DECLARE-TIMI 58

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Wiviott SP, et al. "Dapagliflozin and cardiovascular outcomes in type 2 diabetes". The New England Journal of Medicine. 2019. 380(4):347-357.
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Clinical Question

In patients with type 2 diabetes and at risk for cardiovascular disease, does the use of Dapagliflozin reduce the risk of major adverse cardiovascular events (MACE)?

Bottom Line

In patients with type 2 diabetes and risk of cardiovascular disease, the use of Dapagliflozin did not significantly reduce the risk of MACE. Dapagliflozin did result in lower hospitalization rates due to heart failure.

Major Points

Dapagliflozin is a selective inhibitor of sodium glucose cotransporter-2 (SGLT-2) used in the control of type 2 diabetes. The cardiovascular profile of dapagliflozin was previously not specified as it relates to safety. In this randomized, double-blind, multinational, placebo-controlled, phase 3 trial conducted in 882 cities in 33 countries, patients at risk for atherosclerotic cardiovascular disease were observed for 4-8 weeks on either a placebo or dapagliflozin to assess the primary safety outcome of major adverse cardiovascular events. Patients were also assessed on secondary safety outcomes of renal dysfunction and death from any cause.

The trial was fairly large involving 17,160 patients at risk for the events resulting in an acceptable sample size; 8,852 patients received the treatment and 8,578 patients received the placebo . The study found that the use of dapagliflozin in patients with cardiovascular risk will result in lower hospitalization with no significant effect on major adverse cardiovascular events. There is a possibility of bias being introduced due to the premature permanent drug discontinuation for various reasons including adverse events. A second outcome of hospitalization was added due to outside information pointing to a lower hospitalization rate with SGLT-2 inhibitors. It was stated that this was not added due to their trail and they had an adaptive design.


Guidelines

Adapted from ADA guidelines (2019)

  • In patients with type 2 diabetes and atherosclerotic CV disease, sodium-glucose cotransporter 2 (SGLT-2) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1) are recommended. A
  • SGLT-2 inhibitors are preferred in patients with athersclerotic CV disease who are at risk of heart failure or if heart failure coexists. C
  • Consider SGLT-2 inhibitor or GLP-1 receptor agonist in patients with type 2 diabetes and chronic kidney disease. It has shown to reduce risk of chronic kidney disease progression, CV events or both. C


Design

  • randomized, double-blind, multicenter, placebo-controlled, phase 3b trial
  • n = 17,160 patients completed run-in phase and underwent randomized
    • 10 mg Dapagliflozin daily (n=8,852)
    • Matching 1:1 Placebo (n=8,578)
  • Enrollment: 2013 - 2019
    • First patient was enrolled in 2013
    • Last patient completed in 2019
  • Setting: conducted in 882 sites in 33 countries
  • Median follow-up: 4.2 years
  • Analysis: intention-to-treat analysis
  • Primary outcome: MACE (cardiovascular death, myocardial infarction, or ischemic stroke)


Population

Inclusion Criteria

  • Provision of informed consent prior to any study specific procedures
  • Female or male ≥ 40 years of age
  • Diagnosed with Type 2 Diabetes Mellitus
  • High risk for CV event defined as having either established CV disease and/or multiple risk factors:
    • Established CV disease (ischemic heart disease, cerebrovascular disease, peripheral arterial disease)
    • OR
    • No known cardiovascular disease AND at least 2 factors in addition to type 2 diabetes mellitus: Males ≥ 55 years old and females ≥ 60 years old and Dyslipidemia, hypertension OR tobacco use

Exclusion Criteria

  • CrCl < 60 mL/min
  • Pregnant or breastfeeding patients
  • Chronic cystitis and/or recurrent urinary tract infections
  • Hematuria
  • History of bladder cancer or radiation therapy to lower abdomen/pelvis
  • History of any other malignancy within 5 years
  • Excluded medications
    • Pioglitazone
    • Rosiglitazone
    • Previous treatment with other SGLT2 inhibitor
    • Chronic treatment with an oral steroid at a dose equivalent to oral prednisolone ≥10 mg
  • Acute cardiovascular event <8 weeks prior to randomization
  • Systolic BP >180 or diastolic BP >100 mmHg at randomization
  • Diagnosis of type 1 diabetes mellitus, maturity onset diabetes of the young (MODY), or secondary diabetes mellitus
  • Any reason the investigator believes the patient won’t be compliant Aspartate Transaminase (AST) or Alanine Transaminase (ALT) >3x the upper limit of normal or total bilirubin >2.5x the upper limit of normal
  • HbA1c ≥ 12% or HbA1c < 6.5%
  • Condition that may render patient unable to complete study and/or a likely fatal outcome within 5 years


