In this retrospective cohort study using US Medicare data, the authors compared the cardiovascular benefits and overall safety between SGLT2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors in people with type 2 diabetes and frailty. New users of any one of the study drug classes were stratified into three frailty classes (non-frail, pre-frail or frail) according to a validated claims-based frailty index (Kim et al, 2018).
The primary cardiovascular effectiveness outcome was time to the first occurrence of a composite of myocardial infarction, stroke, hospitalisation for heart failure (HHF) or all-cause mortality. The primary safety outcome was the first occurrence of a composite of lower-limb amputation, fracture, severe hypoglycaemia, acute kidney injury, diabetic ketoacidosis (DKA), severe genital or urinary tract infection, acute pancreatitis or a non-malignant biliary event.
SGLT2 inhibitors versus DPP-4 inhibitors
In 120 000 propensity-score-matched pairs, over a mean follow-up of 10.6 months, the incidence of the primary cardiovascular outcome was significantly lower with SGLT2 inhibitors (hazard ratio [HR] 0.72), driven by lower overall rates of myocardial infarction, HHF and all-cause mortality. Relative rate reductions were similar across the frailty strata; however, there were larger absolute rate reductions among frailer people receiving an SGLT2 inhibitor, with a number needed to treat (NNT) of 159, 66 and 39 in non-frail, pre-frail and frail participants, respectively.
The primary safety outcome was also reduced in SGLT2 inhibitor recipients (HR 0.81), driven by lower rates of acute kidney injury, hypoglycaemia, severe urinary tract infection and fracture compared with DPP-4 inhibitors. However, rates of DKA, genital infections and, concerningly, lower-limb amputations were higher with SGLT2 inhibitors. Again, relative rate reductions were similar between frailty classes, while absolute rate reductions were greater in those with pre-frailty and frailty.
GLP-1 RAs versus DPP-4 inhibitors
In 114 000 matched pairs, over a mean follow-up of 10.7 months, GLP-1 RAs were more effective at reducing the primary cardiovascular outcome (HR 0.74). GLP-1 RAs were associated with greater rate reductions – both absolute and relative – in frail and pre-frail participants. Rates of acute myocardial infarction, ischaemic stroke, HHF and all-cause mortality were reduced in particular. Frail participants had a greater absolute rate reduction in HHF and mortality in the GLP-1 RA group.
The safety outcome was reduced in GLP-1 RA recipients (HR 0.90), with reductions seen in non-frail and pre-frail participants, but with a neutral effect in frail participants. GLP-1 RA users had lower rates of acute kidney injury and hypoglycaemia, and there was no evidence for effect heterogeneity by frailty.
SGLT2 inhibitors versus GLP-1 RAs
In 90 000 matched pairs, over 9.6 months, SGLT2 inhibitors were associated with reduced risk of the primary cardiovascular outcome versus GLP-1 RAs (HR 0.92), driven by reductions in HHF. The largest absolute rate reduction in HHF occurred in frail participants.
The primary safety outcome was also reduced in SGLT2 inhibitor recipients, with no heterogeneity by frailty. Overall rates of acute kidney injury and hypoglycaemia were reduced, while DKA and genital infection rates were increased in SGLT2 inhibitor recipients.
The authors conclude that, compared with DPP-4 inhibitors, both SGLT2 inhibitors and GLP-1 RAs were associated with lower risk of cardiovascular events and death, without increasing the overall risk of adverse events, regardless of frailty status.