In this large, pooled analysis of prospective, randomized, controlled clinical trials in patients with type 2 diabetes, more than half of the patients previously uncontrolled on 0, 1 or 2 OADs with baseline HbA1c of 8.7–9.1% achieved a target HbA1c ≤7.0% after 24 weeks of treatment with the addition of basal insulin, while continuing the oral agent(s). Patients taking MET alone before the initiation of basal insulin had the greatest HbA1c reductions and the largest proportion of patients achieving glycaemic goal at week 24 compared with patients taking an SU alone or in combination with MET. Hypoglycaemia rates were low overall. Patients on MET only at baseline also had the lowest rate of symptomatic and severe hypoglycaemia and the lowest weight gain after 24 weeks of treatment with insulin glargine in spite of a higher insulin dose on average. The results from this pooled analysis were supported by a meta-analysis of five eligible studies from the trial cohort in which the OR of achieving glycaemic goals at week 24 was significantly higher and risk of symptomatic hypoglycaemia was significantly lower for patients taking MET alone before initiation of basal insulin compared with those taking an SU alone or in combination with MET.
These data illustrate that adding basal insulin in patients whose hyperglycaemia remained uncontrolled on 0/1 OAD (and particularly to MET monotherapy) resulted in greater HbA1c reductions and lower rates of hypoglycaemia after 24 weeks than adding basal insulin to 2 OADs. These findings provide evidence-based clinical trial support for the success of the tier 1 consensus strategy from the ADA/EASD [1
], recommending the addition of basal insulin (or SU therapy) to MET monotherapy plus lifestyle intervention at step 2 (i.e. if MET plus lifestyle intervention alone is unable to achieve glycaemic control).
Moreover, these preliminary observations suggest the value of adding basal insulin to MET monotherapy early in the clinical management of type 2 diabetes as a viable option for achieving glycaemic control, because patients on 0/1 OAD in the trials analysed here were at an earlier stage of their type 2 diabetes. These findings have notable clinical implications, given that a common strategy in real-world clinical practice is to delay insulin initiation in patients with type 2 diabetes for as long as possible. Although patient concerns and other barriers to the implementation of insulin therapy are important to consider, clinical evidence continues to accumulate highlighting the urgent need to overcome these barriers to maximize patient benefit by initiating insulin therapy earlier in the course of the disease. This is certainly possible in today's treatment landscape, with the availability of long-acting basal insulin formulations that can be administered once daily and titrated using simple algorithms. In addition, insulin pen delivery devices make injections easier and more convenient for patients. Keys to implementing this strategy include increasing physician awareness of the importance of earlier insulin initiation and patient education regarding the need for improved glycaemic control if targets are not being met.
Strengths of this analysis are its large size (including data from more than 2000 patients treated with basal insulin in 11 clinical trials evaluated in the pooled analysis), wide geographic variation and reliance on data from prospective, controlled trials. In addition, although the sample sizes for each of the OAD treatment groups differed substantially, these differences were eliminated when evaluating effects with a meta-analysis. Specifically, the number of patients on MET monotherapy prior to randomization was much smaller than those in the other two groups, and the results from the meta-analysis were consistent with the pooled analysis in that adding basal insulin to MET monotherapy provided beneficial glycaemic control.
One major limitation of this analysis was that only studies of insulin glargine were evaluated in both the pooled and meta-analyses; thus, applicability to other basal insulin formulations (e.g. NPH insulin and insulin detemir) is unknown. It should also be noted that our analyses focus on the number and type of OADs that were used at initiation of basal insulin glargine. The OADs were to be maintained over 24 weeks of treatment in all studies; however, we did not assess if any changes did occur in OADs during the course of this study. Therefore, these results provide important information to be considered by clinicians specific to deciding when to initiate insulin therapy in people failing OAD treatment. The best approach for optimizing and maintaining glycaemic control over time should be individualized for each patient. Furthermore, this study addresses outcomes following 24 weeks of treatment; the impact on longer term outcomes such as clinical complications or death was not assessed. Another limitation of this analysis is that although statistical pooling of data in pooled- and meta-analyses increases statistical power and may result in more precise estimates of therapeutic effect, these are hypotheses generating analyses; additional randomized controlled clinical trials are needed to draw reliable conclusions.
In conclusion, patients adding basal insulin glargine to 0/1 OAD at baseline, who are in earlier stages of type 2 diabetes, showed a greater reduction in HbA1c with lower risk of hypoglycaemia than those failing 2 OADs at baseline. In particular, adding insulin glargine to MET monotherapy was well tolerated and resulted in a significant proportion of patients achieving the glycaemic goal of HbA1c ≤7.0% with a low risk of hypoglycaemia and weight gain, in spite of a higher insulin dose used on average. These findings suggest that some patients may benefit from the initiation of basal insulin earlier in the management of type 2 diabetes than often occurs in this clinical practice, which further corroborates the guidance outlined for the clinical management of type 2 diabetes by the ADA and EASD.