SGLT-2 inhibitors more effective than sulfonylureas, DPP-4 inhibitors as second-line therapy

Adding sodium-glucose cotransporter-2 (SGLT-2) inhibitors to metformin was more effective in improving glycemic control, weight, and blood pressure than adding sulfonylureas or dipeptidyl peptidase-4 (DPP-4) inhibitors to metformin, new research shows.

To compare the efficacy of the three commonly prescribed second-line antidiabetic drugs, researchers linked primary care, hospital, and death data in England from 2015 to 2021. A total of 75,739 adults with type 2 diabetes were included, 25,693 (33.9%) who initiated treatment with sulfonylureas, 34,464 (45.5%) who started DPP-4 inhibitors, and 15,582 (20.6%) who began SGLT-2 inhibitors. The most commonly prescribed drugs in each class were gliclazide, sitagliptin, and empagliflozin (SGLT-2 inhibitor). Findings were published by The BMJ on May 8.

Between baseline and one year of follow-up, SGLT-2 inhibitors reduced HbA1c levels more than sulfonylureas (mean difference, −2.5 mmol/mol; 95% CI, −3.7 to −1.3) or DPP-4 inhibitors (mean difference, −3.2 mmol/mol; 95% CI, −4.6 to −1.8). SGLT-2 inhibitors were also more effective than sulfonylureas or DPP-4 inhibitors in reducing body mass index and systolic blood pressure. Major adverse cardiac events among patients were not significantly lower in patients taking SGLT-2 inhibitors than the other drugs, but they did have a reduced risk of hospitalization for heart failure compared with those taking DPP-4 inhibitors (hazard ratio [HR], 0.32; 95% CI, 0.12 to 0.90) and sulfonylureas (HR, 0.46; 95% CI, 0.20 to 1.05). Compared with sulfonylureas, SGLT-2 inhibitors also appeared to reduce risk for a 40% or greater decline in estimated glomerular filtration rate (HR, 0.42; 95% CI, 0.22 to 0.82).

One limitation to the study was that not enough people were included in follow-up to detect outcome differences for major adverse kidney events or cardiovascular disease-specific mortality, the study authors noted. The study also did not include glucagon-like peptide-1 (GLP-1) receptor agonists.

"This study provides evidence that SGLT-2 inhibitors might offer clinically important benefits when provided in routine clinical practice compared with common alternative oral antidiabetic drugs that are added to metformin for people with type 2 diabetes mellitus," the authors wrote. More research is needed to determine the long-term efficacy and cost-effectiveness of increasing use of SGLT-2 inhibitors in patients with diabetes, they added.

The findings are in line with a recent ACP clinical guideline update. Published April 19 in Annals of Internal Medicine, the guideline recommended adding an SGLT-2 inhibitor or GLP-1 receptor agonist as second-line therapy and against adding a DPP-4 inhibitor.