM is often caused by activating mutations in the genes that encode the sulfonylurea receptor (ABCC8) or its associated ATP-dependent potassium channel (KCNJ11), which is easily identified using genetic sequencing. In many of these cases, the genetic defect can be overcome by high doses of sulfonylureas that targets the sulfonylurea receptor/potassium channel complex. These patients can safely stop multiple daily insulin injections even years after diagnosis, demonstrating that the use of pharmacogenetic information in patient care can improve not only the quality of care but also quality of life.
Another area where personalised therapy has been useful is targeting specific phenotypes with more appropriate medication, particularly, with the advent of newer diabetes medication. For example, obese type 2 diabetic patients now have the option of treatment with GLP1 agonist therapy that suppresses appetite as well as improving insulin secretion which targets both obesity and diabetes at the same time.
Q. Are there any new technologies or evolving areas in personalised medicine that are increasingly being applied to the assessment of risk factors as well as the treatment of diabetic patients?
SS: Newer technologies to diagnose and risk stratify diabetes are available in the diagnosis of monogenic forms of diabetes. In recent years, next generation sequencing has enabled the sequencing of 26 genes implicated in monogenic diabetes simultaneously rather than having to screen each gene individually. This is particularly helpful in patients who display a phenotype of diabetes that is likely to be monogenic, however, where the phenotype does not specifically suggest a particular gene mutation. This has reduced both the time required for a result and the cost significantly.
Q. How is personalised medicine (with regards to diabetes) applied within Imperial College London Diabetes Centre in particular?
SS: Imperial College London Diabetes Centre has a unique service where patients attending the clinic have detailed physical phenotyping including height, weight, waist circumference, waist-hip ratio, blood pressure, and anti-smoking advice, as well as detailed biochemical phenotyping including glucose, HbA1c, renal function, urine albumin creatinine ratio, serum lipids, and autoantibodies taken, with the results available by the time the consultation starts (within 30-45 minutes). This information is processed by specialised software, which automatically calculates cardiovascular risk and estimated glomerular filtration rate to assess renal function. Therefore, by the time a physician sees a patient they have sufficient information on clinical biomarkers to make a reasonable attempt at diagnosing the specific type of diabetes and its associated complications.
All this information gives us a detailed overview and the ability to personalise care for each patient. At Imperial College London Diabetes Centre, we practice a multidisciplinary approach, supported by a large team of diabetologists, family physicians, general practitioners, cardiologists, nephrologists, ophthalmologists, diabetes educators, nurses, dieticians, pharmacists, and podiatrists.
Imperial College London Diabetes Centre prides itself on setting up its first clinic exploring the genetics of diabetes in the region in collaboration with the Clinical Genetics Department at University of Exeter, UK. The clinic is using specific genetic screening methods to accurately diagnose monogenic diabetes. Patients with this uncommon form of diabetes are often misdiagnosed as type 1 or type 2 diabetics and receive incorrect treatment for their needs. Since its inception in 2016, the Clinic has served 165 patients with monogenic diabetes and other genetic endocrine disorders, successfully relieving six patients of insulin due to screening that allowed for targeted treatment to correctly manage their condition. Another benefit of this clinic has been the identification of other family members as well as providing genetic counselling for future generations.
Another point of view…
“There is a lot of hope that we can use biologic markers like genetic variants to predict risk of diabetes more accurately and tailor treatment. At Johns Hopkins Medicine International, researchers are looking at personalising the care of diabetes on multiple fronts, including the ‘-omics’, but also figuring out how to individualise care based on patient preferences. This is making its way into the clinics but is still in the early stages. There is a lot of work to understand how we can use ‘-omics’, including the gut’s microbiome, to assess risk and response to medications.”
Dr Nisa Maruthur, Assistant Professor of Medicine, Johns Hopkins University School of Medicine