CV efficacy, safety of GLP-1 receptor agonists a class effect
The cardiovascular (CV) efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists in type 2 diabetes (T2D) appear to be a class effect, according to a systematic review and meta-analysis of four major GLP-1 CV safety trials.
“Overall, this meta-analysis shows a consistent finding of [CV] safety across all GLP-1 receptor agonist drugs evaluated and suggests that this class of glucose-lowering drugs seems to reduce three-point [major adverse CV events (MACE)], CV mortality, and all-cause mortality, albeit with possible differences between individual drugs reflected in the individual trial results,” said the researchers.
“The capacity of … GLP-1 receptor agonist[s] to reduce MACE in patients with T2D at moderate-to-high CV risk and to do so without detrimental effects on other safety parameters represents a major therapeutic advance,” they said.
Using data from the ELIXA*, LEADER**, SUSTAIN 6***, and EXSCEL# trials, researchers assessed the CV efficacy and safety of lixisenatide (≤20 µg QD), liraglutide (1.8 mg QD), semaglutide (0.5 or 1.0 mg QW), and extended-release exenatide (2 mg QW) vs placebo in 33,457 adult patients with T2D.
Patients on GLP-1 receptor agonists demonstrated a significant reduction in the relative risk of three-point MACE namely CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke compared with those on placebo (hazard ratio [HR], 0.90, 95 percent confidence interval [CI], 0.82–0.99; p=0.033). [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30412-6; IDF 2017, abstract 293]
The risk reduction remained significant with regards to CV mortality (HR, 0.87, 95 percent CI, 0.79–0.96; p=0.007) and all-cause mortality (HR, 0.88, 95 percent CI, 0.81–0.95; p=0.002), while there was no impact on fatal or nonfatal MI (HR, 0.94; p=0.18), fatal or nonfatal stroke (HR, 0.87; p=0.052), or hospitalization for unstable angina or heart failure (HR, 1.09; p=0.39 and HR, 0.93; p=0.20, respectively).
“[The study findings] … lend support to the hypothesis that the CV effects of GLP-1 receptor agonists might be mediated via antiatherogenic mechanisms that decrease CV risk over time. These mechanisms might include direct and indirect effects of GLP-1 receptor agonists on common CV risk factors, anti-inflammatory pathways, cardiac output, ischaemic conditioning, and endothelial function,” said the researchers.
They acknowledged that use of aggregate as opposed to patient-level data limited the ability to examine other subgroups, while the short follow-up period (2–4 years) did not allow for discernment of potential outcomes with longer term use.
Promising CV safety
There was also little difference between patients on GLP-1 receptor agonists and placebo in terms of the safety outcomes analysed, ie, the incidence of severe hypoglycaemia (odds ratio [OR], 0.93; p=0.56), pancreatitis (OR, 0.90; p=0.54), or pancreatic cancer (OR, 0.83; p=0.70), though there was significant between-trial heterogeneity with regards to pancreatic cancer and severe hypoglycaemia incidence.
According to the researchers, the definitions of severe hypoglycaemia varied slightly between trials as did the management of concomitant antihyperglycaemic treatment, factors that could have potentially affected severe hypoglycaemia rates. The reasons for the discordance in pancreatic cancer incidence is unknown, though the researchers did not rule out a chance finding.
Trial heterogeneity suggests a per-patient approach
The findings of these individual trials have been varied, thus raising “important questions about the generalizability of GLP-1 receptor agonist trials to the drug class as a whole”, said the researchers.
“[A]lthough there were differences between individual drugs with respect to their effect on CV outcomes in the separate trials, [o]verall, these data show a favourable risk-benefit profile for GLP-1 receptor agonists,” they said, suggesting that the choice of drug for each patient should be evidence-based and take into consideration factors such as convenience, tolerability, and price.
Professor Simeon Taylor from the University of Maryland School of Medicine, Baltimore, Maryland, US, agreed. “[T]here is considerable inter-individual variation with respect to the magnitude of clinical benefit, suggesting that a personalized medicine strategy might enable physicians to select the best drug for each patient,” he said in a commentary, emphasizing the stronger risk reduction observed with liraglutide and extended-release exenatide on obese compared with non-obese patients. [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30413-8]
“Future research will be necessary to clarify how BMI or other clinical criteria should be taken into account when predicting the magnitude of clinical benefit likely to be provided by specific drugs used for the treatment of T2D,” he said.