SGLT2 inhibitors provide CV and renal benefits beyond glycaemic control in T2DM
Patients with type 2 diabetes mellitus (T2DM) are at high risk of developing heart failure (HF) and progressive kidney disease. Recent cardiovascular (CV) outcome trials of sodium-glucose co-transporter 2 (SGLT2) inhibitors in T2DM patients have demonstrated significant CV benefits and potential renoprotective effects that extend beyond glucose lowering. At the Endocrinology, Diabetes & Metabolism Hong Kong (EDMHK) 2nd Annual Meeting, Professor Richard Gilbert of the St. Michael’s Hospital, Toronto, Canada, discussed the clinical significance of these findings with an emphasis on HF and kidney endpoints.
Prevention of HF: A major emerging therapeutic goal in T2DM
HF is a frequent, fatal and underrecognized complication of diabetes. [Diabetologia 2012;55:2154-2162]
“Patients with undiagnosed HFpEF typically present with a small but significant reduction in exercise capacity,” noted Gilbert. “Dyspnoea on exertion develops gradually over many years, eventually resulting in an emergency department visit with acute pulmonary oedema. As endocrinologists, we should focus on appropriate screening and preventive treatment strategies for patients with T2DM well before they develop HF. We now have therapies that can effectively prevent HF.”
“In a small study, treatment of T2DM patients with the SGLT2 inhibitor, empagliflozin, for 6 months resulted in improved peak oxygen consumption – an index of cardiorespiratory fitness – during cardiopulmonary exercise testing, suggesting a reversal of exercise dyspnoea,” remarked Gilbert.
Additionally, a meta-analysis of CV outcome trials of SGLT2 inhibitors in T2DM patients showed an almost 30 percent reduction in the risk of hospitalization for HF (HHF) in patients with no history of HF. [Lancet 2019;393:31-39]
Empagliflozin confers benefits on CV outcomes and mortality
The EMPA-REG OUTCOME trial examined the effects of empagliflozin on CV morbidity and mortality in 7,020 patients with T2DM at high risk of CV events. Compared with placebo, empagliflozin demonstrated a 38 percent reduction in the risk of CV death (hazard ratio [HR], 0.62; 95 percent confidence interval [CI], 0.49 to 0.77; p<0.001). [N Engl J Med 2015;373:2117-2128] This protective effect of empagliflozin translates into 1.0–4.5 years of additional life expectancy. [Circulation 2018;138:1599-1601]
Empagliflozin also conferred benefits on other outcomes, including all-cause death (HR, 0.68; 95 percent CI, 0.57 to 0.82; p<0.001), HHF (HR, 0.65; 95 percent CI, 0.50 to 0.85; p=0.002), and the composite of HHF or CV death (HR, 0.66; 95 percent CI, 0.55 to 0.79; p<0.001). [N Engl J Med 2015;373:2117-2128]
The CV benefits in the Asian subgroup of EMPA-REG OUTCOME were consistent with those observed in the overall population. (Figure 1) [Circ J 2017;81:227-234]
Based on recent CV outcome data from SGLT2 inhibitor trials, the 2019 European Society of Cardiology (ESC) guidelines on diabetes, pre-diabetes and CV diseases recommend the use of SGLT2 inhibitors to lower the risk of HHF in patients with T2DM (class IA recommendation). The guidelines also specifically recommend SGLT2 inhibitors for T2DM patients at high risk of HF. [Eur Heart J 2020;41:255-323]
Furthermore, a meta-analysis of HHF data from the CANVAS and EMPA-REG OUTCOME studies revealed a modest HHF reduction of 23 percent (HR, 0.77; 95 percent CI, 0.61 to 0.98) among patients who used metformin concomitantly at baseline vs a 50 percent reduction in those who did not (HR, 0.50; 95 percent CI, 0.37 to 0.67) (p=0.03 for baseline metformin vs no metformin use). (Figure 2) [Neuen et al, AACE 2019, abstract 259]
Early detection and prevention of kidney disease progression
“In the last 20 to 30 years, preventive therapies have enabled dramatic reductions in rates of diabetes-related complications, such as acute MI and stroke. In contrast, end-stage renal disease [ESRD] has declined at a much lower rate despite increased use of renoprotective agents, such as angiotensin converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs],” noted Gilbert. [N Engl J Med 2014;370:1514-1523]
Gilbert pointed out that although albuminuria (measured as urinary albumin-to-creatinine ratio [UACR]) is a well-established biomarker of kidney disease, it may be absent in some patients with reduced estimated glomerular filtration rate (eGFR).
“Age-related decline in eGFR occurs at a rate of about 1 mL/min/1.73 m2, and a majority of these cases are normoalbuminuric. Therefore, eGFR may serve as a better indicator of impaired renal function.”
Gilbert urged caution when interpreting study results involving composite kidney outcomes. The SUSTAIN-6 trial, for example, reported significantly fewer new or worsening nephropathy cases (composite of macroalbuminuria, doubling of serum creatinine level, ESRD and renal death) with the GLP-1 RA, semaglutide, vs placebo (p=0.005). However, when individual components were analyzed, it was evident that this renal benefit was mainly driven by a reduction in progression to macroalbuminuria, and the effects on other kidney endpoints were insignificant. [N Engl J Med 2016;375:1834-1844]
A meta-analysis of renal outcome data from four GLP-1 RA trials further confirmed this finding. GLP-1 RAs significantly reduced the relative risk of the composite kidney outcome by 18 percent (HR, 0.82; 95 percent CI, 0.75 to 0.89; p<0.001), but the effect was nonsignificant when macroalbuminuria was excluded (HR, 0.92; 95 percent CI, 0.80 to 1.06; p=0.24). [Circulation 2019;139:2022-2031]
Conversely, a meta-analysis of three SGLT2 inhibitor trials revealed significant relative risk reduction in the composite kidney outcome with (HR, 0.62; 95 percent CI, 0.58 to 0.67; p<0.001) or without (HR, 0.55; 95 percent CI, 0.48 to 0.64; p<0.001) the inclusion of macroalbuminuria. [Circulation 2019;139:2022-2031]
In the EMPA-REG OUTCOME study, empagliflozin demonstrated significantly reduced incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine level, initiation of renal-replacement therapy, or renal death) (12.7 percent vs 18.8 percent; HR, 0.61; 95 percent CI, 0.53 to 0.70; p<0.001) vs placebo, with a number needed to treat (NNT) of 22 for 10 years (HR, 0.54; 95 percent CI, 0.40 to 0.75).
SGLT2 inhibitors: Renal benefit across all baseline eGFR and UACR categories
A meta-analysis of four SGLT2 inhibitor trials showed that the renoprotective effects (in reducing substantial loss of kidney function, ESRD, or renal death) were achieved across all levels of baseline eGFR and UACR categories. [Lancet Diabetes Endocrinol 2019;7:845-854]
“Unlike with angiotensin-converting enzyme inhibitors, patients who benefited the most from SGLT2 inhibitor therapy were those with preserved kidney function. Hence, SGLT2 inhibitor treatment should be initiated early,” advised Gilbert.
Based on favourable results demonstrated in CV outcome trials, SGLT2 inhibitors have gained guideline recommendation for lowering the risk of HHF in patients with T2DM. Albuminuria is a useful biomarker for kidney disease, but it cannot be used as a surrogate outcome marker for the renoprotective effect of diabetes therapy. SGLT2 inhibitors are effective in all stages of kidney disease, regardless of baseline eGFR or severity of albuminuria.