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After 10 years of the disease, high glycemic toxicity was revealed, and this innovative solution became an option after intensive treatment with insulin pump

 Last Update: 2022-11-15
 Source: Internet
 Author: User

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the powerful, safe, convenient, innovative treatment drug basal insulin GLP-1RA injection clinical real case sharing
.

Innovative treatments in the field of diabetes never stop, and it is the common aspiration
of developers and clinicians to find treatment options and drugs that are effective, safe and convenient.
In recent years, the combination therapy of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) has gradually entered the field of clinical treatment, and its complementary mechanism and application advantages such as reducing the adverse reactions brought by traditional insulin therapy such as hypoglycemia and weight gain have been widely recognized
.
In March this year, the world's first basal insulin GLP-1RA injection, insulin degludecide liraglutide injection (IDegLira), was launched in China, providing a new option for the clinical treatment of type 2 diabetes mellitus (T2DM).

Let's walk into the specific case sharing provided by Professor Qin Yingfen from the Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, the patient's disease course is as long as 10 years, and after the combination of 2 oral hypoglycemic drugs (OAD) in the past, glycosylated hemoglobin (HbA).
_1c 10.
8%, fasting blood glucose (FPG) 6.
49mmol/L, postprandial blood glucose (PPG) 18.
56mmol/L, poor
blood sugar control.
What is the urgent task in the face of such patients? How should the follow-up treatment be adjusted? How does this innovative hypoglycemic drug benefit patients?

Case data

Patient male, 54 years old, complaint: found high blood sugar for more than 10 years, black shadow in left eye for 3 days
.

▎ Present medical history

In 2012, it was found that the blood sugar was high in the local hospital, the FPG was about 15mmol/L, and T2DM was diagnosed, and oral metformin sustained-release tablets were given 1 tablet three times a day (TID) + gliclazide 1 tablet once daily (QD).
Control blood sugar; In 2017, under the guidance of doctors in the local town hospital, gliclazide was increased to 2 QDs, and blood glucose was not monitored after that; Since 2020, blurred vision, numbness in the extremities and extremities, and symptoms have gradually worsened; On February 7, 2022, there was no obvious cause of black shadow of the left eye, no eye pain, eye swelling, photophobia, tearing and other discomfort, so he went to the ophthalmology outpatient clinic of our hospital for treatment, and now the patient is going to our outpatient clinic to regulate blood sugar, and the outpatient is planned to be admitted to the hospital
"T2DM".

▎ Past history

Hypertension was found for 1 year; In 2000, it was found that "hepatitis B big three yang" was not regularly diagnosed and treated
.

▎ Personal history

history of smoking for 2 years; history of hyperthyroidism; Have a history of
fertility.

▎Family history

Denial of similar family and genetic histories
.

▎Physical examination

Height: 170cm, weight: 65kg, body mass index (BMI): 22.
5kg/m², body temperature: 36.
6°C, breathing: 20 times/min, heart rate: 96 times/min, blood pressure: 148/87mmHg
。

There were no abnormalities on cardiac, lung, and abdominal examinations, and the dorsal foot artery pulse was normal
.

▎Laboratory examination

HbA_1c：10.
80%，FPG：6.
49mmol/L，2h-PPG：18.
56mmol/L；

Urine routine: occult blood 1+, urine protein 2+, glucose 4+;

Liver function: glutamyl transpeptidase 209U/L, aspartate aminotransferase 69U/L, alanine aminotransferase 118U/L;

Six electrolytes: no abnormalities;

Blood lipids: total cholesterol 6.
72mmol/L, high-density lipoprotein cholesterol 1.
98mmol/L, low-density lipoprotein cholesterol 3.
95mmol/L;

There were no obvious abnormalities in blood routine, renal function, coagulation function, D-3-hydroxybutyric acid (blood ketone body), cardiac enzymes, hypersensitive troponin, parathyroid hormone measurement, and thyroid function.

Table 1 Results of Steamed Bun Meal Glucose Tolerance Test (OGTT).

