Metformin (Glucophage)

Metformin lowers blood sugar through two routes: it throttles glucose production in the liver and improves insulin sensitivity in muscle and fat tissue. Unlike insulin or sulfonylureas it does not force blood sugar down, it pulls back an overshooting own production. That is why on its own it practically never causes hypoglycaemia.

Mechanistically a large part runs through inhibition of mitochondrial complex I and the resulting activation of AMPK, the cellular energy sensor. That same pathway is the reason for the longevity reputation and, as set out below, for the conflict with muscle growth.

This information is for research and educational purposes only. No medical advice.

AMPK is the counterpart of mTOR. AMPK becomes active when the cell reports an energy shortfall and then switches to saving and cleaning up. mTOR becomes active when energy and amino acids are plentiful and switches to building. Metformin pushes that balance towards AMPK.

For metabolism that is good. For a building phase it is exactly the wrong switch, because muscle growth runs through mTOR. Several investigations show smaller strength and muscle gains under metformin at equal training. That is not a marginal finding, it is a direct consequence of the mechanism.

In a diet phase it matters considerably less, since improved insulin sensitivity is the dominant effect there.

UKPDS 34 (Lancet 1998) is the trial that made metformin a first-line agent. In overweight type 2 diabetics it cut diabetes-related endpoints by 32 percent and all-cause mortality by 36 percent, and it did so better than other agents at equal blood sugar reduction.

UKPDS 80 (NEJM 2008) followed participants for ten years after the trial ended. The advantage persisted, even though the groups' blood sugar values had long since converged. This legacy effect is one of the most interesting findings in diabetology.

DPP (NEJM 2002) tested prevention in prediabetes: metformin cut new diabetes cases by 31 percent. The lifestyle intervention in the same trial achieved 58 percent, nearly double. That belongs in an honest account, because the more effective measure was not the drug.

The 2014 observational study (Diabetes Obes Metab) is the origin of the longevity hype: in that analysis, diabetics on metformin outlived matched non-diabetics. That is a striking finding, but it is an observational study and not proof of efficacy. The randomised longevity trial is still outstanding.

• Gut complaints: diarrhoea, nausea, bloating. For most people dose-dependent and temporary if titrated slowly and taken with food.
• Vitamin B12 deficiency: measurable with use over months. Needs checking.
• Blunted training adaptation: smaller strength and muscle gains. The mechanism, not a side effect in the narrower sense.
• Lactic acidosis: very rare, but the classic warning. Relevant with impaired kidney function, severe illness, or before investigations with iodine contrast media, where it is paused beforehand.
• Metallic taste: harmless, but commonly reported.

Store dry, at room temperature and protected from light. Keep out of reach of children.