Once-Weekly Dulaglutide Benefit in REWIND, Longest CVOT to Date

Becky McCall

June 10, 2019

SAN FRANCISCO — The once-weekly injectable glucagon-like peptide-1 (GLP-1) agonist dulaglutide (Trulicity, Lilly) for the treatment of type 2 diabetes has significantly reduced the risk of major adverse cardiovascular events (MACE) in the REWIND cardiovascular (CV) outcomes trial, primarily by reducing the risk of stroke. 

After top-line results were released late last year, the full data were presented here at the American Diabetes Association (ADA) 2019 Scientific Sessions by study chair Hertzel Gerstein, MD, professor of medicine at McMaster University and Hamilton Health Sciences, Ontario, Canada, and simultaneously published in the Lancet, alongside an exploratory analysis on renal outcomes.

"The REWIND trial was an ambitious study that conclusively assessed the effects of dulaglutide on people with type 2 diabetes both with and without prior cardiovascular disease (CVD)," said Gerstein. "The reduction in CV events observed in a wide range of people with diabetes regardless of sex, baseline CVD, age, or HbA1c level is compelling," he added.

REWIND Adds to Body of Evidence on GLP-1 Agonists

In an accompanying editorial, also published in the Lancet, Subodh Verma, MD, PhD, David Mazer, MD, and Vlado Perkovic, MD, all from the University of Toronto, Ontario, Canada, write: "The magnitude of benefit on the composite CV outcome (12%) was modest and numerically lower than that seen in the positive GLP-1 agonist studies — namely, LEADER, SUSTAIN-6, and HARMONY — but consistent with the overall effect size from a meta-analysis of all previous GLP-1 receptor agonist trials."

But they highlight the fact that the population studied in REWIND does differ somewhat.

"Compared with previous studies of GLP-1 receptor agonists, individuals included in the REWIND trial were at a lower risk of CV events."

"The study enrolled the largest primary prevention cohort as far as we are aware, thus far, and showed no heterogeneity in efficacy relative to those with established atherosclerotic vascular disease."

And "the REWIND trial, to our knowledge, had the longest follow-up (5.4 years), highest proportion of women (46%), and lowest baseline median HbA1c (7.2%), as well as showing efficacy over and above excellent background therapy, which, similar to other GLP-1 receptor agonist studies, was independent of baseline glycemia, duration of diabetes, and weight," they observe.

Sophia Zoungas, MD, from Monash University, Melbourne, Australia, who was the independent commentator on the REWIND results at the conference, said: "REWIND adds to and extends the body of evidence that intermediate- or long-acting GLP-1 receptor agonists, in particular dulaglutide, are superior to standard of care for MACE including in people with CV risk factors."

"There is a mild suggestion that we don't see the benefits in myocardial infarction in primary prevention as we have observed in the established secondary prevention CV outcome trials, and this might need further analysis," Zoungas pointed out.

Indeed, say Varma, Mazer and Perkovic: "The primary outcome seemed to be driven largely by a reduction in stroke; a trend that was also observed with semaglutide in SUSTAIN-6."

Move Metformin Aside? Combine GLP-1 Agonists and SGLT2 Inhibitors?

Zoungas continued by saying, "We prioritize therapy [in type 2 diabetes] based on established CVD, comorbidities, and other important parameters, but now guidelines may change further to prioritize treatment based on CV risk factors, and we possibly need recommendations that atherosclerotic CVD or CV risk factors need an intermediate- or long-acting GLP-1 receptor with proven CV benefit."

And in the future, she said, "We might want to look at whether GLP-1 receptor agonists with proven CV benefits should be used first-line with lifestyle interventions and move metformin aside."

"Also, is there added benefit by combining CV benefit agents — so GLP-1 agonists with SGLT2 inhibitors [for example] — and if so, in which populations? Are these GLP-1 agonists truly disease modifying?"

Varma, Mazer, and Perkovic have similar thoughts: "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."

REWIND Population Representative of Clinical Practice

The REWIND study was designed to assess whether dulaglutide is safe in terms of CV outcomes when added to the existing diabetes drug regimen of the participants, who all had type 2 diabetes, as per the 2008 guidance of the US Food and Drug Administration.

Only 31% of participants had established CVD and, along with the average age of patients of 66 years, the population is representative of patients seen in clinical practice, the researchers emphasized.

Conducted across 24 countries, the multicenter, randomized, double-blind, placebo-controlled trial involved 9901 adults with a mean duration of diabetes of 10.5 years.

Participants were randomly assigned (1:1) to a weekly subcutaneous injection of dulaglutide (1.5 mg) or placebo, in addition to their other diabetes medication, and followed-up at least every 6 months for incident CV and other serious clinical outcomes.

The primary outcome was the first occurrence of the composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or death from CV causes (including unknown causes), which was assessed in the intention-to-treat population.