▎Other auxiliary examinations

Fundus examination: light mixing of lenses, opacity of the vitreous, flat retina, scattered yellow-white exudation and bleeding points; Optical coherence tomography: macular edema of both eyes, retinal exudation;

Bone density: osteopenia, increased risk of fracture;

Color ultrasound (urinary system + abdomen): 1.
Fatty liver sonogram; 2.
echophore such as the spleen area (may be paraspleen); 3.
Enhanced parenchymal echo of both kidneys; 4.
Local calcified acoustic image
of the prostate.

▎Admission diagnosis

Type 2 diabetes with poor glycaemic control

Type 2 diabetic retinopathy (both eyes)

Diabetic peripheral neuropathy

Diabetic nephropathy (DKD G2A3)

Hypertension grade 2 is very high-risk

Vitreous volume blood (left eye)

Macular edema (left eye)

Chronic hepatitis B

Abnormal liver function

▎Treatment plan

insulin pump (basal rate 0.
8U/h + high-dose insulin aspart 6-6-6U before three meals); Cagliflozin 1 tablet QD; irbesartan 2 tablets QD; compound glycyrrhizin; entecavir 1 capsule QD; Dicyclic alcohol 1 tablet TID
.

Table 2 Blood glucose status of patients during hospitalization

▎Discharge treatment plan

IDegLira: 16 doses before dinner;

Cagliflozin 1 tablet QD
.

Table 3 Out-of-hospital blood glucose follow-up

Figure 1 Instant Sense Report February 23 ~ March 9

Fig.
2 Daily glucose summary

Doctors share

Medical community: What are the characteristics of this patient? What considerations did you choose IDegLira when choosing an out-of-hospital long-term treatment plan?

Professor Qin Yingfen:

This case is characterized by a middle-aged male patient with T2DM, with a slow onset and a course of disease for more than 10 years
.
Patients who used OAD regularly in the past but had poor glycemic control (metformin sustained-release tablets 1 TID + gliclazide 2 tablets QD), HbA_1c up to 10.
8%, FPG 6.
49mmol/L, PPG up to 18.
56mmol/L, and suffered He has developed a variety of chronic complications of diabetes such as diabetic retinopathy, vitreous hemorrhage (left eye), diabetic nephropathy, diabetic peripheral neuropathy, etc.
, and chronic hyperglycemic toxicity has appeared, and further treatment
is urgently needed.
At the same time, the patient has chronic hepatitis B and impaired
liver function.

When selecting a treatment strategy for this patient, the Expert Consensus on Intensive Insulin Therapy for Short-term Type 2 Diabetes (2021 Edition) ^[1] (hereinafter referred to as the "Intensive Consensus") clearly states that he is receiving hypoglycemic drugs for more than 3 months.
Patients with T2DM who have markedly elevated blood sugar, large fluctuations in blood sugar, or symptoms of hyperglycemia or even ketosis can be treated with short-term intensive insulin therapy
.
In line with the patient's situation, the insulin pump was selected as a short-term insulin intensive treatment regimen in the hospital, which has more efficacy advantages for patients with significantly elevated blood glucose (HbA_1c≥9%) and large blood glucose fluctuations^[1].
。 For patients with a long course of disease, insulin intensive therapy for 1~2 weeks can generally reduce glucose toxicity ^[1]
.
We set a basal dose of 0.
8U/h + 6-6 U of high-dose insulin aspart 6-6 U before meals for the pump we selected for this patient for a period of 7 days
.
During this process, the basal rate of the insulin pump was dynamically adjusted according to the patient's blood glucose profile, and the dose
of insulin aspart was adjusted.
After one week of intensive treatment, the patient's FPG dropped to 5.
6mmol/L, and the high glucose toxicity was alleviated
.
So we began to consider follow-up strategies
for patients with short-term intensive insulin therapy that could be used for a long time outside the hospital.

