SGLT2i e outcome cardiovascolare: ultime evidenze dagli RCT al RWE. Gian Paolo Fadini

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1 3 CONGRESSO CONGIUNTO SID - AMD SICILIA Palermo (PA) 29 novembre 30 novembre 2018 SGLT2i e outcome cardiovascolare: ultime evidenze dagli RCT al RWE Gian Paolo Fadini Professore Associato di Endocrinologia Dipartimento di Medicina. Università di Padova Istituto Veneto di Medicina Molecolare

2 Il prof. Gian Paolo Fadini dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Abbott. AstraZeneca. Boehringer. Eli Lilly. MSD. NovoNordisk. Novartis. Sanofi Dichiara altresì il proprio impegno ad astenersi. nell ambito dell evento. dal nominare. in qualsivoglia modo o forma. aziende farmaceutiche e/o denominazione commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci. strumenti. dispositivi medico-chirurgici. ecc.).

3 SGLT2i & CVD in T2D From RCTs to RWE and back EMPA-REG CVD-Real 2 CANVAS CVD-Real CVD-Real Nordic DECLARE 26/09/ /04/ /10/ /05/ /12/ /06/2018 In <3 yrs abundant evidence for the 3 avaialble SGLT2i

4 SGLT2i & CVD in T2D From RCTs to RWE and back EMPA-REG Outcome 100% in 2 nd prevention MACE HR 0.86 ( ) n=7072 CV death HR 0.62 ( ) Death HR 0.68 ( ) HHF HR 0.65 ( )

5 EMPA-REG

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7 SGLT2i & CVD in T2D From RCTs to RWE and back SGLT2i protect from adverse CV outcomes in T2D patients with estabilished CVD Do they work in patients without established CVD?

8 SGLT2i & CVD in T2D From RCTs to RWE and back CVD-Real 1,299,915 new users of SGLT2 inhibitor or other glucose-lowering drug fulfilling the eligibility criteria 160,010 SGLT2 inhibitor 1,139,905 other glucose-lowering drug 5487 (3%) excluded during 1:1 match process 1:1 propensity match 985,382 (86%) excluded during 1:1 match process 154,523 SGLT2 inhibitor 154,523 other glucose-lowering drug Established CVD 13% Microangiopathy 27% CKD 3%

9 CVD-Real Type of SGLT-2 inhibitor

10 CVD-Real

11 SGLT2i & CVD in T2D From RCTs to RWE and back CVD-Real Nordic MACE HR 0.78 ( ) CV death HR 0.53 ( ) Death HR 0.51 ( ) HHF HR 0.70 ( ) Established CVD 25% Microangiopathy 25% CKD 1%

12 SGLT2i & CVD in T2D From RCTs to RWE and back CVD-Real 2 (75% dapa) CVD 27% Micro 52% CKD 2%

13 CVD-Real 2

14 SGLT2i & CVD in T2D From RCTs to RWE and back SGLT2i protect from adverse CV outcomes in T2D patients with estabilished CVD According to RWE. SGLT2i can protect from adverse CV outcomes also T2D patients without established CVD Can this be confirmed in RCTs?

15 SGLT2i & CVD in T2D From RCTs to RWE and back EMPA-REG Outcome 100% in 2 nd prevention MACE HR 0.86 ( ) n=7072 CV death HR 0.62 ( ) Death HR 0.68 ( ) HHF HR 0.65 ( ) CANVAS trial program 65.6% in 2 nd prevention MACE HR 0.86 ( ) n=10142 CV death HR 0.87 ( ) Death HR 0.87 ( ) HHF HR 0.67 ( )

16 CANVAS

17 SGLT2i & CVD in T2D From RCTs to RWE and back DECLARE Patients N= N= (59.4%) without atherosclerotic CVD Median f-up 4.2 years Endpoints Safety: 3p MACE Efficacy: Coprimary: 3p MACE & <CV Death or HHF> Secondary Renal composite All-cause mortality

18 Lancet. 10 Nov 2018 DECLARE CANVAS EMPA-REG OUTCOME egfr Categories 51% 56% 52% 40% 19% 26% 25% 22% 9% <60 ml/min/1.73 m 2 60 to <90 ml/min/1.73 m 2 90 ml/min/1.73 m 2

19 DECLARE

20 DECLARE

21 DECLARE

22 DECLARE

23 Lancet. 10 Nov 2018

24 How DECLARE enriches state of the art 3p MACE CVD & HHF

25 How DECLARE enriches state of the art Sensitivity analysis by renal function 3p Renal HHF MACE outc.

26 How DECLARE enriches state of the art Background risk in the placebo group

27 Key secondary endpoint (MACE) Diabetic Diabetic + Evo: LDL 31 mg/dl Non-diabetic + Plb: LDL 94 mg/dl Non-diabetic

28 SGLT2i & CVD in T2D From RCTs to RWE and back Other important take-home messages after intergrating DECLARE into state of the art: CV protection by SGLT2i mainly refers to HHF egfr drives the risk Residual risk remains high Renal protection even more important

29 SGLT2i & CVD in T2D From RCTs to RWE and back SGLT2i protect from adverse CV outcomes in T2D patients with estabilished CVD According to RWE. SGLT2i can protect from adverse CV outcomes also T2D patients without established CVD DECLARE confirms that SGLT2i protect from adverse CV outcomes also in T2D patients without established CVD What about safety?

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33 Canagliflozin and amputations Source Point 95% C.I. estimate CANVAS 1.97 ( ) FAERS 2.40 ( ) EASEL 1.99 ( )

34 DECLARE

35 META-ANALYSIS

36 SGLT2i & CVD in T2D From RCTs to RWE and back SGLT2i protect from adverse CV outcomes in T2D patients with estabilished CVD According to RWE. SGLT2i can protect from adverse CV outcomes also T2D patients without established CVD DECLARE confirms that SGLT2i protect from adverse CV outcomes also in T2D patients without established CVD Data on GTI and DKA are highly consisent. while only canagliflozin showed excess risk of amputations Back to the real world

37 SID DARWIN-T2D DApagliflozin Real World evidence in Type 2 Diabetes Characteristic DECLARE DARWIN-T2D Age, yrs Sex male, % BMI, kg/m Duration, yrs HbA1c, % 8.3 8,6 egfr, ml/min/1.73 mq Insulin, % CVD, %

38 SID DARWIN-T2D DApagliflozin Real World evidence in Type 2 Diabetes Estimated CV risk Effective reduction of A1c. body weight. blood pressure (Fadini et al. DOM 2018) 150 Baseline * Follow-up AER (mg/g) Dapa Comparators Effective reduction in AER without egfr worsening (Fadini et al. DOM 2018b)

39 RCTs SGLT2i RWE