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Real-World Benefits for SGLT-2 Inhibitors

Dec 9, 2017

Patients with type 2 diabetes usually do not die from diabetes, but from cardiovascular disease and strokes.

Adults with type 2 diabetes and established cardiovascular disease treated with an SGLT-2 inhibitor have lower risks for all-cause mortality, and hospitalization for heart failure and major adverse CV events compared with those treated with other antihyperglycemic agents, data from  population-based cohort studies show.


Even when we compare the DPP-4 Inhibitors to SGLT-2 inhibitors in observational studies, where they evaluated cardiovascular outcomes in patients with type 2 diabetes treated with the SGLT-2 inhibitor dapagliflozin compared with a group treated with DPP-4 inhibitors in a real-world setting. The authors identified 10,227 users of dapagliflozin and 30,671 individuals taking a DPP-4 inhibitor. Compared with the DPP-4 inhibitor group, the dapagliflozin group had significantly lower risks of major adverse cardiovascular events (HR, 0.79), hospitalization for heart failure (HR, 0.62), and all-cause mortality (HR, 0.59) as well as non-significantly lower risks of MI, stroke, and cardiovascular mortality.

From the results, it was concluded that compared with DPP-4 inhibitors, dapagliflozin was associated with lower mortality and adverse cardiovascular event risks in patients with type 2 diabetes.

Observational studies are also critical in filling a knowledge gap to inform about the real-world effectiveness of new therapies and potential serious adverse events not readily detected in clinical trials.

In the current EASEL study, they evaluated data from the U.S. Department of Defense Military Health System on 25,258 adults with type 2 diabetes who initiated SGLT-2 inhibitors (n = 12,269; mean age, 65.8 years; 56.7% men; 36.7% white) or non-SGLT-2 inhibitor antihyperglycemic agents (n = 12,269; mean age, 65.9 years; 55.1% men; 33.6% white) between April 1, 2013 and Dec. 31, 2016, to determine the effect of drug choice on CV risk. The newly initiated SGLT-2 inhibitors included canagliflozin (Invokana), empagliflozin (Jardiance) and dapagliflozin (Farxiga). Follow-up was a median 1.6 years. Participants had similar diabetes duration of 5.7 years and CVD duration of 4.4 years.

The outcomes included an endpoint of all-cause mortality and hospitalization for heart failure and major CV events, including all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke.

What they discovered was that patients who initiated SGLT-2 inhibitors had lower incidence rates of all-cause mortality (1.29 vs. 2.26 events per 100 person-years; HR = 0.57; 95% CI, 0.49-0.66) and hospitalization for heart failure (0.51 vs. 0.9 events per 100 person-years; HR = 0.57; 95% CI, 0.45-0.73) compared with non-SGLT-2 initiators. It was also discovered that SGLT-2 initiators had a lower incidence rate for major adverse CV events compared with non-SGLT-2 initiators (2.31 vs. 3.45 per 100 person-years; HR = 0.67; 95% CI, 0.6-0.75). No differences were observed for the rates of nonfatal MI and nonfatal stroke between the two groups.

As with all drugs, there are side effects. For one of the SGLT-2 inhibitors canaglifozin, it had twice the rate of below-the-knee amputations compared with non-SGLT-2 initiators (0.17 vs. 0.09 per 100 person-years; HR = 1.99; 95% CI, 1.12-3.51).

The CVD-REAL study is a population study that observed the cardiovascular outcomes of patients initiating one of three SGLT-2 inhibitors in a real-world setting compared with other glucose-lowering agents. The CVD-REAL Nordic was a sub-study in the three Nordic countries where dapagliflozin accounted for 94% of SGLT-2 inhibitor prescribed. Propensity matching resulted in an excellent balance of baseline characteristics in the groups. The study showed SGLT-2 inhibitors were associated with a reduction of CV death, MI, and stroke (22%); CV mortality (47%); and heart failure admissions (30%). Benefits of similar magnitude were observed in EMPA-REG OUTCOME.

However, findings in the US cohort of CVD-REAL, of whom 75% received canagliflozin with a 62% reduction of mortality, are discordant with CANVAS results, where no reduction of mortality was observed. This disparity suggests that magnitude of the benefit observed could be exaggerated due to indication bias.

The CVD-REAL Nordic population study, in a largely primary prevention cohort, suggests that dapaglifozin has a large impact on CV outcomes. However, the true magnitude of the benefit remains uncertain. Randomized controlled trials remain the gold standard to assess the magnitude of the treatment effect, and we await the results of the DECLARE study that will include over 17,000 patients, of which two-thirds will be for primary prevention.

The end result is that the findings underscore the potential CV benefit and a rare but serious risk that physicians and patients should monitor for when initiating this or any class of medication.

In conclusion, SGLT-2 inhibitors are associated with lower risks of CV events and all-cause mortality compared with other drugs used to treat type 2 diabetes in a real-world clinical setting and a broad TD population.

Practice Pearls:

  • SGLT-2 inhibitors are associated with lower risks of CV events.
  • SGLT-2 can reduce the risk of death for a person with type 2 diabetes.
  • SGLT-2s, like all drugs, do have adverse events, which patients need to be aware of, such as possible amputation.


Persson MD, DMSc, Frederik. Thomas Nystrom MD, PhD, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diabetes, Obesity and Metabolism. http://onlinelibrary.wiley.com/doi/10.1111/dom.13077/abstract. Sept 27, 2017

Kosiborod, Mikhail, Matthew A. Cavender, et al. Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study. Circulation 2017; Healio iTJ Journal. http://circ.ahajournals.org/content/early/2017/05/16/CIRCULATIONAHA.117.029190 Nov, 2017