Effective, safe and simple: new basal insulin analogues "unlock" new skills in volume adjustment

*Only for medical professionals to read and refer to scientifically adjust the basal insulin dose in order to achieve a balance between curative effect and risk
.

 As the disease progresses, pancreatic β-cell function gradually declines, and insulin therapy has become an important means of hyperglycemia management for type 2 diabetes (T2DM) [1]
.

In the course of insulin therapy, dosage adjustment is an important step to achieve blood glucose control
.

Only through scientific and reasonable dosage adjustment can effective blood glucose control be obtained and the risk of hypoglycemia can be reduced [1]
.

 Insulin dosage adjustment methods include doctor-led dosage adjustment and patient self-dose adjustment
.

Basal insulin is usually used as the initial treatment of insulin.
After the initial basal insulin treatment, the insulin dose needs to be adjusted in time according to the fasting blood glucose while avoiding hypoglycemia as much as possible [1]
.

However, in clinical practice, if an appropriate insulin dosage regimen is not selected, it may cause hyperglycemia and hypoglycemia, leading to blood glucose fluctuations
.

 So how should the basal insulin dose be adjusted and optimized to achieve a balance between curative effect and risk? Current status of basal insulin dose adjustment: Doctors take the lead before answering the above questions, it is good to review the current status of domestic basal insulin dose adjustment
.

 The ORBIT study is a large-sample observational study in China, which can help us understand the situation of insulin dose adjustment in real-world T2DM patients who have failed oral hypoglycemic therapy and initiated basal insulin therapy[2]
.

A study included 12,865 patients in the ORBIT study for analysis.
The results found that among patients using basal insulin, doctor-led basal insulin dose adjustment accounted for the largest proportion (40.
1%) in clinic, and that doctor and patient co-led insulin dose adjustment Accounted for 19.
8%, only 15.
3% of patients undergoing self-dose adjustment, and up to 24.
8% of patients without insulin dose adjustment [3]
.

 In fact, both doctor-led dose adjustment and patient self-dose adjustment can achieve better results and good safety, and should be actively practiced clinically
.

 Doctor-led dosage adjustment: The practical "2-4-6" program is doctor-led basal insulin dosage adjustment.
How to ensure the efficacy and safety of the program? Clinical trials such as the Treat-to-Target study provide evidence
.

 The "2-4-6" program is a commonly used basal insulin dose adjustment program.
Its method is relatively simple and easy to master, and it has achieved better clinical effects [4]
.

The large-scale clinical study that supports this dose adjustment program is the Treat-to-Target study conducted from 2000 to 2001.
The study used weekly adjustments to the basal insulin dose, with the target fasting blood glucose ≤ 5.
6 mmol/L.
The specific adjustment program is shown in the table.
1[5]
.

For overweight T2DM patients with poor control of 1 or 2 oral hypoglycemic agents, adjust the dose of insulin glargine U100 or intermediate-acting insulin according to this plan, and inject once a day before going to bed.
Insulin glargine U100 group glycosylated hemoglobin (HbA1c) ≤ 7 % And the proportion of patients without nighttime hypoglycemia is higher (33.
2% vs 26.
7%), and the risk of hypoglycemia is significantly reduced [5]
.

Table 1 The basal insulin dose adjustment scheme in the Treat-to-Target study [5] coincides with the Treat-to-Target study in that the BRIGHT study also adopted a similar insulin titration scheme
.

The BRIGHT study is the world's first randomized controlled study to compare the efficacy and safety of insulin glargine U300 and insulin degludec U100 head-to-head in T2DM patients.
The dosage adjustment scheme used is shown in Table 2 [6]
.

Studies have shown that for T2DM patients who have not previously used insulin therapy but have poor blood sugar control, insulin glargine U300 and insulin degluargine U100 have similar incidences of hypoglycemia during the entire study period and during the dose maintenance period, but insulin glargine U300 is in the dose The incidence of hypoglycemia at any time during the adjustment phase is lower [6], suggesting that the dosage adjustment program can take into account both effectiveness and safety
.

Table 2 BRIGHT study basal insulin dose adjustment plan [7] Based on evidence-based evidence, the "Chinese Expert Guidance Recommendations for the Clinical Application of Basic Insulin in Adults with Type 2 Diabetes (2020 Edition)" recommends that before the set blood glucose target value is reached, according to fasting The blood glucose was adjusted by 2~6IU basal insulin every week until the fasting blood glucose reached the target (Table 3) [1]
.

 Table 3 "Chinese Expert Guidance and Recommendations for the Clinical Application of Basic Insulin in Adults with Type 2 Diabetes" Chinese doctors' dosage adjustment program[1] Generally speaking, clinicians use the "2-4-6" program to adjust the dosage of basic insulin with a balance of effectiveness and safety , Clinical practice is also more convenient
.

 Patient self-dose adjustment: Effectiveness, safety, and simplicity are the key points.
What cannot be ignored is that patient self-dose adjustment is an important part of insulin dosage adjustment.
Patients should be encouraged to achieve better blood glucose control [7]
.

