Dulaglutide Cardiovascular Outcomes: REWIND Trial 9901, HR 0.88

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What question did REWIND ask?

REWIND was a double-blind, placebo-controlled cardiovascular outcomes trial run at 371 sites in 24 countries [1]. It enrolled men and women aged 50 or older with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors [1]. The trial randomized 9,901 people 1:1 to once-weekly subcutaneous dulaglutide 1.5 mg or placebo and followed them for a median of 5.4 years [1]. The primary endpoint was the first occurrence of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes, including unknown causes, analyzed in the intention-to-treat population [1].

The trial included people with cardiovascular risk factors as well as people with established cardiovascular disease. About 31.5% had established cardiovascular disease; the rest had cardiovascular risk factors [1].

What did REWIND find?

The primary composite occurred in 12.0% of dulaglutide patients and 13.4% of placebo patients, a hazard ratio of 0.88 (95% CI 0.79 to 0.99; p=0.026) [1]. In absolute terms, that is a 1.4 percentage-point difference over a median 5.4 years [1].

The label also reports fatal or non-fatal stroke at 3.2% with dulaglutide versus 4.1% with placebo (HR 0.76) [2]. All-cause death was 10.8% versus 12.0% (HR 0.90), and that difference was not significant [1].

Gastrointestinal adverse events were common: 47.4% of dulaglutide patients versus 34.1% of placebo patients reported one during follow-up [1].

What does the FDA label cover?

The current Trulicity label has two indications: glycemic control in adults and pediatric patients 10 years and older with type 2 diabetes, and reduction of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors [2]. The cardiovascular indication is for adults; it is not a pediatric indication [2]. Trulicity is not approved for weight loss or chronic weight management [2].

REWIND used dulaglutide 1.5 mg once weekly [1]. In the label, adults start at 0.75 mg once weekly; after 4 weeks the dose may increase to 1.5 mg for additional glycemic control, and if more control is needed it can increase in 1.5 mg steps after at least 4 weeks on the current dose, to a maximum of 4.5 mg once weekly [2]. Pediatric patients start at 0.75 mg and may increase to a maximum of 1.5 mg once weekly after at least 4 weeks [2].

What safety issues matter in a cardiovascular trial?

The label carries a boxed warning for thyroid C-cell tumors seen in rats; human relevance is unknown, and dulaglutide is contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [2]. Other label warnings include acute pancreatitis, hypoglycemia when used with insulin or an insulin secretagogue, serious hypersensitivity reactions, acute kidney injury from volume depletion, severe gastrointestinal reactions, diabetic retinopathy complications, acute gallbladder disease, and pulmonary aspiration during general anesthesia or deep sedation [2]. On retinopathy, the label says diabetic retinopathy complications have been reported in a cardiovascular outcomes trial and advises monitoring patients with a history of diabetic retinopathy [2].

The label also says dulaglutide delays gastric emptying and may reduce the rate of absorption of oral drugs; it advises monitoring levels of narrow-therapeutic-index oral drugs such as warfarin [2]. When starting dulaglutide in someone on insulin or a sulfonylurea, the label says to consider reducing the insulin or sulfonylurea dose to reduce hypoglycemia risk [2].

How does dulaglutide compare with tirzepatide on cardiovascular outcomes?

SURPASS-CVOT compared tirzepatide with dulaglutide 1.5 mg in 13,165 adults with type 2 diabetes and atherosclerotic cardiovascular disease [3]. The composite of cardiovascular death, myocardial infarction, or stroke occurred in 12.2% on tirzepatide and 13.1% on dulaglutide, with a hazard ratio of 0.92 (95.3% CI 0.83 to 1.01) [3]. The trial was designed as a noninferiority comparison, and tirzepatide met noninferiority; superiority was not met [3].

What REWIND does not answer

REWIND tested dulaglutide 1.5 mg, not the 3 mg or 4.5 mg doses [1]. It does not tell us whether the cardiovascular effect is larger at higher doses. The trial enrolled only adults aged 50 or older with type 2 diabetes [1]. It does not answer whether dulaglutide reduces cardiovascular events in people without type 2 diabetes. The all-cause mortality difference was not significant [1].