Metformin has new effects!

Metformin is the first choice and commonly used drug for the treatment of type 2 diabetes, but in recent years it has been discovered many new miraculous effects, so many people call it a "magic drug", and it is almost "a monthly boast".
Frequency too
.

Recently, Nikolaj Rittig, a clinical research expert at the Steynor Diabetes Center of Aarhus University Hospital in Denmark, and his team published a new clinical research result in the AP&T journal: Metformin can significantly reduce the hepatic venous pressure gradient in patients with portal hypertension caused by liver cirrhosis (HVPG), in nearly half of patients, HVPG has reached a clinically significant decline, which indicates that metformin has the potential to become a new therapy for the treatment of portal hypertension in patients with liver cirrhosis [1]
.

 Portal hypertension is one of the main complication of liver cirrhosis and one of the main causes of death.
Portal vein blood that fails to enter the liver directly enters the systemic circulation, which will cause vasodilation of the abdominal wall and esophageal and gastric varices.
Once the blood vessel ruptures and bleeding, it may cause the digestive tract.
Hemorrhage, hepatic encephalopathy and ascites, etc.
, are a huge threat to the patient's life
.

The specific mechanism of portal hypertension caused by liver cirrhosis (picture source: Mayo Clinic Proceedings) Clinically, there are two drugs for the treatment of portal hypertension, one is vasoconstrictor drugs, and the other is vasodilator drugs
.

Among them, the most commonly used is the non-selective β-receptor blocker carvedilol, which can block the α1 receptor and the non-selective β receptor, causing the expansion of two types of capillaries, thereby reducing peripheral resistance and lowering Blood pressure [2-3], but long-term use of these drugs can cause unbearable side effects in some patients, such as fatigue, dizziness, bradycardia or erectile dysfunction
.

Moreover, the therapeutic effect of existing drugs is not very good.
Clinically, HVPG>5mm Hg is defined as portal hypertension.
When HVPG≥12mm Hg, there is a risk of variceal bleeding; if therapeutic drugs can reduce HVPG by 20 % Or HVPG<12mm Hg, it can significantly reduce the risk of varicose vein bleeding and death, which can be regarded as a clinically significant curative effect [4]
.

Only about 40% of patients receive treatment with non-selective β-receptor blockers to achieve therapeutic efficacy
.

Why did researchers choose metformin? This is because nitric oxide (NO) seems to play a particularly important role in the pathogenesis of portal hypertension and liver fibrosis [5].
The activation of AMPK can increase the bioavailability of NO [6], so drugs that can activate AMPK include It may improve portal hypertension and bring clinical benefits, including metformin
.

Data from animal experiments show that both the specialized AMPK activator (AICAR) and metformin can reduce HVPG[7-8]
.

The reason why metformin is a miracle drug is that the scope of its impact is too wide (picture source: International Journal of Molecular Sciences).
However, the evidence-based medical evidence of the previous use of metformin is not sufficient.
Whether metformin can really reduce portal hypertension still needs clinical practice.
Research to prove, so the researchers designed a single dose of randomized, double-blind, placebo trials
.

A total of 31 patients with liver cirrhosis took metformin or placebo, and HVPG was tested 90 minutes after the intervention (15 patients in the placebo group and 16 patients in the metformin group)
.

The relevant indicators of the two groups of patients before and after treatment are shown in the figure below.
Compared with the baseline level, the HVPG of the metformin group was reduced by 16%, while there was no significant change in the placebo group, and 46% of the patients in the metformin group reached the aforementioned efficacy target , That is, HVPG is reduced by 20% or HVPG is less than 12mm Hg; the researchers also tested the hepatic venous wedge pressure (WHVP) and found that the metformin group was significantly reduced by about 15% compared with baseline.
Hepatic portal pressure (FHVP) was not observed in the two groups To a significant difference
.

Comparison of liver and systemic hemodynamic indicators before and after treatment.
Next, the researchers tested hemodynamic related indicators, including liver blood flow, plasma flow, liver sinusoidal resistance, internal clearance and partial clearance of ICG, and oxygen consumption.
The results of the drug group and the metformin group were similar, and no significant changes were observed, indicating that metformin may reduce HVPG mainly by reducing hepatic vascular resistance, but no significant difference in vascular resistance between the two groups was observed in the experiment
.

