Early Diabetes and Dyslipidaemia Treatment Optimisation. Presentation by Dr Chan Wan Xian Cardiologist, Echocardiologist Heart Failure Intensivist Asian Heart & Vascular Centre www.ahvc.com.sg

1. SGLT2 inhibitors in Heart failure:
A prized addition to HF treatment options
Dr Chan Wan Xian
Consultant Cardiologist
Heart Failure Specialist
Echocardiologist

2. Heart failure, a world-wide burden

4. Based on the Framingham Heart Study, the mortality rate after diagnosis of HF in the USA was around 10% at 30 days, 20-30% at 1 year and only 45-
60% over 5 years of follow-up, which means only 1 in 2 patients survived after being diagnosed with heart failure in 5 years

5. Cardiac Function Decreases With Each Hospitalization
Adapted from Gheorghiade M et al. Am J Cardiol. 2005;96:6A.

6. Diabetes was 3-fold more common in Southeast Asian compared to white patients with HF, despite
younger age and less obesity, and more strongly associated with poor outcomes in Asian patients
than white patients. These results underscore the importance of ethnicity-tailored aggressive
strategies to prevent diabetes and its complications.

7. Diabetes and heart failure are interlinked
Diabetes Heart Failure
• Patients with HF have a four-
fold higher prevalence of
T2DM (20%) than patients
without HF (4–6%), and this
rises to 40% in T2DM patients
hospitalized for HF
• Metabolic impairment is
intrinsic to HF
pathophysiology, and insulin
resistance is present in up to
60% of patients with HF
• Diabetes is present in 35-45% of
patients with chronic heart
failure, whether they have a
reduced or preserved ejection
fraction
• DM increases hospitalisation
and mortality in HFrEF and
HFpEF patients by 75%

8. Systemic interdependence of heart failure and type 2 diabetes mellitus
Pathophysiology of DM and HF overlaps

9. Current HF Mx guidelines

10. Unmet needs in HF Mx
• Prevention of heart failure in individuals with risks
• Disease modifying therapies to reduce mortality and improve
prognosis in HF patients
• Convincing therapeutic options in need for patients with HFpEF
• Managing cardiorenal syndrome

11. N Engl J Med 2015;373:2117-28.

15. CV outcomes
Trial
EMPA-REG
OUTCOME
NEJM 2015
CANVAS
PROGRAM
NEJM 2017
DECLARE TIMI 58
NEJM 2019
VERTIS CV
NEJM 2020
No of patients/
drug
Entry criteria Outcomes
DM+ASCVD risk
DM+ASCVD risk
DM+ASCVD risk
DM+ASCVD risk
7020 pts
Empagliflozin
8238 pts
Ertugliflozin
17160 pts
Dapagliflozin
10142pts
Canagliflozin
↓30% HF hosp
↓27% HF hosp
↓14% CV
death/MI/CVA
↓33% HF hosp
↓38% CV death
↓35% HF hosp

16. CV outcomes
Trial
EMPA-REG
OUTCOME
NEJM 2015
CANVAS
PROGRAM
NEJM 2017
DECLARE TIMI 58
NEJM 2019
VERTIS CV
NEJM 2020
No of patients/
drug
Entry criteria Outcomes
DM+ASCVD risk
DM+ASCVD risk
DM+ASCVD risk
DM+ASCVD risk
7020 pts
Empagliflozin
8238 pts
Ertugliflozin
17160 pts
Dapagliflozin
10142pts
Canagliflozin
↓30% HF hosp
↓27% HF hosp
↓14% CV
death/MI/CVA
↓33% HF hosp
↓38% CV death
↓35% HF hosp

17. Clinical Benefit of Cardiorenal Effects
of Sodium-Glucose Cotransporter 2 Inhibitors
J Am Coll Cardiol 2020;75:435–47

18. Cardiorenal protection mechanisms of SGLT2i

19. 68-year-old woman at high risk for CV events and HF
• Type 2 DM，HBA1C 7.7%
• Hypertension, Hyperlipidemia
• Had PCI a year ago to pLAD, presented with angina
• Currently asymptomatic, mild ankle edema
• BMI 30 BP 145/85
• Creatinine 97umol/L, eGFR 55 mL/min−1/1.73 m−2, microalbuminuria
• Current medications: Aspirin 100mg om, Atorvastatin 40mg ON, Metformin
1000mg bd, Gliclazide 60mg bd, Enalapril 10mg bd, Carvedilol 6.25mg bd
• Comes for regular follow up
• What can we do to further reduce his cardiovascular risks?

