Cardiorenal effects of SGLT2 inhibitors: who might benefit?

Figures & data

Table 1: Putative mechanisms of cardiorenal protection associated with SGLT2 inhibitors^16,18,19

Heart Improved energy metabolism due to increased ketones Improved cardiac remodelling, improved autophagy and lysosomal degradation Inhibition of the Na^+/H^+ exchange Reduced inflammation Reduced ischaemic reperfusion injury Reduced oxidative stress Reduced epicardial fat mass

Kidney Increased diuresis and natriuresis Glucosuria Initial reduction in plasma volume Restoration of tubuloglomerular feedback and glomerular afferent arteriolar autoregulation Improvement of tubular oxygenation Reduction of reactive oxygen species Reduction in uric acid Inhibition of the Na^+/H^+ exchange Improved energy metabolism Reduced inflammation and fibrosis

Vasculature Reduced inflammation Reduced blood pressure Increased provascular progenitor cells Improved vascular function

Body Reduced blood glucose Weight loss Inhibition of sympathetic nervous system Increased erythropoietin and haematocrit

Table 2: Cardiovascular and kidney outcomes in CV outcome studies

Study	Baseline characteristics^a	SGLT2 inhibitor and follow-up duration	CV outcomes Hazard ratio (95% CI)^b	Kidney outcomes Hazard ratio (95% CI)
Patients with type 2 diabetes and high CV risk (established ASCVD)
EMPA-REG OUTCOME^Citation20,Citation21	T2D and ASCVD N = 7 020 Mean age 63 BMI 31 kg/m^2 DOD > 10 years 52% eGFR 60–90 ml/min 26% eGFR < 60 ml/min 76% CAD 47% previous MI 23% previous stoke 21% PAD 10% HF	Empagliflozin 10 mg or 25 mg (pooled) versus placebo, once daily 3.1 years (median)	MACE (PEP): HR 0.86 (0.74–0.99) CV death or HHF: HR 0.66 (0.55–0.79) HHF: HR 0.65 (0.50–0.85) CV death: HR 0.62 (0.49–0.77) All cause death: HR 0.68 (0.57–0.82)	Incident or worsening nephropathy (progression to macroalbuminuria; doubling of the serum creatinine with eGFR ≤ 45 ml/min; initiation of renal-replacement therapy; or death from kidney disease): HR 0.61 (0.53–0.70) Progression to macroalbuminuria: HR 0.62 (0.54–0.72) Doubling of the serum creatinine with eGFR ≤45 ml/min: HR 0.54 (0.40–0.75) Annual rate of decline in eGFR: slower in the empagliflozin group (−0.19 versus −1.67 ml/min/year; p < 0.001)
CANVAS^Citation22	T2D and high CV risk N = 10 142 Mean age 63 BMI 32 kg/m^2 DOD 13.5 years eGFR 76.5 ml/min 72% ASCVD 66% CAD 19% cerebrovascular disease 21% PAD 90% hypertension 23% microalbuminuria 8% macroalbuminuria	Canagliflozin 100 mg with optional increase to 300 mg at week 13 (pooled) versus placebo, once daily 2.4 years (median)	MACE (PEP): HR 0.86 (0.75–0.97) CV death or HHF: HR 0.78 (0.67–0.91) HHF: HR 0.67 (0.52–0.87)	Progression of albuminuria (> 30% increase in albuminuria and change from either normoalbuminuria to microalbuminuria or macroalbuminuria or from microalbuminuria to macroalbuminuria): HR 0.73 (0.67–0.79) 40% reduction in eGFR, renal-replacement therapy, or renal death: HR 0.60 (0.47–0.77)
VERTIS-CV^Citation26	T2D and ASCVD N = 8 246 Mean age 64 BMI 32 kg/m^2 DOD 13 years eGFR 76 ml/min 22% CAD 23% cerebrovascular disease 19% PAD 23% HF 48% previous MI	Ertagluflozin 5 mg or 15 mg (pooled) versus placebo, once daily 3.5 years (median)	HHF: HR 0.70 (0.54–0.90)
Patients with type 2 diabetes and primary or secondary CV prevention
DECLARE-TIMI 58^Citation24	T2D N = 17 160 Mean age 64 BMI 32 kg/m^2 DOD 11 years eGFR 85.2 ml/min 41% secondary prevention cohort with established ASCVD 59% primary prevention cohort with multiple risk factors	Dapagliflozin 10 mg versus placebo, once daily 4.2 years (median)	CV death or HHF Overall: HR 0.83 (0.73–0.95) ASCVD subgroup: HR 0.83 (0.71–0.98) HHF Overall: HR 0.73 (0.61–0.88) ASCVD subgroup: HR 0.78 (0.63–0.97) Multiple risk factor subgroup: HR 0.64 (0.46–0.88)	Worsening kidney function (≥ 40% decrease in eGFR, ESKD, or death from renal cause): Overall: HR 0.53 (0.43–0.66) ASCVD subgroup: HR 0.55 (0.41–0.75) Multiple risk factor subgroup: HR 0.51 (0.37–0.69)

