News & Commentary

SGLT-2 Inhibitors, GLP-1 Agonists A Cut Above DPP-4 Inhibitors


Well, this doesn’t look like good news for the DPP-4 inhibitors. That is one way to look at the results of a massive meta-analysis that compared the dipeptidyl peptidase 4 (DPP-4) inhibitors with two other classes of glucose-lowering agents for people with diabetes, the sodium-glucose cotransporter 2 (SGLT-2) inhibitors and the glucagon-like peptide 1 (GLP-1) agonists.

The DPP-4 inhibitors include Januvia (sitagliptin), Onglyza (saxagliptin), and Tradjenta (linagliptin). Invokana (canagliflozin), Jardiance (empagliflozin), and Farxiga (dapagliflozin) are SGLT-2 inhibitors. Byetta (exenatide), Bydureon (also exenatide), Trulicity (dulaglutide), Saxenda (liraglutide), and Victoza (also liraglutide) are GLP-1 agonists. The DPP-4 inhibitors and SGLT-2 inhibitors are oral agents. The current crop of GLP-1 agonists are injected subcutaneously.

A British research team compared these three classes of drugs because they are often positioned as the next step after metformin hasn’t worked to bring the blood sugar level of someone with diabetes under control.

The team’s meta-analysis, published in the April 17, 2018, issue of JAMA, included an impressive number of trials (236) and study participants (176,310). Most of the included studies (213) were not head-to-head trials; rather, they were studies that compared outcomes of patients who took one of the glucose-lowering agents against those of patients in control groups taking a placebo or no treatment. The researchers say their “network” meta-analysis can help make up for the lack of side-by-side comparisons in trials by using statistical and network analysis techniques that, among other things, compares relative effects on control groups.

Ranking drugs, best to worst

All-cause mortality

Each line represents a drug class and shows the probability of its rank from best to worst. The peak of the line represents the most likely ranking. For all-cause mortality, best is the most likely ranking of the SGLT-2 inhibitors and worst the most likely ranking of the DPP-4 inhibitors.

Zheng SL et al., JAMA, April 17, 2018

So this is what they found: Compared with control groups, the SGLT-2 inhibitors and GLP-1 agonists were associated with reductions in all-cause mortality—and they had set all-cause mortality as the primary outcome for the meta-analysis. More precisely, the SGLT-2 inhibitors were associated with an absolute risk reduction in all-cause mortality of 1% and the GLP-1 agonists with a reduction of 0.6%. If that doesn’t sound like much, the study team, led by Sean Zheng, cited research that has shown that lowering blood pressure (by how much wasn’t mentioned) translates into an absolute risk reduction in all-cause mortality of 0.5%.

As for the DPP-4 inhibitors, they identified an association with a small increase (0.1%) in all-cause mortality compared with controls.

Results for cardiovascular mortality and heart failure events produced the same basic pattern: best results for SGLT-2 inhibitors; next, the GLP-1 agonists; and then the DPP-4 inhibitors.

Although most of the analysis was by class, not individual drugs, the researchers did share that when the 16 different drugs studied in the trials were analyzed separately, only one SGLT-2 inhibitor (empagliflozin) and two GLP-1 agonists (exenatide and lira­glutide) reduced all-cause mortality compared with controls.

It wasn’t all good news for the SGLT-2 inhibitors. They were associated with an increased risk of genital infections. And the researchers said they could not rule out the possibility of a “clinically meaningful safety signal for SGLT-2 inhibitors and amputation.” But they also noted that DPP-4 inhibitors were associated with an increased risk of acute pancreatitis.