The patient's steamed bun meal test showed that the islet function was acceptable, and after one week of intensive treatment with insulin pump, the FPG reached the standard, and the PPG was still high, and the control of FPG and PPG should be taken into account when considering the follow-up
treatment plan.
The Reinforcement Consensus^[1] points out that patients who are young, have a high BMI, have a small amount of intra-meal insulin during intensive therapy, and have certain islet function are more suitable for switching to basal insulin combined with OAD regimen or basal insulin combined with GLP-1RA regimen
.
Combining the characteristics of patients and the recommendations of the "Strengthening Consensus", coupled with the patient's desire to reduce injections, we decided to choose the innovative drug IDegLira
.
It can act on insulin receptors and GLP-1 receptors at the same time, exogenous supplementation of insulin while endogenous regulation, to achieve complementary regulatory metabolic effects [^2], can take into account both FPG and PPG, the number of injections is also more convenient, 1 injection at any time per day, not affected by meals ^[3].
。 Because patients also have metabolic disorders such as hypertension and dyslipidemia, it has been shown in the IDegSierra phase III clinical trial (DUAL series) to significantly improve cardiometabolic indicators, including systolic blood pressure and lipid profile (total cholesterol, very low density lipoprotein cholesterol, triglycerides, etc.
) ^[4,5].
。

At the same time, IDegLira's use in sequential treatment after intensive insulin therapy is also supported
by evidence-based medical evidence.
A study presented at the 2022 European Association for the Study of Diabetes (EASD) Annual Meeting evaluated the efficacy and safety of subsequent early switching to IDegLira for hypoglycemia in T2DM patients receiving intensive insulin therapy to correct severe hyperglycemia ^[6].
The results showed that after switching to IDegLira treatment for 4 months, the patient's HbA_1c decreased from 12.
3±1.
8% at baseline to 6.
3±0.
9% (p<0.
0001), and the dose changed from 42.
4±10.
3 U to 20.
6 ± average daily basal + mealtime insulin dose 5.
7 doses of IDegLira
.
Adverse events (AEs) occurred less and no serious AEs
occurred.
At follow-up after 4 months of treatment, the proportion of individuals with HbA_1c <7% and no hypoglycemia was 73%.

It can be seen that in selected patients with T2DM, after correcting severe hyperglycemia with intensive insulin therapy, early use of IDegLira to reduce blood glucose can bring significant improvement in blood glucose in the short term and has a good
safety profile.

The patient had a history of "hepatitis B big three yang" and was not regularly diagnosed and treated, and the liver function of admission showed glutamyl transpeptidase 209U/L, aspartate aminotransferase 69U/L, alanine aminotransferase 118U/L
.
For clinical medication of patients with liver insufficiency, it is necessary to pay attention to whether the damage to liver function is aggravated, and drugs
with relatively small damage to liver function should be selected as much as possible.
IDegLira has a good safety profile for liver and kidney, and clinical trial results showed no difference
in the pharmacokinetics of insulin degludeca between healthy subjects and subjects with hepatic and renal insufficiency.
Clinical studies have also shown that compared with subjects with normal renal function, liraglutide exposure is reduced by 33%, 14% and 27% in subjects with mild, moderate and severe renal insufficiency, respectively, so IDegSierra can be used in patients with mild, moderate or severe renal insufficiency while strengthening blood glucose monitoring and individualized dose adjustment
。 In addition, in a single-dose clinical trial evaluating the pharmacokinetics of liraglutide in subjects with different degrees of hepatic insufficiency, liraglutide exposure was reduced by 13-23% in subjects with mild to moderate hepatic insufficiency compared with healthy subjects, so IDegLira can be used in patients with mild or moderate hepatic insufficiency while blood glucose monitoring should be enhanced and individualized dose adjustment
should be made.

Both the above features and clinical evidence suggest that IDegLira is the appropriate regimen
for this patient.
Therefore, we chose this treatment plan for patients, and in practice, we really got good results
.

Medical community: High-quality blood glucose management has always attracted much attention, requiring multiple aspects to be evaluated
at the same time, such as blood glucose compliance rate and hypoglycemia.
Recently, with the development of continuous glucose monitoring (CGM) technology, the glucose target range time (Timein Range, TIR） This indicator is being paid more attention
to by clinicians.
Seeing that CGM is also used in your case, would like to know your experience and your evaluation of the technology for clinical care and management guidance, such as which patients are applicable?