^a Baseline characteristics approximated for active treatment group. ^bRisk reduction can be calculated by subtracting HR from 1; e.g. for HR 0.65, risk reduction is 0.35 = 35%.

ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CAD: coronary artery disease; CI: confidence interval; CVD: cardiovascular disease; DOD: duration of diabetes (median); eGFR: estimated glomerular filtration rate (ml/min/1.72 m²); ESKD: end-stage kidney disease; HHF: hospitalisation for heart failure; HF: heart failure; HR: hazard ratio; MACE: major adverse cardiovascular events (CV death, myocardial infarction or ischaemic stroke); MI: myocardial infarction; PAD: peripheral artery disease; PEP: primary endpoint; T2D: type 2 diabetes.

Table 3: Compelling indications for SGLT2 inhibitors in patients with type 2 diabetes

Indication	Potential benefits
At high or very high risk of cardiovascular events^Citation11,Citation43	To reduce hospitalisations for heart failure and prevent or reduce progression of kidney disease
With established ASCVD^Citation1,Citation11	To reduce hospitalisations for heart failure, major cardiovascular events, and cardiovascular death; to prevent or reduce progression of kidney disease

Table 4: Patients with type 2 diabetes who are at risk of ASCVD¹¹

Very high risk	Target organ damage: left ventricular hypertrophy, proteinuria or eGFR < 30 ml/min/1.72 m^2, or retinopathy 3 or more major risk factors: age, hypertension, dyslipidaemia, smoking, obesity
High risk	Duration of diabetes 10 years or more without target organ damage, plus any additional risk factor (age, hypertension, dyslipidaemia, smoking, obesity)
Moderate risk	Young patients (aged < 50 years) with diabetes duration less than 10 years and without other risk factors (hypertension, dyslipidaemia, smoking, obesity)

eGRF: estimated glomerular filtration rate.

Table 5: KDIGO classification of chronic kidney disease: prognosis of CKD by GFR and albuminuria categories⁵⁹

Colours show the risk of progression, morbidity and mortality. Green, low risk (if no other markers of kidney disease, no CKD); yellow, moderately increased risk; orange, high risk; red, very high risk. Numbers indicate a guide to the frequency of visits (number of times per year).⁵⁹

Table 6: Outcomes in SGLT2 inhibitor studies of patients with heart failure or CKD

