Conference Coverage

GLP-1 RA dulaglutide yields cardiac gains, even in non–at-risk patients



– A large, long-term study is linking yet another glucagon-like peptide–1 receptor agonist diabetes drug to positive cardiovascular outcomes: Patients with type 2 diabetes and heart disease risk factors who took dulaglutide for about 5 years during the REWIND study had a 12% lower risk of major adverse cardiovascular events, compared with those who took placebo.

These new findings on cardiac risk are unusual compared with other newer-generation diabetes drugs, because a high percentage of the participants did not have existing cardiovascular disease. In addition, the study population had a higher percentage of women, compared with previous studies.

“We feel very strongly that the participants were similar to the ... ambulatory patients with type 2 diabetes with cardiovascular risk who are routinely seen in clinical practice,” study coauthor Jeffrey L. Probstfield, MD, of the University of Washington, Seattle, saidin a presentation at the annual scientific sessions of the American Diabetes Association. The findings were published simultaneously in The Lancet (2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.

Dulaglutide’s serious adverse-effect profile was similar to that of placebo, the study authors noted, and the drug also showed benefits in renal outcomes, as reported in a separate study (Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31150-3.

The Food and Drug Administration has mandated that six glucagon-like peptide–1 receptor agonists (GLP-1 RAs) – albiglutide (Tanzeum), exenatide (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), semaglutide (Ozempic) and dulaglutide (Trulicity) – undergo testing of cardiovascular outcomes. Dulaglutide is the fourth, following albiglutide, liraglutide, and semaglutide, to show consistent, statistically significant reduction in major adverse cardiovascular events (MACE).

For the double-blind, randomized, placebo-controlled REWIND study, researchers recruited 9,901 participants who were at least 50 years old with type 2 diabetes, a hemoglobin A1c (HbA1c) level of 9.5% or less, and a body mass index of more than 23 kg/m2. The participants came from 371 sites in 24 countries, including the United States and Canada. More than 80% were taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and other blood pressure drugs were also common.

The average mean age was 66 years; 46% of the participants were women, three-quarters were white, and 31% had previous cardiovascular disease. Previous GLP-1 RA studies of this type had markedly lower percentages of women – the other studies comprised 30%-39% women – and included higher percentages of participants with previous cardiovascular disease (73%-100%).

Of the participants in the current study, 4,949 were assigned to receive dulaglutide and 4,952 to receive placebo. They were followed for a median 5.4 years. About 57% never stopped using the drug, and 11% of those in the drug group and 7.5% in the placebo group stopped use because of adverse effects.

In regard to diabetes outcomes, HbA1c levels fell in the drug group by a mean –0.61% (95% confidence interval, –0.65 to –0.58; P less than .0001), compared with placebo. Their weight decreased by a mean –1.5 kg (95% CI, -1.7 to -1.3; P less than .0001) Systolic blood pressure and LDL cholesterol levels were slightly lower in the drug group, but heart rate was higher.

On the heart front, MACE fell by 12% in the drug group, compared with placebo (hazard ratio, 0.88; 95% CI, 0.79-0.99; P = .026). “The effect of the intervention begins [within] the first year and continued in a progressive, proportional fashion throughout the follow-up period,” said study lead author Hertzel C. Gerstein, MD, of McMaster University and Hamilton Health Sciences, Hamilton, Ont.

Dr. Hertzel C. Gerstein, McMaster University, Hamilton, Ont.

Dr. Hertzel C. Gerstein

There was an especially large decline in the number of nonfatal stroke cases in the drug group, compared with placebo (135 vs. 175, respectively; HR, 0.76; 95% CI, 0.61-0.95; P = .017). The drug did not have a statistically significant effect on cardiovascular death.

The researchers found no difference in the drug’s effects on MACE in subgroups including age, gender, ethnicity, duration of diabetes, and history of cardiovascular disease.

They also reported a decline in a renal composite outcome (first macroalbuminuria, sustained decline in estimated glomerular filtration rate of 30% or more, chronic renal replacement) in the drug group (HR, 0.85; 95% CI, 0.77-0.93; P = .0004).

Rates of serious adverse effects were similar in the drug and placebo groups. Gastrointestinal adverse effects – including nausea, constipation, and diarrhea – were as expected, Dr. Gerstein said.

“The addition of dulaglutide could be considered for both primary and secondary cardiovascular prevention in middle-aged patients with type 2 diabetes and cardiovascular risk factors,” Dr. Gerstein said.

In an independent commentary at the meeting presentation, Sophia Zoungas, MBBS (Hons), FRCP, PhD, of Monash University, Melbourne, praised the study and applauded the findings.

Dr. Sophia Zoungas, Monash University, Melbourne

Dr. Sophia Zoungas

However, she called attention to the results that pinpointed higher levels of microvascular-related eye outcomes (HR, 1.24; 95% CI, 0.92-1.68) and fatal myocardial infarction (HR, 1.29; 95% CI, 0.72-2.30) in the dulaglutide group. Both of those outcomes were rare – 171 eye outcomes and 46 fatal myocardial infarctions overall. She also questioned whether the adherence rates would be as high in a real-world setting.

Eli Lilly funded the study. Three of the authors were employees of Eli Lilly, eight reported financial relationships with the company, five reported financial relationships with other firms, and the remaining authors reported no competing interests.

SOURCE: Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.

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