SGLT2i Mechanism of Action

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DECLARE-TIMI 58

DESIGN: Randomized, double-blind , placebo controlled trial

INTERVENTION: Dapagliflozin 10mg once daily vs. matching placebo, added to existing antihyperglycemic therapy

INCLUSION: T2DM, Age ≥40yrs, A1C 6.5-11.9%, CrCl ≥60mL/min, multiple risk factors for ASCVD (59.4%) or established ASCVD (40.6%)

EXCLUSION: Acute CV event in prior 8 weeks (ACS, TIA, stroke, decompensated HF, any revascularization, sustained VT

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DECLARE-TIMI 58

OUTCOMES:

• Largest percentage (~60%) of primary prevention patients (EMPA-REG OUTCOME: 100% ASCVD, CANVAS: 66% ASCVD).
• Statistically significant CV benefits shown in this trial are mostly due to the participants (~40%) with established ASCVD
• No head-to-head trials comparing dapagliflozin, canagliflozin, and empagliflozin. If they were compared, would dapagliflozin have inferior CV outcomes?

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ESC

ESC

ESC

Diabetes Canada 2018 did not include DECLARE-TIMI 58

Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet (London, England). 2019; 393(10166):31-39. 

Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet (London, England). 2019; 393(10166):31-39. 

Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet (London, England). 2019; 393(10166):31-39. 

Heart Failure

EJECtion Fraction?

Kato ET, Silverman MG, Mosenzon O, et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation. 2019; 139(22):2528-2536.

Kato ET, Silverman MG, Mosenzon O, et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation. 2019; 139(22):2528-2536.

Mechanism Hypotheses

• Reduction of glycemia-related cardiotoxicity
• Natriuretic action leading to reduction of plasma volume and interstitial fluid to reduce cardiac volumes
• Increased ketones leading to favourable energy balance -shift from myocardial usage of glucose to ketones
• ?Enhanced synthesis of erythropoietin leading to increase oxygen delivery

Packer M. Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion. Cardiovascular diabetology. 2019; 18(1):129.

Design

• Multicenter, double-blind, parallel-group, randomized, controlled trial
• 410 centers in 20 countries (14% North America)
• Enrollment: 2017-2018
• Analysis: Intention-to-treat
• Primary outcome: Composite of worsening HF or CV death

DAPA-HF Investigators

Exclusions

• Unacceptable side effects associated with SGLT2i
• Type 1 Diabetes
• Hypotension/ sBP <95 mm HG
• Estimated glomerular filtration rate (eGFR) ≤30 ml/m/1.73m2
• Current decompensated HF or HF hospitalization <4 weeks prior
• MI, unstable angina, stroke, or TIA within 3 months to enrolment

DAPA-HF Investigators

DAPA-HF Investigators

DAPA-HF Investigators

16.3% vs. 21.2% (HR 0.74; 95% CI 0.65-0.85; P<0.001)

DAPA-HF Investigators

9.6% vs. 11.5% (HR 0.82; 95% CI 0.69-0.98; P not given)

DAPA-HF Investigators

10.0% vs. 13.7% (HR 0.70; 95% CI 0.59-0.83; P not given)

DAPA-HF Investigators

DAPA-HF Investigators

11.6% vs 13.9% (HR 0.83; 95% CI 0.71-0.97; P not given)

DAPA-HF Investigators

Pooled: 6.1±18.6 vs 3.3±19.2 (HR 1.18; 95% CI 1.11-1.26; P<0.001)

DAPA-HF Investigators

DAPA-HF Investigators

Weaknesses/Uncertainties

• Half of the patients did have diabetes (PARADIGM) 35%)
• Short term study: 18 months (PARADIGM 27 months)
• NT-proBNP not widely available
• Pharma designed, conducted, and anlyzed
• Subgroup NYHA III/IV did not have same benefit (majority of patients NYHA II)
• Doses were not reported of HF therapy, unclear if at target
• Unclear benefit with ARNI (10% of population) and post-hoc analysis found attenuation of benefit
• GU infections not reported (EMPA 6.4%, DECLARE TIMI 0.9%)

Mehchanism Hypotheses

• Reduction of glycemia-related cardiotoxicity
  • Benefit both DM and no DM
• Natriuretic action leading to reduction of plasma volume and interstitial fluid to reduce cardiac volumes
  • Volume status was optimized, only 10-15% delcine in NT-proBNP, diuretic dosing not effected
• Increased ketones leading to favourable energy balance -shift from myocardial usage of glucose to ketones
  • Ketogenesis primarily in diabetics but benefit both DM and no DM
• ?Enhanced synthesis of erythropoietin leading to increase oxygen delivery
  • Benefit seen in ischemic and non-ischemic CM
• Mechanism still unclear

Packer M. Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion. Cardiovascular diabetology. 2019; 18(1):129.

Bhatt DL, Verma S, Braunwald E. The DAPA-HF Trial: A Momentous Victory in the War against Heart Failure. Cell metabolism. 2019; 30(5):847-849.

Bhatt DL, Verma S, Braunwald E. The DAPA-HF Trial: A Momentous Victory in the War against Heart Failure. Cell metabolism. 2019; 30(5):847-849.

CCS

Guidelines

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