Study	Baseline characteristics^a	SGLT2 inhibitor and follow-up duration	CV outcomes Hazard ratio (95% CI)^b	Kidney outcomes Hazard ratio (95% CI)
Patients with heart failure (including patients with and without T2D)
DAPA-HF^Citation25	HFrEF; NYHA class II, III or IV N = 4 744 Mean age 66 BMI 28 kg/m^2 42% T2D 38% AF eGFR 66.0 ml/min 48% HHF in preceding 12 months	Dapagliflozin 10 mg versus placebo, once daily 18.2 months (median)	CV death, HF hospitalisation or urgent HF visit (PEP): HR 0.74 (0.65–0.85) T2D: HR 0.75 (0.63–0.90) No T2D: HR 0.73 (0.60–0.88) Worsening HF (HHF or urgent visit for HF): HR 0.70 (0.59–0.83) CV death: HR 0.82 (0.69–0.98) CV death or HF hospitalisation: HR 0.75 (0.65–0.85)
EMPEROR-Reduced^Citation27	HFrEF; NYHA class II, III or IV N = 3 730 Mean age 67 BMI 28 kg/m^2 50% T2D 36% AF eGFR 62 ml/min 72% hypertension 31% HHF in preceding 12 months	Empagliflozin 10 mg versus placebo, once daily 16 months (median)	CV death or HHF (PEP): HR 0.75 (0.65–0.86) T2D: HR 0.72 (0.60–0.87) No T2D: HR 0.78 (0.64–0.97) HHF: HR 0.70 (0.58–0.85)	Annual rate of decline in eGFR: slower in the empagliflozin group (−0.55 versus −2.28 ml/min/year; p < 0.001) Composite renal outcome (chronic dialysis or kidney transplantation, or sustained reduction of eGFR ≥ 40%, or sustained estimated GFR < 15 ml/min in patients with a baseline eGFR ≥ 30 ml/min, or sustained eGFR < 10 ml/min in patients with a baseline eGFR < 30 ml/min): HR 0.50 (0.32–0.77)
EMPEROR-Preserved^Citation28	HFpEF; NYHA class II, III or IV N = 5 988 Mean age 72 BMI 29.8 kg/m^2 49% T2D 51% AF eGFR 61 ml/min 91% hypertension 23% HHF in preceding 12 months	Empagliflozin 10 mg versus placebo, once daily 26.2 months (median)	CV death or HHF (PEP): HR 0.79 (0.69–0.90) T2D: HR 0.79 (0.67–0.94) No T2D: HR 0.78 (0.64–0.95) HHF: HR 0.73 (0.61–0.88)	Annual rate of decline in eGFR: slower in the empagliflozin group (−1.25 versus −2.62 ml/min/year; p < 0.001)
DELIVER^Citation74	HFpEF; NYHA class II, III or IV N = 6 263 Mean age 72 BMI 29.8 kg/m^2 45% T2D 56% AF/flutter eGFR 61.0 ml/min 41% prior HHF	Dapagliflozin 10 mg versus placebo, once daily 2.3 years (median)	CV death, HF hospitalisation or urgent HF visit (PEP): 0.82 (0.73–0.92) T2D: HR 0.83 (0.70–0.97) No T2D: HR 0.81 (0.68–0.96) Worsening HF (HHF or urgent visit for HF): HR 0.79 (0.69–0.91) HHF: HR 0.77 (0.67–0.89) Worsening HF or CV death: HR 0.77 (0.67–0.89)	No predefined renal endpoints
Patients with CKD and T2D
CREDENCE^Citation23	T2D and CKD N = 4 401 Mean age 63 BMI 31 kg/m^2 DOD 15.8 years Mean eGFR 56.2 ml/min 50% CVD 97% hypertension 15% HF	Canagliflozin 100 mg versus placebo, once daily 2.62 years (median)	CV death, MI or stroke: HR 0.80 (0.67–0.95) CV death or HHF: HR 0.69 (0.57–0.83) HHF: 0.61 (0.47–0.80) CV death, MI, stroke, or HHF or hospitalisation for angina: HR 0.74 (0.63–0.86)	Composite of ESKD (dialysis, transplantation, or a sustained eGFR of < 15 ml/min), a doubling of the serum creatinine level, or death from renal or CV causes (PEP): HR 0.70 (0.59–0.82) ESKD: HR 0.68 (0.54–0.86) Doubling of the serum creatinine level: HR 0.60 (0.48–0.76) Dialysis, kidney transplantation, or renal death: HR 0.72 (0.54–0.97)
Patients with CKD (including patients with and without T2D)
DAPA-CKD^Citation29	CKD eGFR ≥ 25 to ≤ 75 ml/min; mean 43 ml/min; 59% < 45 ml/min; 14% < 30 ml/min) N = 4 304 Mean age 61 BMI 29.4 kg/m^2 67% T2D 38% CVD 11% HF	Dapagliflozin 10 mg versus placebo, once daily 2.4 years (median)	CV death or HHF: HR 0.71 (0.55–0.92) All-cause death: HR 0.69 (0.53–0.88)	Worsening kidney function (sustained decline in the eGFR of ≥ 50%, ESKD, or renal death): HR 0.56 (0.45–0.68) Worsening kidney function or CV death (PEP): Overall: HR 0.61 (0.51–0.72) T2D: HR 0.64 (0.52–0.79) No T2D: HR 0.50 (0.35–0.72) ESKD: HR 0.64 (0.50–0.82)
EMPA-KIDNEY^Citation65,Citation75	CKD at risk of progressive disease eGFR ≥ 20 to < 45 ml/min or eGFR ≥ 45 to < 90 ml/min with uACR ≥200 mg/g Mean eGFR 37.5 ml/min; 34% < 30; 44% ≥ 30–< 45; 21% ≥ 45 ml/min KDIGO risk category: 26% low, moderate or high; 74% very high N = 6 609 Mean age 63.9 BMI 29.7 kg/m^2 46% diabetes 44% T2D 26% CVD 10% HF 7% PAD	Empagliflozin 10 mg versus placebo, once daily	Composite outcome of kidney disease progression or cardiovascular death (PEP) (kidney disease progression is defined as ESKD, renal death, a sustained decline in eGFR to < 10 ml/min or a ≥ 40% eGFR decline): HR 0.72 (0.64–0.82) Hospitalisation for any cause: HR 0.86 (0.78–0.95)	Progression of kidney disease: HR 0.71 (0.62–0.81) ESKD or CV death: HR 0.73 (0.59–0.89)

^a Baseline characteristics approximated for active treatment group. ^bRisk reduction can be calculated by subtracting HR from 1; e.g. for HR 0.65, risk reduction is 0.35 = 35%.

