Metformin

Clomiphene drives ovulation while metformin addresses the insulin resistance underneath it, tested head to head against each drug alone in the PPCOS trial.

The original GLP-1 plus metformin combination, tested in the LEADER cardiovascular outcomes trial and still the fallback when weekly agonists are not tolerated or not available.

Metformin suppresses hepatic glucose output while semaglutide restores glucose-dependent insulin secretion, the best evidenced combination in this dataset and standard clinical practice.

Tirzepatide's registration trials were run on a metformin background, and the pairing separates hepatic glucose control from incretin signalling cleanly.

Lowering a high prolactin removes one driver of insulin resistance, and metformin handles the rest, which is why the pairing shows up in prolactinoma patients with metabolic syndrome.

Metformin suppresses the hepatic glucose output that survodutide's glucagon arm actively drives up, which is the specific reason the pairing makes more sense than it does with a pure GLP-1.

Both improve endothelial function through different pathways, and tadalafil's nitric oxide signalling has a plausible but unproven effect on insulin sensitivity on top of metformin's.

Both improve insulin sensitivity by different routes in men with obesity and low testosterone, and testosterone undecanoate has trial evidence for reducing type 2 diabetes incidence.

Both are argued to converge on the NAD+ and AMPK axis from different directions, which is a tidy story with essentially no human evidence behind the combination.