Three SGLT2 inhibitors associated with decreased CVD risk in real-world setting
Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic)
A multinational observational analysis
Improving glucose control alone has not been shown to reduce the cardiovascular (CV) risk, however, SGLT2 inhibitors empagliflozin and canagliflozin have been associated with a convincing CV risk reduction [1-5]. It remains to be shown whether these effects will be seen for all SGLT2 inhibitors and whether these findings can be translated into real-world clinical settings.
In this study, it was evaluated whether new use of SGLT2 inhibitors compared with new use of other glucose-lowering drugs, were associated with changes in CV mortality and disease risk, including MACE and hospital events for heart failure (HF).
For this purpose, an observational analysis was performed based on national registry data from Denmark, Norway, and Sweden (CVD REAL). This included all patients with type 2 diabetes mellitus (T2DM) who started a new glucose-lowering drug after the introduction SGLT2 inhibitors (2012 or 2013) until the end of 2015 (n=435,629). Propensity scores (1:3) were used to match each patient who initiated an SGLT2 inhibitor (n=91,320) with patients who initiated other glucose-lowering drugs (n=68,490).
CV outcomes were CV mortality, MACE including CV mortality, myocardial infarction (MI) and ischemic or hemorrhagic stroke, hospital event for HF, non-fatal MI and non-fatal stroke. Other predefined outcomes were all-cause mortality, atrial fibrillation (AF) and severe hypoglycemia.
- Mean follow-up time was 0.9 years, with a total of 80,669 patient-years. The exposure time was about 18,000 years (94%) for dapagliflozin, 1000 years (5%) for empagliflozin and 250 years (1%) for canagliflozin.
- The HRs for CV mortality (0.53, 95% CI 0.40-0.71, P<0.0001), all-cause mortality (0.51, 95% CI 0.45-0.58, P<0.0001), MACE (0.78, 95% CI 0.69-0.87, P<0.0001), hospital events for HF (0.70, 95% CI 0.61-0.81, P<0.0001) and severe hypoglycemia (0.76, 95% CI 0.65-0.90, P=0.001) showed that new users of SGLT2 inhibitors were at reduced risk compared with new users of other glucose-lowering drugs.
- Non-fatal MI (HR 0.87, 95% CI 0.73-1.03, P=0.112), non-fatal stroke (HR 0.86, 95% CI 0.72-1.04, P=0.113) and AF (HR 0.95, 95% CI 0.84-1.08, P=0.456) did not differ significantly between the two groups.
- Only all-cause mortality showed significant heterogeneity in the size of the effect estimate between countries (P=0.002).
- In patients with and without CV disease (CVD) at baseline, SGLT2 inhibitors were associated with reduced risk of CV mortality (HR with 0.60, 95% CI 0.42-0.85 and HR without 0.55, 95% CI 0.34-0.90). However, for MACE, reduced associated risk was only present in patients with CVD at baseline (HR with 0.70, 95% CI 0.59-0.83, HR without 0.90, 95% CI 0.76-1.07).
- Neutral risk associations were found for both CV mortality and MACE in patients younger than 65 years (HR 1.10, 95% CI 0.65-1.84 and 1.01, 95% CI 0.85-1.20, respectively), whereas HRs were 0.45 (95% CI 0.32-0.65) and 0.66 (95% CI 0.56-0.78) respectively for patients of 65 years or older.
In a real-world clinical setting, new use of an SGLT2 inhibitor was associated with a decreased CVD and CV mortality risk compared with the new use of other glucose-lowering drugs in diabetic patients. This is consistent with results of CV outcome trials of drugs in this class. Moreover, as more than 90% of SGLT2 inhibitor exposure time was contributed by dapagliflozin, the finding lend support for a possible class effect, as findings were complementing to what has previously been shown in CV outcome trials with empagliflozin and canagliflozin. These findings could be useful for health-care practitioners treating diabetic patients at high CVD risk.