The results of this retrospective observational study show that patients with type 1 or type 2 diabetes, who switch from a predominantly basal-bolus NPH-based regimen to a glargine-based basal-bolus regimen derive significant improvement in glycaemic control (adjusted mean decrease in HbA1c by 0.38% and 0.31%, respectively) within 12 months, without any significant increase in weight, use of prandial boluses, total insulin dose or OAD intensity. These findings add to a weight of evidence supportive of improved glycaemic control when patients switch from other insulins, either NPH [29, 30] or premixed insulins , to glargine. The relevance of our findings are strengthened by the nature and size of our sample (701 patients in an everyday clinical practice setting), the quality of baseline data (available for at least 12 months prior to switching from NPH to glargine), the completeness of follow-up data after switching (at least 3 monthly follow-up over 12 months), and the use of linear interpolation and multiple regression techniques in our analysis. Sensitivity analyses showed that the magnitude of improvement in HbA1c was greatest in patients with the poorest glycaemic control (mean adjusted decreases of 0.57 and 1.07% in type 1, and 0.47 and 0.97% in type 2 diabetes patients with baseline HbA1c levels ≥ 8% and ≥ 10%, respectively) (Table 2), and comparable with that reported in trials of patients newly commencing insulin therapy . A reduction of 1% in HbA1c is associated with a 14% reduction in myocardial infarction, a 14% reduction in all-cause mortality, a 37% reduction in microvascular complications, and a 21% reduction in overall diabetic complications . Thus, the additional reduction in HbA1c achieved by switching to a glargine-based regimen can be considered clinically meaningful, both in the overall population and the subgroups which had a ≥ 1% greater reduction, given the potential to translate to clinical outcomes benefits in the longer-term.
While we have highlighted the strengths of our study, we also acknowledge a number of potential limitations. First, we recognise that retrospective observational studies do not provide the same robust level of evidence as randomised controlled trials. In our study, the decision to switch from NPH to glargine treatment was not standardised but instead based on the judgement of the individual treating clinician. The data were collected from a large number of primary practice units which is likely to introduce a considerable level of heterogeneity to the main findings. As well, the level of data collection did not permit investigation of potential influences on glycaemic control including differences in racial background , body mass index [29, 34], frequency of NPH and glargine use (once vs. twice daily) , concurrent use of OADs with glargine , time of administration of glargine (morning vs. bedtime) [37, 38] and patient compliance [39, 40]. Second, it was not possible to reliably assess data concerning hypoglycaemic episodes in patients who switch from a NPH-based regimen to a glargine-based regimen. A lack of consistency in recording these data in the THIN database meant that there is strong likelihood that we underestimated the real incidence of hypoglycaemia and only captured the most severe episodes. The incidence of hypoglycaemia may also reflect the self-reporting methods used, as patients and physicians were not requested to provide specific details of each episode. The limitations of the database also did not allow assessment of the nature (e.g. nocturnal) or severity of hypoglycaemic episodes before and after the switch. A higher number of hypoglycaemic episodes were noted after the switch from NPH to glargine. However, the overall rate of hypoglycaemia was low so the results should interpreted with caution. Should this trend be real, the significant improvement in glycaemic control observed with glargine in both diabetic cohorts may have made patients more susceptible to episodes of hypoglycaemia.
Despite these shortcomings, observational studies such as the current report are generally regarded as an ideal approach to assess the actual health outcomes of patients in routine care, more so than randomised controlled trials. This is because the level of care patients receive in clinical trials is often of a higher standard and not representative of that provided in daily clinical practice [18, 19]. As well, clinical trials usually have limited scope for titration of other glucose-lowering drugs, a relatively short observational period, and potential for population bias which may prevent extrapolation of their findings to everyday practice [41, 42]. In the current study, there were no limitations regarding patient inclusion criteria or clinical criteria for switching insulin treatment, which is likely to widen the implications of our findings. Furthermore, while high rates of missing data and patient drop-outs are common criticisms of observational studies, the current study provided interpolated data for 90% of patients during the months preceding and immediately following the switch and for 67% 12 months later. Interpolated HbA1c data was used in 60% of patients. However, the main analysis performed in our study was based on the adjusted change in HbA1c which only used actual and complete data values. It is reassuring to note that our findings are supported by other analyses from different populations and geographic locations and using different methods of data collection .
The implications of these results for decision makers are that improvement in control of glycaemia, as measured by HbA1c, can be directly related to treatment efficacy and the costs of subsequent care. Using a discrete event simulation model, we recently reported that that for UK patients with sub-optimally controlled type 2 diabetes, taking into account effects on HbA1c and reduction in hypoglycaemia, glargine can be considered as a cost-effective treatment option with a cost per quality-adjusted life year of less than £10,000 . In addition, preliminary data from a similar analysis using the THIN database indicates that for patients with type 1 or type 2 diabetes who switch from NPH to glargine, treatment with glargine is a cost-effective strategy according to conventional thresholds .
A noteworthy finding from our study is that despite dissemination of clinical guidelines for diabetes management, glycaemic control is still less than optimal in a large proportion of patients in primary practice in the UK. Approximately two-thirds of patients in the study failed to achieve an HbA1c level ≤ 7%. These data highlight the need for additional treatment strategies. These may include higher doses and more aggressive titration (in the current study, evidence that glargine had no significant effect on weight is suggestive of suboptimal treatment), greater use of OAD therapy in patients with type 2 diabetes (only 20% were prescribed OAD therapy at the time of the switch), as well as the use of educational programmes [45–48].