A study of the descriptive epidemiology and clinical effectiveness of treatment for type 2 diabetes using routine general practice data

The prevalence of type 2 diabetes is increasing in the UK. Many people with type 2 diabetes require glucose-lowering therapy including insulin when lifestyle interventions fail to provide adequate glucose control. Some epidemiological studies report an association between insulin use in type 2 diabetes and an increased risk of serious adverse events when compared with other glucose-lowering therapies. However, these findings should be interpreted with caution due to the risk of confounding by indication. The aim of this thesis was to characterise the epidemiology of type 2 diabetes and to investigate the risk of serious adverse events associated with increasing insulin dose in people with type 2 diabetes prescribed insulin therapy. A series of retrospective, observational studies were conducted using data from the Clinical Practice Research Datalink. People with type 2 diabetes were identified and prevalence and incidence rates calculated. The risk of all-cause mortality, major cardiovascular events and cancer in people with type 2 diabetes who progressed to insulin with or without metformin were evaluated using multivariate models. Between 1991 and 2010, the estimated incidence and prevalence of clinically diagnosed and recorded type 2 diabetes increased three-fold. During the same period, the estimated number of people with diagnosed and recorded type 2 diabetes treated with insulin increased seven-fold. Estimated insulin dose was associated with an increased risk of all-cause mortality in people with type 2 diabetes receiving insulin monotherapy (aHR 1.54, 95% CI 1.32–1.78, for 1 unit/kg/day increase in insulin dose) and in those treated with insulin with or without metformin (1.48, 1.31–1.70). However, the use of metformin in combination with insulin was associated with a reduction in risk compared with insulin alone (0.60, 0.52–0.68). Due to the limitations associated with observational studies, further research is required in order to improve our understanding of the risks and benefits of exogenous insulin in type 2 diabetes

Association between insulin monotherapy versus insulin plus metformin and the risk of all-cause mortality and other serious outcomes: a retrospective cohort study

Aims To determine if concomitant metformin reduced the risk of death, major adverse cardiac events (MACE), and cancer in people with type 2 diabetes treated with insulin. Methods For this retrospective cohort study, people with type 2 diabetes who progressed to insulin with or without metformin from 2000 onwards were identified from the UK Clinical Practice Research Datalink (≈7% sample of the UK population). The risks of all-cause mortality, MACE and incident cancer were evaluated using multivariable Cox models comparing insulin monotherapy with insulin plus metformin. We accounted for insulin dose. Results 12,020 subjects treated with insulin were identified, including 6,484 treated with monotherapy. There were 1,486 deaths, 579 MACE (excluding those with a history of large vessel disease), and 680 cancer events (excluding those in patients with a history of cancer). Corresponding event rates were 41.5 (95% CI 39.4–43.6) deaths, 20.8 (19.2–22.5) MACE, and 21.6 (20.0–23.3) cancer events per 1,000 person-years. The adjusted hazard ratios (aHRs) for people prescribed insulin plus metformin versus insulin monotherapy were 0.60 (95% CI 0.52–0.68) for all-cause mortality, 0.75 (0.62–0.91) for MACE, and 0.96 (0.80–1.15) for cancer. For patients who were propensity-score matched, the corresponding aHRs for all-cause mortality and cancer were 0.62 (0.52–0.75) and 0.99 (0.78–1.26), respectively. For MACE, the aHR was 1.06 (0.75–1.49) prior to 1,275 days and 1.87 (1.22–2.86) after 1,275 days post-index. Conclusions People with type 2 diabetes treated with insulin plus concomitant metformin had a reduced risk of death and MACE compared with people treated with insulin monotherapy. There was no statistically significant difference in the risk of cancer between people treated with insulin as monotherapy or in combination with metformin

Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin

Introduction Insulin analogues have become increasingly popular despite their greater cost compared with human insulin. The aim of this study was to calculate the incremental cost to the National Health Service (NHS) of prescribing analogue insulin preparations instead of their human insulin alternatives. Methods Open-source data from the four UK prescription pricing agencies from 2000 to 2009 were analysed. Cost was adjusted for inflation and reported in UK pounds at 2010 prices. Results Over the 10-year period, the NHS spent a total of £2732 million on insulin. The total annual cost increased from £156 million to £359 million, an increase of 130%. The annual cost of analogue insulin increased from £18.2 million (12% of total insulin cost) to £305 million (85% of total insulin cost), whereas the cost of human insulin decreased from £131 million (84% of total insulin cost) to £51 million (14% of total insulin cost). If it is assumed that all patients using insulin analogues could have received human insulin instead, the overall incremental cost of analogue insulin was £625 million. Conclusion Given the high marginal cost of analogue insulin, adherence to prescribing guidelines recommending the preferential use of human insulin would have resulted in considerable financial savings over the period

