Discussion
cardiovascular disease, cardiovascular or renal disease, try-before-you-choose, TriMaster, diabetes
DIABETIC KETOACIDOSIS, CARDIOVASCULAR DISEASE, TYPE 2 DIABETES, DISEASES, DIABETES
TriMaster was a crossover study examining patient preference for second and third line glucose-lowering therapy in type 2 diabetes, enabling patients to directly compare their own lived experience of three different drugsMost patients’ preference was for the drug resulting in the best glucose control. The drug with the lowest HbA1c was preferred by 53% of participants even prior to being given information on their HbA1c on the three different therapies. After being fed back HbA1c and weight, 70% preferred the drug with the lowest HbA1c. This is consistent with patients feeling better with good glucose levels and being educated that a lower HbA1c is desirable, and is in line with a recent systematic review of “discrete choice experiment” studies of patient preference in diabetes, where control of blood glucose (reflected in HbA1c) was identified as the most important attribute relating to patient preferenceAn unexpected result was that weight change was less important to the participants when choosing the preferred treatment. When given information on their weight on all three therapies only 45% of participants chose the drug resulting in the lowest weight for them. This is in contrast to other studies which have indicated that weight is an important attribute in treatment choiceN-of-1 trials and crossover trials have clear advantages in allowing within-person comparisons of outcomes, and have been proposed as being the ultimate way to achieve “personalised medicine” as it uses the individual’s experience of the alternative medications to inform their choiceN-of-1 or crossover trials are particularly attractive for studies that test precision medicine approaches that aim to target the optimal treatment for a patient based on their baseline characteristics. N-of-1 trials are appropriate for stable long-term chronic conditions, where the response to a therapy can be observed and quantified relatively quickly. The within-person comparisons they afford means they have considerable advantages over parallel group trials in terms of reduced variability and sample size. However, these trials are longer due to the sequential administration of therapies and careful consideration of study design is required to ensure sufficient washout to minimise potential carryover effects. In addition, statistical analysis can be challenging, particularly when dealing with withdrawals or missing data, as conventional imputation approaches such as ‘last one carried forward’ are not appropriateThe approach used in TriMasterOur study has not examined the long-term outcome of the try-before-you-choose approach. The next step would be a clinical trial comparing directly allocating therapy to a patient with an approach where patients can experience alternative drugs before choosing their preferred option. Further study is needed to assess if the n-of-1 approach, when applied in type 2 diabetes, results in long-term benefits that have been seen in n-of-1 studies in other diseases including increased patient empowerment, improved adherence, and reduced costs which have been seen in other diseasesTo offer an n-of-1 type approach to patients in clinical practice would require some practical modifications to the formal clinical trial we propose. In clinical care, it would not be possible for patients to be blinded, so choice of medication could be influenced by prior beliefs of the patient or clinician regarding the benefits and risks of the therapies, but this would still allow patients to make decisions informed by their own personal experience. Given the short time periods on each drug, this approach is best for determining initial efficacy and short-term side effects. It would not be so helpful for uncommon and rare serious side-effects such as diabetic ketoacidosis, so these would need to be discussed with the patient at the time of their final preference. This n-of 1 approach will require changes in approach from healthcare professionals, but could be fitted to time with normal routine review periods (3-4 months) after initiating new therapy.A major strength is that this is a crossover study examining patient preference for therapy in type 2 diabetes, enabling patients to directly compare their own lived experience of the three different drugs. Previous studiesThere are limitations to our study. Since the study started, the landscape has changed with new evidence of cardiovascular and renal benefits of SGLT2-inhibitors and the cardiovascular benefits of GLP-1 inhibitors; this would be factor influencing therapy choice in patients with pre-existing cardiovascular or renal disease. However, in our study 81% of patients did not meet criteria for agents with specific cardiovascular or renal benefits, so for those at low risk of cardiovascular disease the equipoise of choice of different therapies still stands. A further limitation is that each treatment period was only 4 months, so might not have been long enough to participants to experience the full effect of the medication on glycaemic control and side effects. We only examined one drug in each class and the side effects and/or efficacy profile of other DPP4i and SGLT2i could be different. Finally, the population in our trial was predominantly (95%) self-reported White ethnicity. Further work is needed to determine whether the findings from our work are similar in other ethnicities.In our randomised crossover trial of three oral glucose-lowering therapies in type 2 diabetes (TriMaster), we showed variability in patient preference for different drugs. Most patients preferred the drug that gave them lowest HbA1c and least side effects. In the absence of a specific indication for a particular drug, or where prediction models