Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis

Background and aims Glucose lowering agents that reduce the risk of major adverse cardiovascular events (MACE) would be considered a major advance. The reduction of cardiovascular risk by sodium-glucose cotransporter 2 inhibitors (SGLT-2i) has been confirmed by some large-scale randomized controlled studies (RCTs) and systematic reviews of RCTs, but exact indicators of cardiovascular risk remained controversial. Whether consistent results can be obtained in clinical practice is unclear. Therefore, in this meta-analysis, we analyzed the real-world effect of SGLT-2i on cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM). Methods We did a real-world systematic review and meta-analysis of cardiovascular outcome of SGLT-2i in patients with T2DM. We searched PubMed and Embase for trials published up to October 23, 2019. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. The primary outcome was MACE and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region. Results Fourteen trials enrolling 3,157,259 patients were included. SGLT-2i reduced MACE (OR, 0.71; 95% CI 0.67,0.75, P<0.001) and ACM (OR, 0.53; 95% CI 0.49,0.57, P<0.001) compared to other glucose lowering drugs (oGLD). Compared with oGLD, SGLT-2i had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI 0.49,0.69, P<0.001) and HF (OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. SGLT-2i significantly reduced the risk of severe hypoglycemia (OR, 0.78; 95% CI 0.69,0.90, P<0.001) and lower limb amputation (OR, 0.83; 95% CI 0.71,0.98, P<0.001), but it may increase the risk of diabetic ketoacidosis. Subgroup analysis showed SGLT-2i reduced the risk of MACE, ACM, HHF, MI, stroke, CVM and HF with a similar benefit regardless of the incidence of CVD was (20–30)% or < 15%, (15–30)% or <15% have been treated with GLP-1 receptor agonists (GLP-1RA), >80% or <70% have been treated with statins or both GLP-1RA and statins. SGLT-2i reduced the risk of ACM in low-risk population (P<0.001). No inconsistencies were found when stratification was performed at 1 or (3–4) years of follow-up except for BKA followed up for 1 year. SGLT-2i showed similar cardiovascular benefits in the Nordic countries, Asia and the United States. Conclusions The predominant impact of SGLT-2i is on cardiovascular outcome driven predominantly by reduction in MACE, ACM, HHF, MI, stroke, CVM, HF, but not UA or AF. SGLT-2i has robust benefits on reducing MACE, ACM, HHF, MI, stroke, CVM and HF regardless of a history of usage rate of GLP-1RA and/or statins and /or metformin. SGLT-2i does not increase the risk of severe hypoglycemia and lower limb amputation.

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Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis

10.21203/rs.3.rs-16511/v1 ◽

2020 ◽

Author(s):

Chun-xing Li ◽

Shuo Liang ◽

Lingyan Gao ◽

Hua Liu

Keyword(s):

Heart Failure ◽

Systematic Review ◽

Type 2 Diabetes ◽

Real World ◽

Cardiovascular Events ◽

Meta Analysis ◽

Cardiovascular Outcome ◽

Glucose Lowering

Abstract Background Glucose lowering agents that reduce the risk of major cardiovascular events would be considered a major advance. Despite the reduction of cardiovascular risk by sodium-glucose cotransporter 2 inhibitors (SGLT-2i) has been confirmed by some large randomized controlled studies and systematic reviews, exact indicators of cardiovascular risk remained controversial. Whether consistent results can be obtained in clinical practice is unclear. Therefore, in this meta-analysis, we examined the real-world effect of SGLT-2i on cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM).Methods We did a real-world systematic review and meta-analysis of cardiovascular outcome of SGLT-2i in patients with T2DM. We searched PubMed and Embase for trials published up to October 23, 2019. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. The primary outcome was major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region.Results Fourteen trials enrolling 3,157,259 patients were included. SGLT-2i reduced MACE (OR, 0.71; 95% CI 0.67,0.75, P<0.001) and ACM (OR, 0.53; 95% CI 0.49,0.57, P<0.001) compared to other glucose lowering drugs (oGLD). Compared with oGLD, SGLT-2i had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI 0.49,0.69, P<0.001) and HF(OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. Subgroup analysis showed SGLT-2i reduced the risk of MACE, ACM, HHF, MI, stroke, CVM and HF with a similar benefit regardless of the incidence of CVD was (20-30)% or < 15%, (15-30)% and <15% have been treated with GLP-1 receptor agonists (GLP-1RA), >80% and<70% have been treated with statins or both GLP-1RA and statins. SGLT-2i reduced the risk of ACM in low-risk population (P<0.001). No inconsistencies were found when stratification was performed at 1 or (3-4) years of follow-up. SGLT-2i showed similar cardiovascular benefits in the Nordic countries, Asia and the United States.Conclusions The predominant impact of SGLT-2i is on cardiovascular outcome driven predominantly by reduction in MACE, ACM, HHF, MI, stroke, CVM, HF, but not UA or AF. SGLT-2i have robust benefits on reducing MACE, ACM, HHF, MI, stroke, CVM and HF regardless of a history of usage rate of GLP-1RA and/or statins and /or metformin.

