Certain CV risk reductions with SGLT2 inhibitors limited to patients with atherosclerotic CVD
The benefits of SGLT2* inhibitors on certain cardiovascular (CV) outcomes may be restricted to patients with atherosclerotic cardiovascular disease (CVD), according to a systematic review and meta-analyses of three randomized controlled trials.
“[F]or particular outcomes the clinical effects of SGLT2 inhibitors depend on the patient population in which they are used ... the present meta-analysis ... showed that the clinical benefit of SGLT2 inhibitors in reducing the risk of myocardial infarction [MI], stroke, or CV death was present only in patients with established atherosclerotic CVD and not in those with multiple risk factors,” said the researchers. In contrast, heart failure hospitalization and renal disease progression risk reductions were apparent regardless of atherosclerotic CVD status, they said.
The findings were obtained from a systematic review and meta-analyses of the randomized, placebo-controlled EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58 trials** of SGLT2 inhibitors comprising 34,322 patients with type 2 diabetes (T2D; mean age 63.5 years, 35.1 percent female). Of these, 60.2 percent had established atherosclerotic CVD, while 39.8 percent had multiple risk factors but no atherosclerotic CVD. There were 3,342 MACE***, 2,028 CV deaths or hospitalization for heart failure events, and 766 renal outcomes.
The risk of CV death or hospitalization for heart failure was reduced with SGLT2 inhibitors (hazard ratio [HR], 0.77, 95 percent confidence interval [CI], 0.71–0.84; p<0.0001) regardless of atherosclerotic CVD status or history of heart failure. [Lancet 2018;doi:10.1016/S0140-6736(18)32590-X]
While SGLT2 inhibitors reduced the incidence of MACE overall (HR, 0.89, 95 percent CI, 0.83–0.96; p=0.0014), this benefit was observed specifically among patients with atherosclerotic CVD (HR, 0.86, 95 percent CI, 0.80–0.93) and not among patients with multiple risk factors but no atherosclerotic CVD (HR, 1.00, 95 percent CI, 0.87–1.16; pinteraction=0.0501).
In terms of the specific MACE components, SGLT2 inhibitors reduced the risk of MI (HR, 0.89, 95 percent CI, 0.80–0.98; p=0.0177) and CV death (HR, 0.84, 95 percent CI, 0.75–0.94; p=0.0023), again specifically in patients with atherosclerotic CVD (HR, 0.85 and 0.80, respectively) with no effect among those with multiple risk factors, but had no impact on stroke (HR, 0.97, 95 percent CI, 0.86–1.10; p=0.64) regardless of atherosclerotic CVD status.
SGLT2 inhibitors also reduced the risk of CV death and heart failure hospitalization (HR, 0.77, 95 percent CI, 0.71–0.84; p<0.0001) and all-cause mortality (HR, 0.85, 95 percent CI, 0.78–0.93; p=0.0002).
The risk of renal disease progression (worsening renal function, end-stage renal disease, or renal-related death) was also reduced with SGLT2 inhibitors (HR, 0.55, 95 percent CI, 0.48–0.64; p<0.0001) regardless of atherosclerotic CVD status, and was particularly evident among those with better baseline renal function (33 percent vs 56 percent reduction in patients with eGFR <60 vs ≥90 mL/min/1.73 m2; pinteraction=0.0258). However, reduction in the risk of heart failure hospitalization was greatest among patients with poorer renal function at baseline (40 percent vs 12 percent reduction in patients with eGFR <60 vs ≥90 mL/min/1.73 m2; pinteraction=0.0073).
While the overall mechanisms behind the findings are yet undetermined, the impact of SGLT2 inhibitors on the reduction in heart failure hospitalization may have been due to the renoprotective effects of this drug class and SGLT2 inhibitor-induced natriuresis, said the researchers.
The greatest risk reduction with SGLT2 inhibitors was seen with heart failure hospitalization (31 percent) and renal disease progression (45 percent), they continued. “Reductions in both the progression of kidney disease and hospitalization for heart failure and their attendant interventions and downstream complications might then reduce the risk of both CV and all-cause death.”
“[The meta-analyses] provides compelling evidence that SGLT2 inhibitors should now be considered as first-line therapy after metformin in most people with T2D, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” commented Professors Subodh Verma, Peter Jüni, and C David Mazer from St Michael’s Hospital, University of Toronto, Ontario, Canada. [Lancet 2018;doi:10.1016/S0140-6736(18)32824-1]