SGLT-2 Inhibitors Associated with Lower Heart Failure Hospitalization Tighter glycemic control is not associated with lower risk of HF hospitalization: A Meta-Analysis

A new meta-analysis published in the Journal of American College of Cardiology showed that sodium glucose co-transporter (SGLT)-2 inhibitors are more effective than glucagon-like peptide (GLP)-1 agonists and dipeptidyl peptidase (DPP)-4 inhibitors in reducing the risk of Heart Failure (HF) hospitalization in patients with type 2 diabetes mellitus.

This meta-analysis was done using data from nine placebo-controlled, randomized clinical trials on 87,162 individuals. It showed that (SGLT)-2 inhibitors are more effective than placebo in the reduction of HF hospitalizations (RR 0.56; 95% CrI [credibility interval] 0.43 to 0.72). When compared with (GLP)-1 agonists and (DPP)-4 inhibitors, (SGLT)-2 inhibitors were significantly associated with a decreased risk of HF hospitalization (RR 0.59; 95% CrI 0.43 to 0.79) and (RR 0.50; 95% CrI 0.36 to 0.70) respectively. Dr. Adam D. DeVore (Duke Clinical Research Institute) and Dr. Jennifer B. Green (Duke Clinical Research Institute) commented in an accompanying editorial, “These findings suggest that specific drug classes, rather than glycemic targets, should be the focus of HF prevention efforts.”

Blood sugar control is not the secret

The meta-regression analysis showed that there was no association between the reduction of hemoglobin A1c and the risk of HF hospitalization. Therefore, the authors suggested that the degree of blood sugar control was not the pathophysiologic basis of the lower risk of HF hospitalization associated with (SGLT)-2 inhibitors. The authors suggested alternative mechanisms -other than lowering glucose levels- that might explain the effectiveness of (SGLT)-2 inhibitors in the reduction of HF hospitalizations such as its diuretic effect (hence decreasing the preload) and shift of the metabolic substrate from fatty acids to ketone bodies (hence improving myocardial energy consumption). (SGLT)-2 inhibitors may be evaluated in HF patients without diabetes to make use of these beneficial effects.

Dr. DeVore and Dr. Green explained, “It is possible that achievement of a reasonable degree of glycemic control early in the course of diabetes provides some protection against the development of HF over the long term.” However, they added, “This advantage may be lost in patients with more established and complicated disease. In such patients, the selection of particular antihyperglycemic drug classes may be more important to reducing HF risk.” 

The EMPA-REG OUTCOME and CANVAS trials were conducted to assess the cardiovascular outcomes of the (SGLT)-2 inhibitors empagliflozin and canagliflozin respectively. The two trials showed similarities between the two drugs such as decreased HF hospitalization that was observed in patients with or without a history of HF. Both drugs demonstrated this effect within a few months of starting the treatment. This finding further supports the theory that (SGLT)-2 inhibitors reduces HF hospitalization due to mechanisms other than glucose lowering. Dr. DeVore and Dr. Green concluded, “We are likely to learn more about the role of (SGLT)-2 inhibitors in cardiovascular disease through observational data as these medications are adopted into practice, as well as ongoing clinical trials of (SGLT)-2 inhibitors as treatments for HF with reduced or preserved ejection fraction.”