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Sodium-glucose cotransporter 2 (SGLT-2) inhibitors came out on top in a large meta-analysis of clinical trials that compared the newer classes of diabetes drugs head-to-head in terms of mortality, cardiovascular, and safety endpoints.

Dipeptidyl peptidase 4 (DPP-4) inhibitors fared the worst in the analysis, and glucagon-like peptide 1 (GLP-1) agonists were in the middle, reported Sean Zheng, BM BCh, of the Royal Brompton Hospital in London, and colleagues.

"No cardiovascular outcome trials have directly compared the efficacy of these classes. When no head-to-head trial exists, network meta-analysis can be used to estimate the effect," Zheng's group wrote in the . "Of the three classes tested, SGLT-2 inhibition may be preferred over the incretin-based therapies based on their association with lower mortality and their favorable adverse event profile."

Compared with control groups, SGLT-2 inhibitors were associated with reduced all-cause mortality (hazard ratio 0.80, 95% CI 0.71 to 0.89), as were GLP-1 agonists (HR 0.88, 95% CI 0.81 to 0.94). However, DPP-4 inhibitors were not (HR 1.02, 95% CI 0.94 to 1.11).

Compared with DPP-4 inhibitors, both SGLT-2 inhibitors and GLP-1 agonists were associated with reduced all-cause mortality (HR for SGLT-1 inhibitors 0.78, 95% CI 0.68 to 0.90; HR for GLP-1 agonists 0.86, 95% CI 0.77 to 0.96). There was no significant difference when SGLT-2 inhibitors and GLP-1 agonists were compared with each other.

Study Details

The systematic review and meta-analysis included 236 clinical trials with a total of more than 176,000 patients. The trials were randomized clinical trials that enrolled patients with type 2 diabetes; had a follow-up of at least 12 weeks; and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with each other, placebo, or no treatment. Important cardiovascular outcomes trials such as , , and were included.

The investigators performed a Bayesian hierarchical network meta-analysis. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, heart failure events, myocardial infarction (MI), and safety endpoints such as adverse events and hypoglycemia.

The study only analyzed outcomes by drug class, not individual drugs. "Although this substantially increases power to detect treatment effects, there is a key assumption that within-class treatments are interchangeable," Zheng's group said. In addition, the analyses did not address the effect of treatments on glycemic control, they noted.

"As with any medical intervention, patient preference and tolerance is important," Zheng said in an email to 番茄社区app. "This is particularly significant when you consider that these treatments may be lifelong."

The researchers reported that cardiovascular mortality was reduced compared with controls for SGLT-2 inhibitors (HR 0.79, 95% CI 0.69 to 0.91) and GLP-1 agonists (HR 0.85, 95% CI 0.77 to 0.94), but not for DPP-4 inhibitors (HR 1.00, 95% CI 0.91 to 1.11).

Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with lower cardiovascular mortality (HR 0.79, 95% CI 0.66 to 0.94), as were GLP-1 agonists (HR 0.85, 95% CI 0.74 to 0.98). Again, there was no difference when SGLT-2 inhibitors and GLP-1 agonists were compared with each other.

SGLT-2 inhibitors were associated with reduced heart failure events when compared with controls (HR 0.62, 95% CI 0.54 to 0.72), with DPP-4 inhibitors (HR 0.55, 95% CI 0.46 to 0.67), and with GLP-1 agonists (HR 0.67, 95% CI 0.57 to 0.80). Risk for heart failure was not significantly different when GLP-1 agonists and DPP-4 inhibitors were compared with controls, but the risk was lower for GLP-1 agonists compared with DPP-4 inhibitors (HR 0.82, 95% CI 0.70 to 0.95).

Only SGLT-2 inhibitors were associated with reduced MI risk compared with controls (HR 0.86, 95% CI 0.77 to 0.97). All three drug classes were linked with increased hypoglycemia risk compared with controls.

Finally, SGLT-2 inhibitors were associated with reductions in serious adverse events compared with controls (HR 0.90, 95% CI 0.85 to 0.96), with DPP-4 inhibitors (HR 0.91, 95% CI 0.84 to 0.98), and with GLP-1 agonists (HR 0.92, 95% CI 0.85 to 0.99).

For GLP-1 agonists, there was a higher risk for adverse events leading to trial withdrawal compared with controls (HR 2.00, 95% CI 1.70 to 2.37), with SGLT-2 inhibitors (HR 1.80, 95% CI 1.44 to 2.25), and with DPP-4 inhibitors (HR 1.93, 95% CI 1.59 to 2.35).

A Win for SGLT2 Inhibitors?

"I feel that SGLT-2 inhibitors are a great choice when it comes to patients with diabetes," Zheng told 番茄社区app. "We have shown that they reduce your risk of death and have other beneficial cardiovascular effects, for example on heart failure. GLP-1 agonists are a useful alternative, though they may not be tolerated by patients who do not like injections or who develop the gastrointestinal side effects. Although DPP-4 inhibitors are effective in reducing blood sugars, the absence of improved cardiovascular outcomes suggests that drugs from the other two classes may be preferable."

Robert Eckel, MD, of the University of Colorado Denver, agreed with Zheng, though he had a few reservations about the study.

"This is an impressive systematic review and meta-analysis, and the inclusion/exclusion criteria are appropriate," said Eckel in an email to 番茄社区app. However, the contribution of glycemic lowering was not assessed in the meta-analysis, and there were only a small number of trials that directly compared outcomes between diabetes drugs, he noted.

"Nevertheless, if the price of the three classes of agents were identical, the SGLT2 inhibitors should be the next choice beyond metformin for most patients, and perhaps considered as the drug of choice (but metformin is cheap)," said Eckel, who was not involved in the study.

DPP-4 inhibitors may be more appropriate for patients with kidney disease, Zheng said. "Little is known about the performance and safety of SGLT-2 inhibitors and GLP-1 agonists in patients with poor renal function. DPP-4 inhibitors are licensed in patients with low clearance, while insulin remains a commonly used agent in this population," he said.

SGLT-2 inhibitors may have a role in patients with heart failure, Zheng said. "Given the large improvement in heart failure outcomes, there is currently great interest in the use of SGLT-2 inhibitors in patients who have or are at risk of heart failure. With trials testing SGLT-2 inhibitors in participants with heart failure ongoing, we will learn more over the next few years."

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