Researchers also tested the pro-inflammatory factors (IL-1β, IL-6, TNF-α and TGF-β) in the hepatic veins.
Whether it was in the metformin group or the placebo group, the concentration of the hepatic vein pro-inflammatory factors was There was no significant change before and after treatment, only the concentration of IL-6 showed a slight upward trend, and it was positively correlated with the baseline level of HVPG
.

Previous acute effects of intravenous non-selective beta-blockers therapy showed that a 9-12% reduction in HVPG may be sufficient to improve the risk of varicose bleeding and mortality, and may also reduce the risk of other complications such as hepatorenal syndrome
.

In this clinical study, metformin reduced the overall HVPG of patients by 16%, and nearly half of the patients’ HVPG reduction reached the curative effect threshold.
This indicates that metformin has reached the standard for clinical treatment of portal hypertension and has certain clinical value
.

However, it should also be pointed out that the results of this paper are limited to short-term observations after treatment.
Whether long-term metformin treatment can significantly reduce HVPG and truly improve the clinical outcome of patients with portal hypertension remains to be further studied.
The efficacy of other AMPK agonists is also worthwhile Explore further in the future
.

References: [1](2021).
Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension.
Alimentary Pharmacology & Therapeutics.
[2]Da vid, Kockerling, Rooshi, Nathwani, Roberta, & Forlano, et al.
(2019).
Current and future pharmacological therapies for managing cirrhosis and its complications.
World Journal of Gastroenterology.
[3]D'Amico G, Pagliaro L, Bosch J.
Pharmacological treatment of portal hypertension: an evidence- based approach [published correction appears in Semin Liver Dis 2000;20(3):399].
Semin Liver Dis.
1999;19(4):475-505.
[4]D Lebrec.
(1981).
Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study.
N Engl J Med, 305.
[5]Garcia-Pagan, J.
, C.
, Gracia-Sancho, J.
, & Bosch.
(2012).
Functional aspects on the pathophysiology of portal hypertension in cirrhosis.
JOURNAL OF HEPATOLOGY.
[6]Chen, Z.
, Peng, IC, Sun, W.
, Su, MI, Hsu, PH, & Fu, Y.
, et al.
( 2009).
Amp-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase ser633.
Circulation Research, 104(4), 496.
[7]Tripathi, DM, Erice, E.
, Lafoz, E.
, H García-Calderó, Sarin, SK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor in charge | Tan ShuoResponsible Editor | Tan ShuoResponsible Editor | Tan ShuoResponsible Editor | Tan ShuoResponsible Editor | Tan ShuoJOURNAL OF HEPATOLOGY.
[6]Chen, Z.
, Peng, IC, Sun, W.
, Su, MI, Hsu, PH, & Fu, Y.
, et al.
(2009).
Amp-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase ser633.
Circulation Research, 104(4), 496.
[7]Tripathi, DM, Erice, E.
, Lafoz, E.
, H García-Calderó, Sarin, SK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor in charge | Tan ShuoJOURNAL OF HEPATOLOGY.
[6]Chen, Z.
, Peng, IC, Sun, W.
, Su, MI, Hsu, PH, & Fu, Y.
, et al.
(2009).
Amp-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase ser633.
Circulation Research, 104(4), 496.
[7]Tripathi, DM, Erice, E.
, Lafoz, E.
, H García-Calderó, Sarin, SK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor in charge | Tan Shuo(2009).
Amp-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase ser633.
Circulation Research, 104(4), 496.
[7]Tripathi, DM, Erice, E.
, Lafoz, E.
, H García-Calderó, Sarin , SK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor | Tan large(2009).
Amp-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase ser633.
Circulation Research, 104(4), 496.
[7]Tripathi, DM, Erice, E.
, Lafoz, E.
, H García-Calderó, Sarin , SK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor | Tan largeSK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor in charge | Tan ShuoSK, & Bosch, J.
, et al.
(2015).
Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
American Journal of Physiology Gastrointestinal & Liver Physiology, 309(5), G301.
[8]Yan, L.
, Huang, C.
, Ceng, C.
, & H Zhan….
(2014).
Metformin enhances nitric oxide production and diminishes rho kinase activity in rats with hyperlipidemia.
Lipids in Health and Disease, 13(1).
Editor in charge | Tan ShuoResponsible Editor | Tan ShuoResponsible Editor | Tan Shuo