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.

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.

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.