​Low water fall, "stable" to win: the application of basal insulin in clinical practice

*Only for medical professionals to read for reference.
The abnormal blood glucose of diabetic patients is not only manifested as an increase in overall blood glucose level, but also accompanied by an increase in blood glucose fluctuations, which is extremely harmful.

In 2021, the American Diabetes Association pointed out in its "Diabetes Medical Diagnosis and Treatment Standards" that the time within the target range (TIR) ​​that reflects blood glucose fluctuations can be used to assess blood glucose control status [1].

For diabetic patients, the ideal blood sugar control should not only meet the standard of glycosylated hemoglobin (HbA1c), but also reduce the amplitude of blood sugar fluctuations and improve TIR.

 Since blood glucose fluctuations have become a clinical problem that needs to be solved, how can we "stabilize" to win in the process of hypoglycemic treatment? Blood glucose fluctuations: the latent "hidden killer" so-called blood glucose fluctuations refer to the unstable state of blood glucose levels changing between their peaks and troughs, including short-term blood glucose fluctuations, that is, intraday and intraday blood glucose fluctuations, and long-term blood glucose fluctuations, namely HbA1c variability [2].

 In terms of intra-day blood sugar fluctuations, it is like a latent "hidden killer", which is even more harmful to chronic complications of diabetes than persistent hyperglycemia.

Blood glucose fluctuations activate oxidative stress pathways, damage endothelial cell function, exacerbate chronic inflammation, and cause vascular damage, and increase the risk of diabetic macrovascular and microvascular complications such as coronary heart disease and diabetic retinopathy [2].

Many factors push “wave” to fuel the flames of postprandial hyperglycemia as the main cause of intra-day blood glucose fluctuations [3], and poorly controlled fasting blood glucose (FPG) has precisely become the “pushing hand” for the inevitable increase in postprandial blood glucose.

A study on the 24-hour blood glucose profile of 16 patients with type 2 diabetes (T2DM) who had not been treated or stopped taking oral hypoglycemic agents for at least 3 weeks and 14 normal controls showed that the postprandial blood glucose of those with high FPG also increased.
high.After using basal insulin to reduce FPG, even if the increase in postprandial blood glucose relative to basal blood glucose remains the same, the absolute value decreases with the decrease of basal blood glucose, indicating that reducing FPG can help improve the 24-hour blood glucose profile [4].

 So, how to choose drugs to reduce blood sugar fluctuations and achieve a stable hypoglycemic effect? Let’s look at a case first: Case profile ■ Patient with medical history, male, 29 years old, business manager, hospitalized in January 2019 due to "acute pancreatitis", checked fasting venous blood glucose 16.
86mmol/L, urine ketone 4+, blood gas analysis indicated " Metabolic acidosis", glycosylated hemoglobin (HbA1c) 13.
6%, diagnosed as "diabetes, diabetic ketoacidosis?" After insulin treatment, blood sugar fluctuated greatly, and insulin aspart was given at hospital discharge on February 3 (early 5U- 5U mid-night, subcutaneous injection before three meals) and insulin glargine (12U, subcutaneous injection before going to bed).

 ■ Treatment and follow-up On March 14, 2019, the patient was followed up at the outpatient clinic.
Blood glucose was 28.
05mmol/L, HbA1c10.
4%, and the hypoglycemic regimen was adjusted to insulin degludec (14U, subcutaneous injection in the morning) combined with metformin (0.
5g/time, each time 2 times a day).

 On March 22, the patient began to use the instantaneous scanning blood glucose monitoring system (Figure 1).
On March 25, insulin degludec was increased to 16 U, and acarbose (50 mg/time, 3 times a day) was added.

 Figure 1 Blood glucose monitoring from March 22 to 25 March 28 to April 2 Fasting blood glucose control is more ideal, blood glucose control tends to be stable, TIR is significantly improved (Figure 2), blood glucose 5.
0mmol/L on April 4, HbA1c8.
7%, type 2 diabetes is considered based on insulin and C-peptide release test and diabetes autoantibody test (Figure 3).

  Figure 2 Blood glucose monitoring from March 28th to April 2nd Figure 3 Patient review of pancreatic islet function and diabetes antibody results May 7 (all hypoglycemic drugs have been stopped for half a month), review blood glucose 7.
04mmol/L, HbA1c7.
7% .

