Putting effects of SGLT2 inhibitors into perspective
The DECLARE-TIMI 58 trial  investigated the effects of treatment with dapagliflozin on cardiovascular outcomes in people with type 2 diabetes in a double blind randomized placebo controlled manner. It is the third published trial investigating cardiovascular outcomes of SGLT2 inhibitors, following EMPA-REG (for empagliflozin)  in 2015 and CANVAS (canagliflozin)  in 2017. Of these three trials, DECLARE-TIMI 58 has been the largest by a fair margin, including more than 17000 patients with type 2 diabetes who either had multiple risk factors for atherosclerotic cardiovascular disease or established cardiovascular disease.
No reduction of major cardiovascular events
Participants were followed up for a median 4.2 years. In the primary safety analysis, dapagliflozin was found to be non-inferior to placebo with regard to the rate of major adverse cardiovascular events (MACE, defined as cardiovascular death, myocardial infarction and ischemic stroke), but unlike previous outcome trials with SGLT2 inhibitors, no superiority could be shown for this endpoint in the primary efficacy analysis, with a MACE rate of 8.8% for dapagliflozin vs. 9.4% for placebo (hazard ratio (HR) 0.93; 95%-confidence interval (CI) 0.84–1.03; p=0.17).
Less hospitalization for heart failure with dapagliflozin
In contrast, the second co-primary analysis found dapagliflozin to be superior regarding a composite endpoint of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; HR 0.83; 95%CI 0.73–0.95; p=0.005). This was mainly driven by a 27% lower rate of hospitalization for heart failure (HR 0.73; 95%CI 0.61-0.88), while the rates for cardiovascular death did not show significant differences (HR 0.98; 95%CI 0.82–1.17). Of note, this composite co-primary endpoint had been amended to the ongoing trial after the EMPA-Reg results had become available, which had shown a more pronounced effect of empagliflozin on cardiovascular death and heart failure than on the rate of MACE.
Potential renal benefits of dapagliflozin
The composite renal endpoint (decrease of glomerular filtration rate by ≥ 40% to ≤ 60 mL/min/m² or new end-stage renal disease or death from cardiovascular or death from renal cause) occurred in 4.3% in the dapagliflozin group and 5.6% in the placebo group (HR 0.76; 95%CI 0.67-0.87) while death from any cause did not differ between groups (6.2% vs 6.6%; HR 0.93; 95%CI 0.82-1.04). However, as the pre-specified testing sequence required both primary efficacy endpoints to show differences, results of the two secondary endpoints should be interpreted with caution and considered as hypothesis generating only.
Differences between different SGLT inhibitors...?
At first glance, it may appear a bit disappointing that DECLARE-TIMI 58 failed to show any superiority regarding the rate of major cardiovascular events, particularly when compared to the results of the EMPA-Reg and the CANVAS, both of which had shown reduction of the rate of MACE with SGLT2-inhibitor treatment for empagliflozin and canagliflozin, respectively.
Although the authors do not rule out any drug-specific differences in the effects of the various SGLT-2 inhibitors, there were also other marked differences between the trials that could have led to the apparently different results.
… or just differences in trial design?
While all participants of EMPA-Reg and two third of the participants of CANVAS had established cardiovascular disease, these patients were a minority of 41% in DECLARE TIMI. This focus on patients without history of CVD but multiple risk factors might have been an obstacle to reach significant results regarding the rate of MACE.
Actually, if only participants with established CVD are considered, the rate of MACE was 13.9% for dapagliflozin vs 15.3% for placebo. (HR 0.90; 95%CI 0.79-1.02). This indicates event rates and treatment differences which were quite comparable to the ones found in this population in EMPA-Reg (10.5 % for empagliflozin vs 12.1% for placebo), and the hazard ratio for MACE was also similar to the one reported in the CANVAS trial (HR 0.86; 95%CI 0.75 - 0.97).
Possible Class effects of SGLT2 inhibitors
Likewise, a meta-analysis based on all three outcome studies was published in Lancet last month . In this analysis, 60.2% out of 34322 patients had established atherosclerotic cardiovascular disease. There was an overall moderate reduction of major cardiovascular events by 11% (HR 0.89; 95%CI 0.83-0.96; p=0.0014), however, the benefit was only found in patients with existing atherosclerotic cardiovascular disease (HR 0.86; 95%CI .80-0.93), but not in those without (HR 1.00; 95%CI 0.87-1.16).
In addition, SGLT2 inhibitors reduced the risk of progression of renal disease by 45 % (HR 0.55; 95%CI0.48-0.64; p<0.0001) and the risk of cardiovascular death or hospitalization for heart failure by 23% (HR 0.77; 95%CI 0.71-0.84;p<0.0001), and unlike the effects on MACE, these robust benefits were similar in people with and without atherosclerotic cardiovascular disease.