This real-world study observed that around half of T2DM patients initiating BI therapy due to uncontrolled hyperglycemia on OADs were prescribed concomitant with metformin. BI therapy with metformin showed higher rates of glycemic control, less increment of insulin dose and less weight gain compared with BI without metformin after 6-month follow-up. These results suggest that metformin-based BI therapy regimen can be advantageous for patients with suboptimal glycemic control on OADs in improving glycemic control and reducing weight gain.
In this real-world study, the overall proportion of patients using metformin prior to BI therapy was 65.2%, in which 72.2% continued metformin after BI therapy. After BI therapy, the overall proportion of metformin use was 53.1%. An observational study done in the US reported more than 70% patients taking metformin before insulin therapy and 80.3% patients continued it after insulin initiation. The proportion of metformin use after insulin therapy was also higher (63.8%) in Pilla et al.’s study (23). Another study with commercial insurance data also reported 72.7% patients taking metformin before insulin initiation and metformin was continued in 84.6% patients after insulin therapy. (24) Given its low price, safety profile, and potential cardiovascular protection, metformin is recommended as first-line glucose lowering drug for treating T2DM unless contraindication or intolerance, which is also suggested being continued in combination with other agents including insulin (9, 10, 25). Nevertheless, 35% of patients were not treated by metformin before BI therapy and more than one fourth of patients stopped metformin after initiating BI in our study, which may suggest the underuse of metformin in Chinese patients with T2DM in spite of possible contraindication or intolerance among some patients. One reason might be clinicians tending to stop metformin to avoid risks from complex treatment, especially for those with contraindication. Nevertheless, this study didn’t collect information on patient’s estimated glomerular filtration rate (eGFR) or side effects of metformin. Further studies about factors associated with metformin discontinuation after BI therapy are required.
In our study, the sub-analysis tends to provide higher estimates of the effectiveness and safety for BI with metformin over without metformin than the full population analysis. Patients in full population analysis who switched to other treatment regimens might be those with suboptimal glycemic control at the initial BI treatment. Therefore, compared with sub-analysis, the full population analysis containing patients that switched treatment regimen during follow-up may also dilute inter-group differences if a higher proportion of patients switching to other regimens in BI with metformin group remained having suboptimal glycemic control than those in BI without metformin group. In terms of safety, as patients could not tolerate prescribed regimen or experienced adverse events, they tend to not continue with the initial regimen. In this way, exclusion of these patients in the sub-analysis might make a study drug appear safer than it really is. However, given the wide acknowledged safety profile of metformin (12), risks of hypoglycemia or other adverse effects caused by BI with metformin should be low in our study. Despite of some discordances between the full population analysis and the sub-analysis, they both illustrated the advantages of metformin-based BI therapy in increasing glycemic control and insulin dose.
Most previous randomized studies reported the superiority of insulin combined with metformin in reducing HbA1c, weight gain, insulin dose or hypoglycemia compared with insulin alone or insulin plus other OADs, whereas they were not always concordant with each other (14, 16–18). In a study by Hollander et al., insulin plus metformin was reported to be associated with more HbA1c reduction, less weight gain and lower hypoglycemia rates compared with insulin plus sulfonylurea (17). Nevertheless, in a study by Lund et al., insulin plus metformin showed less weight gain (2.22 vs. 4.73 kg) but equivalent HbA1c reduction (from 8.15 ± 1.32 to 6.72 ± 0.66% vs. 8.07 ± 1.49 to 6.90 ± 0.66%) compared with insulin plus repaglinide (26). Strowig et al. also reported lower weight gain (0.5 vs. 4.4 kg) and fewer hypoglycemic episodes (0.6 vs. 2.0/1.7 episodes/person/month) in insulin plus metformin group compared with insulin alone or insulin plus troglitazone but a comparable average reduction in HbA1c with insulin plus metformin as with insulin alone (both from 8.8 ± 1.2 to 7.1 ± 1.0%) (16). However, previous randomized studies did not specify the type of insulin as basal insulin (16, 26) or the participants as insulin-naïve patients who initiated BI therapy due to suboptimal glucose control on OADs (17). Given the current guidelines consistently recommend timely initiating insulin therapy when glycemic target cannot be maintained by OADs in addition to lifestyle management, and that BI is considered as the most appropriate initial insulin regimen,(9, 10) this real-world study correspondingly investigated the effectiveness and safety of initiating BI plus metformin in Chinese T2DM patients of which the results can further support its application in China.
Strengths of this analysis are its large size, wide geographic variation and reliance on data from prospective, real-world clinical practice, which make the findings in our study more representative for a broader population of those patients and more capable of reflecting actual medication practice and its effectiveness and safety than in traditional randomized clinical trials. In addition, appropriate adjustments for various potential clinical and non-clinical factors improved the robustness of this statistical analysis.
One major limitation of this study was the possibility of confounding, which was one of the common flaws in observational studies. Although propensity score-adjusted regression model was applied to address confounding by covariates of baseline characteristics and factors at 6-month follow-up were also controlled, some differences between groups may be still present. Moreover, given its large size, the statistical difference may not necessarily conclude the clinical relevance. Another limitation is that data on eGFR reflecting renal function and gastrointestinal side effects were not collected. Finally, as this study only evaluated the outcomes of glycemic control, weight and hypoglycemia due to the short follow-up period, the impact on long-term outcomes such as microvascular or macrovascular complications and death were not assessed.