The Predominant Effect of Metformin
Metformin's principal therapeutic action is to decrease hepatic glucose production—particularly by suppressing gluconeogenesis—which directly lowers fasting blood glucose levels. 1, 2, 3
Primary Mechanism of Action
The FDA-approved drug label explicitly states that metformin "decreases hepatic glucose production" as its primary mechanism, alongside decreased intestinal glucose absorption and improved peripheral insulin sensitivity. 3 This hepatic effect is the predominant mechanism responsible for metformin's glucose-lowering efficacy in type 2 diabetes.
Why the Liver is the Primary Target
Metformin reduces basal hepatic glucose production by approximately 15-20%, which accounts for the majority of its glucose-lowering effect, particularly on fasting blood glucose. 4
The American Diabetes Association consensus guidelines emphasize that metformin's "major effect is to decrease hepatic glucose output and lower fasting glycemia." 1
This hepatic suppression occurs primarily through inhibition of gluconeogenesis and, to a lesser extent, glycogenolysis. 4, 5
Why the Other Options Are Incorrect
Intestinal Glucose Absorption (Option 1)
- While metformin does decrease intestinal glucose absorption to some degree, this is a minor, secondary effect and not the predominant mechanism. 3, 6
Urinary Glucose Excretion (Option 2)
- Metformin does NOT increase urinary glucose excretion—this mechanism is characteristic of SGLT-2 inhibitors (like empagliflozin or canagliflozin), not metformin. 2
- This is a common misconception that should be avoided in clinical practice.
Appetite Suppression (Option 3)
- Reduced appetite is an adverse effect of metformin (causing gastrointestinal symptoms), not a therapeutic mechanism. 1, 2
- The weight neutrality or modest weight loss seen with metformin is primarily due to reduced hepatic glucose production and improved insulin sensitivity, not appetite suppression. 1, 7
Clinical Implications of Metformin's Hepatic Action
Metformin typically reduces HbA1c by 1.0-1.5 percentage points when used as monotherapy, with the greatest impact on fasting glucose rather than postprandial glucose. 1, 2, 7
Because metformin does not stimulate insulin secretion, it does not cause hypoglycemia when used alone—insulin levels remain unchanged or may decrease during treatment. 2, 3
The hepatic mechanism explains why metformin is most effective in patients with elevated fasting glucose and why it works best in the presence of endogenous insulin. 3, 8
Common Clinical Pitfall
The most important pitfall is confusing metformin's mechanism with that of SGLT-2 inhibitors. Metformin works primarily on the liver to suppress glucose production, while SGLT-2 inhibitors work on the kidneys to increase urinary glucose excretion—these are entirely different drug classes with distinct mechanisms. 1, 2