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Are all SGLT2 inhibitors linked to reduced cardiovascular mortality?

August 14, 2017

By Will Boggs MD

NEW YORK (Reuters Health) - Cardiovascular disease and mortality rates are lower in patients with type 2 diabetes who start taking sodium-glucose co-transporter-2 (SGLT2) inhibitors instead of other glucose-lowering drugs, according to results from the CVD-REAL Nordic study.

“Before the recent entrance of the SGLT2 inhibitor drug class, blood glucose-lowering drugs have never shown beneficial risk reducing effects on cardiovascular outcomes, and their use has been limited to blood glucose control only,” Dr. Johan Bodegaard from AstraZeneca Nordic-Baltic, Oslo, Norway, told Reuters Health by email. “Our results indicate that the SGLT2 inhibitor class, already widely available in many countries, also has a beneficial effect on cardiovascular risk in a broader type 2 diabetes population.”

Two recent studies showed significant cardiovascular risk reduction with empagliflozin and canagliflozin, but whether these benefits extend to all SGLT2 inhibitors is unclear.

Dr. Bodegaard and colleagues used registry data from Denmark, Norway, and Sweden to investigate whether new use of SGLT2 inhibitors was associated with changes in cardiovascular mortality and disease risk, compared with new use of other glucose-lowering drugs.

Among 91,320 patients with a total follow-up of 80,669 patient-years, SGLT2 inhibitor initiation was associated with 47% lower cardiovascular mortality (0.27 vs. 0.53 events per 100 patient-years for other drugs), 22% fewer major adverse cardiovascular events (1.64 vs. 2.12 events per 100 patient-years, respectively), 30% fewer hospital events for heart failure (0.98 vs. 1.40), and 49% lower all-cause mortality (1.05 vs. 2.09), compared with initiation of other glucose-lowering drugs.

SGLT2 use was also associated with a significantly lower risk of severe hypoglycemia (0.79 vs. 1.05 events per 100 patient-years), according to the August 3 Lancet Diabetes and Endocrinology online report.

Results were consistent in all 3 registries.

In subgroup analyses, patients with or without cardiovascular disease at baseline had lower cardiovascular mortality with SGLT2 inhibitors, but only patients with baseline cardiovascular disease experienced significant reductions in major adverse cardiovascular events with SGLT2 inhibitors.

Among patients younger than 65, risks for cardiovascular mortality and major adverse cardiovascular events were similar between SGLT2 inhibitors and other glucose-lowering drugs.

“While the primary cardiovascular risk management of patients with type 2 diabetes is still based on lifestyle improvement, cholesterol, and lowering blood pressure, the recent findings suggest that it is possible to use blood glucose-lowering drugs from the SGLT2 inhibitor drug class for additional risk control," Dr. Bodegaard said by email.

“Although randomized clinical trials are the gold standard to assess treatment effects, the limitation is the external validity, since patients are selected and the follow-up is structured,” he added. “Observational studies like ours could in the future be increasingly used to complement results from clinical trials in a real-world setting.”

Dr. David Fitchett from St. Michael’s Hospital and University of Toronto, Canada, who wrote an editorial related to this report, told Reuters Health by email, “These results from an observational trial are consistent with the direction of the findings of the randomized controlled clinical trials EMPAREG OUTCOMe and, to a lesser extent, CANVAS. However, the magnitude of the benefit from an SGLT2 inhibitor seems excessive and unlikely.”

“We will only know the true magnitude of the benefit of dapagliflozin when the clinical trial results of DECLARE are released in 2019,” he said. “However, the results do support the likelihood of a class effect of SGLT2 inhibitors.”

“All patients with type 2 diabetes with a history of significant coronary artery disease, myocardial infarction, stroke, peripheral vascular disease, and A1C >7% should be considered for treatment with an SGLT2 inhibitor,” Dr. Fitchett concluded. “The evidence is very strong for empagliflozin. Canagliflozin likely has benefit but has important side effects as well (increased amputations and bone fractures), and the evidence for dapagliflozin is from observational studies such as CVD Real Nordic with all the limitations of such studies.”

Dr. Sanjay Kaul from Cedars-Sinai Medical Center, Los Angeles, California, recently reviewed cardiovascular outcomes with various antidiabetic drug classes. He told Reuters Health by email, “The overall findings of this report are consistent with what was observed with SGLT2 inhibitors in cardiovascular outcome trials. Taken together, these findings are reassuring to clinicians and provide evidentiary support for their consideration as first or second-line therapy in mitigating cardiovascular risk in patients with type 2 diabetes.”

He concluded, “The cardiovascular protective effects seen in high-risk patients enrolled in randomized controlled trials are generalizable to the average patient with type 2 diabetes in a real-world clinical setting. This has important clinical implications in terms of preventive treatment strategies if confirmed in ongoing randomized trials.”

AstraZeneca sponsored the study, employed 2 of the 12 authors, and had various relationships with 9 other authors and with Dr. Firchett.


Lancet Diabetes Endocrinol 2017.

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