In patients 50 years with type 2 diabetes and CV disease or risk factors, dulaglutide reduced CV outcomes

Abstract

Question In patients 50 years of age with type 2 diabetes and previous cardiovascular (CV) disease or risk factors, does dulaglutide reduce risk for CV events? Methods Design Randomized placebo-controlled trial (Researching Cardiovascular Events with a Weekly Incretin in Diabetes [REWIND] trial). ClinicalTrials.gov NCT01394952. Allocation Concealed.* Blinding Blinded* (patients, {clinicians, data collectors, and outcome adjudicators}). Follow-up period Median 5.4 years. Setting 371 clinical centers in 24 countries. Patients 9901 adults 50 years of age (mean age 66 y, 54% men) who had type 2 diabetes mellitus, hemoglobin (Hb) A1c9.5% on stable doses of 2 oral glucose-lowering drugs (with or without basal insulin therapy), and body mass index 23 kg/m2, and completed a 3-week run-in period with 100% adherence to weekly placebo injections. Patients 50 years also had to have vascular disease. Patients 55 years had to have myocardial ischemia; coronary, carotid, or lower-extremity artery stenosis >50%; left ventricular hypertrophy; estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2; or albuminuria. Patients 60 years had to have 2 of tobacco use, dyslipidemia, hypertension, or abdominal obesity. Exclusion criteria included eGFR <15 mL/min/1.73 m2, plans for revascularization, a coronary or cerebrovascular event in the past 2 months, severe hypoglycemia in the past year, cancer in the past 5 years, or life expectancy <1 year. Intervention Subcutaneous dulaglutide, 1.5 mg once per week (n =4949), or placebo (n =4952), via preloaded syringes. Outcomes A composite of nonfatal myocardial infarction (MI), nonfatal stroke, or death from CV or unknown causes. Secondary outcomes included components of the primary composite outcome, fatal MI, fatal stroke, non-CV death, all-cause death, hospitalization for heart failure or urgent visit, hospitalization for unstable angina, microvascular eye outcomes (photocoagulation, antivascular endothelial growth factor therapy, or vitrectomy), microvascular renal outcomes (new macroalbuminuria, sustained decline in eGFR 30% from baseline, or long-term renal replacement therapy), study drug discontinuation, and adverse events. Patient follow-up 97% (intention-to-treat analysis). Main results The significant efficacy results are in the Table; groups did not differ for other outcomes. Conclusion In patients 50 years of age with type 2 diabetes and previous cardiovascular (CV) disease or risk factors, dulaglutide reduced risk for CV outcomes compared with placebo. Dulaglutide vs placebo in adults 50 y of age with type 2 diabetes and cardiovascular (CV) disease or risk factors Outcomes Events/100 person-y At a median 5.4 y Dulaglutide Placebo RRR (95% CI) NNT (CI) Primary composite 2.35 2.66 11% (1 to 20) 67 (38 to 803) Nonfatal stroke 0.52 0.69 24% (5 to 39) 121 (75 to 582) Microvascular renal outcome 3.47 4.07 14% (6 to 21) 38 (25 to 81) Abbreviations defined in Glossary. RRR, NNT, and CI calculated from placebo event rates and hazard ratios in article. Nonfatal myocardial infarction (4.1% vs 4.3%; hazard ratio [HR] 0.96, CI 0.79 to 1.16), nonfatal stroke, or death from CV or unknown causes (6.4% vs 7.0%; HR 0.91, CI 0.78 to 1.06). New macroalbuminuria, sustained decline in estimated glomerular filtration rate 30% from baseline, or long-term renal replacement therapy. Commentary The REWIND, PIONEER 6, and PIONEER 4 trials provide evidence for benefits of GLP-1RAs for treating type 2 diabetes. GLP-1RAs have several benefits beyond glucose lowering, such as weight loss and negligible hypoglycemia risk, which make them an attractive treatment option for patients with type 2 diabetes. With results from REWIND, we now have evidence that 3 GLP-1RAs on the market are also associated with CV benefit in patients with, or at high risk for, CV disease (1, 2). Liraglutide was the first GLP-1RA shown to reduce risk for CV events in a population of whom the majority had CV disease and high CV risk (4-y placebo event rate 15%) (1). A subsequent trial showed that subcutaneous semaglutide reduced risk for CV events in a lower-risk population (4-y placebo event rate 8.9%) (2), and its weekly administration offered greater convenience than daily liraglutide for some patients. The REWIND trial showed that another weekly GLP-1RA, dulaglutide, reduced risk for major CV events in patients at substantially lower CV risk than in other trialsonly 32% of patients had CV disease, and the 5-year placebo event rate was 2.7%. These findings suggest that the CV benefits of GLP-1RAs probably extend to patients with type 2 diabetes and CV risk factors, rather than only patients with CV disease. As with the CV benefits of some SGLT2 inhibitors (3, 4), the CV benefits of GLP-1RAs are probably not a result of glucose lowering alone (5). Both GLP-1RAs and SGLT2 inhibitors have beneficial effects on weight and blood pressure, and GLP-1RAs may also improve endothelial function, endothelial cell responses to ischemia, and platelet function (6). All approved GLP-1RAs are administered by subcutaneous injection, which, along with cost and gastrointestinal side effects, remains a barrier to their use. However, evidence is accumulating for the safety and efficacy of oral semaglutide, the first orally administered GLP-1RA. It has been shown to be superior to the commonly used oral medication, sitagliptin, for HbA1c and weight reduction (7). Results of PIONEER 6 provide evidence of the CV safety of oral semaglutide. Patients who received oral semaglutide had nonsignificantly lower rates of CV events and death than placebo-treated patients, with relative risk reductions comparable to those of REWIND and other GLP-1RA trials (1, 2). Although noninferiority was confirmed, statistically significant CV superiority was not shown. Because the trial was designed to test for noninferiority, its short duration (16 mo) and low number of events probably limited the power to determine a CV benefit of oral semaglutide. PIONEER 4 was the first trial to directly compare oral semaglutide with another GLP-1RA. Compared with liraglutide, the most commonly used GLP-1RA, oral semaglutide showed a similar reduction in HbA1c and, surprisingly, greater weight loss. Gastrointestinal side effects and discontinuation rates were similar between the 2 treatments, making oral semaglutideonce it is approveda comparably effective and tolerable GLP-1RA option for patients wanting to avoid injections. That it must be taken daily on an empty stomach with half a glass of water 30 minutes before food intake may be cumbersome for some patients, who may favor the convenience of weekly subcutaneous semaglutide or dulaglutide. Patients at higher CV risk may also prefer the weekly options due to their proven CV benefit. The results of these trials add to the growing evidence regarding GLP-1RA treatment to help guide treatment decisions. These results further endorse the CV benefits of GLP-1RAs in lower-risk populations and provide support for oral semaglutide as a promising alternative to current subcutaneously administered agents. Whether oral semaglutide has comparable CV-lowering benefits to subcutaneous GLP-1RAs remains to be confirmed.