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JAMA Comparison: SGLT2 Inhibitors, GLP-1 Agonists Offer Lower Mortality in Type 2 Diabetes


Guidance for primary care physicians prescribing type 2 diabetes therapies comes at an opportune time. A major rift over guidelines for glycemic control has opened between the American College of Physicians, a professional association of internists, and diabetes specialists, including endocrinologists and diabetes educators.

With so many options for treating type 2 diabetes (T2D), what is the best choice? A meta-analysis published in JAMA finds that when it comes to reducing mortality and cardiovascular risk, 2 of the newer classes stand apart from a third.

In a review of 236 randomized controlled trials that involved more than 176,000 patients, sodium glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists offered significantly lower all-cause mortality than control groups, while dipeptidyl peptidase 4 (DPP-4) inhibitors did not.

The review also found that SGLT2 inhibitors and GLP-1 agonists were significantly associated with lower cardiovascular mortality than control groups, and SGLT2 inhibitors were also associated with lower rates of heart failure events.

Guidance for primary care physicians prescribing T2D therapies comes at an opportune time. A major rift over guidelines for glycemic control has opened between the American College of Physicians (ACP), a professional association of internists, and diabetes specialists including endocrinologists and diabetes educators. In early March, the ACP updated a guideline to allow for glycated hemoglobin (A1C) goals to range between 7% and 8%, higher than targets recommended by diabetes experts.

In his March letter to readers of Evidence-Based Diabetes Management™, Robert A. Gabbay, MD, PhD, FACP, chief medical officer and senior vice president of Joslin Diabetes Center, wrote that the ACP guideline made no sense with the availability of SGLT2 inhibitors and GLP-1 agonists, which give physicians more tools for T2D care than ever.

"To me, the greatest surprise in the ACP recommendations is the lack of concern for our younger patients with T2D,” Gabbay wrote. “Data from CDC show T2D incidence is occurring at younger ages, but with today’s treatments, these patients should have decades of life ahead of them.”

Sean L. Zheng, BM, BCh, MA, MRCP, from the National Heart and Lung Institute at Imperial College, London, United Kingdom, and co-authors reviewed trials that compared the 3 drug classes against placebo or each other; the analysis captured major cardiovascular outcomes trials of recent years, including EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), TECOS (sitagliptin), and ELIXA (lixisenatide). The authors limited their analysis to randomized controlled trials with follow-up of at least 12 weeks.

Overall, they found that SGLT2 inhibitors were most likely to be associated with lower rates of all-cause and cardiovascular mortality, followed by GLP-1 agonists. SGLT2 inhibitors ranked best for heart failure and myocardial infarction outcomes, while GLP-1 agonists ranked best for stroke outcomes.

The authors noted that no cardiovascular outcomes trial offering direct comparisons of the drug classes exists, nor is one likely. Thus, they understood their study can offer guidance to clinicians. “When no head-to-head trial exists, network meta-analysis can be used to estimate the effect,” they wrote.

Of note, the GLP-1 agonist study participants had higher body mass index than those for the other drug classes. At present, GLP-1 agonists are available only as injectable drugs, but 1 (semaglutide) is being studied in an oral form.

Details of the meta-analysis are as follows:

  • Compared with control groups, SGLT2 inhibitors had an absolute risk reduction of 1% for all-cause mortality and 0.8% for cardiovascular mortality.
  • GLP-1 agonists offered an absolute risk reduction of 0.6% in all-cause mortality and 0.5% in cardiovascular mortality.
  • For heart failure, SGLT2 inhibitors offered an absolute risk reduction of 1.1%.
  • GLP-1 agonists had a higher rate of adverse events leading to withdrawal from the trial than SGLT2 inhibitors and DPP-4 inhibitors. Most of these were gastrointestinal events.

The SGLT2 inhibitor results recall those seen recently in the large real-word study CVD-REAL, which has tracked claims and registry data for a variety of drugs in this class across multiple countries. Two waves for results have found about 50% reduced risk of all-cause mortality, along with reduced risk of hospitalization for heart failure and other benefits. The authors note that 2 new trials are now focusing directly on the effects of SGLT2 inhibitors on heart failure: EMPEROR HF for empagliflozin, and Dapa-HF for dapagliflozin.

Dapagliflozin has not yet reported results for its cardiovascular outcomes trial, DECLARE, but those results are anticipated in late 2018.


Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association between use of sodium-glucose co-tranporter-2 inhibitors, glucagon-like peptide-1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes. JAMA. 2018;319(15):1580-1591. doi:10.1001/jama.2018.3024.

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