SGLT2 inhibition and cardiovascular outcomes: lessons from recent clinical trials
Sodium-glucose co-transporter 2 (SGLT2) is a glucose transporter and SGLT2 inhibitors can improve glycaemic control. They block kidney reabsorption of filtered glucose and thereby reduce blood glucose levels. So far, only one clinical trial evaluating SGLT2 inhibitor results on CV outcome has been published10. This trial is called the EMPA REG OUTCOME trial in which empagliflozin is evaluated. Two other trials investigating the SGLT2 inhibitors canagliflozin (CANVAS) and dapagliflozin (DECLARE-TIMI) are currently ongoing.
EMPA REG OUTCOME is the first diabetes trial that shows a positive outcome in the primary endpoint: triple MACE including CV death, non-fatal myocardial infarct (MI) and non-fatal stroke. It is a double blind randomised placebocontrolled trial with the aim to examine the long-term effects of empagliflozin versus placebo, in addition to standard of care treatment in type 2 diabetes patients with a high CV risk. In this trial, patients received standard of care and were, on top of that, treated with either placebo (n=2333), empagliflozin 10 mg (n=2345) or empagliflozin 25 mg (n=2342). The trial was ended when 691 patients experienced triple MACE. This resulted in a median ontreatment time of 2.6 years and observation time of 3.2 years. At the end of the study, 99% of patients were still alive.
At baseline, median age was 63.1 years, 72% were male and a bit less than half of the patients were current or ex-smoker. Fifty-seven percent of patients had diabetes for more than 10 years and over a quarter had chronic kidney disease. Patients were at a high risk of CV events of which 75% had coronary disease, including 10.5% with heart failure. For this, patients were well-treated with CV and/or antidiabetic medicine.
*In EMPA REG OUTCOME, a 14% reduction of the primary triple MACE outcome was seen in HF patients treated with empagliflozin, as compared with those on placebo*
Results of this trial showed a drop of 0.7% in HbA1c in patients treated with empagliflozin during the first 12 weeks. After these first weeks, investigators were allowed to adjust glycaemic medication. This resulted in a final HbA1c decrease of 0.24%, which was insufficient to reach the local target. Also the systolic and diastolic blood pressure (BP) dropped during these first weeks (4 mmHg systolic) which was sustained throughout the study. A similar pattern was observed for weight (reduction of 4 kg), whereas the haematocrit increased (3-4%).
There was a 14% reduction of the primary triple MACE outcome for patients treated with empagliflozin as compared with placebo (HR 0.86; 95% CI: 0.74-0.99, P=0.0382), which was already observed during the first months of the study. This result was driven by a 38% reduction in CV death (HR 0.62; 95% CI: 0.49-0.77, P<0.0001). This effect is noticeable early during the trial, but since the curves further separated throughout the trial, this suggests an ongoing benefit. Subgroup analysis showed that older patients (≥65 yrs), males, Asian people, patients with a low HbA1c, body mass or average renal function (eGFR 60-90 mL/min) have a non-statistical increased benefit regarding CV death probabilities. The type of CV deaths that most significantly
reduced, were sudden death (28%) and unexplained CV deaths (40%). Contribution of MI or stroke (16%), worsening HF (14%) or cardiogenic shock was only modest (2%). Furthermore, all-cause mortality was significantly reduced by 32%, with CV death accounting for about two third of the reduction.
Regarding HF outcome specifically, HF hospitalisation (hHF), hHF or CV mortality, investigator-reported HF, hHF or HF mortality, and the introduction of loop diuretics as a surrogate for acute HF, were investigated in the trial. hHF (HR 0.65; 95% CI: 0.50-0.85, P=0.0017) as well as hHF/CV mortality (HR 0.66; 95% CI:0.55-0.79, P<0.001) and hHF or HF mortality (HR 0.61; 95% CI: 0.47-0.79, P=0.002) in empagliflozin-treated patients were persistently reduced throughout the study. No difference in treatment benefit was seen in investigator-reported HF and serious HF. The reduction of hHF/CV mortality between empagliflozin and placebo-treated patients was similar for patients with or without prior HF at baseline. Furthermore, there was no difference in risk for CV mortality nor for risk of hHF observed, between patients taking loop diuretic at baseline and those who did not. HHF patients had a high risk of mortality: the placebo group showed almost 24.2% of CV mortality and 30.5% all-cause mortality, which was nonsignificantly reduced by empagliflozin treatment to 14.3% and 21.4% respectively.
No serious adverse events were reported. The frequency of most events was not increased by empagliflozin, however candida infections were relatively more common in empagliflozin-treated patients (6.8% with 10 mg, 6.8% with 25 mg versus 1.8% with placebo). Interestingly, the incidence of acute kidney injury was lower in empagliflozintreated patients (5.2% in 10 mg, 5.3% in 25 mg versus 6.6% in placebo).
Altogether, during 3 years of treatment this reflects a benefit of 25 lives and 14 fewer hHFs, but at the costs of 53 additional genital infections, per 1000 DM patients who are at increased risk for CV disease. The number needed-to-treat was 39 patients, which is consistent with other preventive CV medications. Thus in the EMPA REG OUTCOME trial with high-risk DM patients, empagliflozin treatment was associated with a large early mortality benefit and reduced frequency of hospitalisations. The treatment benefit was consistent with both doses and not associated with serious events.