Blog entry by Meguid El Nahas

Anyone in the world
N Engl J Med. 2015 Sep 17. [Epub ahead of print]

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.


Background The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. Methods We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. Results A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME number, NCT01131676 .).


Inhibitors of SGLT2 (sodium-glucose cotransporter-2) inhibitors are hypoglycemic agents that have shown benefit in the management of heart failure in their capacity as potent osmotic diuretic effect through increased glycosuria.

In this study, Zinman et al show a benefit in all cause and cardiovascular mortality in patients at high cardiovascular risk due to T2DM.

It is intriguing that the only difference related to CVD outcomes, in this study, is heart failure; all other causes of CVD death such as myocardial infarctions or strokes dont seem different in those on SGLT2 inhibitors and placebos.

The only difference between the two groups seem to depend on a significant reduction in heart failure, related hospitalisation and death.

This, along with a reduction in weight and BP in the SGLT2 inhibitors treated group, implies that the beneficial effect is primarily related to the diuretic effect of this agent. Unfortunately, the placebo group did not incorporate additional diuretic therapy to match that of the two SGLT2 inhibitors arms.

The questions that warrant consideration is:

Is this agent worth precribing for its protective effect on CVD death due to heart failure in its capacity as an expense diuretic...?

notwithstanding its considerable potential side effects including urosepsis (fourfold higher in this study in those treated with SGLT2 inhibitors compared to placebo), genital candidiasis, and even urogenital malignancies...

not to mention and undoubted higher cost that diuretics such as chlorthalidone known to be protective in patients at high CVD risk as shown in the ALLHAT study?

Also, in this high risk group of patients with high CVD risk who are often on ACE inhibitors, and who often suffer from CKD, is there an increased risk of AKI associated with the use of excessive SGLT2 inhibition-induced excessive diuresis?

Whilst the authors make optimistic mechanistic claims, I remain unconvinced that the reported benefit is no more than one due to optimisation of diuresis and management of hypervolemia and fluid retention causing heart failure.

Is Empaglifozin, an expensice Chlorthalidone?!



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