Dulaglutide reduces cardiorenal risk in a broad range of T2D patients
Once-weekly subcutaneous injections of dulaglutide in patients with type 2 diabetes (T2D) reduced cardiovascular (CV) events, particularly non-fatal stroke, regardless of their CV history in the longest cardiovascular outcomes trial (CVOT) to date for a GLP-1* receptor agonist, REWIND**. The CV benefits come with potential renal benefits, with the largest effect seen for macroalbuminuria in an exploratory analysis.
This confirms dulaglutide safety with respect to cardiorenal outcomes, independent of glucose lowering.
During a median follow-up of 5.4 years, the primary outcome (first occurrence of the composite of non-fatal myocardial infarction [MI], non-fatal stroke, or death from CV or unknown causes) occurred in 12 percent of patients in the dulaglutide arm (incidence rate, 2.4 per 100 person-years) vs 13.4 percent of those in the placebo arm (incidence rate, 2.7 per 100 person-years), for a hazard ratio (HR) of 0.88 (95 percent confidence interval [CI], 0.79-0.99; p=0.026). [Lancet 2019; doi.org/10.106/S0140-6736(19)31149-3]
Effect consistent across all components of the composite outcome
“The effect of the intervention begins before the first year, and continues in a progressive, proportional fashion throughout the full follow-up period of over 5 years,” said lead author Dr Hertzel Gerstein from the McMaster University and Hamilton Health Sciences in Ontario, Canada, at ADA 2019. As for the individual components of the primary outcomes, there was no discernible effect on non-fatal MI (HR, 0.96), with a neutral effect for CV death (HR, 0.91), and a 24-percent reduction (HR, 0.76) in non-fatal stroke with dulaglutide.
For every 60 patients with T2D and CV risk factors treated with dulaglutide, one CV event was prevented. No between-group differences were seen for all-cause mortality.
“Adding dulaglutide [to baseline antidiabetic regimens] safely reduces CV outcomes in middle-aged and older patients who are similar to those seen in community practice and with a broad range of glycaemic control,” said Gerstein. “The reduction in CV events observed in a wide range of patients with diabetes regardless of sex, baseline CVD, age, or HbA1c level is compelling.”
Renal outcome clearest for macroalbuminuria
From a renal perspective, the composite outcome of the first occurrence of new macroalbuminuria, a sustained decline in eGFR of ≥30 percent from baseline, or chronic renal replacement therapy, as evaluated in the exploratory analysis, occurred in 17.1 percent of patients in the dulaglutide arm (incidence rate, 3.5 per 100 person-years) and in 19.6 percent of those in the placebo arm (4.1 per 100 person-years) for an HR of 0.85 (95 percent CI, 0.77–0.93; p=0.0004). The clearest effect was for new macroalbuminuria (HR, 0.77; p<0.0001), with HRs of 0.89 (p=0.066) for a sustained decline in eGFR of ≥30 percent and 0.75 (p=0.39) for chronic replacement therapy.
Similar effects of dulaglutide were observed in subgroups defined by eGFR***, baseline albuminuria, and use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). These were true for subgroups defined by age, sex, duration of diabetes, and HBA1c.
In the sensitivity analysis of renal effect, dulaglutide was associated with a reduced incidence of a sustained eGFR decline of ≥40 percent (HR, 0.70; p=0.0004) and ≥50 percent (HR, 056; p=0.0002), with corresponding HRs of 0.76 and 0.74 for the respective composite renal outcomes.
Largest primary prevention cohort in CVOT
REWIND included 9,901 patients (mean age 66 years, 46 percent women,) with a mean duration of diabetes of 10.5 years, inadequate glycaemic control, and an eGFR of at least 15mL/min per 1.73m2, randomized to dulaglutide 1.5 mg once weekly (n=4,949) or placebo (n=4952), in addition to baseline antihyperglycaemic regimens. It is the first major CVOT for an antidiabetes therapy to include a large primary prevention cohort, said Gerstein. “Only 31.5 percent of participants had prior CVD, making REWIND the largest primary prevention cohort in a CVOT with a GLP-1 receptor agonist.”
Risk reduction was comparable in both the primary prevention and secondary prevention cohorts (with atherosclerotic vascular disease with or without a history of MI or ischaemic stroke). Dulaglutide therapy also modestly reduced HbA1c by 0.6 percent, weight by 1.5 kg, systolic blood pressure (BP) by 1.7 mm Hg, and similarly reduced kidney disease. There was a slight increase in heart rate but was well tolerated.
Dulaglutide could then be considered for both primary and secondary CV prevention in middle-aged patients with T2D and CV risk factors, said Gerstein. The C V benefit, plus the potential renal benefit, provides yet additional reasons to use dulaglutide across a broad spectrum of patients with T2D.
‘Superior to standard of care’
“REWIND adds to and extends the growing body of evidence that intermediate- or long-acting GLP-1 receptor agonists, in this case dulaglutide, is superior to standard care for the three-point MACE+, even in people with CV risk factors,” said independent commentator for the REWIND findings Dr Sophia Zoungas from the Monash University in Melbourne, Australia. “There are going to be numerous potential mechanisms of action beyond glucose, BP and weight effects, and we look forward to those mechanistic studies to understand better the role of inflammation, endothelial function, and other CV protective effects.”
How does dulaglutide fare against other GLPs?
The magnitude of MACE reduction with dulaglutide in REWIND, though numerically lower (12 percent) than those seen in other GLP-1 studies [13 percent in LEADER, 26 percent in SUSTAIN 6, and 22 percent in Harmony Outcomes], was consistent with the overall effect size observed in other GLP-1 receptor agonist CVOT trials, said Dr Subohd Verma and colleagues from the University of Toronto, Ontario, Canada, in an accompanying commentary. A likely difference was that patients in the REWIND trial were at a lower risk of CV events. [Lancet 2019;doi:org/10.1016/S0140-6736(19)31267-X]
“We now have evidence from the DECLARE-TIMI 58 and REWIND trials that SGLT2 inhibitors and GLP-1 receptor agonists afford CV superiority even in primary prevention; with SGLT2 inhibitors preventing heart failure and GLP-1 receptor agonists preventing atherosclerotic events, and both potentially affording renal protection,” said Verma et al. “If we are to reduce the burgeoning pump, pipes, and filter complications of diabetes, we will need to overcome clinical inertia, and embrace these disease-modifying therapies early, and preferably, in combination. The REWIND trial makes a strong case in this regard.”