DECLARE-TIMI 58 - Dapagliflozin & CV events in type 2 diabetes

in

Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM

Bottom line: In patients with type 2 diabetes with existing ASCVD or with multiple CV risk factors, dapagliflozin did not reduce the risk of a composite of major adverse cardiovascular events; however, it did reduce the risk of HF hospitalizations (NNT 125) at 4.2 years. Dapaglifozin increases the risk of fungal genital infections (NNH 125) & DKA (NNH 500).

Overall assessment of the evidence for SGLT2 inhibitors shows several differences between agents in this class; empagliflozin appears to have the greatest potential for benefit, whereas canagliflozin has the highest potential for harm.

Context: Summaries of EMPA-REG with empagliflozin & CANVAS with canagliflozin

Patients (n=17,160)

  • Included

    • T2DM with HbA1c 6.5%-12.0%

    • + CrCl 60+ mL/min

    • + either

      • Established atherosclerotic cardiovascular disease (ASCVD; IHD, ischemic CVA, PAD) & 40+ y/o

      • Multiple risk factors: Male 55+ y/o or female 60+ y/o + tobacco use, HTN, or LDL >3.3 mmol/L

  • Key exclusion criteria:

    • Adherence <80% during run-in or considered “at risk for poor medication adherence”

    • Previous SGLT2 inhibitor use

    • Steroid use with equivalent of prednisone 10+ mg/d

    • ACS, decompensated HF or stroke within 8 weeks

    • BP >180/100

    • Recurrent UTIs

  • Baseline characteristics:

    • 64 y/o, male (63%), white (80%), North American (32%)

    • ASCVD (41%): CAD (33%), PAD (6%), CVA (8%)

    • HF (10%)

    • Diabetes duration median 11 y,

    • HbA1c median 8.3%

    • BP 135/85

    • eGFR 85 (7% with eGFR <60)

    • Meds

      • Antihyperglycemics: Metformin (82%), sulfonylurea (43%), insulin (41%), DPP-4i (17%), GLP1 agonist (4%)

      • ASA (61%), ACEI/ARB (81%), beta-blocker (53%), statin or ezetimibe (75%), diuretic (41%)

Intervention & control

  • I: Dapagliflozin 10 mg once daily

  • C: Matching placebo

  • Co-interventions: Other antihyperglycemics per standard of care, excluding SGTL2i or glitazones

Results @ median 4.2 years

Efficacy

  • No reduction in major adverse cardiovascular events (composite of CV death, MI or ischemic stroke): Dapagliflozin 8.8% vs placebo 9.4%

    • Hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03

    • CV death: 2.9% in both groups

    • MI: 4.6% vs 5.1% (HR 0.89, 95% CI 0.77-1.01)

    • Ischemic stroke: 2.7% in both groups

  • Reduction in composite of CV death or HF hospitalization: 4.9% vs 5.8%

    • HR 0.83 (95% CI 0.73-0.95)

    • Driven by a reduction in HF hospitalization: 2.5% vs 3.3% (NNT 125, HR 0.73, 95% CI 0.61-0.88)

    • Originally a secondary outcome; switched to co-primary outcome before unblinding of outcomes due to favorable results on this outcome in EMPA-REG & CANVAS.

  • No reduction in death: 6.2% vs 6.6% (HR 0.93, 95% CI 0.82-1.04)

Safety

  • Increased:

    • Diabetic ketoacidosis (DKA): 0.3% vs 0.1% (NNH 500; HR 2.18, 95% CI 1.10-4.30)

    • Genital infection (generally fungal): 0.9% vs 0.1% (NNH 125)

  • Reduced:

    • Serious adverse events: 34.1% vs 36.2% (HR 0.91, 95% CI 0.87-0.96)

  • No difference in

    • D/C due to adverse event: 8.1% vs 6.9% (HR 1.15, 95% CI 1.03-1.28)

    • Amputation: 1.4% vs 1.3%

    • Symptomatic volume depletion: 2.5% vs 2.4%

    • UTI: 1.5% vs 1.6%

Effect on surrogate endpoints:

  • HbA1c -0.4%

  • Wt -1.8 kg

  • SBP/DBP -2.7/-0.7

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Computer-generated block-randomization sequence;

    • Centralized randomization by interactive voice/web response system to blinded kit containing intervention or matching placebo;

    • Low loss-to-follow-up (0.3%);

    • Analyzed by intention-to-treat.

  • Single-blind (patient) placebo run-in phase lasting 4-8 weeks to assess for non-adherence

    • Unclear risk of selection bias: 25,698 entered run-in phase -> 17,160 randomized (i.e. high rate of exclusion during placebo run-in)

Other Evidence

  • A meta-analysis of the 3 major CV outcome trials of SGLT2 inhibitors (CANVAS, DECLARE & EMPA-REG) shows the following overall patterns:

    • CV efficacy

      • Only empagliflozin clearly reduces all-cause & CV mortality (in patients with existing ASCVD, RRR 32%);

      • SGLT2 inhibitors reduce the risk of major adverse CV events (composite of CV death/MI/stroke) in patients with existing ASCVD (RRR 14%), but not in those without ASCVD;

      • SGLT2 inhibitors do not reduce/increase stroke;

      • All SGLT2 inhibitors reduce the risk of HF hospitalization (RRR ~30%), regardless of prior ASCVD or HF.

    • Safety

      • All SGLT2 inhibitors increase the risk of DKA (RR increase by 120%);

      • Only canagliflozin increases the risk of amputations (RR increase 26%) & fractures (RR increase by 11%).