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Effectiveness of premixed insulin to achieve glycaemic control in type 2 diabetes: A retrospective UK cohort study

Abstract Aim To investigate the effectiveness of premixed insulin for achieving glycaemic outcomes in clinical practice in the UK. Materials and Methods Electronic medical record data from The Health Improvement Network database were captured for adults with type 2 diabetes (T2D) uncontrolled (HbA1c ≥9%) on two or more oral antihyperglycaemic drugs (OADs) initiating premixed insulin. Effectiveness of premixed insulin was assessed by the probability and incidence of achieving glycaemic outcomes (target HbA1c <7.5% [<58 mmol/mol] and a ≥1% or ≥2% HbA1c reduction) over 24 months. Results Data from 974 participants (mean age 62 years; 56% male; 52% obese or extremely obese; mean HbA1c 11.3% [100 mmol/mol]; hypertension 64%, dyslipidaemia 23% and nephropathy 21%) were analysed. The probability of achieving HbA1c  <7.5% was highest during months 3‐6 (18.2%), while the cumulative probability of achieving this target plateaued between months 15‐24 (15.7%‐16.0%). Incidence of achieving all glycaemic outcomes plateaued after 12 months and differed by baseline HbA1c, but not OAD use. Factors affecting some glycaemic outcomes included a body mass index >40 kg/m2 and co‐morbidities including nephropathy and stroke. Conclusions In people with uncontrolled T2D (HbA1c ≥9%), glycaemic outcome achievement on premixed insulin was low at 6 months with little additional clinical benefit beyond 12 months, suggesting a high unmet need for early, timely treatment changes with more effective, simpler therapies.

worldwide. 1 In the UK, an estimated 4.7 million people have diagnosed or undiagnosed diabetes, which is expected to rise to more than 5.5 million by 2030. 2 Poor glycaemic control in people with T2D can lead to an increased risk of microvascular and macrovascular complications, such as cardiovascular disease, chronic kidney disease and diabetic foot syndrome. 3,4 Many guidelines consider a target HbA1c of ≤7.0% (≤53 mmol/mol) as appropriate for managing most adults with T2D. [5][6][7][8] However, individualized HbA1c targets based on life expectancy, frailty, patient preferences, co-morbidities and risk of adverse effects, including hypoglycaemia and hypoglycaemia awareness, are also recommended. [5][6][7][8] Due to the progressive decline in β-cell function in people with T2D, drug therapy will need to be intensified over time to maintain glycaemic control. 9 According to the UK National Institute for Health and Care Excellence (NICE) guidelines, people with T2D require drug intensification if they are inadequately controlled (HbA1c ≥7.5% [≥58 mmol/mol]) by either a single oral antihyperglycaemic drug (OAD) or by two OADs. 8 Furthermore, the UK NICE guidelines recommend insulin-based treatment as an option for people with T2D inadequately controlled (HbA1c ≥7.5%) with two OADs, and premixed insulin (a combination of neutral protamine Hagedorn insulin and a short-acting insulin) as a treatment option for those with HbA1c ≥9% (≥75 mmol/mol). 8 Previous studies have shown that in the UK, 22.8% of people with T2D are receiving insulin therapy, 10 of whom~40% are using premixed insulin. 11,12 Treatment with premixed insulin is commonly used as both initial insulin therapy and when intensification is required, although initial insulin treatment comprising the addition of basal insulin to OADs is currently recommended for the majority of people with T2D, [5][6][7][8] as most individuals usually maintain sufficient β-cell function to respond to OADs. Twice-daily doses of premixed insulin are a more convenient means of spreading insulin across the day compared with administering basal insulin and prandial insulin separately, 5 with an improved postprandial glucose level compared with basal-only insulin regimens. 13,14 However, a high proportion of people with T2D still fail to achieve HbA1c ≤7% with premixed insulin, 15,16 and evidence suggests that premixed insulin may be associated with a higher risk of hypoglycaemia compared with basal insulin analogues. [13][14][15][16] It should be noted that the NICE guidelines suggest relaxing the HbA1c goal for people for whom reaching HbA1c ≤7% may not be feasible, including people with comorbidities for T2D such as established cardiovascular disease. 8 Furthermore, premixed insulin regimens are strict, requiring either two or three daily injections based on carbohydrate intake estimation with each meal, 17 and people with diabetes are more likely to skip insulin injections if their treatment regimen includes multiple daily injections, interferes with their daily activities or increases the risk of hypoglycaemia. 18,19 In this retrospective cohort study, we investigated the real-world effectiveness of premixed insulin for achieving glycaemic control in routine clinical practice in the UK. after premixed insulin initiation, and at least two HbA1c measurements in the 15-720 days after premixed insulin initiation); and no insulin treatment in the 12 months prior to premixed insulin initiation.
Individuals who received glucagon-like peptide-1 receptor agonists prior to initiating premixed insulin were not excluded. THIN, set up in 2003, is a database of anonymized primary care records from~850 general practices in the UK and has been used in more than 1000 publications to date.
Follow-up for participants ranged from their index date until whichever of the following occurred first: they achieved the glycaemic outcome under analysis; they required additional antihyperglycaemic therapy (intensification); they discontinued premixed insulin; their last record in the database; they died; or the end of the study period. The study period was from 1 January 2009 (to include a 12-month baseline period) to 31 December 2018. Information on the treatment algorithms followed by healthcare professionals while using premixed insulin is not reliably recorded in THIN database.
The study was conducted in accordance with ethical principles that are consistent with the Declaration of Helsinki, International Conference on Harmonisation, Good Clinical Practice, Good Pharmacoepidemiology Practice, and the applicable legislation on noninterventional studies and real-world evidence and epidemiology studies.