Professor Qin Yingfen:

High-quality blood glucose compliance, also known as high-quality compliance, requires both blood glucose and safety
.
Current clinical methods of glucose monitoring include HbA_1c, self-glucose monitoring (SMBG) and CGM
.
Among them, HbA_1c reflects the average blood glucose of patients in the past 2~3 months, which is difficult to reflect the characteristics of blood glucose fluctuations or hypoglycemia, and has delay; SMBG needs to measure fingerstick blood glucose multiple times throughout the day, and to a certain extent, blood glucose fluctuations and hypoglycemia can be observed throughout the day, but such multiple monitoring is difficult to adhere to in the out-of-hospital treatment environment, and is affected
by the diet and exercise of the day.

CGM can provide TIR for 14 consecutive days (generally required 3.
9~10.
0mmol/L, more stringent requirements 3.
9~7.
8mmol/L)^[7], Continuous, comprehensive, and reliable blood glucose information such as the time or percentage of blood glucose above the target range within 24 hours (TAR), and the time or percentage of blood glucose below the target range (TBR) within 24 hours, can help understand the trend of blood glucose fluctuations in patients, and can detect occult hyperglycemia and hypoglycemia that are not easily detected by traditional monitoring methods, especially postprandial hyperglycemia and nocturnal asymptomatic hypoglycemia ^[8].
。

TIR as a new indicator for
assessing glycemic control in patients with diabetes.
The TIR International Consensus^[⁹^], published in 2019, states that the TIR control target for adult T2DM patients is >70%.

In this case, the patient was treated with IDegLira, HbA _1c is controlled at 5.
5%, and the average TIR is as high as 91%, achieving high-quality blood glucose standards
.
Clinically, CGM has significant advantages in diabetic patients with large blood sugar fluctuations such as type 1 diabetes, initial or poorly controlled T2DM, fragile diabetes, gestational diabetes, perioperative period, diabetes mellitus complicated by liver and kidney disease, hormone or chemotherapy drug use, intensive care and other diabetic patients ^[4], which can be used as a monitoring method for this part of the population.
Assists in achieving high-quality blood glucose standards
.

Expert resume
Professor Qin Yingfen

Director of the Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University
Chief physician, medical doctor, doctoral supervisor
Member of the Fifth National Standing Committee of the Endocrinology and Metabolism Physician Branch of the Chinese Medical Doctor Association
Member of the 11th National Committee of the Endocrinology Branch of the Chinese Medical Association
Chairman of the 7th Guangxi Endocrinology Branch of Chinese Medical Association
Vice Chairman of the Fifth Session of Guangxi Diabetes Branch of Chinese Medical Association
Vice Chairman of Guangxi Endocrinology and Metabolism Branch of Chinese Medical Doctor Association
Deputy Head of the Rare Disease Group of the Endocrinology Branch of the Chinese Medical Association

References:

[1] Expert Consensus on Short-term Intensive Insulin Therapy for Type 2 Diabetes.
Chinese Journal of Diabetes.
2022; 14(01):21-31.
[2]Buse JB, et al.
Diabetes Care.
2014; 37(11):2926-33.
[3] Mu Yiming, Hu Bei.
Journal of Clinical Pharmacotherapy.
2022; 20(06):16-20.
[4]Linjawi S, et al.
Diabetes Ther.
2017; 8(1):101-114.
[5]Lingvay I, et al.
JAMA.
2016; 315(9):898-907.
[6] EASD 2022.
Early deescalation with IDegLira in patients with type 2 diabetes using short-term intensive insulin therapy to correct severe hyperglycaemia.
[7] Diabetes Branch of Chinese Medical Association.
Chinese Journal of Diabetes.
2021; 13(04):315-409.
[8]Fonseca VA，Grunberger G，Anhalt H，et al.
Endocr Pract.
2016; 22:1008-1021.
[9]Battelino T, et al.
Diabetes Care.
2019 Aug; 42(8):1593-1603.

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