In this multicenter, observational study conducted in a nationally representative sample of T2DM patients with suboptimal glycemic control by OADs in China, approximately a quarter of patients initiated BI with a basal-bolus regimen, in which 97.8% initiated a full basal-bolus regimen. Patients initiating basal-bolus were mainly in-patients (81.5%). Other factors associated with initiating basal-bolus were tertiary Hospital, younger age, higher BMI, longer diabetes duration, more complications, higher HbA1c level, low SMBG frequency, one OAD used before, no concomitant OADs and NPH insulin. Glycemic control rates (HbA1c < 7%) at 6 months were 37.6% and 41.8% in basal-bolus and BI only, respectively (p < 0.0001). Compared with BI only, basal-bolus only showed significantly higher glycemic control in patients with no complications, baseline HbA1c < 9% and ≥ 2 OADs used before (55% vs. 48.1%, P = 0.0315).
The proportion (24.6%) of initiating BI with the basal-bolus regimen in this study was higher than previous studies. One study by Kim et al. reported that basal-bolus insulin only accounted for 1.6% when initiating BI,(13) whilst another study by Patrick et al. reported 13% patients using basal-bolus as the BI initiation regimen.(14) In comparison, patients in the current study had a higher average HbA1c level (9.6%) than Kim et al.’s study (9.2%),(13) whilst Chinese guidelines recommend initiating BI when HbA1c ≥ 7% after 3 months of OAD treatment.(8) Nevertheless, our study observed a mean diabetes duration of 6.4 years, which was shorter than previous studies ranging from 8.9 to 11.7 years.(11, 13, 15−17) This might be due to a low proportion of early diabetes diagnosis since only 30.1% of Chinese diabetes patients were aware of their condition,(7) contributing to a severer hyperglycemia with a shorter duration of diagnosed T2DM. Accordingly, the high proportion of patients initiating basal-bolus insulin might be due to a previous late diagnosis of T2DM and delayed BI initiation in China.
Bolus insulin reduces postprandial glucose excursions, which was added to BI by two options: a stepwise approach or a full basal-bolus approach.(18) In the stepwise approach, bolus insulin is begun with one dose before the largest meal of the day and then progressively escalated to two and then possibly three pre-meal doses. In the full basal-bolus approach, three doses of bolus insulin were all added before each meal at a time. In our study, 97.8 percent of patients used a full basal-bolus regimen. It is possible that the majority of patients in our study needed a more intensive antidiabetic therapy to reach the glycemic target due to delayed insulin initiation, which could be reflected from the relatively high HbA1c level at the baseline.
Although the full basal-bolus regimen might also offer an individualized treatment regimen through titration of bolus doses similar to the stepwise approach,(18) it would be initially challenging for some patients who had no insulin injection experience before to immediately transit from OADs to a complex regimen of 4–5 total daily injections of basal-bolus insulin. Moreover, the success of this regimen requires consistent carbohydrate intake counting for those who wish to vary their carbohydrate intake from meal to meal and day to day, which means that physicians should consider the patient’s ability and willingness to track carbohydrate intake and perform the necessary, sometimes complex, calculations.(19, 20) Previous randomized clinical trials have observed that stepwise bolus insulin intensification achieved glycemic control non-inferior or close to a full basal-bolus regimen with significantly lower hypoglycemia risk, less weight gain and better patient satisfaction.(21, 22) Due to the fact that it would be burdensome for patients to comply with the full basal–bolus regimen, patient’s adherence, insulin dose titration and SMBG should be emphasized for them. Moreover, approximately a half and 60% of patients initiating with basal-bolus switched to other insulin regimens after 3 months and 6 months, respectively. This might be because some physicians and patients especially those inpatients only used a short-term intensive insulin therapy and those hospitalized would switch to other insulin regimens after discharge from hospital.
