What changes has the new generation of basal insulin brought about?

A new generation of basal insulin analogues with a unique prolonged action mechanism have been used clinically.

Basal insulin therapy is a commonly used insulin therapy program.

In recent decades, researchers have been continuously developing new basal insulins and applying them in clinical practice.

In 1936, the birth of protamine zinc insulin (PZI) significantly prolonged the action time of insulin; in 1946, the more stable neutral protamine zinc insulin (NPH) was successfully developed, which can basically cover the whole body by injecting twice a day.
Day basal insulin requirement 2.

However, PZI and NPH have obvious absorption peaks, which cannot completely simulate the physiological basic insulin secretion curve, which easily leads to blood glucose fluctuations and even hypoglycemia2.

Since the 1990s, scientists have changed the amino acid sequence and structure of insulin to develop basal insulin analogues that have longer-lasting effects, more stable effects, and better mimic the physiological basic insulin secretion, such as insulin detemir, insulin glargine U100, Insulin glargine U300, and a new generation of basal insulin analogue-insulin degludec 2.

 Both are basal insulin analogues with very different mechanisms.
Insulin degludec and insulin glargine U300 are basal insulin analogues newly marketed in recent years.
Although they are both basal insulin analogues, there are differences in the mechanism of action.

Unlike insulin glargine U300, which is concentrated by the dosage form and forms subcutaneous microprecipitation to prolong the action time2, insulin degludec removes the threonine at B30 of human insulin, and the lysine at B29 is connected to a 16 through a glutamate linker.
The carbofatty diacid side chain forms a soluble polyhexamer long chain after subcutaneous injection, which makes insulin deglubber form an insulin reservoir at the injection site, which greatly delays its absorption into the bloodstream, and slowly releases zinc ions.
, Dissociate from the end of the long chain of polyhexamers, and enter the blood circulation3.This structural change makes the drug action curve more stable, with a half-life of up to 25 hours, and less variability, achieving ultra-long and stable pharmacokinetics, lowering the risk of hypoglycemia, and being more in line with physiological insulin secretion3 .

 Four “stunning skills” in the body: a new generation of basal insulin analogues can better meet the treatment needs.
The four key factors for considering basal insulin include hypoglycemic efficacy, variability in hypoglycemic efficacy, risk of hypoglycemia and dosage.

In the case of insulin degludec and insulin glargine U300, is there any difference in the hypoglycemic efficacy, the risk of hypoglycemia, the variability of the hypoglycemic efficacy, and the amount of insulin? ￭The BRIGHT study 10 is a multi-center, open-label, positive control, two-arm, 24-week non-inferiority randomized controlled study (RCT).
The study included type 2 diabetes with poorly controlled oral hypoglycemic drugs ( T2DM) patients were randomly divided into insulin glargine U300 (n=466) and insulin degluargine (n=463) groups, aiming to compare the effectiveness of insulin glargine U300 and insulin degluargine in T2DM patients without insulin treatment Sex and safety.

The results showed that after 24 weeks of treatment, compared with the insulin glargine U300 group, the insulin deglubber group improved fasting blood glucose significantly (-3.
95 vs -3.
53mmol/L, Figure 1).

 Figure 1 Insulin degludec is better than insulin glargine U300 in improving fasting blood glucose.
CONFIRM study 11 is a retrospective data analysis that included 4,056 patients with T2DM who had poorly controlled oral hypoglycemic agents.
The primary endpoint was glycation after 180 days of follow-up The change in hemoglobin (HbA1c) from baseline.

Studies have shown that compared with the insulin glargine U300 group, the insulin degludec group has significantly better improvement of HbA1c (-1.
5% vs -1.
2%, P=0.
029, Figure 2).

 Figure 2 Insulin degludec is better than insulin glargine U300 in improving HbA1c.
Variability of hypoglycemic efficacy A randomized, double-blind, crossover study of 12 included 57 patients with type 1 diabetes, and they were randomly divided into insulin degluargine group and insulin glargine U300 In the group, the area under the curve of the glucose infusion rate of the two drugs at steady state was compared by the glucose clamp test to evaluate the variability of the hypoglycemic efficacy.The results showed that in every 6-hour interval, the hypoglycemic effect of insulin degludec was evenly distributed, and the hypoglycemic effect of insulin glargine U300 showed a U-shaped distribution.
The hypoglycemic effect of 0-6 hours and 18-24 hours was significantly stronger.

The intraday variability ratio of insulin degludec and insulin glargine U300 in hypoglycemic efficacy was 0.
63 (95%CI 0.
54-0.
73; P <0.
0001, Figure 3).
The intraday variability of insulin degluargine in hypoglycemic efficacy was lower than that of insulin glargine U300 37%.

 Figure 3 The intra-day variability of insulin degluargine's blood sugar lowering efficacy is lower than that of insulin glargine U300.
￭Hypoglycemia risk CONFIRM study 11 aims to compare the efficacy and safety of insulin deglubber and insulin glargine U300 in the treatment of T2DM patients in the real world.

After 180 days of treatment, compared with insulin glargine U300, the overall risk of hypoglycemia in the insulin glargine group was 30% lower than that of insulin glargine U300 [RR 0.
70 (95% CI 0.
50-0.
99)] (Figure 4).

 Figure 4 Insulin degludec has a lower risk of hypoglycemia.
It is worth noting that in this study, the proportion of patients who discontinued treatment in the insulin glargine group was 267% lower than that in the insulin glargine U300 group [OR 0.
73 (95% CI 0.
63-0.
85); P ＜0.
001]; The difference in the incidence of hypoglycemia between the two groups may be an important reason for the low proportion of patients who discontinued the treatment of insulin deglubber.

