Does dapagliflozin (Farxiga) improve cardiovascular outcomes in patients with type 2 diabetes mellitus and cardiovascular disease?
The only cardiovascular benefit to treatment with dapagliflozin was a reduction in the likelihood of hospitalization; 125 patients would need to be treated for 10 years to prevent one hospitalization. For patients with type 2 diabetes and heart failure, that might tip the scales in favor of dapagliflozin (or another sodium glucose co-transporter 2 [SGLT2] inhibitor) as a second or third drug choice. The researchers promote a reduction in the composite of cardiovascular death or hospitalization for heart failure, but there is no reduction in cardiovascular death. This composite is good marketing, but bad science. (Level of Evidence = 1b)
Dapagliflozin is one of several SGLT2 inhibitors that induce glucosuria to lower blood glucose levels. In the current study, researchers identified patients 40 years or older with type 2 diabetes and established cardiovascular disease or men who were 55 years or older (60 or older for women) with one or more cardiovascular risk factors in addition to age. Patients had to have an A1C level between 6.5% and 12% and creatinine clearance of at least 60 mL per minute per 1.73 m2 (1 mL per second per m2). After a four- to eight-week placebo run-in period, approximately 25% of the patients who were initially enrolled were excluded, largely because they did not meet the laboratory criteria (although the stated purpose of the run-in period in the study protocol document was to identify nonadherent patients). Patients could receive other medications to treat their diabetes at the discretion of their physician.
A total of 17,160 patients were randomized to receive dapagliflozin, 10 mg, or placebo. Groups were balanced, with a mean age of 64 years, a mean body mass index of 32 kg per m2, with 41% of patients having cardiovascular disease, and 59% having multiple risk factors. They were contacted regularly and followed up for a median of 4.2 years. The primary outcome was the composite of cardiovascular death, acute myocardial infarction, or ischemic stroke. There was no difference between groups for the primary outcome or for secondary individual outcomes of cardiovascular death, all-cause mortality, ischemic stroke, or myocardial infarction. There were significantly fewer hospitalizations due to heart failure in the intervention group (2.5% vs. 3.3%; number needed to treat [NNT] = 125 over four years) and fewer patients with progression of renal disease in the intervention group (1.5% vs. 2.8%; NNT = 77 over four years). The authors highlight the composite outcome of cardiovascular death or hospitalization for heart failure, an outcome not prespecified in their protocol, and one that makes no sense scientifically because there was no difference in cardiovascular deaths—all of the benefit in this composite outcome was due to fewer heart failure admissions. Nevertheless, this is the featured outcome in the figures and abstract. Patients given dapagliflozin had more genital infections serious enough to discontinue the study medicine or be classified as severe (0.8% vs. 0.1%) and more episodes of diabetic ketoacidosis (0.3% vs. 0.1%).
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Setting: Outpatient (any)
Reference: WiviottSDRazIBonacaMPet alDECLARE–TIMI 58 InvestigatorsDapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med2019;380(4):347–357.