| Outcomes and assessments
The primary objective of the study was to investigate the realworld effectiveness of premixed insulin, assessed as the probability of reaching glycaemic control (defined as HbA1c <7.5% [<58 mmol/ mol]), the incidence of reaching glycaemic control (HbA1c <7.5%), and the mean change in HbA1c, all over 24 months post-premixed insulin initiation. Sensitivity analyses evaluated improvement in glycaemic control as the incidence of achieving a ≥1% or ≥2%  Table S1 (Appendix S1).

| Statistical analysis
Sample size was calculated based on assessing the percentage change in mean HbA1c from baseline to 6 months or the first available measurement of HbA1c with sufficient precision, powered based on two-sided significance (α = 0.05). Based on preliminary sample counts, it was calculated that the study should includẽ Kaplan-Meier curves were generated for participants stratified by HbA1c category at baseline (≥9% and ≤10%, >10% and ≤11%, and >11%), age group (18-44, 45-54, 55-64, 65-75 and >75 years), and number of OADs at baseline (2 and ≥3); and prespecified pairwise log-rank regression analyses were performed stratified by age group, baseline HbA1c and the number of OADs used at baseline.
Cox proportional-hazards regression models were used to assess any associations between baseline characteristics and glycaemic control outcomes postpremixed insulin initiation following confirmation of the proportionality of hazards (e.g. Schoenfeld residual test). Alternative semi-parametric methods were used if the proportionality assumption was violated. Baseline characteristics were included as covariates following a stepwise procedure (backwards until P < .2). Data are presented as hazard ratios (HR) and 95% confidence intervals (CIs) for each outcome.
For Kaplan-Meier estimates and Cox regression analyses, the event of interest was achieving glycaemic control. Participants were censored at treatment intensification, premixed insulin discontinuation, death, or end of follow-up. Adjustment for multiplicity was unnecessary.
The influence of missing values was limited by the requirement for participants to have complete data at baseline and in the followup period, and at least one valid HbA1c measurement both at baseline and during the follow-up period.
The cumulative incidence of achieving glycaemic control plateaued after month 12 and increased faster in participants with a baseline HbA1c of 9%-10% or >10%-11% than in those with a baseline HbA1c >11% ( Figure 1A). The cumulative incidence of achieving glycaemic control was also significantly higher in those with baseline HbA1c 9%-10% than in those with baseline HbA1c >11% (P = .0060).
It was also significantly higher in participants aged 65-75 years compared with those aged 45-54 years (P = .017). There were no other notable differences in the cumulative incidence of achieving glycaemic control according to age or the number of OADs used at baseline.
According to the Cox proportional hazards models, participants with baseline HbA1c 9%-10% were significantly more likely to achieve glycaemic control compared with those with HbA1c >11% (HR 1.54, 95% CI 1.11-2.14; P < .05; Figure 2). No other available baseline characteristics had a clinically significant effect on achieving glycaemic control ( Figure 2). The mean (SD) number of GP visits in the year prior to index date was similar for those who did and did not achieve

