Which Drug Should Diabetics be Prescribed if Metformin Fails?

Tight glucose control tempers insidious progress of diabetes. Nevertheless, lifestyle modifications and metformin monotherapy eventually fail to control blood glucose sufficiently in most patients.

Adding sulfonylureas, dipeptidyl-peptidase-4 (DPP-4) inhibitors, or thiazolidinediones (TZD) to metformin therapy can extend the efficacy of oral diabetes treatment. Although previous studies have examined the time until treatment failure (eg, durability) of each medication individually as initial therapy, limited evidence has addressed dual therapy in treatment-experienced patients.

Now, study results published ahead-of-print in Annals of Medicine report that metformin and DPP-4 inhibitor dual therapy provides less durable glycemic control than the addition of sulfonylureas or TZD to metformin.

This retrospective study examined a cohort of 20,070 patients newly treated with sulfonylureas, DPP-4s, or TZDs following metformin therapy failure. The researchers behind it followed patients until they required a third glucose-lowering therapy or for 5 years if a third agent wasn’t added.

TZDs provided the most durable glycemic control combined with metformin (8% failure rate) compared with sulfonylureas use (15% failure rate) or DPP-4 inhibitors (23% failure rate).

These findings are similar to the relative durability of monotherapy options seen in the ADOPT trial.

Previous researchers determined that patients using DPP-4 inhibitors were less likely to need insulin after 6 years than sulfonylurea users. However, the cohort had lower mean HbA1C levels at baseline (8%) than the current study’s population did (9%).

TZDs were associated with a nearly 4-pound weight gain on average, sulfonylureas were associated with slight weight loss, and DDP-4 inhibitors were associated with a nearly 4-pound weight loss.

Statin therapy, female sex, tobacco smoking, longer diabetes duration, and higher baseline HbA1C levels increased the likelihood of treatment failure.

The study didn’t include sodium-glucose transporter-2 and glucagon-like peptide-1 inhibitors because the population was too small at the time of enrollment.

No randomized controlled trials investigating the relative durability of dual therapy options exist in the literature.

This retrospective trial found that metformin and TZD dual therapy was the most durable option for patients with diabetes, followed by metformin with sulfonylureas and metformin with DPP-4 inhibitors.