 ￭Insulin Dose BRIGHT study 10 also showed that at 24 weeks of treatment, the dose of insulin deglubber group was reduced by 20.
4% compared with insulin glargine U300 group (0.
43 vs 0.
52 U/kg/d) (Figure 5).

 Figure 5 The dose of insulin degludec group was reduced compared with insulin glargine U300 group.
The four key factors of basal insulin were summarized, including hypoglycemic effect, variability of hypoglycemic effect, risk of hypoglycemia, and dosage.

Nowadays, a new generation of basal insulin analogues with a unique prolonged action mechanism have been used clinically.

Evidence-based evidence shows that compared with insulin glargine U300, insulin degludec has better hypoglycemic efficacy, less variability in hypoglycemic efficacy, lower risk of hypoglycemia, and lower doses, meeting the above four major factors and clinical treatment needs.
It is the preferred basal insulin.

Expert profile: Professor Liu Libin, Deputy Dean, Union Hospital, Fujian Medical University, Director, Department of Endocrinology and Metabolism, Union Hospital, Fujian Medical University, Director, Fujian Institute of Endocrinology, Standing Committee Member, Endocrinology Branch, Chinese Medical Association, Member of Endocrinology and Metabolism Physicians Branch, Chinese Medical Association, Fujian Province Executive director of the Association, Chairman of the Endocrinology Branch of the Fujian Medical Association, "Chinese Journal of Endocrinology and Metabolism" Editorial Board Sources: 1.
Ran Xingwu, Mu Yiming, Zhu Dalong, etc.
Chinese Expert Guidance Recommendations on the Clinical Application of Basic Insulin in Adults with Type 2 Diabetes ( 2020 edition)[J].
Chinese Journal of Diabetes 2020, 28(10): 721.
2.
Gu Weijun.
Pharmacokinetic and pharmacodynamic characteristics of insulin glargine 300U/mL[J].
Drug Evaluation, 2019, 16(17): 6-9.
3.
Guo Lixin.
The historical changes of basal insulin: longer, more stable and safer[J].
Drug Evaluation, 2018, 15(11):14-16.
4.
Mauricio D, Meneghini L, Seufert J, et al.
Glycaemic control and hypoglycaemia burden in patients with type 2 diabetes initiating basal insulin in Europe and the USA[J].
Diabetes Obes Metab, 2017, 19: 1155-1164.
5.
Ji L, Zhang P, Zhu D, et al.
Observational Registry of Basal Insulin Treatment (ORBIT) in patients with type 2 diabetes uncontrolled with oral antihyperglycaemic drugs: Real-life use of basal insulin in China[J].
Diabetes Obes Metab, 2017, 19(6):822-830.
6.
Lajara R, Cengiz E, Tanenberg RJ.
The role of the new basal insulin analogs in addressing unmet clinical needs in people with type 1 and type 2 diabetes[J].
Current Medical Research and Opinion, 2017:1-11.
7.
Rosenstock J, Dailey G, Massi-Benedetti M, et al.
Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes[J].
Diabetes Care, 2005;28(4):950–955.
8.
Kai-Jen, Tien, Yi- Jen, et al.
Basal insulin therapy: Unmet medical needs in Asia and the new insulin glargine in diabetes treatment.
[J].
J Diabetes Investig, 2019, 10: 560–570.
9.
Bun CW, Fu CJ, Su-Yen G, et al.
Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience[J].
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2017, 10:521-532.
10.
Julio R, Alice C, Robert R, et al.
More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial[J].
Diabetes Care, 41(10): 2147-2154.
11 Joseph, Tibaldi, Martin, et al.
A comparative effectiveness study of degludec and insulin glargine 300U/mL in insulin- naïve patients with type 2 diabetes.
[J].
Diabetes Obesity & Metabolism, 2019, 21(4):1001- 1009.
12.
Heise T, Nrskov M, Nosek L, et al.
Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300U/mL in type 1 diabetes[J].
Diabetes Obes Metab, 2017, 19: 1032-39 source: medical author: LIU Li Bin proofread: Zangheng Jia Editor: Pan YingDiabetes Care, 41(10):2147-2154.
11.
Joseph, Tibaldi, Martin, et al.
A comparative effectiveness study of degludec and insulin glargine 300U/mL in insulin- naïve patients with type 2 diabetes.
[J].
Diabetes Obesity & Metabolism, 2019, 21(4):1001-1009.
12.
Heise T, Nrskov M, Nosek L, et al.
Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300U/mL in type 1 diabetes [J] Diabetes Obes Metab, 2017, 19:.
1032-39 source: medical author: LIU Li Bin proofread: Zangheng Jia Editor: Pan YingDiabetes Care, 41(10):2147-2154.
11.
Joseph, Tibaldi, Martin, et al.
A comparative effectiveness study of degludec and insulin glargine 300U/mL in insulin- naïve patients with type 2 diabetes.
[J].
Diabetes Obesity & Metabolism, 2019, 21(4):1001-1009.
12.
Heise T, Nrskov M, Nosek L, et al.
Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300U/mL in type 1 diabetes [J] Diabetes Obes Metab, 2017, 19:.
1032-39 source: medical author: LIU Li Bin proofread: Zangheng Jia Editor: Pan YingLower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300U / mL in type diabetes 1 [J] Diabetes Obes Metab, 2017, 19:.
1032-39 Source: medical Author: LIU Li Bin proofread: Edited by Zang Hengjia: Pan YingLower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300U / mL in type diabetes 1 [J] Diabetes Obes Metab, 2017, 19:.
1032-39 Source: medical Author: LIU Li Bin proofread: Edited by Zang Hengjia: Pan Ying