In this exploratory study we demonstrated that poorly controlled patients with long-standing T2DM and at least twice-daily iPremix can be safely and effectively treated with once-daily Lixi and iGlar. A majority of patients achieved clinically significant A1c level and weight reductions. A tendency towards an amelioration of postprandial glucose profiles during the day, except dinner, was seen using comparable insulin doses. Adverse events reported in a few patients were mostly mild hypoglycemia and mild gastrointestinal complaints.
Latest guidelines from the American Diabetes Association recommend to consider a combination of injectable therapies in patients insufficiently treated with combined oral drugs and basal insulin . In these subjects one option is to start with a combination of GLP1-RA and basal insulin; other options include adding fast-acting insulin before the largest meal or changing to twice-daily premixed insulin injections. Further therapeutical escalation is needed in those patients not reaching A1c target goals or patients intolerant to this combination. However, so far there are no recommendations regarding patients not achieving treatment goals and/or suffering from hypoglycemia during treatment with multiple daily injections of premixed insulin. This highlights the clinical need for approaches that allow changing the therapeutic strategy in subjects with usually long-standing diabetes treated with high insulin doses. With our proof of principle study we could demonstrate that patients with established premixed insulin therapy injected at least twice daily can be safely switched to a combination therapy of GLP1-RA lixisenatide and basal insulin glargine administered once daily.
This small study corroborates recent findings of randomized controlled trials (RCTs) investigating the effects and safety of various combinations of once-daily Lixi with either iGlar compared to iGlar alone on top of metformin, or basal insulin compared to metformin and basal insulin, oral agents, or compared to placebo alone [5, 7, 9, 10, 12]. A further study—the LixiLan O trial—tested combined Lixi and iGlar and iGlar or Lixi alone . In these studies better glycemic and postprandial control, significant lower A1c levels and weight loss were shown for combined iGlarLixi. Study findings of the LixiLan or GetGoal trials report comparable rates of hypoglycemic events (25–40% vs. 33%) and gastrointestinal adverse events (15–40% vs. 22%) in the combined iGlar and Lixi groups as found in our study [5, 7–10]. After initiation of Lixi with basal insulin a significant dose reduction of nearly 6 units was reported in the GetGoal L trial, which is of similar magnitude to that reported in our study .
One of the advantages of combined Lixi and iGlar treatment was a sufficient decrease of postprandial glucose levels after breakfast and lunch, but no suppression of glucose levels after dinner was noticed. This might be caused by the half-life of 2–4 h of the short-acting GLP-RA lixisenatide and displays a potential weakness of once-daily injected iGlar and Lixi combinations. Conversely, bigger studies including the LixiLan O trial demonstrated sufficient glucose level reductions throughout the day and also around dinner or thereafter after 30 weeks, albeit increasing glucose levels observed in daily profiles throughout the day .
In our study, the prevalence of responders with A1c reductions of at least 0.4% (4 mmol/mol, 5 of 9 patients, 56%) was low. In 44% of patients combined therapy did not reduce A1c sufficiently. In an RCT a glucose deterioration was found in 38% of patients with T2DM switched from insulin to exenatide, whereas in those who continued insulin glycemic control deteriorated in 19% . Worse glycemic control was associated with higher baseline insulin need, longer duration of T2DM, and lower C-peptide concentrations, which proposes a limitation of beta cell secretary function [13, 14]. However, reports of associations of duration of T2DM with GLP1-RA response are heterogeneous, as low and high diabetes duration as well as no association were reported . We are not able to show C-peptide levels; however, we observed higher response defined by A1c reduction of at least 0.4% (19 mmol/mol; i.e., responders) in patients with higher baseline A1c level (responders vs non responders: 9.6% vs 8.3%, 81 vs 67 mmol/mol p < 0.05, U test), lower but insignificant baseline BMI (30.2 vs 31.9 kg/m2, ns), comparable diabetes duration (12.6 vs 11.5 years, ns) and baseline insulin dose (54 vs 58 IU, ns).
However, because of the pilot and proof of principle character of this study a few limitations are evident. First of all we did not conduct an RCT. As we intended to prove the feasibility of the conversion of the glucose-lowering therapy in an outpatient setting we decided to investigate this in an observational study design. Thus no direct comparison of effects is possible as no direct control group is available and our assumptions are based on these observations. Moreover, as a result of the study design we have a low intraindividual variance using dependent variables with comparison of pre and post combined therapy. Furthermore the durations of home glucose profiling receiving either iPremix (1 week) or combined treatment (12 weeks) were different, making direct comparisons difficult. Finally, the reliability of self-monitoring of blood glucose (SMBG) is limited.
The basal insulin dose was initially set at 60% of the daily iPremix. As shown in Fig. 1 we constantly had to increase the iGlar dose throughout the study to decrease high fasting glucose levels. Because of insufficient iGlar doses the majority of patients had to correct with fast acting iGlu at least on an irregular daily basis. This aspect might also be a reasonable explanation for the unsatisfactory fasting glucose levels after 12 weeks on combined Lixi and iGlar in our study collective, whereas recently published LixiLan trials could demonstrated sufficient reduction of fasting glucose [7, 8]. As a consequence no reduction of insulin dose seems to be necessary and should be performed in future investigations. Another weakness of the study is the very low number of patients included, which makes generalization of results difficult. However, this study was only designed to prove the principle of safe treatment potential of combined GLP1-RA and long-acting basal insulin analogue, which was demonstrated with our results.