The present systematic review and network meta-analyses provide an evidence-based comparison of efficacy and safety between second-generation basal insulins vs. NPH or first-generation basal insulins for T1D adults. The efficacy evaluated in terms of the change in HbA1c did not show significant differences between the second-generation basal insulins vs. NPH or first-generation basal insulins. In addition, sensitivity analysis showed this result is consistent in follow-up durations from either ≥ 24 weeks or ≥ 12 weeks.
This result of efficacy is consistent with Bain et al. (2020) that concluded no significant differences among insulin analogs in T1D adults (Bain et al. 2020). However, this result is inconsistent with another network meta-analysis (Tricco et al. 2021) that showed second-generation basal insulin degludec was superior to NPH in reducing HbA1c. The inconsistent results between Tricco et al. (2021) and our study arised in the inclusion criteria. We only focused on RCTs for T1D adults (aged ≥ 18 years) with ≥ 24 or ≥ 12 weeks of follow-up, while Tricco et al. (2021) mixed observational studies, children, pregnant women with irrespective follow-up duration (8 days to 2 years).
Hypoglycemia has been considered to be the barrier to achieve stringent HbA1c levels (Cryer 2008; Mathieu et al. 2017). In this study, we investigated level one and level two hypoglycemia (International Hypoglycaemia Study Group 2017), including nocturnal one, and analyzed safety in the number of patients experiencing hypoglycemia and in the number of hypoglycemic events per person-year to provide comprehensive safety information. This meta-analysis found that the second-generation basal insulins were associated with significantly fewer patients experiencing severe hypoglycemia than NPH, with certainty evidence from moderate to low. Furthermore, the number of nocturnal confirmed hypoglycemic events per person-year of the second-generation basal insulins was significantly lower than NPH and first-generation basal insulins, with certainty evidence from moderate to high. For other hypoglycemia outcomes, no significant differences were detected in terms of neither RR nor HR. The inconsistent results from RR and HR were obtained here due to different measures of the event numbers and whether considering the time-dependent unit. Therefore, both RR and HR are suggested to be taken into consideration for assessing the safety of basal insulins.
Severe hypoglycemia has been well documented as a life-threaten event. Nocturnal confirmed hypoglycemia that is mainly affected by basal insulins can be considered less aware owing to the night. However, nocturnal confirmed hypoglycemia affects the patient quality of life and has a risk of escalating to a severe level (International Hypoglycaemia Study Group 2017). Therefore, the benefits of the second-generation basal insulins can be addressed. Stable pharmacodynamic profiles of the second-generation basal insulins may be a major factor (Heise et al. 2012; Becker et al. 2014). However, the evidence levels were not strong. Therefore, attention should be paid to these results.
The NICE network meta-analysis in T1D adults (NG17) (NICE (National Institute for Health and Care Excellence) 2015) and its update found no difference among basal insulins in the rate of severe hypoglycemic events (Dawoud et al. 2018; Bain et al. 2020). Our results are in line with these reports. However, based on the number of patients experiencing severe hypoglycemia, we found differences between second-generation basal insulins and NPH. Compared with Tricco et al. (2021), our result differed in detecting the statistical differences in the number of patients experiencing nocturnal hypoglycemia. Tricco et al. (2021) showed that degludec was statistically superior to NPH in the incidence of nocturnal hypoglycemia. However, we only detected differences in the rate of nocturnal confirmed hypoglycemia events. The differences may arise from the different inclusion criteria. Furthermore, we found that they included a study reported by Pieber et al. (Pieber et al. 2007), which was argued to have apparent inherent biases (Alcolado et al. 2008) and thus was excluded in this study. Compared to direct meta-analyses, we found a consistent difference that second-generation basal insulins had a lower rate of nocturnal hypoglycemic events than first-generation glargine U100 (Ratner et al. 2013; Vora et al. 2014; Liu et al. 2018; Díez-Fernández et al. 2019).
Basal insulin therapy can commonly cause weight gain in T1D. Weight gain negatively alters lipid levels and blood pressure, thereby increasing the risk of cardiovascular disease (Purnell et al. 1998; Russell-Jones and Khan 2007). Weight gain also affects the waist-to-hip ratio (Purnell et al. 1998), which may affect patients’ self-perception, especially young people, leading to psychological insulin resistance (Brod et al. 2009). Our results showed no differences between second-generation basal insulins and NPH or first-generation basal insulins, except for the comparison between detemir and degludec U100. Detemir significantly resulted in less weight gain than degludec U100 with moderate certainty evidence. Therefore, when tailoring the treatment concerning weight gain, detemir and glargine U300 could be selected.
The strength of this study is the new insights into the harms concerning the second-generation basal insulins vs. other basal insulins in T1D adults by evaluating different categories of hypoglycemia in detail and changes in body weight. Meanwhile, we updated the results of the efficacy. The current network meta-analysis applied the GRADE approach and used rigorous methodology by adhering to the AMSTAR 2.0 critical appraisal tool and the PRISMA and Cochrane’s guidelines. In addition, we quantitively evaluated the certainty evidence of each comparison. The information provided here may help select an appropriate basal insulin type for T1D adult patients under different backgrounds, which could be considered as a clinical imperative.
Several limitations should be considered when interpreting the results. First, the quality of RCTs in adults enhanced the information accuracy here; however, information may be limited. Second, due to the lack of information from RCT, we did not adjust the potential confounders, such as bolus (meal) insulin, frequency, injection device-dependent, and newly initiating effects on the efficacy and safety. Third, the trials involved in this network meta-analysis were limited in the number, varying from 8 to 14. Fourth, open-label design and sponsorship from pharmaceutical manufacturers in almost all included trials and differences in study design across trials. Finally, heterogeneity was observed for some comparisons, which may be accounted for different protocol designs. In the future, we expect more consolidated protocols and study designs in the RCTs and hopefully to update the present evidence.
In conclusion, based on the present eligible studies, second-generation basal insulins achieved similar HbA1c levels compared with NPH and first-generation basal insulins with moderate to high certainty evidence. For hypoglycemia, second-generation basal insulins showed partial merits. For the weight gain, glargine U300 was comparable to detemir, while degludec U100 resulted in more weight gain than detemir. With the caution of the limitations of this study, the information can help tailor basal insulin for T1D adults via evidence-informed practice.