Patterns of retinal thickness prior to and following treatment with fluocinolone acetonide 190 µg intravitreal implant for diabetic macular edema

Objectives: To compare retinal thickness before and after treatment with the fluocinolone acetonide (FAc) 190 µg intravitreal implant in people with diabetic macular edema (DME) using data from the Iluvien Clinical Evidence study in the UK (ICE-UK). Methods: For this retrospective cohort study, data on people attending any one of 13 participating ophthalmology departments and treated with FAc intravitreal implant between April 1, 2013 and April 15, 2015 were collected for 12 months prior to and at least 12 months after implantation. Cross-sectional and longitudinal patterns of central foveal thickness (CFT) were compared before and after FAc implant. Results: There were 208 people who contributed data from 233 individual eyes treated with the FAc implant. Mean age was 68.1 years and 62% were male. Median (interquartile range) CFT decreased from 462 µm (354–603 µm) at time of implant to 309 µm (222–433 µm) at 12 months post-implant (p < .001). Over the same period, a reduction of ≥10%, ≥25%, and ≥50% in CFT was observed in 113 (65%), 87 (50%), and 37 (21%) treated eyes, respectively. Eyes with a CFT of ≥400 µm at the time of implant were significantly more likely to achieve a reduction in CFT of ≥10%, ≥25%, and ≥50% at 12 months (all p < .001) compared with eyes with a CFT of <400 µm at implant. Both retinal thickness and changes in retinal thickness were loosely correlated with visual acuity. Conclusion: A marked reduction in retinal thickness was observed in people following FAc intravitreal implant for DME. The response was related to the degree of retinal thickness prior to treatment

Healthcare resource utilization and related financial costs associated with glucose lowering with either exenatide or basal insulin: a retrospective cohort study

Aims Type 2 diabetes is a major health problem placing increasing demands on healthcare systems. Our objective was to estimate healthcare resource use and related financial costs following treatment with exenatide‐based regimens prescribed as once‐weekly (EQW) or twice‐daily (EBID) formulations, compared with regimens based on basal insulin (BI). Materials and methods This retrospective cohort study used data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES). Patients with type 2 diabetes who received exenatide or BI between 2009 and 2014 as their first recorded exposure to injectable therapy were selected. Costs were attributed to primary care contacts, diabetes‐related prescriptions and inpatient admissions using standard UK healthcare costing methods (2014 prices). Frequency and costs were compared between cohorts before and after matching by propensity score using Poisson regression. Results Groups of 8723, 218 and 2180 patients receiving BI, EQW and EBID, respectively, were identified; 188 and 1486 patients receiving EQW and EBID, respectively, were matched 1:1 to patients receiving BI by propensity score. Among unmatched cohorts, total crude mean costs per patient‐year were £2765 for EQW, £2549 for EBID and £4080 for BI. Compared with BI, the adjusted annual cost ratio (aACR) was 0.92 (95% CI, 0.91‐0.92) for EQW and 0.82 (95% CI, 0.82‐0.82) for EBID. Corresponding costs for the propensity‐matched subgroups were £2646 vs £3283 (aACR, 0.80, 0.80‐0.81) for EQW vs BI and £2532 vs £3070 (aACR, 0.84, 0.84‐0.84) for EBID vs BI. Conclusion Overall, exenatide once‐weekly and twice‐daily‐based regimens were associated with reduced healthcare resource use and costs compared with basal‐insulin‐based regimens

Comparison of data characterizing the clinical effectiveness of the fluocinolone intravitreal implant (ILUVIEN) in patients with diabetic macular edema from the real world, non-interventional ICE-UK study and the FAME randomized controlled trials

