Wednesday, April 10, 2019

Wisdom Wednesday: Metformin for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Clinical Question
How effective is metformin in the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis?

Evidence-based Answer
Metformin does not seem to be an effective treatment for nonalcoholic steatohepatitis. There are no studies evaluating whether metformin improves long-term patient-oriented outcomes such as progression from NAFLD to nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, or death from liver failure. Metformin does not improve anatomic outcomes (histologic or ultrasound features of the liver) or biochemical outcomes (alanine transaminase [ALT] and aspartate transaminase [AST] levels, or insulin resistance) in adults. Metformin does not improve liver histologic or biochemical outcomes, or body mass index (BMI) in adults with nonalcoholic steatohepatitis. (Strength of Recommendation: C, based on a meta-analysis of randomized, controlled trials [RCTs] evaluating laboratory parameters.) Similarly, metformin does not improve histologic or biochemical outcomes, or BMI in children and adolescents with NAFLD. (Strength of Recommendation: C, based on RCTs evaluating laboratory parameters.)

Evidence Summary
Adults With NAFLD
No studies have evaluated patient-oriented outcomes of metformin therapy for NAFLD or nonalcoholic steatohepatitis. An RCT found no improvement in liver histology on biopsy.[1,2] Two placebo-controlled RCTs (N = 113) evaluating the effect of metformin (850 to 1,700 mg per day) on ALT and AST levels, insulin resistance, and BMI found no differences. One RCT (n = 48) found a small decrease in BMI. Another RCT (n = 2,153) found no improvement in ALT levels after treatment with metformin (850 mg twice per day) vs. placebo.[2]

Adults With Nonalcoholic Steatohepatitis
Two RCTs (N = 52) evaluating metformin (500 to 1,000 mg per day) in patients with nonalcoholic steatohepatitis found that it did not improve liver histology, ALT and AST levels, BMI, or insulin resistance.[1,3]

Children With NAFLD
Two RCTs (N = 172) evaluating metformin (1,000 to 1,500 mg per day) vs. placebo in children with obesity and NAFLD found no improvement in liver histology on biopsy, ALT and AST levels, BMI, or insulin resistance.[4,5] A smaller RCT (n = 50; mean age: 15 years) found that metformin (850 mg twice per day) improved ultrasound scores for fatty liver but did not improve ALT and AST levels.[6]

Recommendations From Others
An evidence-based guideline from the American Association for the Study of Liver Diseases, the American College of Gastroenterology, and the American Gastroenterological Association states that metformin has no significant effect on liver histology and is not recommended as a treatment for liver disease in adults with nonalcoholic steatohepatitis.[7]

My Take:
I am showing you the full abstract (minus the references) to give you a sense of what these studies look like.

Metformin is commonly used to treat type II diabetes. It works by preventing the liver from releasing glycogen (stored glucose) from the liver when cortisol is released from the adrenal glands. In normal physiology, cortisol is released in response to dropping blood sugar levels. The release of glycogen raises glucose levels back to the normal range. This is a vital hormonal response when we are sleeping and unable to eat, fasting (intermittent or otherwise) and in response to stress.

Off label use of metformin for PCOS (polycystic ovarian syndrome), NASH and NAFLD has been practiced for more than 20 years. This study questions the valve of such off label use.
Physicians are allowed to use a drug for purposes other than those for which the drug has been tested (off label use) if their clinical experience indicates it has value. Remember that evidenced-based research only accounts for one-third of the criteria for clinical decision making. Clinical experience and patient preference are the other two-thirds. However, one can’t help but question the clinical experience that led to this off label use.

Bottom Line:
Currently, no conventional medical treatment is available for NASH or NAFLD so I can see how physicians turned to metformin. However, Silymarin, the active target compound in Milk Thistle has been shown to be effective in the treatment of both of these liver diseases. Clinically, I have also found combining Silymarin with lecithin (phosphatidylcholine) enhances this benefit.

Source: Am Fam Physician. 2019;99(4):262-263

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