Baseline Characteristics

  • Average age: Dapagliflozin 63.9 years old, Placebo 64 years old
  • Female: Dapagliflozin 36.9%
  • Male: 62.6%
  • Ethnicity: White 79.6%, Black 3.5%, Asian 13.4%, Other 3.5%
  • Region:
    • North America 31.9%
    • Europe 44.5%
    • Latin America 10.9%
    • Asia Pacific 12.7%
  • Average body mass index: Dapagliflozin 32.1
  • Average systolic blood pressure: Dapagliflozin 135.1 mmHg
  • Average glycated hemoglobin: Dapagliflozin 8.3%
  • Glucose lowering therapies
    • Insulin: Dapagliflozin 41.6%
    • Metformin: Dapagliflozin 81.8%
    • Sulfonylurea: Dapagliflozin 42.1%
    • DPP-4:Dapagliflozin 16.5%
    • GLP-1 agonists: Dapagliflozin 4.6%
  • Cardiovascular therapies
    • Antiplatelet: Dapagliflozin 61.1%
    • ACE inhibitor or ARB: Dapagliflozin 81.3%
    • Beta-blocker: Dapagliflozin 52.4%
    • Statin or ezetimibe: Dapagliflozin 74.9%
    • Diuretic: Dapagliflozin 40.6%


Interventions

  • There was a 4-8 week run-in period with a placebo. Those left in the trial were randomly assigned 10 mg of dapagliflozin daily or a placebo at a 1:1 ratio.

Outcomes

Primary Outcomes

MACE
8.8% Dapagliflozin vs. 9.4% Placebo (CI 0.84-1.03)
Cardiovascular death or hospitalization for heart failure
4.9% Dapagliflozin vs 5.8% Placebo (CI 0.73-0.95)
NNT = 111

Secondary Outcomes

Renal composite
4.3% Dapagliflozin vs 5.6% Placebo (CI 0.67-0.87)
NNT = 76
Death from any cause
6.2% Dapagliflozin vs 6.6% Placebo (CI 0.82 to 1.04)


Subgroup Analysis

(Significant Values favoring Dapagliflozin Included):

  • Total Cohort
Hospitalization (CI 0.73-0.95)
  • Risk Group
ASCVD
Hospitalization (CI 0.71-0.98)
MRF

History of Heart Failure

Yes
Hospitalization (CI 0.63-0.99)
No
Hospitalization (CI 0.72-0.99)
  • eGFR
    • >90mL/min
      60-90mL/min
Hospitalization (CI 0.66-0.95)
    • <60mL/min


Adverse Events

(significant safety events listed)

Serious Adverse Events
34.1% Dapagliflozin vs 36.2% Placebo (CI 0.87-0.96)
Adverse event leading to discontinuation
8.1% Dapagliflozin vs 6.9% Placebo (CI 1.03-1.28)
Major hypoglycemic event
0.7% Dapagliflozin vs 1.0% Placebo (CI 0.49-0.95)
Diabetic ketoacidosis
0.3% Dapagliflozin vs 0.1% Placebo (CI 1.10-4.30)
Genital Infection
0.9% Dapagliflozin vs 0.1% Placebo (CI 4.19-16.68)
Acute kidney injury
1.5% Dapagliflozin vs 2.0% Placebo (CI 0.55-0.87)

Criticisms

  • There was potential bias due to early discontinuation.
  • There was no improvement of MACE, which was the original primary outcome.
  • The addition of decreased hospitalization may have been an afterthought to improve the study outcomes.
  • Some patients received other blood sugar lowering agents (other than SGLT2-i’s), but this was at the discretion of each physician. Since this was not constant throughout the study, it may have impacted results.
  • The run-in period was 4-8 weeks, meaning not all patients received the placebo for the same amount of time before starting the trial.
  • Funded by the manufacturer of Dapagliflozin (AstraZeneca), potential conflict of interest.

Funding

  • This trial was supported by AstraZeneca and Bristol-Myers Squibb.

Further Reading

American Diabetes Association: Diabetes Care 2019 Jan; 42(Supplement 1): S90-S102. https://doi.org/10.2337/dc19-S009 (Accessed 4/8/2019)

Wiviott, S. D., Itamar Raz, Marc P. Bonaca et. al. (2019, January 24). Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes | NEJM. 2019;380(4):347-357