Explanation of pharmacological effects of Miglinide calcium in the new version of the medical insurance catalog


Defective β-cell insulin secretion is one of the central aspects of the pathogenesis of type 2 diabetes. Coinciding with the successful entry of the new mealtime insulinotropic agent, Miglinide calcium, into the new version of the National Health Insurance Catalog, Diabetes International invited Prof. Zhigang Zhao of the Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, to make a professional analysis of the advantages of the action of the new insulinotropic agent from the perspective of pharmacology.
 
 
  Zhigang Zhao, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
 

Importance of early phase and insulinotropic agents targeting pathophysiologic core
Defective β-cell secretion and insulin resistance are two major components of the pathogenesis of type 2 diabetes. It has been found that defective early phase insulin secretion is an important cause of postprandial hyperglycemia. Glargine-type stimulants directly stimulate pancreatic β-cells to secrete insulin, and their most important feature is to improve early-phase insulin secretion, with fast onset of action, short duration of action, mainly to reduce postprandial glucose, and with low risk of hypoglycemia and little influence by renal function.
 

Pharmacologic characteristics of the new physiologic-mode insulinotropic agent mignonide calcium
After more than 50 years of development since the birth of the first generation of sulfonylureas in the 1950s, the glinide agonist Miglinide calcium was introduced in 2004. The unique pharmacological characteristics of Miglinide Calcium make it more advantageous in hypoglycemic therapy than sulfonylureas and other glinides.
 
Molecular structure:The molecular structure of sulfonylureas such as glibenclamide consists of a sulfonylurea group and chloroanisic acid. Some of the later developed glibenclamide analogs do not have a sulfonylurea moiety, but are still similar to glibenclamide in molecular structure, with more binding sites and slightly less selectivity. Miglinide calcium, on the other hand, was randomly selected from a library of compounds and binds mainly to the pancreatic islet β-cell Kir 6.2/SUR1 receptor, with higher receptor affinity and selectivity than other glinides.
 
Prodynamic curve: Sulfonylureas such as glibenclamide do not affect early phase insulin secretion, while mignonide calcium not only effectively improves early phase insulin secretion, but also its prodynamic curve has a very high degree of conformity with the simulation of the normal physiological insulin secretion curve, with no "tailing" phenomenon (Figure 1). This indicates that the secretion pattern of calcium mignonide is consistent with the physiological pattern.
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Fig. 1. The proliferation curves of different insulinotropic agents.

Mechanism: All existing insulinotropic agents stimulate endogenous insulin secretion by binding to sulfonylurea receptor 1 (SUR1), a potassium ATP-dependent (KATP) channel of the pancreatic β-cell membrane, which causes closure of the KATP channel. Differences in proinsulin secretion depend on the pharmacokinetic properties of the different drugs, the affinity for binding to SUR1, and the rate of dissociation. Miglinide calcium promotes insulin secretion through two main pathways of action, which are characterized by a "fast on-fast off" pattern (Figure 2). The first pathway is to bind to Kir6.2/SUR1 on pancreatic β-cells, which closes the KATP channel and causes Ca2+ inward flow, leading to vesicle degranulation and insulin release. The second pathway, on the other hand, enters the β-cell and activates the endoplasmic reticulum Ryanodine receptor, which releases Ca2+, leading to vesicle degranulation and insulin release.

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Figure 2. Insulinotropic pathway of action of calcium miglinide.

Pharmacokinetics: Miglinide calcium is mainly metabolized by UGT1A9 and UGT1A3, with minimal metabolism by CYP2A9, resulting in fewer interactions with inducers or inhibitors of the P450 family of enzymes, and a greatly reduced risk of accumulation and hypoglycemia due to drug interactions (Figure 3). Miglinide calcium has a rapid peak blood concentration and rapid onset of action. Studies have shown that a single oral dose of mignonide calcium 5 mg, 10 mg, and 20 mg administered to healthy adult males 5 minutes before a meal resulted in maximum blood levels about 15 minutes after administration, with a half-life of about 1.2 hours (Figure 4). With respect to the risk of hypoglycemia occurrence, the risk of hypoglycemia with mignonide calcium was similar to that of placebo.

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  Figure 3. Miglinide calcium is not dependent on the P450 enzyme system for metabolism and has a low risk of drug-drug interactions
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  Figure 4. Miglinide calcium peaks quickly and has a rapid onset of action.
 

Miglinide Calcium from Basis to Clinical Manifestations 

Treatment with mignonide calcium in patients with newly diagnosed type 2 diabetes mellitus was found to result in greater postprandial glucose reductions, higher rates of HbA1c attainment, and more significant improvements in glycemic fluctuations. A Japanese post-marketing survey showed that the incidence of hypoglycemia in elderly patients (≥65 years of age) treated with mignonide calcium was not significantly different from those <65 years of age. Miglinide calcium did not increase the risk of hypoglycemia in type 2 diabetic patients with comorbid hepatic/renal disease. Miglinide calcium treatment of hemodialysis patients with type 2 diabetes resulted in a 1.1% reduction in HbA1c. Miglinide calcium does not require dose adjustment in patients with CKD stage 3, 4, or renal transplantation; it is used in dialysis patients starting from a low dose of 5 mg before meals.Moreover, it was found that there were no significant changes in hepatic and renal function assessments after miglinide calcium treatment.

Miglinide calcium, as a mealtime glucose regulator, promotes secretion in correlation with blood glucose levels after meals, is easy to take, and the dose can be adjusted according to the therapeutic effect by taking the drug with a meal (orally within 5 minutes before a meal). Given the pharmacological characteristics of Miglinide calcium's binding receptor fast opening and closing, promoting secretion fast starting and falling, restoring the physiological pattern of early-phase insulin secretion, the risk of hypoglycemia is significantly reduced, which is a very good insulin promoter for the control of postprandial blood glucose, especially used in the elderly population and middle-aged people who do not have a regular diet. The inclusion of Miglinide calcium in the updated national medical insurance catalog is a great affirmation of its hypoglycemic effect, and also brings more choices for diabetic patients and clinicians to carry out hypoglycemic treatment.

Other Dynamics


Mitiglinide Calcium Capsules The new version of the medical insurance catalog of clinical application advantages of analysis

Early-phase insulin secretion defect is a characteristic manifestation of abnormal insulin secretion pattern in type 2 diabetes mellitus patients, and insulinotropic agents have an important role in the treatment of type 2 diabetes mellitus. Coinciding with the successful entry of the new mealtime insulinotropic agent, Miglinide calcium, into the new version of the national health insurance catalog, Diabetes International invited Prof. Mou Yiming of the General Hospital of the Chinese People's Liberation Army to explain the advantages of the application and the applicable population of Miglinide calcium, and to analyze the benefits that will be provided to the patients after its entry into the health insurance.


Explanation of pharmacological effects of Miglinide calcium in the new version of the medical insurance catalog

Defective β-cell insulin secretion is one of the central aspects of the pathogenesis of type 2 diabetes. Coinciding with the successful entry of the new mealtime insulinotropic agent, Miglinide calcium, into the new version of the National Health Insurance Catalog, Diabetes International invited Prof. Zhigang Zhao of the Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, to make a professional analysis of the advantages of the action of the new insulinotropic agent from the perspective of pharmacology.


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