Modify risk rather than merely relying on blood sugar lowering drugs in diabetes: DECLARE-TIMI

Modify risk rather than merely relying on blood sugar lowering drugs in diabetes, finds DECLARE-TIMI Phase IIIB trial.

Researchers, based on their findings from Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction (DECLARE-TIMI) 58 urge to modify risk rather than a mere lowering of blood sugar for type 2 diabetes.

The goal of diabetes treatment is to avoid acute decompensation, prevent or delay disease complications, decrease mortality, and maintain a good quality of life. It is clear that good control of blood sugar makes it possible to reduce the incidence of microvascular complications (retinopathy, nephropathy, and neuropathy whereas good control of blood sugar per se does not seem to be as a determinant in the prevention of macrovascular complications.Nevertheless primary endeavour of every treating doctor is to bring down blood sugar and glycated haemoglobin within limits.

The trial, DECLARE-TIMI 58 is a multi-national, randomized, double-blind, placebo-controlled Phase IIIB trial. DECLARE–TIMI 58 is a superiority trial and designed to test the hypothesis that in patients with type 2 diabetes mellitus long-term treatment with dapagliflozin, an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor, will reduce one or both of the co-primary endpoints: (1) the incidence cardiovascular death, myocardial infarction, or ischemic stroke or (2) the incidence of cardiovascular death or hospitalization for heart failure.

The trial will seek to definitively exclude unacceptable cardiovascular risk from dapagliflozin in these patients. It has randomized approximately 17,150 patients with type 2 diabetes mellitus and either known cardiovascular disease (secondary prevention cohort) or at least two risk factors for cardiovascular disease (primary prevention cohort). DECLARE-TIMI 58 is an event-driven trial, and we estimate that subjects will be followed for a median of 4.5.

The three researchers Itamar Raz, Ofri Mosenzon, and Avivit Cahn from Hebrew University of Jerusalem, Jerusalem, Israel presented their proposal and findings at the 55^th Annual Meeting of the European Association for the Study of Diabetes (EASD), held from September 16 – 20.

According to Dr. Raz:

• In DECLARE-TIMI 58, nearly 60% of 17,160 patients had no established atherosclerotic CV disease (eASCVD), but had risk factors for ASCVD.


• The broad range of CV risk yielded overall low background placebo event rates vs other CV outcome trials of SGLT2 inhibitors.


• The median 4.2 years of follow-up powered the trial to show a robust reduction in hospitalization for heart failure (HF) and adverse renal outcomes.


• Myocardial infarction (MI) was shown to raise the risk of a major adverse CV event (MACE).


• In DECLARE-TIMI 58, 3584 patients had a history of MI. Dapagliflozin reduced MACE risk significantly vs placebo.


• Patients with HFrEF are at increased risk of hospitalization for HF and for CV death.


• DECLARE-TIMI 58 included 671 such patients. Dapagliflozin reduced the composite endpoint of CV death/hospitalization for HF, as well as all individual endpoints.

Dr. Raz called for new guidelines regarding SGLT2 inhibitors.

According to Dr. Mosenzon:

• In DECLARE-TIMI 58, both cardiorenal (sustained ≥40% reduction in eGFR to eGFR <60 mL/min/1.73 m², ESRD, and renal or CV death); and renal-specific (above excluding CV death) outcomes were reduced by 24% and 47%, respectively, with dapagliflozin vs placebo.


• Important components of these outcomes, such as sustained ≥40% reduction in eGFR to <60 mL/min/1.73 m² and ESRD were also reduced by dapagliflozin. The latter result was impressive, considering that 93% of participants exhibited normal or mildly decreased renal function at baseline.


• Cardiorenal and renal-specific outcomes according to baseline urinary albumin-to-creatinine ratio (UACR) indicated the impact of even UACR normoalbuminuric levels on risk of adverse renal outcomes.


• Dapagliflozin reduced UACR significantly.


• Results of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated the renal benefit of canagliflozin on proteinuric CKD.


• Expanding these observations to nonproteinuric disease is crucial.


• Most patients in DECLARE-TIMI 58 exhibited preserved renal function and no proteinuria, confirming renal improvement with SGLT2 inhibitors.

According to Dr. Cahn,

• A paucity of data on SGLT2 inhibitors in the elderly (≥65 years of age) and very elderly (age ≥75 years) has led to cautious use in this population.


• DECLARE-TIMI 58 included 7907 elderly and 1096 very elderly patients.


• Dapagliflozin reduced the composite of CV death or hospitalization for HF and safety with respect to MACE significantly, regardless of age.


• Relative risk reduction for the cardiorenal composite outcome (sustained ≥40% reduction in eGFR to <60 mL/min/1.73 m², ESRD, and renal or CV death) was 18% to 28%.


• Safety outcomes were balanced and reduced with dapagliflozin vs placebo, regardless of age.


• Genital infections that led to discontinuation and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin than placebo.


• At 1, 2, and 3 years, patients of all ages taking dapagliflozin were more likely to attain HbA1c <7.0% (except those ≥75 years of age at year 3) or <8.0%, or to reduce their HbA1c by ≥0.5%.


• Patients of all ages who took dapagliflozin were more likely to lose 5% of their weight throughout the study.

"Dapagliflozin demonstrated consistent efficacy and safety across age groups," she concluded.

Should patients without established ASCVD take medications not shown to improve their cardiorenal prognosis?

Dapagliflozin protected a mixed population of patients with ASCVD or risk factors for it in DECLARE-TIMI 58. Second-line SGLT2 inhibitors prevent cardiorenal events in most patients.

Stepwise care escalation also remains unaddressed because glycemic targets alone are often not met.

Treatment might advance according to not only HbA1c but also cardiorenal risk. Dual therapy could begin earlier to reduce this risk.