From the Journals

MACE benefits with dapagliflozin improve with disease duration



Treatment with the sodium-glucose transporter 2 inhibitor dapagliflozin reduced the risk for cardiovascular disease or hospitalization for heart failure (CVD/HHF) in patients with diabetes, regardless of the duration of the disease, but had a greater protective benefit against major adverse cardiovascular events (MACE) and renal events in patients with longer disease duration, according to new findings from a post hoc analysis of the DECLARE-TIMI 58 trial.

The positive effect of dapagliflozin in patients with MACE – which includes myocardial infarction (MI), CVD, and ischemic stroke – may have been driven by lower rates of MI and ischemic stroke with the drug, compared with placebo, in patients with longer disease duration, wrote Harpreet S. Bajaj, MD, and colleagues. Their report is in Diabetes, Obesity and Metabolism (2020 Feb 23. doi: 10.1111/dom.14011).

It has been previously reported that the risk for complications in diabetes increases with increasing duration of the disease. Recent studies with SGLT-2 inhibitors have shown that the drugs improve cardiovascular and renal outcomes in diabetes, and they are recommended by the American Diabetes Association as second-line therapy in patients with atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. The European Society of Cardiology and the European Association for the Study of Diabetes recommend that patients with diabetes patients who have three or more risk factors, or those with a disease duration of more than 20 years, should be deemed very high risk and be considered for early treatment with SGLT2 inhibitors.

“The MACE benefit observed with dapagliflozin in this study in patients with diabetes duration of [more than] 20 years, clearly supports that notion,” the authors wrote.

In DECLARE-TIMI 58, 17,160 patients with type 2 diabetes received dapagliflozin or placebo and were followed for a median of 4.2 years. Of those patients, 22.4% had a disease duration of fewer than 5 years; 27.6%, a duration of 5-10 years; 23.0%, 10-15 years; 14.2%, 10-15 years; and 12.9%, more than 20 years. The median duration of disease was 11 years.

Patients in all the age groups had similar reductions in CVD/HHF, compared with placebo, with hazard ratios of 0.79 (disease duration of 5 or fewer years), 0.86, 0.92, 0.81, and 0.75 (duration of 20 years), respectively (interaction trend P = .760).

Treatment with dapagliflozin reduced the incidence of MACE, but the benefit was more apparent in patients with longer-term disease: HR, 1.08; 1.02; 0.94; 0.92; and 0.67, respectively (interaction trend P = .004). Similar trends were seen with MI (interaction trend P = .019) and ischemic stroke (interaction trend P = .015).

The researchers also reported improved benefits in renal-specific outcome with increasing disease duration, with HRs ranging from 0.79 in patients with diabetes duration of fewer than 5 years, to 0.42 in those with a duration of more than 20 years (interaction trend P = .084).

Limitations of the study include the fact that the information about diabetes duration relied on patient reports, and that the original trial was not powered for all subgroup interactions. This authors emphasized that this was a post hoc analysis and as such, should be considered hypothesis generating.

All but two of the authors reported relationships with Astra Zeneca, which funded the study, and other drug companies.

SOURCE: Bajaj HS et al. Diabetes Obes Metab. 2020 Feb 23. doi: 10.1111/dom.14011.

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