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REWIND – Let’s Review

Dulaglutide, a Glucagon-Like-Peptide-1 Receptor Agonist, and Cardiovascular Outcomes

Kennedy Swanson-Moore, Pharm.D. Candidate 2020

Amanda Stahnke, Pharm.D., BCACP

Glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) work by stimulating insulin release from glucagon-like-peptide 1 receptors on pancreatic beta cells, slowing gastric emptying, reducing glucagon release and increasing satiety.¹ A 1.5% reduction in hemoglobin A1c (HbA1c) is typically seen with these agents. Prior to June 2019, the only GLP-1 RAs shown to improve cardiovascular (CV) outcomes were liraglutide (Victoza) and semaglutide (Ozempic). In the LEADER trial, liraglutide demonstrated a lower rate of the primary composite outcome (death from CV causes, non-fatal myocardial infarction (MI), or non-fatal stroke) among patients with type 2 diabetes mellitus (T2DM) and CV disease or those at high risk for CV events compared to placebo (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.78-0.97; p < 0.001 for noninferiority; p = 0.01 for superiority).²  Of note, secondary outcomes individually of non-fatal MI and non-fatal stroke did not reach significance, but were numerically lower in the liraglutide group.² Semaglutide also demonstrated a lower rate of the primary composite outcome of CV death, non-fatal MI, or non-fatal stroke in patients with T2DM with CV disease or at high risk of CV events compared to placebo (HR 0.74; 95% CI 0.58-0.95; p < 0.001 for noninferiority; p = 0.02 for superiority-post hoc) in the SUSTAIN-6 trial, though this difference was driven primarily by non-fatal stroke.³

The most recent GLP-1 RA CV outcome trial published was Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND). The purpose of this trial was to test if the addition of dulaglutide (Trulicity) to current antihyperglycemic medication regimens would safely reduce the incidence of CV events in middle-aged or older patients with T2DM compared to placebo. The study design was a multicenter, randomized, double-blind, placebo-controlled, phase-3 superiority trial. The primary composite outcome was first occurrence of non-fatal MI, non-fatal stroke, and death from CV causes or unknown causes. Secondary outcomes included composite microvascular outcomes (eye and renal outcomes), hospital admission for heart failure (HF) or urgent care visit, and hospital admission for unstable angina.⁴  

An initial 3-week long, single-blind, run-in period, where all patients received placebo was completed, during which patients were able to remain on their antihyperglycemic therapy as long as that did not include a dipeptidyl-peptidase-4 inhibitor (DPP4-I) or other GLP-1 RAs. For those patients who were taking a DPP4-I or GLP-1 RA, the agent was discontinued at the start of the run-in period.  Once 100% adherence was confirmed after the run-in period, the patients who still met criteria were then randomly assigned to two treatment groups. One group received weekly dulaglutide 1.5mg subcutaneous injections and the second group received an identically matched placebo injection. Patients were then screened at 2 weeks, 3 months and 6 months then every 3 months thereafter for drug dispensing and at 6-month intervals for a detailed assessment of CV event occurrence, adverse drug reactions, vital signs, lab tests, electrocardiography and questionnaires.⁴

The study analyzed all efficacy and safety outcomes using the intent-to-treat population, which included all randomly assigned patients. Kaplan-Meier estimates and Cox proportional hazard models were utilized for statistical analysis. At least 9600 participants and 1200 primary outcomes were needed to provide 90% power to detect a HR < 0.82 or 80% power to detect a HR < 0.85. Overall, 9901 patients were randomly assigned after the run-in period, 4,949 patients in the dulaglutide group and 4,952 patients in the placebo group. Baseline characteristics were similar between both groups. The mean age was 66.2 years, females represented 46% of the study population, the median HbA1c was 7.2%, and one-third of patients had previous CV disease. The median duration of T2DM was 9.5 years and the median follow-up time frame was 5.4 years.⁴

Of the 9901 patients that were randomized, 97.1% of patients had known primary composite outcome status at the end of the trial. The primary composite outcome occurred in 12% of patients treated with dulaglutide, which equated to 2.4 out of 100 person years, and 13.4% of patients in the placebo group, which equated to 2.7 out of 100 person years (HR 0.88; 95% CI 0.79-0.99; p = 0.026). Similarly to the outcomes seen in SUSTAIN-6, this finding was driven by the difference in non-fatal stroke. The number needed to treat (NNT) for patients with a previous CV event, additional CV risk factors, or primary composite outcome were 18, 60, and 72, respectively.⁴

Dulaglutide significantly reduced HbA1c by a least-square mean of 0.61% compared to placebo (p < 0.001) without increasing hypoglycemia and significantly reduced composite microvascular outcomes (HR 0.87; 95% CI 0.79-0.95; p = 0.002). Positive effects on systolic blood pressure, bodyweight and low-density lipoprotein were also seen. A statistically significant increase in heart rate by 1.87 beats per minute (p < 0.0001) was noted. Gastrointestinal (GI) adverse events were reported more in the dulaglutide treatment group (47.4%) compared to placebo (34.1%) (p < 0.0001), but occurrence of severe and prespecified adverse events did not differ significantly between groups.⁴

Strengths of this trial include sufficient power, appropriate inclusion and exclusion criteria, blinding, and similarity between baseline characteristics of treatment groups. Another strength is median trial duration of 5.4 years as this is longer than previous GLP-1 RA trials (LEADER 3.8 years, SUSTAIN-6 ~2 years).^2-4 However, potential limitations of the trial include lack of dulaglutide dose titration and bias. A significant difference in incidence of GI adverse events and a 25% drop out rate was seen in the dulaglutide group. Though this adverse event is anticipated, the lack of a standard dose titration in the dulaglutide group may have contributed. Although all trials have some degree of bias, the REWIND trial may have been inclined to have post-hoc significance bias and funding bias. An interim analysis was conducted, which allowed the p-value to be adjusted in order to declare superiority for the primary composite outcome and final analysis. Lastly, Eli Lily and company is the manufacturer of dulaglutide, funder of this trial, and contributed to many aspects of the trial, including design, implementation and data interpretation.⁴

Overall, the REWIND trial demonstrated that adding dulaglutide to standard therapy in patients with T2DM who had previous CV disease or CV risk factors may reduce the combined endpoint of non-fatal MI, non-fatal stroke, and death from CV or unknown causes. Dulaglutide also showed benefits in terms of reducing glucose, HbA1c, weight, and blood pressure.⁴ This trial, in addition to LEADER and SUSTAIN-6, make a strong case for the use of GLP-1 RAs for CV protection in patients T2DM with or at risk for CV disease.

References

1. Clinical Pharmacology [Internet]. Dulaglutide. c2019. [cited 2019 July 30]. Available from https://www-clinicalkey-com.proxy.library.umkc.edu/pharmacology/monograph/3927?sec=monmech.
2. Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in Patients with type 2 diabetes. N Engl J Med. 2016; 375:311-322.
3. Marso S, Bain S, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375:1834-1844.
4. Gerstein H, Colhoun H, Dagenais G, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized, placebo-controlled trial. Lancet. 2019; 394:121-130. http://dx.doi.org/10.1016/S0140-6736(19)31149-3.