Secondary outcomes comprised each component of the primary composite CV outcome, a composite clinical microvascular outcome including retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality.

The primary composite outcome occurred in 594 patients (12.0%) in the dulaglutide group and in 663 patients (13.4%) in the placebo group, for a risk reduction of 0.88 (95% CI, 0.79 - 0.99; P = .026), which was consistent across subgroups, reported Gerstein.

All three components of the MACE primary endpoint showed a significant reduction with dulaglutide compared to placebo including CV death (HR, 0.91; 95% CI, 0.78 - 1.06) and nonfatal heart attack (HR, 0.96; 95% CI, 0.79 - 1.16), with the strongest effect seen in nonfatal stroke (HR, 0.76; 95% CI, 0.61 - 0.95).

No difference was seen between groups in hospital admission for heart failure. 

Dulaglutide was also found to modestly reduce weight by around 1.5 kg (P = .0001) and systolic blood pressure by 1.7 mmHg (P = .0001).

Adverse events for dulaglutide were consistent with the GLP-1 receptor agonist class — gastrointestinal adverse events occurred in 47.4% of dulaglutide patients compared with 34.1% of placebo patients (P < .0001). But the incidence of serious gastrointestinal adverse events was the same in both groups (2.4%), reported Gerstein.

Renal Outcomes in REWIND

Helen Colhoun, MD, University of Edinburgh, UK, presented the exploratory analysis of renal outcomes from REWIND, which was published as a separate article in the Lancet.

Renal outcomes were secondary endpoints of REWIND and consisted of a composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (urinary albumin-to-creatinine ratio > 33.9 mg/mmol), a sustained decline in estimated glomerular filtration rate of ≥ 30% from baseline, or chronic renal replacement therapy.

The composite microvascular outcome occurred in 17.1% of participants in the dulaglutide group and 19.6% of those in the placebo group (HR, 0.85; 95% CI, 0.77 - 0.93; P = .0004), reported Colhoun.

"These analyses suggest that use of dulaglutide to lower glucose concentrations in people with type 2 diabetes is likely to confer additional renal benefits," say the authors of the renal analysis.

"There was no significant difference in renal adverse events between groups, with a hazard ratio of 0.9 [P = .46]," Colhoun added.

Putting Findings in Context: REWIND the Cardiorenal Clock in Diabetes?

Five previous CV outcomes trials have been conducted for GLP-1 agonists:  lixisenatide (ELIXA; n = 6068), albiglutide (HARMONY Outcomes; n = 9463), liraglutide (LEADER; n = 9340), injectable semaglutide (SUSTAIN-6; n = 3297), and long-acting exenatide (EXSCEL; n = 14,752).

Participants in these trials either all had previous CVD (ELIXA and HARMONY Outcomes) or the vast majority did, ranging from 73% to 83% (LEADER, SUSTAIN-6, and EXSCEL). Follow-up in these trials ranged from 1.6 to 3.8 years.

Three of these studies have been positive — namely, LEADER, SUSTAIN-6, and HARMONY, with hazard ratios for the primary CV outcomes of 0.87 with liraglutide in LEADER, 0.74 with semaglutide in SUSTAIN-6, and 0.78 with albiglutide in HARMONY.

The results suggested that GLP-1 agonists might only reduce CV outcomes in people with type 2 diabetes and previous CVD.

But now REWIND provides evidence that this is also the case in a primary prevention population.

As observed by Varma, Mazer, and Perkovic: "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."

Based on these final results, Gerstein and coauthors point out that "dulaglutide could be considered for the management of glycemic control in middle-aged and older people with type 2 diabetes with either previous CVD or CV risk factors."

Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk, and Sanofi; speakers honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, Kowa, and Cirius. Colhoun reports research grants from Eli Lilly, AstraZeneca, Regeneron, Pfizer, Roche, Sanofi, and Novo Nordisk; speakers honoraria from Eli Lilly and Regeneron; consulting fees from Eli Lilly, Novartis, Regeneron, Sanofi, and Novo Nordisk; and shares in Bayer and Roche. Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and Valeant, and is also the president of the Canadian Medical and Surgical Knowledge Translation Research Group. He has received honoraria from Amgen, Boehringer Ingelheim, and Octapharma. Perkovic receives research support from the Australian National Health and Medical Research Council, serves on steering committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer; and serves on advisory boards or has spoken at scientific meetings for AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier, Tricida, Vifor, and Vitae. Zoungas reports advisory boards and educational meetings for AstraZeneca, Boehringer-Ingelheim, MSD, Novo Nordisk, and Sanofi.

ADA 2019 Scientific Sessions. Presented June 9, 2019.

Lancet. Published online June 9, 2019. Main results, Exploratory analysis, Editorial

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