Pioglitazone
The combination of metformin and pioglitazone (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union. DPP-4 inhibitors
Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels. DPP-4 inhibitors combined with metformin include a sitagliptin/metformin combination (Janumet), a saxagliptin/metformin combination (Kombiglyze XR, Komboglyze), and an alogliptin/metformin combination (Kazano, Vipdomet).Linagliptin combined with metformin hydrochloride is sold under the brand name Jentadueto. As of August 2021, linagliptin/metformin is available as a generic medicine in the US.SGLT-2 inhibitors 
There are combinations of metformin with dapagliflozin, empgaliflozin and canagliflzoin. Sulfonylureas
Sulfonylureas act by increasing insulin release from the beta cells in the pancreas. They often can be used as secondary therapy if metformin alone is not sufficiently effective at reaching normal blood glucose levels. Metformin is available combined with the sulfonylureas glipizide (Metaglip) and glibenclamide (US: glyburide) (Glucovance). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter is more popular). Meglitinide
Meglitinides are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas, and require higher blood glucose levels to begin to secrete insulin. Both meglitinides, known as nateglinide and repanglinide, is sold in formulations combined with metformin. A repaglinide/metformin combination is sold as Prandimet, or as its generic equivalent.
Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration. Chemistry
Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pKa of metformin is 12.4. The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat. According to the procedure described in the 1975 Aron patent, and the Pharmaceutical Manufacturing Encyclopedia, equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield. Derivatives
A new derivative HL156A, also known as IM156, is potential new drug for medical use. History
The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goats rue (Galega officinalis), a plant used in folk medicine for several centuries.