In type 2 diabetes, early metformin plus vildagliptin reduced treatment failure vs a stepwise approach

Despite this study's findings, clinicians should continue to follow guidelines and use metformin as the first-line drug intervention, then select from other drug classes when there is a compelling indication, advised an ACP Journal Club commentary.

An industry-funded trial of vildagliptin, a dipeptidyl peptidase-4 inhibitor not currently available in the U.S., found that newly diagnosed patients with type 2 diabetes who took the drug in combination with metformin had better glucose control than those taking metformin alone. The trial included 2,001 patients with a baseline HbA1c level of 6.5% to 7.5%, and the primary outcome was time to treatment failure, defined as two HbA1c measurements of at least 7.0% 13 weeks apart.

The study was published Sept. 18, 2019, by The Lancet. The following commentary by Krysta Brown, DO, and Anthony A. Donato, MD, MHPE, was published in the ACP Journal Club section of the Feb. 18 Annals of Internal Medicine.

US and European guidelines recommend sequential add-on therapy for intensification of type 2 diabetes management. In the industry-sponsored VERIFY trial, initial combination therapy reduced risk for first treatment failure compared with metformin alone (stepwise group). Of patients who had a first treatment failure, those in the combination group were less likely to have a second failure than those in the stepwise group (after vildagliptin was added to metformin). The combination and stepwise groups did not differ for hypoglycemic events, mild weight reduction, or adverse events. The trial enrolled a lower-risk population that included few patients with stage 3 to 5 chronic kidney disease (CKD) (3.6%) and excluded patients with New York Heart Association class III or IV symptoms or who had had atherosclerotic cardiovascular disease (CVD) in past 6 months. The study did not report baseline atherosclerotic CVD and was not powered to detect microvascular or macrovascular outcomes.

A follow-up of the UK Prospective Diabetes Study showed a “legacy effect” of intensive therapy, in which microvascular outcomes, but not HbA1c levels, improved after treatment stopped. Combination therapy that lowers HbA1c over 5 years may also lead to improvement in microvascular outcomes. However, until this is shown, it is difficult to make a compelling argument for vildagliptin as a co–first-line drug treatment, or even dipeptidyl peptidase-4 inhibitors as a second choice, given their cost relative to sulfonylureas and thiazolidinediones ($400 US/mo vs $4 to $10 US/mo), and the well-documented cardiovascular and renal benefits of glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium–glucose cotransporter-2 (SGLT-2) inhibitor medications. In any event, vildagliptin is not approved by the US Food and Drug Administration (FDA) and a class effect cannot be assumed for the FDA-approved dipeptidyl peptidase-4 inhibitors based on this trial. For now, the 2018 recommendations remain evidence-based and prudent: Use metformin as the first-line drug intervention, then select from other drug classes when there is a compelling indication—sulfonylureas or thiazolidinediones for price, SGLT-2 inhibitors for congestive heart failure and CKD, or GLP-1RA or SGLT-2 inhibitors for coronary artery disease, and GLP-1RAs for obesity.