20. Impact of Glycemic control
• Intensive glycemic control does not appear to reduce the risk of all-cause mortality, cardiovascular
mortality, heart failure or stroke, it may reduce the risk of nonfatal myocardial infarction (MI)

21. • Optimal glycemic targets for patients with DM and HF should be individualized to reflect comorbidity burden,
including the severity of HF, and to balance the benefits likely to be achieved by lowering HbA1c with the
potential risks
• Treatment decisions need to consider potential benefits and harms of individual glucose-lowering medications
• AHA scientific statement suggest a target range of HbA1c 7% to 8% for most patients with HF ADA/ AHA guidelines

22. 2020 Novel Therapies for CV Risk With T2D Pathway
J A C C V O L . 7 6 , NO . 9 , 2 0 2 0
S E P T E M B E R 1 , 2 0 2 0 : 1 1 1 7 – 4 5

24. Options to reduce CV risks
• Optimise DM glycemic control
• Prescribe glucose lowering medications with evidence based
cardiovascular and mortality benefit
• Optimise cardiovascular risk factors (target HBA1C <7%, BMI <25, BP
<130/80)
• Switch to medications with cardiovascular, renal and mortality
benefits, irrespective of HBA1C (recommend addition of SGLT2
inhibitors)
• Recommend lifestyle modifications options

25. Circulation. 2019;140:e596–e646
European Heart Journal (2016) 37, 2315–2381

26. 42 year old lady
• DM, recently diagnosed stage C HFrEF
• Non-ischemic cardiomyopathy (LVEF 30%) ,coros: normal coronary
arteries
• BP 135/75 BMI 28
• Current medications: Entresto 100mg bd, carvedilol 25mg bd,
spironolactone 25mg om
• Cardiovascular exam unremarkable
• HBA1C 6% Creatinine 88umol/L, eGFR 77 mL/min−1/1.73 m−2
• What are the options to reduce risks of future poor outcomes?

27. Treatment algorithm for guideline directed medical therapy

29. • Decreased CV death 18%
and HF hospitalisation 30%
• Reduced risk of worsening
HF
• Findings in patients with
diabetes were similar to
those in patients
without diabetes

30. Important SGLT2i trials in HF
Trial Entry criteria No of patients Outcomes
DAPA-HF
NEJM 2019
LVEF≤40%, NYHA II-IV
nt pro-BNP ≥600 pg/L
No DM requirement
4744 pts, 18 mths
Dapagliflozin 10mg om vs
placebo
↓CV death 18%
↓HF hospitalisation 30%
EMPEROR-Reduced
NEJM 2020
LVEF≤40%, NYHA II-IV
LVEF 31-40%, if recent
HHF or ↑BNP levels
No DM requirement
3730 pts, 16 mths
Empagliflozin 10mg om vs
placebo
↓HF hospitalisation 30%
NS CV death
SOLOIST-WHF
NEJM 2021
S/S of heart failure
Type II DM
1222 pts, 9 mths
Sotagliflozin 200mg om vs
placebo
↓HF hospitalisation/
visits 30%
NS CV death

31. Comprehensive quadruple therapy saves lives
• Estimated treatment effects of
comprehensive disease-modifying
pharmacological therapy (ARNI, β
blocker, MRA, and SGLT2
inhibitor) versus conventional
therapy (ACE inhibitor or ARB and
β blocker) in patients with chronic
HFrEF
• Hazard ratio (HR) for the imputed
aggregate treatment effects of
comprehensive disease-modifying
therapy versus conventional
therapy on the primary endpoint of
cardiovascular death or hospital
admission for heart failure was
0·38 (95% CI 0·30-0·47)
Lancet 2020 Jul 11;396(10244):121-128.

32. Options to further reduce risks
• Optimise heart failure medications according to good evidence based
medications
• Addition of SGLT2 inhibitors, Dapagliflozin (CV death reduction)
• Lifestyle modifications
• Cardiac rehabilitation for heart failure

34. Safety considerations in SGLT2i use
JA C C V O L . 7 6 , NO . 9 , 2 0 2 0 Das
et al.
S E P T E M B E R 1 , 2 0 2 0 : 1 1 1 7 –
4 5

37. Conclusion
• SGLT2 inhibitors have changed the management of patients with
diabetes and cardiovascular diseases or heart failure
• Now SGLT2 inhibitors have been shown to be beneficial also in heart
failure patients without diabetes and potentially in those with chronic
kidney disease
• It is important to be familiar with the benefit and prescribing details
of this important class of medications so they can be utilised to
improve the clinical outcome of patients

38. Thank you
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