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Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(20)30038-3 ◽

2020 ◽

Vol 8 (5) ◽

pp. 418-435 ◽

Cited By ~ 19

Author(s):

Olivia R Ghosh-Swaby ◽

Shaun G Goodman ◽

Lawrence A Leiter ◽

Alice Cheng ◽

Kim A Connelly ◽

...

Keyword(s):

Heart Failure ◽

Systematic Review ◽

Type 2 Diabetes ◽

At Risk ◽

Cardiovascular Events ◽

Meta Analysis ◽

Cardiovascular Outcome ◽

Glucose Lowering ◽

Cardiovascular Outcome Trials

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Comment on “Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational data

Diabetes Obesity and Metabolism ◽

10.1111/dom.13509 ◽

2018 ◽

Vol 21 (2) ◽

pp. 444-445 ◽

Cited By ~ 1

Author(s):

Patrick B. Ryan ◽

Norm Rosenthal

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Observational Data ◽

Real World ◽

Comparative Effectiveness ◽

Meta Analysis ◽

Sglt2 Inhibitors

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Comparison of New Glucose-Lowering Drugs for Primary and Secondary Prevention of Cardiovascular Disease in Type 2 Diabetes: A Network Meta-Analysis of Cardiovascular Outcome Trials

SSRN Electronic Journal ◽

10.2139/ssrn.3436269 ◽

2019 ◽

Author(s):

Caroline K. Kramer ◽

Chang Ye ◽

Ravi Retnakaran

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Secondary Prevention ◽

Meta Analysis ◽

Cardiovascular Outcome ◽

Primary And Secondary Prevention ◽

Glucose Lowering ◽

Cardiovascular Outcome Trials ◽

Prevention Of Cardiovascular Disease

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Severe Hypoglycemia and Incident Heart Failure among Adults With Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab794 ◽

2021 ◽

Author(s):

Justin B Echouffo-Tcheugui ◽

Arnaud D Kaze ◽

Gregg C Fonarow ◽

Sam Dagogo-Jack

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Relative Risk ◽

Cox Regression ◽

Severe Hypoglycemia ◽

Medical Assistance ◽

Hazard Ratios ◽

Accord Study

Abstract Context The effect of severe hypoglycemia on the incidence of heart failure (HF) is unclear. Objective We evaluated the association of severe hypoglycemia with incident HF among individuals with type 2 diabetes. Methods We included participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Severe hypoglycemia episodes were assessed during the initial 24 months following randomization and defined using two methods: symptomatic, severe hypoglycemic event requiring medical assistance (first definition) or requiring any assistance (second definition). Participants without HF at baseline and during the first 24 months of the study were prospectively followed for incident HF hospitalization. Multivariable Cox regression was used to generate adjusted hazard ratios (HR) for the association of severe hypoglycemia and incident HF. Results Among 9,208 participants (mean age 63 years, 38% female, 62% White), 365 had ≥ 1 episode of severe hypoglycemic. Over a median follow-up of 3 years, there were 249 incident HF events. After multivariable adjustment for relevant confounders, participants with severe hypoglycemia requiring medical assistance had a 68% higher relative risk of incident HF (HR 1.68, 95% CI 1.06-2.66), as compared to individuals who never experienced any episode of hypoglycemia. Severe hypoglycemia requiring any assistance was also associated with a 49% higher relative risk of HF (HR 1.49, 95% CI 1.01-2.21). Conclusion In a large cohort of adults with type 2 diabetes, severe hypoglycemia was independently associated with greater risk of incident HF.

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