So, is there a suitable plan for guiding patients to adjust the self-insulin dose easily? In 2007, a large-scale cohort study published in the journal Diabetes, Obesity and Metabolism-PREDICTIVE 303 study showed that in patients with T2DM who were given insulin detemir once a day, compared with doctors freely adjusting the dose according to the treatment standard, Although the patient's self-dose adjustment every 3 days can achieve the same blood glucose control, the overall incidence of hypoglycemia is higher (6.
44 events/patient/year vs 4.
95 events/patient/year, p <0.
0001) [8]
.

The patient's self-dose adjustment plan is shown in Table 4 [8]
.

The study suggests that if patients need to adjust the dose by themselves, the above-mentioned adjustment methods still need to be improved
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Table 4 The patient's self-dose adjustment program in the PREDICTIVE 303 study [8] The risk of hypoglycemia and the complexity of the titration program are issues that need to be addressed when adjusting the insulin dose [9]
.

The self-dose adjustment program adopted in the AT.
LANTUS study effectively solved the above-mentioned problems
.

This study is a prospective, multi-center, open-label randomized controlled study that compares the efficacy and safety of doctor-led dose adjustment and patient self-dose adjustment in T2DM patients who are injected with insulin glargine once a day , The patient's self-adjustment plan is shown in Table 5 [10]
.

Studies have shown that, compared with doctors adjusting the dose, the patient's adjustment every 3 days makes the HbA1c and fasting blood glucose drop more significantly, and the incidence of severe hypoglycemia is similar to the former (1.
1% vs 0.
9%) [10]
.

Table 5 The self-dose adjustment program for patients in the AT.
LANTUS study [10] The self-adjustment program for adjusting 2IU of basal insulin every 3 days is also recommended by the 2020 version of the "Chinese Expert Guidance and Recommendations for the Clinical Application of Basic Insulin in Adult Type 2 Diabetes" [1]
.

It is worth noting that this recommendation also recommends that patients self-adjust 1IU insulin glargine U300 every day until the fasting blood glucose reaches the target.
The program is simple, effective, and safe, which has been confirmed in the TITRATION study
.

 The TITRATION study is a multi-center, randomized controlled study aimed at evaluating the effectiveness and safety of insulin glargine U300 using the two dose adjustment schemes in the EDITION and INSIGHT studies [11]
.

The INSIGHT study is aimed at fasting blood glucose of 4.
4~5.
5mmol/L, and the patient adjusts the insulin dose by 1IU/d each time.
If the blood glucose is greater than 5.
5mmol/L, increase by 1IU/d (Table 6) [11,12 ]; The insulin dose adjustment plan of the EDITION study is implemented by the doctor, as shown in Table 7 [13,14,15]
.

Studies have shown that the HbA1c reduction of the two dose adjustment schemes of patient self-adjustment and doctor-guided adjustment is equivalent, and there is no significant difference in the confirmation or severe hypoglycemia event rate of the two dose adjustment schemes of patient self-adjustment and doctor-led adjustment (Figure 1) [11]
.

Table 6 The basal insulin adjustment plan in the INSIGHT study [11, 12] Table 7 The basal insulin adjustment plan in the EDITION series study [13, 14, 15] Figure 1 The method of adjusting one unit a day for insulin glargine U300 is effective and safe [11] Therefore In addition to the self-adjustment plan of adjusting 2IU basal insulin every 3 days, the method of adjusting 1IU a day for insulin glargine U300 provides a new option for T2DM patients
.

 Summary: Dose adjustment is an important step in insulin therapy to achieve blood glucose control standards
.

After the initiation of basal insulin therapy, the insulin dose should be adjusted in time based on fasting blood glucose while avoiding hypoglycemia as much as possible [1]
.

The basis for the adjustment of basal insulin dose comes from large-scale evidence-based medical research
.

The "2-4-6" program is more practical for clinicians, and patients can use a variety of self-dose adjustment programs
.

Among them, insulin glargine U300 can self-adjust 1IU per day until the fasting blood glucose reaches the target.
This program is simple, effective, and safe [11], making it an ideal new choice for T2DM patients to adjust the basal insulin dose
.

References [1] Ran Xingwu, et al.
Chinese Journal of Diabetes.
2020;28(10):721-728.
[2]Ji L, et al.
Diabetes Obes Metab.
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[3] Chen J, et al.
Endokrynol Pol.
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[4]Li Caige.
Drug Evaluation.
2015;(11):30-33.
[5]Riddle MC, et al.
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[6]Rosenstock J, et al.
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[7]Khunti K, et al.
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2013 ;15(8):690-700.
[8]Meneghini L, et al.
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[9]Perreault L, et al.
J Am Board Fam Med.
2019 ;32(3):431-447.
[10]Davies M, et al.
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[11]Yale JF, et al.
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[12]HC Gerstein, et al.
Diabet Med.
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[13]Riddle MC, et al.
Diabetes Care.
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[14]Yki-Ja ¨rvinen H, et al.
Diabetes Care.
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[15]Bolli GB, et al.
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