Introduction
Diabetes is a global epidemic, with approximately 425 million adults aged 20–79 years (8.8% of the world’s population) worldwide estimated to have this disease in 2017 [
1]. Among countries, China has the highest number of patients with diabetes, and the number are expected to rise substantially to 129.7 million in 2030 [
2]. Type 2 diabetes mellitus (T2DM) accounts for 95% of all diabetes cases.
T2DM is generally initially treated with one or two oral antidiabetic drugs (OADs), with most treatment regimens including metformin. However, the prevalence of uncontrolled blood sugar in persons with T2DM treated with OADs rises with increasing duration of diabetes, increasing from 23.7% in patients with a disease duration of < 5 years to 39.3, 57.1 and 75.9% among those with a disease duration of 5–9.9, 10–19.9 and ≥ 20 years, respectively [
3]. Following the failure of treatments with OADs, other medications are recommended, with insulin therapies regarded as the mainstay of treatment for T2DM [
4].
The emergence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has provided a new treatment option. GLP-1 RAs are able to lower blood glucose levels by stimulating the incretin system, enhancing the secretion of insulin from pancreatic β-cells in response to ingested glucose, slowing gastric emptying, and augmenting satiety [
5]. Lixisenatide, a once-daily GLP-1 RA, is effective in reducing the glycated hemoglobin (HbAc1) level in patients with T2DM by lowering both the fasting and the postprandial blood glucose levels [
6].
To date, only one head-to-head randomized controlled trial (RCT) has been conducted on the efficacy and safety of lixisenatide versus basal insulin in T2DM patients inadequately controlled on OADs [
2], and as yet there has been no direct comparison in RCTs of lixisenatide and premixed insulin in terms of efficacy and safety. Given this lack of data from RCTs, a mixed-treatment comparison (MTC) may provide useful insights to support clinical and policy decision-making. The aim of this study was to compare the efficacy, safety and cost–utility of lixisenatide, basal insulin and premixed insulin in patients with T2DM inadequately controlled on one to two OADs from the Chinese health insurance perspective.
Discussion
To our knowledge, this is the first study to evaluate the comparative efficacy, safety and long-term cost-utility of lixisenatide versus basal insulin and premixed insulin, respectively, for patients with T2DM inadequately controlled on one to two OADs.
The risk of diabetes-related complications in T2DM patients is reported to be dependent on blood glucose levels and, consequently, glycemic control is fundamental to the management of diabetes. The results of our MTC, based on 11 studies involving 4511 adult T2DM patients inadequately controlled on OADs, suggest that the ability of lixisenatide to control glycemic level is similar to that of basal insulin and premixed insulin. In addition to the efficacy of the medication, adverse effects commonly associated with insulin therapies, such as weight gain and hypoglycemia events, also have a significant impact on the patient’s (quality of) life and pose a substantial cost burden through increased treatment costs and reduced productivity. GLP-1 RAs, such as lixisenatide, can promote satiety and suppress energy intake and thus have a significant beneficial value in terms of weight control compared with insulins [
36]. In addition, lixisenatide was associated with a significantly lower hypoglycemia risk in our NMA, indicating that it should be a more tolerable treatment option. It should be noted that although there were no statistical differences between the lixisenatide treatment arm and basal/premixed insulin treatment arms in terms of HbA1c level, the reduction in HbA1c was numerically greater in the basal or premixed insulin arms than in the lixisenatide arm.
Given the limited healthcare resources in China, the pharmacoeconomic profiles of therapies are regarded as important reference factors affecting healthcare decision-making. In our study, after extrapolating the short-term treatment effects to predict the long-term effects and corresponding costs, we found that lixisenatide, in comparison with basal insulin and premixed insulin, achieved a higher gain in QALYs and was associated with higher direct medical costs over a lifetime horizon. Assuming the WTP threshold was set at three times the GDP per capita in China, lixisenatide is a cost-effective option compared with premixed insulin and basal insulin. A series of one-way and probabilistic sensitivity analyses confirmed the robustness of our outcomes. Moreover, recent analyses have focused on the cost-effectiveness of combination therapy with lixisenatide + basal insulin versus other insulin regimens in T2DM patients inadequately controlled on basal insulin alone, with the results showing that combination therapy with lixisenatide + basal insulin is a cost-effective option in China [
37] and the Republic of Korea [
38].
There are a number of limitations to our study. First, although the population criterion was T2DM patients whose blood sugar level was inadequately controlled on one to two OADs, some trials included patients previously treated with one OAD (metformin) while others included patients treated with two OADs (metformin plus another drug, mostly a sulphonylurea). This variability may have affected the homogeneity of the population. However, the pooling of such populations was required to ensure network connectivity. Secondly, no RCT included in this MTC had a duration of > 30 weeks. Thus, more data are needed to clarify the long-term sustained efficacy and ability to differentiate lixisenatide from basal/premixed insulin. Thirdly, there was a lack of direct comparisons between lixisenatide and premixed insulin, which may have resulted in a greater emphasis on the consistency between direct and indirect evidence. However, in the analysis there was no hint of any evidence of inconsistency. Also, only one study that directly compared lixisenatide to basal insulin was found and included in the MTC. Finally, the transition probabilities and disease progressions used in the CORE Model are based on the UK Prospective Diabetes Study (UKPDS) survey rather than on the Chinese population. Since there are as yet no long-term follow-up data available on Chinese diabetes patients, studies on Western populations are the best source of relevant data. The CUA was based on the assumption that the reduction of symptomatic hypoglycemia and prevention of weight gain that was demonstrated in the MTC can be extrapolated to the lifetime case, which may increase the uncertainty. Caution should be taken in interpreting and utilizing these results.
Conclusion
In summary, lixisenatide showed a similar capacity to basal insulin and premixed insulin to reduce HbA1c, but showed a significantly lower risk of hypoglycemia and a greater body weight loss. Based on this MTC, lixisenatide is a cost-effective treatment alternative for patients with T2DM inadequately controlled on OADs in China, compared with basal insulin and premixed insulin.