| ≥1% HbA1c reduction from baseline
In the sensitivity analysis, the cumulative incidence of improving glycaemic control (defined as a ≥1% reduction in HbA1c from baseline) plateaued after 12 months ( Figure 1B). The cumulative incidence of achieving a ≥1% reduction in HbA1c was significantly lower in participants with baseline HbA1c 9%-10% compared with participants with baseline HbA1c >10%-11% (P <.0005) or >11% (P < .0005). The cumulative incidence of improving glycaemic control was significantly higher in participants aged 65-75 years compared with those aged 45-54 years (P = .011). There were no other notable differences in the cumulative incidence of improving glycaemic control according to age or the number of OADs used at baseline. Based on the Cox proportional hazards models, participants were significantly less likely to achieve a ≥1% reduction in HbA1c if they were 45-54 years of age compared with those aged >75 years (HR 0.78, 95% CI 0.63-0.96; P <.05) or had baseline HbA1c 9%-10% compared with an HbA1c >11% (HR 0.53, 95% CI 0.43-0.66; P <.05; Figure 2). Conversely, participants were significantly more likely to achieve a ≥1% HbA1c decrease if they had experienced stroke (HR 1.58, 95% CI 1.09-2.27; P < .05). No other available baseline characteristics had a significant effect on improving glycaemic control (Figure 2).

| DISCUSSION
In this cohort of people with inadequately controlled (HbA1c ≥9%) T2D in the UK who switched from OADs to premixed insulin, the cumulative probability of achieving glycaemic control defined as an HbA1c <7.5% was generally low and was highest during months 3-6 (18.2%). Likewise, the cumulative incidence of achieving glycaemic control was low, and little additional benefit in terms of achieving glycaemic control was achieved beyond month 12 after initiating premixed insulin. Notably, HbA1c did not decrease further beyond month 6, although the reduction in HbA1c was sustained until month 24. The cumulative incidence of achieving glycaemic control (HbA1c <7.5%) was significantly higher in those with lower baseline HbA1c levels, as might be expected. However, interestingly, in the pairwise log-rank regression analyses, those aged 65-75 years had a significantly higher cumulative incidence of glycaemic control than those aged 45-54 years. This may be because older individuals have more time available to adhere to a strict insulin regimen because of reduced work commitments, a greater awareness in the healthcare profession that older people are a high-risk group, or involvement from other healthcare providers in the treatment and management of T2D in older individuals.
The cumulative incidence of improving glycaemic control (defined as a ≥1% or ≥2% reduction in HbA1c from baseline) also plateaued after 12 months and as expected was lower in those with the lowest baseline HbA1c.
Our results show that despite not reaching glycaemic target (HbA1c <7.5%), many participants remained on premixed insulin at 6 months (n = 204) and 12 months (n = 76). These data provide evidence for the therapeutic inertia and unmet medical need that exists regarding treatment intensification in people with T2D. [5][6][7][8] While therapeutic inertia, a recognized and significant barrier to optimal glycaemic control in people with T2D, occurs at all stages of diabetes treatment, the longest delays are reported for the initiation and intensification of insulin therapy. 20 Delaying insulin therapy is often caused by fear of hypoglycaemia, multiple daily injections and weight gain, leading to patients staying on the same therapy despite not achieving or maintaining glycaemic control. 20 In patients with a high baseline HbA1c, an improvement of ≥1% or ≥2% in HbA1c may be more achievable than reaching HbA1c <7.5%.

AUTHOR CONTRIBUTIONS
All the named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article and had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. RL, KP and AS designed and conceptualized the study. RL contributed to the acquisition of data. RL contributed to the analysis of data. All the authors participated in the interpretation of the data, the writing, reviewing and editing of the manuscript, and had final responsibility for approving the published version.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/dom.14298.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from CEGEDIM Health data. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors at https://www.cegedim-health-data.com/cegedimhealth-data/thin-the-health-improvement-network/ with the permission of CEGEDIM Health data.