■ Case comments The patient started with "diabetic ketoacidosis combined with lipid-derived acute pancreatitis" and was diagnosed with type 2 diabetes after being treated with insulin.

In the early stage of diabetes treatment, the patient’s baseline HbA1c and blood glucose were high.
After basal-meal insulin (aspart combined) treatment, the patient had a high FPG, low TIR level and large blood glucose fluctuations, so insulin glargine was stopped and switched to For longer-lasting and stable insulin degludec, while considering the smaller amount of insulin during meals, we discontinued it and changed to oral metformin combined with acarbose to further optimize the dose of insulin deglu, then FPG gradually decreased, and TIR increased from 8% to 8% 76% had no hypoglycemia, and overall blood glucose fluctuations were significantly improved.

 After stopping the above-mentioned hypoglycemic drugs, only by improving life>
 Low water fall, "stability" to win: the "housekeeping skills" of a new generation of basal insulin analogues It can be seen from the cases that controlling FPG is the basis for controlling blood glucose throughout the day and reducing blood glucose fluctuations.

How did the new generation of basal insulin analogue insulin degludec achieve low water fall and "stability" to win? The new generation of basal insulin analogue insulin degludec has a more stable action curve, with a half-life of up to 25 hours, effectively reducing FPG, and has less variability, less risk of hypoglycemia, and more in line with physiological insulin secretion [5].
In cases, When the patient's insulin glargine was replaced with insulin deglu, the water fall into the boat was low, and the hypoglycemic effect of "stability" appeared.

 Pooled analysis showed that compared with insulin glargine, insulin degludec has lower intraday variability in hypoglycemic efficacy (Figure 4) [6].

 Figure 4 Compared with insulin glargine, the intra-day variability of insulin degludec's hypoglycemic efficacy is lower.
Another prospective before and after control study included a total of 60 patients with T1DM or T2DM, and continuous blood glucose monitoring through dynamic blood glucose monitoring (CGM) To evaluate the effect of insulin glargine or insulin detemir on blood glucose variability after 12 weeks of treatment with insulin deglubber.

The results showed that after the patients switched to insulin deglu, the intra-day and inter-day blood glucose variability were significantly reduced (Figure 5) [7].

Figure 5 Conversion from other basal insulin to degluddulin therapy, the intra-day and inter-day blood glucose variability are significantly reduced.
Summary For diabetic patients, the ideal blood sugar control not only requires glycosylated hemoglobin (HbA1c) to reach the standard, but also reduces blood glucose fluctuations as much as possible The magnitude of the improvement of TIR.

The unique structure of a new generation of basic insulin analogues such as insulin degludec makes the drug action curve more stable, with a half-life of up to 25 hours, and has less variability, lower risk of hypoglycemia, and is more in line with physiological insulin secretion, which can effectively control FPG.
Play a continuous and stable effect of lowering blood sugar, significantly improve TIR, and ultimately achieve the goal of low water landing and "stability".   References: [1] American Diabetes Association.
6.
Glycemic Targets: Standards of Medical Care in Diabetes-2021.
Diabetes Care, 2021, 44(Suppl 1):S73-S84.
[2] Chinese Medical Association Endocrinology Branch.
Diabetes Expert consensus on the management of blood glucose fluctuations in patients.
Drug Evaluation, 2017, 14(017):5-8.
[3] Mu Yiming, Ji Linong, Yang Wenying, et al.
Expert consensus on management of postprandial hyperglycemia in patients with type 2 diabetes.
Chinese Journal of Diabetes , 2016, 024(005):385-392.
[4]Zeng Longyi.
The clinical significance of fasting blood glucose control in the treatment of diabetes.
Chinese Journal of Diabetes, 2012, 20(005):395-396.
[5]Guo Lixin.
Historical changes: longer, more stable and safer.
Drug Evaluation, 2018, 15(11):14-16.
[6]Heise T, Kaplan K, Haahr HL.
Day-to-Day and Within-Day Variability in Glucose -Lowering Effect Between Insulin Degludec and Insulin Glargine (100 U/mL and 300 U/mL): A Comparison Across Studies.
J Diabetes Sci Technol.
2018, 12(2):356-363.
3.
[7]Henao-Carrillo DC, Muñoz OM, Gómez AM, et al.
Reduction of glycemic variability with Degludec insulin in patients with unstable diabetes.
J Clin Transl Endocrinol.
2018, 12:8-12.
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