Effectiveness and Safety of Basal Insulin Therapy in Type 2 Diabetes Mellitus Patients With or Without Metformin Observed in a National Cohort in China

Abstract

Background.

Though many randomized control trials had examined the effectiveness and safety of taking insulin therapy with or without metformin, there are limited real-world data, especially among Chinese type 2 diabetes patients initiating basal insulin (BI) with uncontrolled hyperglycemia by oral agents. This study was designed to assess the effectiveness and safety of BI therapy combined with or without metformin in a real-world national cohort study.

Methods.

Patients with type 2 diabetes mellitus who initiated BI treatment due to uncontrolled hyperglycemia (HbA1c ≥ 7%) by oral antidiabetic drugs (OADs) were recruited in Chinese real-world settings between 2011 and 2013. A total of 12,358 patients initiated BI without bolus insulin and completed a 6-month follow-up were selected as the study population and divided into BI with metformin or BI without metformin group based on whether metformin was simultaneously prescribed or not at baseline. Propensity score adjustment was used to balance baseline covariates between two groups. A sub-analysis was also conducted among 8,086 patients who kept baseline treatment regimen during the follow-up. Outcomes were HbA1c, hypoglycemia, weight gain and insulin dose in two groups.

Results.

53.6% (6,621 out of 12,358) patients initiated BI therapy concomitant with metformin. After propensity score adjustment, multivariate regression analysis controlled with number of OADs, total insulin dose, physical activity and diet consumption showed that BI with metformin group had a slightly higher control rate of HbA1c < 7.0% (39.9% vs. 36.4%, P = 0.0011) at 6-month follow-up, and lower dose increment from baseline to 6-month (0.0064 vs. 0.0068 U/day/kg, P = 0.0035). The sub-analysis with patients remained at same BI therapy further showed that BI with metformin group had higher HbA1c control rate (47.9% vs. 41.9%, P = 0.0001), less weight gain (-0.12 vs 0.15 kg P = 0.0013), and lower dose increment during 6-month follow-up (0.0033 vs. 0.0037 U/day/kg, P = 0.0073) when compared with BI without metformin group.

Conclusion.

In alliance with current guidelines, the real-world findings also support the insulin initiation together with metformin. Continuous patients’ education and clinicians training are needed to improve the use of metformin when initiating BI treatment.

Background

With estimated 113.9 million people in China and 420 million globally affected, diabetes continues to be one of the most common non-communicable diseases and public health priorities worldwide(1, 2). Type 2 diabetes mellitus (T2DM) is the main category of diabetes in adults, which is characterized by steady deterioration of glycemic control due to progressive β-cell dysfunction of insulin secretion frequently on the background of insulin resistance. The objective of T2DM therapy is to safely achieve and maintain glycemic control in order to reduce the risk of microvascular and macrovascular complications, and in the long run, diabetes related mortality. However, as achieving a near-normal glycemic control target becomes increasingly difficult due to disease progression, most patients ultimately require insulin treatment (3–5).

Although timely addition of insulin to oral therapy for T2DM has been recommended to prevent complications by early institution of strict glycemic control and β-cell protection (3), a substantial proportion of patients with suboptimal glucose control tend to delay insulin therapy due to fear of hypoglycemia, along with a reluctance to start injections and gain weight (6), which may further influence adherence to insulin therapy (7). Metformin as first line therapy for T2DM is recommended to be continued after initiating insulin (usually basal insulin (BI)) by current guidelines (8–10) since the regimen of insulin plus concomitant metformin was shown to improve glycemic control, reduce hypoglycemia incidence and weight gain as well as total insulin dose when compared with insulin monotherapy (11–14). In addition, this combination regimen was reported to reduce the risk of death and macrovascular events compared with insulin monotherapy in the long run (15). Though many randomized control trials had examined the effectiveness and safety of taking insulin therapy with or without metformin(16) (14) (17) (18), there are limited real-world data, especially among Chinese T2DM initiating BI due to uncontrolled hyperglycemia by oral antidiabetic drugs (OADs).

Therefore, based on the data of the Observational Registry for BI Treatment (ORBIT) study (19), we analyzed the real-world practice combination of metformin with BI initiation, and compare the effectiveness and safety between BI users with and without metformin in a Chinese real-world setting.

Methods

Results

Among all the recruited 18,995 participants at baseline, 12,358 (65.1%) patients who initiated BI only therapy and completed 6 months follow-up were included in the analysis. Figure 1 shows the patients selection procedure.

Discussion

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.

Conclusions

In conclusion, adopting basal insulin therapy with metformin in T2DM patients with previously suboptimal glycemia control by OADs was associated with better glycemic control and probably lower insulin dose and less weight gain compared with BI without metformin. However, the clinical relevance of these results must be interpreted with caution.

Abbreviations

Declarations

Ethics approval and consent to participate

The ORBIT protocol was approved by the Institutional Review Board (IRB) of Peking University and, when necessary, by local IRBs. Written informed consents were obtained from all patients.

Consent for publication

Not applicable

Availability of data and materials

The data used to support the findings of this study are available from the corresponding author upon request.

Competing interests

L. J. reported receiving consulting and lecture fees from Eli Lilly, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck, Bayer, Takeda, Sanofi, Roche and Boehringer Ingelheim, and research grants from Roche and Sanofi. The other authors declare that they have no conflicts of interest.

Funding

This investigator sponsored study received funding from Sanofi.

Authors’ Contributions

L.J and P.Z. contributed to the study design, conduct, and data interpretation. X.L. and J.J. contributed to the data analysis. H.Z., Y.L., D.Z., M.C. and D.W contributed to the interpretation of findings and drafting of the manuscript.

Acknowledgements

The authors would like to thank investigators from the secondary and tertiary hospitals for their hard work and patients for their participation, without whom this study would not have been possible.

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