Cardiovascular Benefit of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Type 2 Diabetes: A Systematic Review

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality worldwide yet, despite advances in treatment, CVD remains an underestimated and undermanaged condition, with an even greater risk in Type 2 Diabetes Mellitus (T2DM). Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are a promising novel drug class reported to improve Cardiovascular (CV) and renal outcomes in T2DM. Recent large-scale trials have assessed their CV safety with unexpected findings of multiple systemic benefits that could potentially reverse CVD. In this systematic review, we examined ten Randomized Controlled Trials (RCTs) that looked at cardiovascular outcomes in Type 2 diabetics and SGLT-2i. The RCTs were appropriately screened, looking for clear primary or secondary outcomes on CV events, and compared with placebo or other antidiabetic drugs. The RCTs had an average sample population studied of 5,549 participants with a mean follow-up time of 2.66 years. Three of the studies focused on CV parameters and risk factors. The remaining had defined CV composite events, and all consistently observed at least one CV benefit when using SGLT-2i. Our review of SGLT-2i in Type 2 diabetics showed the greatest benefit in reducing Heart Failure (HF) exacerbation and modest lowering of CV complications in high CV risk participants. Overall, there is still uncertainty about the exact mechanisms of SGLT-2i in their CV benefit, and whether they would favor pre-diabetic populations and those at earlier stages of CVD.

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

“…Inclusion criteria were (1) T2D, 92) no previous history of myocardial infarction, (3) stable coronary artery disease (coronary stenosis ≥ 30% and < 80% in at least one native major coronary artery), with or without previous percutaneous coronary intervention (> 6 months), with no evidence of critical restenosis and no indication to myocardial revascularization according to the current guidelines of the European Society of Cardiology [19], (4) glycated hemoglobin [HbA1c]: 7-8.5% or 53-69 mmol/mol on stable standard of care anti-hyperglycemic regimen, (5) diabetes duration < 10 years, (6) fasting C-peptide > 1 ng/ mL (0.33 nmol/L) at screening visit, (7) age: 40-75 years, (8) body mass index (BMI): 25-35 kg/m 2 , (9) women in surgical or natural menopause or with childbearing potential but unwilling to become pregnant during the study and non-breastfeeding women. Exclusion criteria were (1) type 1 diabetes or previous diagnosis of Latent Autoimmune Diabetes of Adults, (2) use of pioglitazone, loop diuretics or basal-bolus insulin therapy for at least 3 months prior to the screening visit or use of systemic steroids less than 3 days prior to the screening visit, (3) NYHA class III or IV, (3) reduced LVEF (≤ 50%), (4) unstable angina, (5) moderate to severe renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m 2 ) or overt proteinuria, (6) severe liver dysfunction, (7) contraindications to adenosine administration, (8) acute urinary tract infection, (9) history of breast, bladder or prostate cancer, (10) coronary artery disease with a coronary stenosis ≥ 80% in a major coronary artery defined by invasive coronary angiography, (11) inability to provide informed, written consent. The study design is illustrated in Additional file 1: Fig.…”

“…Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular (CV) disease [1]. In patients with T2D, large CV outcome trials have shown that sodiumglucose cotransporter-2 inhibitors (SGLT-2i) have beneficial cardioprotective effects [2][3][4][5][6][7], regardless of the presence of established atherosclerotic CV disease or history of heart failure (HF) [6,8], with reduction in major adverse CV events and CV deaths, as well as reduced risk of hospitalization for HF, and reduced progression of renal disease and all-cause mortality [9][10][11][12][13][14]. The multiple mechanisms hypothesized and investigated to explain the beneficial CV effects of SGLT-2i are the subject of continuous and intense debate.…”

Guía mexicana de práctica clínica para el diagnóstico y tratamiento en pacientes adultos con diabetes tipo 2

“…Los resultados mostraron que los iSGLT-2 redujeron los MACE tanto en pacientes que los recibieron combinados con metformina (RM: 0.91; IC95%: 0.84-0.98) o como monoterapia (RM: 0.81; IC95%: 0.71-0.91) 133 . La eficacia y seguridad de los iSGLT-2 ha sido confirmada por otras RS de ECA con alta calidad metodológica 140,[142][143][144][145][146][147] .…”

Control glucémico en pacientes con diabetes mellitus tipo 2 según esquema de tratamiento

“…Los iSGLT2 inhiben el transportador SGLT2 presente en el túbulo contorneado proximal, lo que impide la reabsorción de glucosa y mejora la excreción de glucosa en la orina, y así se mantienen el nivel de glucosa en la sangre y otros parámetros glucémicos. Los iSGLT-2 aumentan la natriuresis, causan contracción del volumen intravascular y alteran la hemodinámica intrarrenal, lo que contribuye a sus efectos benéficos sobre la presión arterial, la reducción del peso corporal y la disminución en la progresión de la albuminuria 12,13 .…”