Mamza, Jil Billy
(2016)
Comparative effectiveness and safety of DPP-4 inhibitors.
PhD thesis, University of Nottingham.
Abstract
Approximately 3 million people throughout the UK suffer with Type 2 diabetes mellitus (T2DM), and are 32% more likely to die early. There remains a lack of evidence for the long-term effectiveness and safety of anti-diabetic drugs in preventing diabetes-related complications, making it unclear how to optimally manage diabetes. Work to date includes observational studies subject to bias, and randomised controlled trials (RCTs), which may not reflect the ‘real world’ situation. The aim of this thesis is to combine such findings via systematic reviews, meta-analyses and retrospective cohort studies to provide more water-tight evidence of the effectiveness and safety of glucose-lowering therapies (GLT) in the long term.
Firstly, a systematic review of observational studies was performed, identifying and providing a simple description of the types of biases and control measures employed in retrospective cohort studies on treatment outcomes of GLTs. Secondly, retrospective cohort studies were conducted to strengthen the evidence of the clinical effectiveness of DPP-4 inhibitors, compare their durability when combined with other anti-diabetic drugs and assess their cardiovascular safety when used in patients with T2DM, using data from The Health Improvement Network (THIN) database. Linear and logistic regression, Cox proportional hazard regression models and propensity score techniques were used to analyse routine clinical data. Thirdly, a meta-analysis was conducted on RCTs investigating the risk of bone fracture following the administration of DPP-4 inhibitor, based on data from an extensive literature search.
Conducting this research has led to a better understanding of how biases may have influenced retrospective cohort studies on oral anti-diabetic drugs. An algorithm was developed to illustrate strategies for addressing biases. Potential clinical factors associated with ‘response’ to DPP-4 inhibitor treatment were found to include the addition of DPP-4 inhibitor to ongoing metformin (MET), or MET plus sulphonylurea (SU) therapy. High HbA1c at the time of treatment intensification and longer duration of diabetes were associated with the lack of HbA1c target attainment. In terms of the durability of second-line glucose-lowering agents, the co-administration of thiazolidinedione with MET was associated with the most durable glycaemic response, followed by a SU and then a DPP-4 inhibitor. Compared with a SU, adding a DPP-4 inhibitor to MET was associated with an increased need for earlier treatment intensification with a third agent. The use of statins, being a female, a smoker, having longer duration of diabetes and higher HbA1c at baseline were identified to be associated with earlier dual therapy failure.
In terms of cardiovascular safety, routine clinical data showed patients who intensified MET + SU dual therapy with a DPP-4 inhibitor were associated with a decreased risk of a composite of non-fatal cardiovascular outcomes and all-cause mortality compared to those who added insulin. Furthermore, the results from meta-analysis showed DPP-4 inhibitors are not associated with increased bone fracture risks in patients with T2DM.
This research is valuable in informing the choices of healthcare professionals in prescribing treatments for T2DM. For the users of this treatment, it is good news that DPP-4 inhibitors are not generally associated with fracture incidence, and that findings support the use of DPP-4 inhibitors as a second line therapeutic option, especially among non-obese patients whose glucose control remains suboptimal following MET treatment. It is recommended that treatment should be characterised on an individual basis. There remains a need for robust RCTs to investigate the influence of obesity and longer treatment durations on the efficacy of co-administering DPP-4 inhibitors to patients who are unresponsive to other oral GLTs.
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