Examining Drug Utilisation Patterns and Optimal Treatment Pathways of Antidiabetic Medications

Student thesis: Phd


Background: Type 2 Diabetes is a chronic metabolic condition which occurs as a result of insufficient insulin production and insulin resistance. This results in less glucose uptake by muscle and fat cells, allowing blood glucose levels to rise in the body. Higher blood glucose levels place patients at an increased risk of diabetes-related complications. The treatment is characterised by the initiation, switching and intensification of antidiabetic medications. The goal for patients with diabetes is to maintain glycaemic control, with blood glucose levels (HbA1c) between 6.5-7.0%(48-53mmol/mol). International guidelines recommend prescribing of metformin at initiation but there is no consensus on optimal agents in a combination regimen. The aim of this thesis was to assess the drug utilisation patterns of first-line therapies and the impact of this pathway on second-line regimens. This entailed: (i.) observing the prescribing of the first-line therapy, (ii.) characterising the medication-taking process of the first-line therapy and effectiveness of the regimens, and (iii.) determining the most effective second-line regimen in delaying the onset of microvascular complications.Methods: Patients with type 2 diabetes, prescribed a first-line antidiabetic regimen, were identified from the Clinical Practice Research Datalink (a large UK anonymised primary care database) between 01/01/05 and 31/12/09, were followed-up until 31/12/12. A multinomial logistic regression model was used to assess the relationship between patient characteristics and the choice of first-line agent. Adherence to first-line therapy was estimated using the Medication Possession Ratio calculation, expressing the percentage of days covered by a drug supply. To assess the factors influencing achievement of glycaemic goals from the first-line therapy, a logistic regression analysis was performed. To investigate second-line regimens, a Marginal Structural Cox model was implemented to explore the causal relationships between the time to development of microvascular complications and the second-line regimens. Results: Of the 72,429 individuals diagnosed with type 2 diabetes, 44,838 started therapy with an antidiabetic medication regimen. Metformin and sulphonylureas were the most frequently prescribed agents at initiation (82.9% and 9.8%,respectively). Deviations from metformin were associated with patients presenting with higher HbA1c levels, lower BMI values and had concurrent prescriptions (immunosuppressants and oral corticosteroids). Achieving glycaemic control, to the target of 6.5% (48mmol/mol), was only met in 22.7% of patients. Characteristics of the patient, choice of first-line agent and medical support influenced the effectiveness of the treatments. Patients at the greatest risk of failing to achieve the target glycaemic goal from therapy had HbA1c levels>8.0% (64mmol/mol) and a BMIgreater than or equal to25kg/m2. Adherence was significantly associated with greater lowering of HbA1c levels but these reductions did not guarantee reaching the ideal glycaemic target. Intensification of the monotherapy to a dual therapy regimen was observed in 30.2% of patients in a mean time of 2 years. The most frequently prescribed second-line regimens consisted of metformin/sulphonylurea (SU) (74.5%), metformin/thiazolidinediones(TZD) (11.3%) and metformin/DPP-4 inhibitors (14.2%). Metformin/SU was the most effective dual therapy regimen for delaying the onset of microvascular diagnoses. The rate of development of these events was significantly higher for the DPP-4 combination in comparison to the SU combination with a hazard ratio of 1.85 (95% CI: 1.53,2.24). A TZD combination resulted in a non-significant increase of 19% in the rate of development compared to the SU combination (HR 1.19; 95% CI: 0.98,1.47). Metformin/SU resulted in the greatest lowering in HbA1c levels (-3.3%; 12mmol/mol) in comparison to the DPP-4 and TZD regimens.Conclusions: It is unlikely that patien
Date of Award1 Aug 2015
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorDarren Ashcroft (Supervisor) & Douglas Steinke (Supervisor)


  • Antidiabetic medication
  • Second-line
  • HbA1c

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