The benefits with GLP-1 RAs are most likely derived through the reduction of atherosclerosis-related events while SGLT-2is seem mostly to reduce heart failure-related events.
In primary prevention, SGLT-2i reduce both the risk of hospitalization for HF and progression of DKD; in secondary prevention, SGLT-2i are effective on the three endpoints, DPP-4i are neutral, while GLP1-RA show mixed results.
Five completed CVOTs with the GLP-1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk.
Glucagon-like peptide (GLP-1) is a naturally occurring incretin used as a promising therapeutic agent in the treatment of acute myocardial infarction, dilated cardiomyopathy, and advanced heart failure.
Several large randomized controlled trials (RCT) indicate that two classes of glucose-lowering medications, oral sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) and injectable glucagon-like peptide-1 receptor agonists (GLP-1RA), confer significant CV benefits, including reductions in: hospitalizations for heart failure (HF), progression of diabetic kidney disease, atherosclerotic CV events, and (with some agents) CV death.
SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82-0.95 and OR 0.87, 95% CI 0.82-0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61-0.77 and OR 0.87, 95% CI 0.82-0.93), and renal composite outcome (OR 0.59, 95% CI 0.52-0.67 and OR 0.86, 95% CI 0.78-0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69-0.90) and renal composite outcome (OR 0.69, 95% CI 0.59-0.80) more than GLP-1 RAs.
GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.
This meta-analysis demonstrated that GLP-1RAs were associated with a significant reduction in major adverse CV events, CV death, stroke and death from any cause, while DPP-4 inhibitors were comparable to placebo for all CV outcomes, including hospitalizations for heart failure.
In comparison, GLP-1 RA appear to preferentially reduce ischemic events (stroke or myocardial infarction) over hospitalization for heart failure, and demonstrated renoprotection in several of the CVOTs.
SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20).
Such CVOTs have demonstrated that the effects of the new antidiabetic drugs on the mutual interactions between T2DM and HF may develop across different phases:Results of such trials can be summarized as: (a) all different classes of novel glucose-lowering drugs have good cardiovascular safety profile; (b) with respect to HF, DPP4 inhibitors might tend to increase risk; (c) sodium-glucose co-transporter 2 inhibitors (SGTLi), significantly reduce it; (d) glucagon-like peptide 1 receptor agonists (GLP1) tend to be neutral.
Based on a large UK cohort in routine clinical practice, adding a GLP-1RA to insulin therapy is associated with a reduction in risk of composite CV events and all-cause mortality but a nonsignificant higher risk of hospitalization for heart failure in overweight patients with T2D.
Prior studies with DPP-IV inhibitors, thiazolidinediones (TZDs), and GLP-1 agonists have demonstrated either a neutral effect on HF or increased HF hospitalizations.
Current evidence suggests that SGLT-2 inhibitors are more effective than either GLP-1 agonists or DPP-4 inhibitors for reducing the risk of hospitalization for HF in type 2 diabetes mellitus.
Consequently, GLP-1 RA drugs in addition to conventional hypoglycemic therapy may reduce hospital admissions for heart failure worsening, by increasing CRTd responders rate.Trial registration NCT03282136.
During a 30 month period, the hazard ratio for heart failure admission to hospital associated with canagliflozin was 0.70 (95% confidence interval 0.54 to 0.92) versus a DPP-4i (n=17 667 pairs), 0.61 (0.47 to 0.78) versus a GLP-1RA (20 539), and 0.51 (0.38 to 0.67) versus a sulfonylurea (17 354 ).
GLP-1 RA actions not only translate on an improvement of well-known cardiovascular risk factors such as glycaemic control, dyslipidaemia, weight, or arterial hypertension but also might show benefits on endothelial function, coronary ischaemia, and heart failure.
After matching each GLP-1 analog user to a sulfonylurea user on the time-conditional propensity scores from prescription-based exposure sets, the hazard ratio of heart failure with GLP-1 use was 0.73 (95%CI: 0.57-0.93).
The GLP-1 agonist liraglutide was recently shown to reduce cardiovascular and all-cause mortality, yet hospitalization for HF was not significantly reduced.
However, no increased risk of hospitalization for HF has been reported with GLP-1RAs in meta-analyses of phase-II/III trials (exenatide, albiglutide, dulaglutide, liraglutide), demonstrating the safety of this pharmacological class, and such findings have been confirmed by three large prospective cardiovascular outcome trials (ELIXA with lixisenatide, LEADER with liraglutide and SUSTAIN-6 with semaglutide).