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Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE-TIMI 58 Study

Sep 29, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: George McConnell, PharmD. Candidate, LECOM School of Pharmacy 

Care of the elderly can be very challenging. Can adding yet another medication actually help?  DECLARE-TIMI 58 explores the role of dapagliflozin.

Despite the prevalence of type 2 diabetes in the elderly and sodium-glucose cotransporter 2 (SGLT2) inhibitors being a common form of treatment for type 2 diabetes, the authors felt that there was not enough data on their use in the elderly (≥65 years) or very elderly (≥75 years). SGLT2 inhibitors have multiple benefits, aside from their ability to lower glucose, including reductions in hospitalizations due to heart failure, improvements in weight and blood pressure, and renal protection. These medications are taken orally and have minimal risk of hypoglycemia. Despite these advantages, the lack of long-term safety data has caused hesitation in their use in the elderly.   

The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 was a double-blinded study that assessed cardiac and renal outcomes of dapagliflozin versus placebo in 17,160 patients with type 2 diabetes, including those with and those without established cardiovascular (CV) disease. Of these, 7,907 were ≥65 years old, and 1,096 were ≥75 years old. This study participants had to be ≥40 years old, have an HbA1c of 6.5-12%, and a creatinine clearance of ≥60 mL/min. The participants were then randomized to receive either 10mg of dapagliflozin daily or a placebo. The dual primary outcome was CV death or hospitalization for heart failure (CVD/HHF) and major adverse CV events (MACE). A secondary result was a sustained decrease of ≥40% in estimated glomerular filtration rate to <60 mL/min/1.73m², new end-stage renal disease, or death from renal or CV causes. The data was then stratified into different age groups: <65, 65-74, and ≥75 years.   

Incidence rates of the primary endpoint were higher with increasing age. Incidence rates of CVD/HHF were 10.9, 14.8, and 26.7 (P < 0.0001), and those of MACE were 20.9, 24.7, and 37.4 cases per 1,000 person-years in age groups <65, 65-74, and ≥75 years, respectively (P < 0.0001). Dapagliflozin reduced the composite CVD/HHF consistently, with HR 0.88 (95% CI, 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in the age groups <65, 65-74, and ≥75 years, respectively (interaction P = 0.5277). The HR for dapagliflozin for MACE was 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in those same groups (interaction P = 0.7352). Rates of HHF were reduced in the dapagliflozin arm, with HR 0.88 (95% CI 0.68, 1.15), 0.60 (0.46, 0.79), and 0.81 (0.50, 1.30), respectively (interaction P = 0.1402). Other components of the primary endpoints were unchanged, as was all-cause mortality. The secondary endpoints were also reduced with dapagliflozin when compared to the placebo, with HR 0.72 (95% CI 0.59, 0.88), 0.80 (0.65, 0.98), 0.82 (0.52, 1.29) in those <65, 65-74, and ≥75 years, respectively (interaction P = 0.7299). Similar results were seen for the renal-specific composite outcome. Further evaluation showed no age-based treatment interactions. HbA1c decreases were seen across all age groups (P < 0.0001), despite the elderly having significantly lower HbA1c values than the younger population at baseline (P < 0.0001). Those receiving dapagliflozin were more likely to obtain an HbA1c of <7%. Those receiving dapagliflozin had greater weight loss (P < 0.0001) and were more likely to attain a 5% weight loss. This 5% weight loss was seen in 37% vs 23.2%, 40.5% vs. 24.6%, and 52.9% vs. 31.2% of those receiving dapagliflozin vs. placebo in ages <65, 65-74, and ≥75 years, respectively (all P < 0.0001). Serious adverse effects were more common in the elderly (P < 0.0001). These events were less common in the treatment arm, regardless of age. Major hypoglycemia (hypoglycemia that requires assistance to treat) was more common with increasing age. Incidence rates were 1.7, 2.6, and 6.5 cases per 1,000 person-years (P < 0.0001). Fractures, volume depletion, and amputation showed no significant difference between the two arms. AKI and major hypoglycemia were less common in the treatment arm. Diabetic ketoacidosis was more common in those receiving dapagliflozin.  

The DECLARE-TIMI 58 study showed CV and renal benefits of using dapagliflozin, regardless of age. This study included many elderly participants and followed them for over four years. It should help prescribers feel confident when prescribing SGLT2 inhibitors, especially dapagliflozin, to the elderly. The HHF benefits occurred, even in those treated with the standard of care. Despite a reduction in MACE, there was not a significant reduction in its incidence. This study provides essential information on the use of SGLT2 inhibitors in the elderly, an area of research that had been previously poorly investigated.  

Practice Pearls: 

  • Those receiving dapagliflozin attained superior glycemic control and had lower rates of hypoglycemia, regardless of age.   
  • This study found no relationship between age and the benefits received from dapagliflozin, meaning it works just as well in the elderly as it does in younger adults.   
  • Hospitalizations for heart failure were decreased even in those already receiving the standard of care.  
  • Dapagliflozin represents an essential add-on for patients, regardless of age.   


Cahn, Avivit, et al. “Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE-TIMI  58 Study. Diabetes Care, American Diabetes Association, Feb. 2020,  care.diabetesjournals.org/content/43/2/468.  


 George McConnell, PharmD. Candidate, LECOM School of Pharmacy