Can glucose‐lowering medications improve outcomes in non‐diabetic heart failure patients? A Bayesian network meta‐analysis

Abstract

AimsThe cardioprotective effects of glucose-lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose-lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta-analysis to evaluate the impact of various glucose-lowering medications on the outcomes of non-diabetic HF patients. Methods and results Medline and Embase were searched for RCTs investigating the use of glucose-lowering medications in non-diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre-defined datasheet. Primary outcomes include serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO 2 ). A Bayesian network meta-analysis was performed to compare the effectiveness of different classes of glucose-lowering medications in improving HF outcomes. Risk-of-bias was assessed using Cochrane Risk-of-Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium-glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT-proBNP, with the significant reduction in NT-proBNP when compared with glucagon-like peptide-1 receptor agonists (GLP1-RA) [mean differences (MD): À229.59 pg/mL, 95%-credible intervals (95%-CrI): À238.31 to À220.91], metformin (MD: À237.15 pg/mL, 95%-CrI: À256.19 to À218.14), and placebo (MD: À228.00 pg/mL, 95%-CrI: À233.99 to À221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1-RA (MD: 8.09%, 95%-CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%-CrI: 4.37 to 7.84). SGLT2i and GLP1-RA were more favourable to placebo in improving PVO 2 , with significant increase of PVO 2 at a MD of 1.60 mL/kg/min (95%-CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%-CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo. Conclusions This Bayesian network meta-analysis demonstrated that SGLT2i, when compared with GLP1-RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO 2 and NT-proBNP in non-diabetic HF patients. Further large-scale prospective studies are needed to confirm these preliminary findings.

Effect of lixisenatide on natriuretic peptides in people with type 2 diabetes and recent acute coronary syndrome: The ELIXA trial

“…These include a recent Bayesian network meta-analysis of three trials that reported no effect in people with HF. 9 In a second meta-analysis 4…”

“…Previous studies have reported mixed effects of GLP‐1 RAs on these natriuretic peptides. These include a recent Bayesian network meta‐analysis of three trials that reported no effect in people with HF 9 . In a second meta‐analysis 4 of nine trials comprising 1079 participants, GLP1‐RAs reduced NT‐proBNP by an average of 0.14 standard deviations versus placebo.…”

Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long‐term mortality in acute myocardial infarction

“…63,64 In fact, the plethora of upcoming trials in the search for the first US Food and Drug Administration-approved medication for non-alcoholic steatohepatitis has led to promising data that describe the combined improvement in both liver and cardiovascular-related outcomes with the use of drugs such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists and sodiumglucose co-transporter-2 inhibitors. 17,[65][66][67][68] Several studies on peroxisome proliferator-activated receptor agonists and sodium-glucose cotransporter-2 inhibitors have also shown the reduction in liver biochemistry and/or hepatic fat content or fibrosis, as well as the improvement in cardiovascular outcomes, such as high-density lipoprotein levels and triglycerides, which are independent of diabetes status. [69][70][71] The present evidence on the combined improvement of hepatic steatosis and cardiovascular risk with current therapeutics appears promising; however, future mechanistic studies are warranted to explore the causal relationship between the two entities independent of metabolic bystanders, as well as the design of randomized controlled trials of pharmacological agents on the effect of hepatic steatosis in patients with AMI, will be an important next step.…”

“…Targeting common biological mechanisms of metabolic dysregulations that underlie hepatic steatosis and coronary artery disease, through exercise and dietary modifications, can help establish the unified goal in addressing liver and cardiovascular‐related endpoints 63,64 . In fact, the plethora of upcoming trials in the search for the first US Food and Drug Administration‐approved medication for non‐alcoholic steatohepatitis has led to promising data that describe the combined improvement in both liver and cardiovascular‐related outcomes with the use of drugs such as peroxisome proliferator‐activated receptor agonists, glucagon‐like peptide‐1 receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors 17,65‐68 . Several studies on peroxisome proliferator‐activated receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors have also shown the reduction in liver biochemistry and/or hepatic fat content or fibrosis, as well as the improvement in cardiovascular outcomes, such as high‐density lipoprotein levels and triglycerides, which are independent of diabetes status 69‐71 .…”

Comparison of mechanistic pathways of bariatric surgery in patients with diabetes mellitus: A Bayesian network meta‐analysis

“…However, several limitations should be accounted for when interpreting the study results. First, the impact of medical therapy on metabolic outcomes may be attenuated given that some trials were conducted before the introduction of newer medication for T2DM, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, which may produce more favorable effects on body weight and glycemic control in patients with overweight and obesity (64,65). In addition, the design of the included studies remained a limiting factor because of unavoidable difference in study protocols and definition of outcomes.…”