In our study, 81.5% of patients using basal-bolus as the insulin initiation regimen were inpatients. It is reasonable that, compared with outpatients, hospitalized patients were mainly those with a higher glycemic level and more complications, therefore needing more intensive initial insulin therapy. While guidelines do not recommend one class or combination of medications over another for the management of hyperglycemia of outpatients,(23−25) basal-bolus has been recommended as the preferred regimen in hospitalized patients in non-intensive care unit settings by clinical practice guidelines.(26, 27) Although many health care professionals are concerned about this regimen’s inconvenience of implementation due to the high number of injections and risk of hypoglycemia,(28) previous studies have showed that inpatient diabetes management using a basal-bolus regimen is effective and well tolerated.(29−32)
Our study indicated that more complications and higher HbA1c level were associated with higher odds of basal-bolus regimen for BI initiation. Those findings further reflect a delay of insulin initiation which lead to an initiation of basal-bolus. We found that in patients with at least one complication, basal-bolus showed higher glycemic control rate than those with BI only only in those with HbA1c ≥ 9% and ≥ 2 OADs used before, but with no significance. However, basal-bolus showed lower glycemic control rate in those with HbA1c < 9% (1 OAD or ≥ 2 OADs) or HbA1c ≥ 9% (1 OAD). Those findings suggest that initiating basal-bolus may not be a better choice than BI only to attain glycemic target in patients who already have had one or more complications unless their HbA1c is no less than 9% and two or more OADs have been used. Nevertheless, in patients with no complication, although the overall glycemic control was lower in basal-bolus than BI only, basal-bolus showed higher glycemic control than BI only in those with HbA1c < 9% and ≥ 2 OAD, HbA1c ≥ 9% and one OAD, and HbA1c ≥ 9% and ≥ 2 OAD unless their HbA1c was less than 9% and only one OADs has been used. Therefore, basal-bolus might be an alternative for insulin initiation in patients with no complication unless their HbA1c is less than 9% and only one OAD has been used before. Moreover, it would be initially challenging and burdensome for them to immediately transit from one OAD to a complex regimen of basal-bolus insulin, which may compromise patients’ adherence.
As achieving timely tight glycemic control is key to optimizing clinical outcomes and delayed insulin initiation may result in suboptimal glycemic control, overcoming clinical inertia of insulin initiation is important for diabetes management. Education of patients about the long-term benefits of lowering their blood glucose and training on how best to achieve this, convenient and well-tolerated insulin therapies with a low risk of hypoglycemia and weight gain,(33) and a patient-driven insulin titration regimens(34) may help patients to initiate insulin therapy timely and increase their adherence to it.
In addition, older age, number of concomitant OADs, and insulin of detemir and glargine were associated with lower odds of basal-bolus insulin. Compared with BI only, initiating basal-bolus might be associated with a higher risk of hypoglycemia and more weight gain in spite of better anti-hyperglycemic effect.(35) Therefore, an insulin regimen of BI only may be preferred for older patients initiating insulin therapy. As some OADs may further lead to side effects such as hypoglycemia and weight gain,(23, 25) which also increased the therapy regimen’s complexity, their use was reduced in a basal-bolus therapy. A previous study reported equivalent glycemic control and hypoglycemia in basal-bolus regimen with insulin analogues compared to basal-bolus regimen with human insulin in hospitalized patients with diabetes.(36) The higher cost of detemir and glargine might also partly explain their reduced association with basal-bolus therapy compared with NPH.
Current guidelines recommend a routine of antihyperglycemic therapy in patients with T2DM where basal-bolus insulin as combination injectable therapy is usually initiated after triple therapy consisting of lifestyle management, metformin and two additional agents.(8, 9) However, our study observed that patients with one OAD used before were more likely to initiate basal-bolus insulin than those with two or more OADs used before, even after stratified by having complications or not, and HbA1c level (< 9.0% or ≥ 9.0%). The reason behind this was unknown. It might be because patients with one OAD and those with two or more OADs used before both tended to keep their previous OAD regimen, and the higher number of concomitant OADs was associated with lower odds of basal-bolus insulin. Also, patients with only one OAD before might have a previously higher glycemia than those with two or more OADs, so they tended to initiate basal-bolus rather than BI only.
Although the present study is based on a large nationally representative sample of Chinese T2DM with insufficient glycemic control by OADs, it is important to consider the results of this study in light of some limitations. First, we only included T2DM patients who were willing to use BI at their insulin initiation, while those willing to initiate other types of insulin such as bolus or premix insulin were excluded. Given that premix insulin is also an option for insulin initiation, further study involving premix insulin would help us picture a more representative insulin initiation status in China. Second, the inclusion criteria of HbA1c level was 7% or higher, which missed those who initiated BI with a HbA1c level lower than 7%, therefore the mean level of HbA1c at insulin initiation might be overestimated. Third, the cross-sectional nature of our study limited causal association between some factors and basal-bolus.