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SAN FRANCISCO -- The GLP-1 receptor agonist dulaglutide (Trulicity) helped to reduce heart events in adults with type 2 diabetes, according to the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial.

Among nearly 10,000 participants, those who received a weekly injection of 1.5 mg of dulaglutide had a 12% reduced risk for experiencing the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes compared with those in the placebo group (HR 0.88, 95% CI 0.79-0.99, P=0.026), reported Hertzel Gerstein, MD, of McMaster University in Ontario, Canada, and colleagues.

Overall, only 12% of those on dulaglutide experienced the composite heart endpoint compared with 13.4% of the placebo group.

The findings were reported at the annual meeting of the American Diabetes Association and simultaneously published in .

In recent years, three other GLP-1 RA's -- liraglutide (Victoza), semaglutide (Ozempic), and albiglutide (Tanzeum) -- as well as a few SGLT-2 inhibitors -- empagliflozin (Jardiance), canagliflozin (Invokana), and dapagliflozin (Farxiga) -- have all shown a significant risk reduction in cardiovascular events in adults with type 2 diabetes, suggesting possible class effects with these drugs.

The , which took place across 471 sites throughout 24 counties, included 9,901 adults with either diagnosed or newly diagnosed type 2 diabetes with an HbA1c of 9.5% or less. Individuals with a body-mass index of less than 23 were excluded from the study. All adults also had to be on at least two oral glucose lowering agents with or without basal insulin.

These participants were also at risk for heart events, as those ages 50 and older had to have vascular disease, and individuals ages 55 and older had to have had myocardial ischemia; coronary, carotid, or lower extremity artery stenosis over 50%; left ventricular hypertrophy; chronic kidney disease; or albuminuria. With an average age of the cohort of 66 years, participants ages 60 and older had to check off as having at least two of the following: tobacco use, dyslipidemia, hypertension, or abdominal obesity.

During the median 5.4 years of follow-up, individuals were instructed to inject themselves at the same time every day and continue their other medication regimen, and they underwent follow-ups every 6 months for cardiovascular events.

The significant risk reduction in the composite endpoint seen with dulaglutide was mainly driven by a drop in nonfatal stroke risk, as the risk reduction for cardiovascular death and nonfatal myocardial infarction was not significantly different between dulaglutide and placebo:

• Nonfatal stroke: HR 0.76 (95% CI 0.61-0.95, P=0.017)

• Nonfatal myocardial infarction: HR 0.96 (95% CI 0.79-1.16, P=0.65)

• Cardiovascular death: HR 0.91 (95% CI 0.78-1.06, P=0.21)

As for other outcomes, all-cause death, heart failure, or urgent visit or hospital admissions for unstable angina, cholelithiasis, or fractures was not significantly different between the groups.

However, a composite secondary outcome for microvascular events -- including eye and renal outcomes -- was significantly lower in the dulaglutide group (18.4% vs 20.6%; HR 0.87, 95% CI 0.79-0.95, P=0.002). This was mainly driven by a 15% reduction in renal events, which included a composite outcome of the first occurrence of new macroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30% or more from baseline, or chronic renal replacement therapy, as follows:

• Eye outcome: HR 1.24 (95% CI 0.92-1.68, P=0.16)

• Renal outcome: HR 0.85 (95% CI 0.77-0.93, P=0.0004)

Although the rate of serious adverse events did not differ between the groups, significantly more patients on dulaglutide had gastrointestinal events (47.4% vs 34.1%), Gerstein and co-authors reported.

In an -- titled "Is it time to REWIND the cardiorenal clock in diabetes?" -- Subodh Verma, MD, PhD, of St. Michael's Hospital in Toronto, and colleagues praised several aspects of the trial, including that REWIND had the largest cohort, the longest follow-up period of a GLP-1 RA cardiovascular outcomes trial, the largest inclusion of female participants, and that the participants were not at a particularly high risk for cardiovascular events at baseline.

"The magnitude of benefit on the composite cardiovascular outcome (12%) was modest, and numerically lower than that seen in the positive GLP-1 receptor agonist studies -- namely, LEADER, SUSTAIN-6, and Harmony Outcomes -- but was consistent with the overall effect size from a meta-analysis of all previous GLP-1 receptor agonist trials," Verma and co-authors explained, adding that this stroke risk reduction was similar to that of semaglutide.

"Although SGLT2 inhibitors and GLP-1 receptor agonists are recommended in patients with established atherosclerotic vascular disease, we now have evidence from the DECLARE-TIMI 58 and REWIND trials that SGLT2 inhibitors and GLP-1 receptor agonists afford cardiovascular 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," Verma, et al. concluded.