Metformin as First-Line Agent for Type 2 Diabetes (T2D) with Various Beneficial Aspect

Bando H

Published on: 2024-05-15

Abstract

Metformin was historically made from guanidine, and has been a first-line agent for type 2 diabetes (T2D). Imeglimin (Twymeeg) was recently developed with a similar molecular structure. In 1998, the UK Prospective Diabetes Study (UKPDS) reported the clinical effect of metformin on reducing cardiovascular risk. For the control of blood glucose, hepatic glucose production (HGP) is important. A gut-brain-liver axis, through gastrointestinal nutrition and hormonal induction, has been identified for HGP suppression. Metformin has multiple action points for the lung, cardiovascular system, liver, gastrointestinal tract, pancreas, and cancer. In the Diabetes Prevention Program (DPP) study, metformin showed an effect on impaired glucose tolerance (IGT) patients.

Keywords

Metformin; Imeglimin (Twymeeg); UK Prospective Diabetes Study (UKPDS); Hepatic Glucose Production (HGP); Gut-brain-liver axis; Diabetes Prevention Program (DPP)

Editorial

Metformin was historically made from guanidine and has been a first-line agent for type 2 diabetes (T2D) [1,2]. Imeglimin (Twymeeg) was recently developed with a similar molecular structure [3,4]. The authors’ et al. have published many reports on imeglimin and metformin in the clinical practice and research of diabetes [5,6]. In this article, some important points regarding metformin will be described, including historical aspects.

There is a medicinal herb that was used in Europe during the Middle Ages. Galega (milk stimulants) for animals include goat' rue, Italian fitch, French lilac, and Spanish sainfoin. Scientific analysis has revealed that guanidine is the main element in these medicines. Molecular structures similar to guanidine include biguanide groups such as biguanide, metformin, phenformin, and buformin. Animal experiments have revealed that guanidines and metformin have a hypoglycemic effect [7]. Although guanidine was found to be toxic, metformin was found to be safe, but its use was not widespread. At that time, insulin was discovered, and insulin could be administered. This situation seemed to be, at least in part, influenced by several factors. In 1957, Jean Sterne reported the effects of metformin on diabetes and introduced metformin to the market under the trade name Glucophage (glucose eater) [8]. After that, metformin has begun to be used as a diabetes treatment in the UK, Europe, and Japan. However, from 1977 to 1980, phenformin and buformin were discontinued in many countries due to the adverse effects of lactic acidosis. The reason for elevated lactic acid in the blood would be the metabolic fact that lactic acid is a substrate for gluconeogenesis in the liver, and this drug suppresses the uptake of lactic acid into the liver. After subsequent re-evaluation of this agent, metformin was approved by the FDA in the United States in 1994–95. Furthermore, it was announced that metformin was evaluated to be highly effective against possible risks [9,10].

In 1998, the UK Prospective Diabetes Study (UKPDS) Group reported the clinical effect of metformin on reducing cardiovascular risk [11]. Metformin has been in use for about 70 years. Approximately 25,000 papers related to metformin have been published during that period. In Japan, the maintenance dose of metformin is 750–1500 mg/day, and the maximum dose is 2250 mg/day. In Europe and the United States, it is usually 2000–3000 mg/day [12]. From the general obtained data, the HbA1c decrease degree would be 1.2% for 1500 mg/day and 1.8% for 2250 mg/day, which indicates the clinical effect and safety of administration of metformin. For BMI difference, HbA1c decrease would be 1.2-1.4% for <20 to 35 kg/m² with almost the same degree, and 1.7% for >35 kg/m².

Regarding the mechanism of diabetes, hepatic glucose production (HGP) has been an important factor. A gut-brain-liver axis, through gastrointestinal nutrition and hormonal induction, has been identified for HGP suppression [13]. Mutual crosstalk has been working on this axis. When metformin is taken before absorption in the GI tract, it activates AMPK in the duodenum of rats, which is thought to be involved in suppressing HGP [14]. When metformin is activated, it will activate multiple action points in several organs [15]. Organs and related actions can be summarized as several systems, such as the lung, cardiovascular system, liver, gastrointestinal tract, pancreas, and cancer (Table 1). Lactic acidosis is very rare. If there is a case, we will treat it using the following two policies: The first is to perform forced diuresis using infusions to remove lactic acid and metformin, such as hemodialysis, and the second is to perform intravenous sodium bicarbonate to correct acidosis [16].

Table 1: Mechanism of Metformin in Multiple Systems.

Lung	Reduces cytokine storm	Reduces expression of proinflammatory cytokines
		Inhibits TNF-alfa/NK-kB/mTPR; pathways
		Promotes anti-inflammatory effects
Cardio-vascular	Reduces CV events	Reduces oxidative stress
		Reduces over activity of hemostasis
		Reduces heart failure events
		Improves dyslipidemia and endothelial function
		Improves neuro-vascular mutual function
Liver	Alters mitochondrial metabolism	Activates AMPK pathway
		Accumulates in mitochondria
		Suppresses hepatic glucose production
		Inhibits gluconeogenesis
		Lowers blood glucose
G-I tract	Alters microbiota	Modifies the profiles of microbiome
		Promotes glucose utilization
		Promotes GLP-1 secretion
Pancreas	Stabilizes function	Ameliorates hyperinsulinemia
Pancreas	Stabilizes function	Decreases insulin secretion
Cancer	Stabilizes function	Reduces proliferation of cancer cells
		Especially colonic and prostate cells
		Suppress enlargement of cancer mass

In other words, the clinical effects of metformin can be summarized into three degrees [15]. They are: i) inhibition of gluconeogenesis: it suppresses the metabolism in the liver from lactic acid and amino acids to pyruvic acid and finally to glucose; ii) improvement of insulin resistance: it promotes the transfer of glucose in the blood to skeletal muscle and adipose tissue; and iii) inhibition of glucose absorption: it suppresses the function of absorbed carbohydrates in meals from the small intestine into the blood stream. The characteristic benefit of metformin would be its usefulness as a combined therapy with other oral hypoglycemic agents (OHAs). As compared data of monotherapy and metformin-based combination therapies, satisfactory results were obtained for about 0.5–1.0% of HbA1c decrease in the cases of sulfonylurea, thiazolidinedione, DPP-4i, SGLT-2i, and GLP-1RA [17].

In the previous study of the Diabetes Prevention Program (DPP), metformin was provided to patients with impaired glucose tolerance (IGT). As a result, a satisfactory decrease in fasting plasma glucose (FPG) and HbA1c was found [18]. Furthermore, another investigation showed clinical efficacy in diabetic patients who showed severe deterioration of glycemic control with the withdrawal of metformin therapy. By re-starting metformin treatment, their glucose variability was proven to be reversible almost completely [19].

In summary, metformin has been the first-line medicine for T2D for many years, and its price has been very low internationally [20]. Then, it will be most convenient and advantageous in any country worldwide. Recently, a novel OHA, imeglimin (Twymeeg), was introduced to clinical practice, whose molecular structure is similar to that of metformin. It is expected that this article will become a useful reference, and further research related to metformin and imeglimin will be developed in the future.

International Journal of Endocrinology and Diabetes

Metformin as First-Line Agent for Type 2 Diabetes (T2D) with Various Beneficial Aspect

Abstract

Keywords

Editorial

References