Table 1.

Recommendations for stratifying CV risk and primary prevention in T2DM.

Source	CV risk stratification methodology	Primary prevention recommendations for SGLT2i
2019 ADA/EASD consensus report [8]	T2DM without eCVD with indicators of high risk •Patients aged ≥55 years •Coronary/carotid/lower extremity artery stenosis >50% •Left ventricular hypertrophy •eGFR <60 mL/min/1.73m2 or albuminuria	No specific recommendation separately for primary prevention Recommendations mention that level of evidence for benefits is greatest for SGLT2ia in patients with and without eCVD but with •HFrEF (EF <45%) or •CKD (eGFR 30 to ≤60 mL/min/1.73m2 or UACR >30 mg/g, particularly UACR >300 mg/g
2019 ESC/EASD guidelines on diabetes, prediabetes, and CVD [21]	Very high CV risk •T2DM + established CVD or •other target organ damageb or •≥3 major risk factorsc High CV risk •T2DM duration ≥10 years without target organ damage+1 any other additional risk factor Moderate CV risk •Person aged <50 years + T2DM duration <10 years + no other risk factors	SGLT2i (empagliflozin, canagliflozin, dapagliflozin) reduce CV events in patients with T2DM who are at high CV riskd
2019 ACC/AHA guideline on the primary prevention of CVD [19]	CV risk stratification is not specific for patients with T2DM (guidelines focused on primary prevention measures for atherosclerotic CVD)	For adults with T2DM and additional atherosclerotic CVD risk factors, it may be reasonable to initiate a SGLT2i to improve glycemic control and reduce CVD risk (class IIB), if glycemic control is not achieved despite lifestyle modification and metformin
2018 ADA cardiovascular disease and risk management guidelines [22]	Increased risk •Person aged ≥50 years + T2DM + one additional major CV risk factor Low risk •Person aged <50 years + T2DM + no major risk factors	No recommendation for primary preventione For patients with eCVD, add a second agent with evidence of cardiovascular risk reduction such as SGLT2i
2016 European guidelines on CVD prevention in clinical practice [23]	•Diabetes is not a CAD-risk equivalent state at diagnosis or in those with short duration of diabetes •Risk levels approach CAD risk equivalence after duration of diabetes for 10 years or with proteinuria/low eGFR •Patients at 40–50 years of age may have a low 10 year risk of CVD due to normal BP/lipid levels/being nonsmokers	No recommendation for primary preventione In patients with T2DM and CVD, the use of SGLT2i should be considered early in the course of the disease to reduce CV and total mortality.
2019 Bashier A et al (consensus recommendations for management of patients with T2DM and CVD) [24]	Patients at high risk for CVD (multiple risk factors for CVD) •Men ≥55 years or women ≥60 years in addition to HTN, dyslipidemia (LDL-C >130 mg/dL) or use of lipid-lowering therapies and smoking •Microalbuminuria or macroalbuminuria (UACR >30 mg/g) •High renal risk: eGFR (45–75 mL/min/1.73m2 and UACR >200 mg/g or equivalent, or eGFR of 15–45 mL/min/1.73m2 regardless of UACR).	Recommend starting SGLT2i •First line: If HbA1c >1.5% of patient-specific target: metformin + SGLT2i with proven CVf/neutral/favorable benefits (metformin dose to be adjusted or with declining eGFR) •Second/third-line therapyg in patients with T2DM and who are at high risk for CVD or renal impairment (Grade A)
2019 Giugliano et al (primary versus secondary cardiorenal prevention in type 2 diabetes: Which newer anti-hyperglycemic drug matters?) [25]	Very high CV risk •Previous CV event at the level of coronary, cerebral, or peripheral vascular districts High CV risk •Clinical instrumental evidence of CVD; stenosis >50% in coronary, carotid, or lower extremity arteries; documented coronary heart disease: exercise test, cardiac imaging); revascularization at any site Moderate-high CV risk •Multiple risk factors, obesity, overweight, hypertension, dyslipidemia, smoking, family history of premature coronary heart disease, low eGFR, presence of albuminuria Mild •Five major variables within target ranges (HbA1c <7% [64 mmol/mol], LDL-C <97 mg/dL, BP < 140/90 mmHg, no smoking, no albuminuria	In primary prevention, SGLT2i reduce risk of hospitalization for heart failure and progression of kidney disease in patients with T2DM.

ACC/AHA: American College of Cardiology/American Heart Association, ADA: American Diabetes Association, BP: blood pressure, CAD: coronary artery disease, CV: cardiovascular, CKD: chronic kidney disease, CVD: cardiovascular disease, eCVD: established cardiovascular disease, eGFR: estimated glomerular filtration rate, EF: ejection fraction, ESC: European Society of Cardiology, EASD: European Association for the Study of Diabetes, GLP-1: glucagon-like peptide 1, HFrEF: heart failure with reduced ejection fraction, HTN: hypertension, LDL-C: low-density lipoprotein cholesterol, MACE: major adverse cardiovascular events, SGLT2i: sodium-glucose co-transporter 2 inhibitors, T2DM: type 2 diabetes mellitus, UACR: urinary albumin creatinine ratio.

^aTo reduce risk of MACE, GLP-1 receptor agonists can also be considered in patients with T2DM without established CVD with indicators of high risk, specifically, patients aged 55 years or older with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m² or albuminuria.

^bProteinuria, renal impairment defined as eGFR <30 mL/min/1.73 m²,left ventricular hypertrophy or retinopathy.

^cAge, hypertension, dyslipidemia, smoking, obesity.

^dEmpagliflozin, canagliflozin, and dapagliflozin reduce CV events in patients with DM and CVD, or in those who are at very high/high CV risk.

^eNo evidence for primary prevention with SGLT2i at this point of time.

^fProven CVD benefits means the agent has a label indication of reducing the CVD events. For SGLT2 inhibitors evidence-based preference is empagliflozin > canagliflozin. SGLT2 inhibitors vary in regard to eGFR pre-requisites for a continued use.

^gDapagliflozin: preferred option for patients with eGFR 60 mL/min/1.73 m².