AF: atrial fibrillation; BMI: body mass index; CI: confidence interval; CKD: chronic kidney disease; CVD: cardiovascular disease; DOD: duration of diabetes (median); eGFR: estimated glomerular filtration rate (ml/min/1.72 m²); ESKD: end-stage kidney disease; HHF: hospitalisation for heart failure; HFpEF: heart failure with preserved ejection fraction (> 40%); HFrEF: heart failure with reduced ejection fraction (< 40%); HR: hazard ratio; KDIGO: Kidney Disease: Improving Global Outcomes; NYHA: New York Heart Association heart failure classification; PAD: peripheral artery disease; PEP: primary endpoint; T2D: type 2 diabetes; uACR: urinary albumin:creatinine ratio.

Bailey CJ, Day C, Bellary S. Renal protection with SGLT2 inhibitors: effects in acute and chronic kidney disease. Curr Diab Rep. 2022;22(1):39–52. https://doi.org/10.1007/s11892-021-01442-z

 PubMed Web of Science ®Google Scholar

Fathi A, Vickneson K, Singh JS. SGLT2-inhibitors; more than just glycosuria and diuresis. Heart Fail Rev. 2021;26(3):623–642. https://doi.org/10.1007/s10741-020-10038-w

 PubMed Web of Science ®Google Scholar

Lopashuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose Co-transporter 2 (SGLT2) inhibitors. JCC Basic Transl Sci. 2020;5(6):632–644. https://doi.org/10.1016/j.jacbts.2020.02.004

 PubMedGoogle Scholar

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128. https://doi.org/10.1056/NEJMoa1504720

 PubMed Web of Science ®Google Scholar

Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–334. https://doi.org/10.1056/NEJMoa1515920

 PubMed Web of Science ®Google Scholar

Neal B, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–657. https://doi.org/10.1056/NEJMoa1611925

 PubMed Web of Science ®Google Scholar

Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425–1435. https://doi.org/10.1056/NEJMoa2004967

 PubMed Web of Science ®Google Scholar

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–357. https://doi.org/10.1056/NEJMoa1812389

 PubMed Web of Science ®Google Scholar

Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. https://doi.org/10.1093/eurheartj/ehz486

 PubMed Web of Science ®Google Scholar

McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. https://doi.org/10.1093/eurheartj/ehab368

 PubMed Web of Science ®Google Scholar

The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee. The 2017 SEMDSA Guideline for the Management of Type 2 Diabetes. J Endocrinol Metab Diab SA. 2017;21(1):S1–S196.

 Google Scholar

American Diabetes Association Professional Practice Committee. Chronic kidney disease and risk management: standards of medical care in diabetes – 2022. Diabetes Care. 2022;45(S1):S175–S184. https://doi.org/10.2337/dc22-S011

 PubMedGoogle Scholar

McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303

 PubMed Web of Science ®Google Scholar

Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–1424. https://doi.org/10.1056/NEJMoa2022190

 PubMed Web of Science ®Google Scholar

Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–1461. https://doi.org/10.1056/NEJMoa2107038

 PubMed Web of Science ®Google Scholar

Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089–1098. https://doi.org/10.1056/NEJMoa2206286

 PubMed Web of Science ®Google Scholar

Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–2306. https://doi.org/10.1056/NEJMoa1811744

 PubMed Web of Science ®Google Scholar

Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–1446. https://doi.org/10.1056/NEJMoa2024816

 PubMed Web of Science ®Google Scholar

EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with Chronic Kidney Disease. N Engl J Med. 2023;388, 2, 117–127. Online ahead of print. https://doi.org/10.1056/NEJMoa2204233

 PubMed Web of Science ®Google Scholar

EMPA-KIDNEY Collaborative Group. Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial. Nephrol Dial Transplant. 2022;37(7):1317–1329. https://doi.org/10.1093/ndt/gfac040

 PubMed Web of Science ®Google Scholar