Objective: To compare the effectiveness and safety of the fluocinolone acetonide (FAc) intravitreal implant between the observational Iluvien Clinical Evidence study in the United Kingdom (ICE-UK) and the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) randomized controlled trials (RCTs) in people with diabetic macular edema (DME). Clinical Trials Registration: NCT00344968. Methods: This study selected patients randomized to receive 0.2 µg/day FAc insert (FAc treated eyes) or sham injection (control eyes) from the FAME RCTs, and patients’ first FAc treated eye and non-FAc treated fellow (control) eye from the ICE-UK study. Outcomes included change in visual acuity (VA), central foveal thickness (CFT), and intraocular pressure (IOP). Results: After 12 months follow-up, mean change in VA was 5.0 letters improvement (p < .001) and 1.6 letters improvement (p = .003) in FAME FAc treated and control eyes, and 3.8 letters (p = .012) and –2.1 letters (p = .056) in ICE-UK FAc treated and control eyes, respectively. Mean change in CFT was –144 µm (p < .001) vs –72 µm (p < .001) in FAME FAc treated and control eyes and –113 µm (p < .001) vs –13 µm (p < .001) in ICE-UK FAc treated and control eyes. For eyes with a follow-up of 12 months, 77 (22.3%) and 15 (8.6%) FAME FAc treated and control eyes and 25 (18.7%) and six (4.3%) ICE-UK FAc treated and control eyes required emergent IOP-lowering therapy. Conclusions: Statistically significant improvements in VA 12 months after FAc implantation were observed in both the real-world study and in the RCTs. The improvement in VA and CFT in the RCTs was marginally greater than in the real-world study; however, recruits in the real-world study had more severe visual morbidity at baseline. Whilst there were many changes in the care of people with DME over this time, these data all support the value of treatment with FAc intravitreal implant

Cisplatin drug delivery using gold-coated iron oxide nanoparticles for enhanced tumour targeting with external magnetic fields

The platinum-based chemotherapeutic drug cisplatin is highly effective in the treatment of solid tumours, but its use is restricted by poor bioavailability, severe dose-limiting side effects and rapid development of drug resistance. In light of this we have tethered the active component of cisplatin to goldcoated iron oxide nanoparticles to improve its delivery to tumours and increase its efficacy. Iron oxide nanoparticles (FeNPs) were synthesised via a co-precipitation method before gold was reduced onto the surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH3)2} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterised by dynamic light scattering, scanning transmission electron microscopy, UV–Vis spectrophotometry, inductively coupled plasma mass spectrometry and electron probe microanalysis. The nanoparticles increase in size as they are constructed, with the synthesised FeNPs having a diameter of 5– 50 nm, which increases to 20–80 nm for the Au@FeNPs, and to 60–120 nm for the Pt@Au@FeNPs. Nanoparticle drug loading was found to be 7.9 10 4 moles of platinum per gram of gold. The FeNPs appear to have little inherent cytotoxicity, whereas the Au@FeNPs are as active as cisplatin in the A2780 and A2780/cp70 cancer cell lines. More importantly the Pt@Au@FeNPs are up to 110-fold more cytotoxic than cisplatin. Finally, external magnets were used to demonstrate that the nanoparticles could be accumulated in specific regions and that cell growth inhibition was localised to those areas

Health-economic evaluation of fluocinolone acetonide 190 µg implant in people with diabetic macular edema

Objectives: To assess healthcare resource use and costs of treating people with clinically significant diabetic macular edema (DME) with fluocinolone acetonide (FAc) 190 µg intravitreal implant in routine clinical practice. Methods: The retrospective Iluvien Clinical Evidence (ICE-UK) study collected data on people prescribed the FAc implant in any one of 13 ophthalmology centers between April 1, 2013 and April 15, 2015. Data were collected for 12 months before and after implantation. Standard UK costs were attributed to healthcare resource use. Results: In total, 208 people contributing 233 FAc-treated eyes were selected. Mean age was 68.1 years and 62% were male. The mean (standard deviation, SD) number of anti-vascular endothelial growth factor (anti-VEGF) injections per FAc treated eye in the 12 months prior to implant was 2.8 (2.5), decreasing to 0.6 (1.4) for the same period after implant (p < .001). The corresponding figures for other steroid injections (dexamethasone and triamcinolone) were 0.14 (0.4) before and 0.08 (0.4) after implant (p = .016). There was no statistically significant difference in the number of laser therapies required in the 12 months before and after FAc implant (mean = 0.12 vs 0.11, respectively; p = .626). Overall, mean (SD) healthcare costs were £2,691 (£1,850) before and £1,239 (£1,203) after FAc implant (p < .001). The unit drug and administration cost per FAc implant was £5,680. Conclusions: Excluding the cost of the FAc implant, healthcare costs were significantly reduced in the 12 months post-implant. FAc implant has a duration of 3 years. This needs to be considered when interpreting the cost associated with the FAc implant