MedicalResearch.com Interview with: Dr David Strain, MRCP MD
Clinical senior lecturer and honorary consultant
University of Exeter Medical School
Institute of Biomedical and Clinical Science
Department of Diabetes and Vascular Research
Royal Devon & Exeter Hospital Exeter EX2 5AX
MedicalResearch.com: What is the Background of the study?
In early 2010 recent diabetes outcome trials such as ACCORD and ADVANCE had put into question the benefit of aggressive HbA1c reduction for all patients particularly in elderly population. After that there were several guidelines that suggested individualizing treatment targets for elderly patients according to their age, co-morbidities, frailty and baseline HbA1c. This featured in the Finnish guidelines and the European Working Party for the management of Diabetes in the Older Person. However this was also completely without any evidence base. I worked with Paivi Paldanius (the final author of the paper and a medical advisor for Novartis) to establish a pragmatic study. We both acknowledged the importance of having a patient-centric, pragmatic and ‘real-life’ approach and as there was already evidence that DPP-4 inhibitors, in this case vildagliptin (due to Päivi’s affiliation), had demonstrated it’s efficacious and had no tolerability issues in the elderly population we decided to go ahead with the study.
It was obvious that we needed to implement a holistic approach and take into account as many clinically relevant parameters as possible, such as age, baseline HbA1c, duration of the disease, co-morbidities and frailty, for implementation of the individualized care. Our primary goal was to request that the physicians acting as investigators would still apply their clinical judgment based on these clinical features of each individual patient but also, follow their local guidelines as in their daily clinical practice. This would later provide us with invaluable information and perspective when interpreting the data and recommending implementation of the results. For assessment of frailty we screened for many different methodologies but Prof Timo Strandberg (known expert of the field and mentioned in the acknowledgements section of our paper) suggested to apply modified Linda Fried’s method for assessment of phenotype of frailty as this method is validated, very pragmatic, reproducible and also feasible to be used for the first time also by a non-geriatric investigator. All investigators were trained to follow these parameters by the protocol. We also wished to evaluate in parallel the conventional HbA1c drop assessment in order to be able to put the potential success of our new endpoint, meeting the individualized target, into perspective and for comparison against other standard data from other studies with DPP-4 inhibitors with elderly. We also wished to simulate a clinical, real-world setting as much as possible and included patients who would seem representative of most elderly T2DM patients.
MedicalResearch.com: What are the main findings of the study?
Dr. Strain: The primary objectives were to determine whether the DPP-4 inhibitor, vildagliptin could achieve the individualized targets in these elderly adults. This it did with an odds ratio of success of 3.16 after adjustment for baseline variables.
The secondary objectives included assessing the safety of the agent, and more importantly exploring the individualized targets that were set. Vildagliptin appeared safe in this elderly population and was just as potent across the all age-ranges with no new safety signals.
MedicalResearch.com: Were any of the findings unexpected?
Dr. Strain: There were many findings additional to the primary objectives which were significant; we observed that basic patient education, communication about and focus on individualized target setting induced a clinically meaningful response even in the placebo group; Indeed 27% of the patients responded to nothing more than a simple educational approach that was individualized to their need rather than the generic “one size fits all” approach of many international guidelines.
The overall the discontinuation rate was also much lower than anticipated in this type of population in other studies with conventional approach. It was also somewhat surprising that the physicians were considerably influenced by stringent HbA1c targets possibly as a result of the local recommendations and the average HbA1c target was 7.0% (53mmol/mol) much lower than we anticipated. This is now an area of further analysis in order to determine what drove the targets that were set. We believe this analysis will provide invaluable information for those trying to implement the recently published guidance for the management of the older person with diabetes. The results of this study support global guidelines’ recommending individualized care, and demonstrate the feasibility of the study design, and the setting of individualized targets.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Strain: This study supports guidelines’ recommendations and demonstrated that the local guidelines need to be synchronized with the international guidelines which recommend individualization of the target setting based on the clinical features of each individual patient. The inclusion of frail elderly patients in our study will open the door for their inclusion in future studies. The study also demonstrates that individualized targets can be used as an endpoint in a clinical study and we trust that many studies will adapt this approach when evaluating the safety and efficacy of treatment modalities, thus follow our lead in providing an evidence-base for global treatment guidelines for patients with T2DM.
What was most also very interesting, however was that by individualizing the goals and setting realistic targets, then spending time talking to patients rather than aggressively chasing targets resulted in nearly a quarter of patients achieving better glycemic control.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Strain: The physicians in our study seemed to be influenced by their local guidelines which might not yet have been updated and there seems to be a gap in the application of the global guidelines. Our short term next goal is to gain a better understand of which factors impacted target setting and if these potential barriers to more optimal treatment can be overcome by communicating our further, secondary findings in peer reviewed journals and by educating colleagues of our findings.
At the University of Exeter Medical School, our longer-term aims are to carry this work forward to a longer term study using clinically meaningful outcomes for an elderly population, such as frailty progression, hospitalizations for any cause and quality of life, using the more conventional outcomes for secondary analyses – we believe that at the age of 75 patients are far more interested in the quality of their remaining years rather than the quantity and this should be the principle focus of studies
Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study
Dr W David Strain MD,Valentina Lukashevich MD,Wolfgang Kothny MD,Marie-José Hoellinger MD,Päivi Maria Paldánius MMedSci
The Lancet – 23 May 2013