As the study suggested, synergism is theoretically possible when treatment combines two drugs that lower blood glucose levels via independent pathways—for instance, when a drug that reduces glucose output by the liver or increases the peripheral uptake of glucose (such as  metformin) is coupled with an agent that reduces glucose absorption in the intestine (an alpha glucosidase inhibitor, such as miglitol) or increases glucose excretion by the kidneys (a sodium glucose cotransporter 2 [SGLT2] inhibitor, such as dapagliflozin).

In a multicenter, double-blind, placebo-controlled study by Chiasson and Naditch, 324 patients received placebo, miglitol, metformin, or miglitol plus metformin for 36 weeks following an 8-week placebo run-in period. The combination of miglitol and metformin provided greater improvement in blood glucose than metformin monotherapy. Specifically, the combination resulted in “a reduction in mean placebo-subtracted HbA1c of -1.78%,” which was “significantly different from treatment with metformin alone” (-1.25; P=.002), and was well-tolerated.4

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Two randomized, double-blind, 3-arm, 24-week trials by Henry and colleagues compared metformin monotherapy, dapagliflozin monotherapy, and combination therapy with metformin plus dapagliflozin in treatment-naïve patients with type 2 diabetes and baseline HbA1c of 7.5% – 12%. The dapagliflozin doses for the two studies were 5mg and 10mg.5

The dapagliflozin plus metformin combination was generally well-tolerated and was effective in reducing HbA1c, fasting plasma glucose (FPG), and weight. In both trials, reductions in HbA1c were significantly greater with the combination regimens (P<.0001). Combination therapy was statistically superior in lowering FPG (P<.0001) and more effective in reducing weight (P<.0001). Furthermore, dapagliflozin 10mg was non-inferior to metformin in reducing HbA1c. Events suggestive of genitourinary infection were more common among patients in the dapagliflozin arms. No major hypoglycemic episodes were reported.5

According to a study by Merovci and colleagues, dapagliflozin, a member of the newest class of antihyperglycemic drugs, induces glucosuria, increases muscle insulin sensitivity and insulin-mediated tissue glucose disposal, and greatly lowers fasting blood glucose levels. Paradoxically, it also increases endogenous glucose production.6 The SGLT2 inhibitors have been used in combination with other antihyperglycemic agents to treat patients with type 2 diabetes who have persistently elevated blood glucose levels.